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  • Contrary to molecular results, this feature is consistent with the common Isospora infections in passerines and differs from those described for Atoxoplasma species. Because of the prevalence, possibility of transmission, and clinical consequences, preventive measures are necessary to avoid outbreaks of isosporoid infections among finch type birds.This study describes early immunological mechanisms that underlie resistance to Teladorsagia circumcincta infection in adult Churra sheep. After a first experimental infection, 6 animals were classified as resistant (RG) and 6 as susceptible (SG) to T. circumcincta infection based on their cumulative faecal egg count (cFEC) at the end of the infection. RG showed higher IgA levels against somatic antigen of T. circumcincta fourth-larvae stage (L4) in serum at day 3 post-infection (pi) (p  less then  0.05) and close to significance at day 21 pi (p = 0.06). Moreover, a strong negative correlation between cFEC and specific IgA was only significant in RG at day 3 pi (r = - 0.870; p  less then  0.05), but absent in SG. At the end of this infection, sheep were treated with moxidectin and infected again 3 weeks later to be slaughtered at day 7 pi. At necropsy, the specific IgA levels in gastric mucosa were similar between groups; the absence differences at day 7 pi could be due to a previous increase in the IgA response, probably around day 3 pi, as described during the first infection. L4 burden, 68% lower in RG than in SG, was influenced by the specific IgA in gastric mucus and the number of γδ T cells. RG group showed a positive correlation between γδ T cells and eosinophils (r = 0.900; p = 0.037); however, this correlation was not found in SG. These results show that these two phenotypes show different early immune response pattern to T. circumcincta infection in Churra sheep.
    The aim of the present paper is to review the role of HER2 antibodies, affibodies and nanobodies as vehicles for imaging and therapy approaches in breast cancer, including a detailed look at recent clinical data from antibody drug conjugates and nanobodies as well as affibodies that are currently under development.

    Clinical and preclinical studies have shown that the use of monoclonal antibodies in molecular imaging is impaired by slow blood clearance, associated with slow and low tumor uptake and with limited tumor penetration potential. Antibody fragments, such as nanobodies, on the other hand, can be radiolabelled with short-lived radioisotopes and provide high-contrast images within a few hours after injection, allowing early diagnosis and reduced radiation exposure of patients. Even in therapy, the small radioactively labeled nanobodies prove to be superior to radioactively labeled monoclonal antibodies due to their higher specificity and their ability to penetrate the tumor.

    While monoclonal antibodies are well established drug delivery vehicles, the current literature on molecular imaging supports the notion that antibody fragments, such as affibodies or nanobodies, might be superior in this approach.
    While monoclonal antibodies are well established drug delivery vehicles, the current literature on molecular imaging supports the notion that antibody fragments, such as affibodies or nanobodies, might be superior in this approach.
    Multiple myeloma (MM) is a bone marrow malignancy that remains mostly incurable. Elotuzumab is an FDA-approved therapeutic monoclonal antibody targeted to the cell surface glycoprotein CS1, which is overexpressed in MM cells. https://www.selleckchem.com/products/mcc950-sodium-salt.html Identifying patients who will respond to CS1-targeted treatments such as elotuzumab requires the development of a companion diagnostic to assess the presence of CS1. Here, we evaluated [
    Zr]DFO-elotuzumab as a novel PET tracer for imaging CS1 expression in preclinical MM models.

    Conjugation of desferrioxamine-p-benzyl-isothiocyanate (DFO-Bz-NCS) to elotuzumab enabled zirconium-89 radiolabeling. MM.1S-CG cells were intravenously injected in NOD SCID gamma (NSG) ****. Small animal PET imaging with [
    Zr]DFO-elotuzumab (1.11MBq/mouse, 7days post-injection), [
    Zr]DFO-IgG (1.11MBq/mouse, 7days post-injection), and [
    F]FDG (7-8MBq, 1h post-injection) was performed. Additionally, biodistribution of [
    Zr]DFO-elotuzumab post-imaging at 7days was also done. In vivo specificity of [
    Zr]DFO-elotuzumab was further evaluated with a blocking study and ex vivo autoradiography.

    [
    Zr]DFO-elotuzumab was produced with high specific activity (56± 0.75MBq/nmol), radiochemical purity (99% ± 0.5), and yield (93.3% ± 1.5). Dissociation constant of 40.4nM and receptor density of 126fmol/mg was determined in MM.1S-CG cells. Compared to [
    Zr]DFO-IgG, [
    Zr]DFO-elotuzumab localized with a significantly higher standard uptake value in tumor-bearing bone tissue (8.59 versus 4.77). Blocking with unlabeled elotuzumab significantly reduced (P < 0.05) uptake of [
    Zr]DFO-elotuzumab in the bones. Importantly, while [
    F]FDG demonstrated similar uptake in the bone and muscle, [
    Zr]DFO-elotuzumab showed > 3-fold enhanced uptake in bones.

    These data demonstrate the feasibility of [
    Zr]DFO-elotuzumab as a companion diagnostic for CS1-targeted therapies.
    These data demonstrate the feasibility of [89Zr]DFO-elotuzumab as a companion diagnostic for CS1-targeted therapies.
    This study aimed to evaluate the potential utility of [
    Ga]Ga-FAPI-04 PET/CT for diagnosing primary and metastatic lesions in patients with liver cancer, as well as to compare it with contrast-enhanced CT (CE-CT), liver MRI, and [
    F]-FDG PET/CT.

    We performed a single-center post hoc retrospective analysis of data obtained from a prospective parent study (NCT04416165). This study included 34 patients diagnosed with or suspected hepatic lesions who underwent concomitant [
    Ga]Ga-FAPI-04 and [
    F]-FDG/CT scans. Moreover, these patients underwent liver MRI (n = 34) and CE-CT (n = 25). Histopathologic (n = 62) or radiographic follow-up (n = 128) served as the reference standard for the final diagnosis.

    Among the 34 patients, 20, 12, and 2 patients presented with hepatocellular carcinomas, intrahepatic cholangiocarcinomas, and benign hepatic nodules, respectively. The sensitivities of CE-CT, MRI, [
    Ga]Ga-FAPI-04, and [
    F]-FDG/CT for detecting primary liver tumors were 96%, 100%, 96%, and 65%, respectively.
    Contrary to molecular results, this feature is consistent with the common Isospora infections in passerines and differs from those described for Atoxoplasma species. Because of the prevalence, possibility of transmission, and clinical consequences, preventive measures are necessary to avoid outbreaks of isosporoid infections among finch type birds.This study describes early immunological mechanisms that underlie resistance to Teladorsagia circumcincta infection in adult Churra sheep. After a first experimental infection, 6 animals were classified as resistant (RG) and 6 as susceptible (SG) to T. circumcincta infection based on their cumulative faecal egg count (cFEC) at the end of the infection. RG showed higher IgA levels against somatic antigen of T. circumcincta fourth-larvae stage (L4) in serum at day 3 post-infection (pi) (p  less then  0.05) and close to significance at day 21 pi (p = 0.06). Moreover, a strong negative correlation between cFEC and specific IgA was only significant in RG at day 3 pi (r = - 0.870; p  less then  0.05), but absent in SG. At the end of this infection, sheep were treated with moxidectin and infected again 3 weeks later to be slaughtered at day 7 pi. At necropsy, the specific IgA levels in gastric mucosa were similar between groups; the absence differences at day 7 pi could be due to a previous increase in the IgA response, probably around day 3 pi, as described during the first infection. L4 burden, 68% lower in RG than in SG, was influenced by the specific IgA in gastric mucus and the number of γδ T cells. RG group showed a positive correlation between γδ T cells and eosinophils (r = 0.900; p = 0.037); however, this correlation was not found in SG. These results show that these two phenotypes show different early immune response pattern to T. circumcincta infection in Churra sheep. The aim of the present paper is to review the role of HER2 antibodies, affibodies and nanobodies as vehicles for imaging and therapy approaches in breast cancer, including a detailed look at recent clinical data from antibody drug conjugates and nanobodies as well as affibodies that are currently under development. Clinical and preclinical studies have shown that the use of monoclonal antibodies in molecular imaging is impaired by slow blood clearance, associated with slow and low tumor uptake and with limited tumor penetration potential. Antibody fragments, such as nanobodies, on the other hand, can be radiolabelled with short-lived radioisotopes and provide high-contrast images within a few hours after injection, allowing early diagnosis and reduced radiation exposure of patients. Even in therapy, the small radioactively labeled nanobodies prove to be superior to radioactively labeled monoclonal antibodies due to their higher specificity and their ability to penetrate the tumor. While monoclonal antibodies are well established drug delivery vehicles, the current literature on molecular imaging supports the notion that antibody fragments, such as affibodies or nanobodies, might be superior in this approach. While monoclonal antibodies are well established drug delivery vehicles, the current literature on molecular imaging supports the notion that antibody fragments, such as affibodies or nanobodies, might be superior in this approach. Multiple myeloma (MM) is a bone marrow malignancy that remains mostly incurable. Elotuzumab is an FDA-approved therapeutic monoclonal antibody targeted to the cell surface glycoprotein CS1, which is overexpressed in MM cells. https://www.selleckchem.com/products/mcc950-sodium-salt.html Identifying patients who will respond to CS1-targeted treatments such as elotuzumab requires the development of a companion diagnostic to assess the presence of CS1. Here, we evaluated [ Zr]DFO-elotuzumab as a novel PET tracer for imaging CS1 expression in preclinical MM models. Conjugation of desferrioxamine-p-benzyl-isothiocyanate (DFO-Bz-NCS) to elotuzumab enabled zirconium-89 radiolabeling. MM.1S-CG cells were intravenously injected in NOD SCID gamma (NSG) mice. Small animal PET imaging with [ Zr]DFO-elotuzumab (1.11MBq/mouse, 7days post-injection), [ Zr]DFO-IgG (1.11MBq/mouse, 7days post-injection), and [ F]FDG (7-8MBq, 1h post-injection) was performed. Additionally, biodistribution of [ Zr]DFO-elotuzumab post-imaging at 7days was also done. In vivo specificity of [ Zr]DFO-elotuzumab was further evaluated with a blocking study and ex vivo autoradiography. [ Zr]DFO-elotuzumab was produced with high specific activity (56± 0.75MBq/nmol), radiochemical purity (99% ± 0.5), and yield (93.3% ± 1.5). Dissociation constant of 40.4nM and receptor density of 126fmol/mg was determined in MM.1S-CG cells. Compared to [ Zr]DFO-IgG, [ Zr]DFO-elotuzumab localized with a significantly higher standard uptake value in tumor-bearing bone tissue (8.59 versus 4.77). Blocking with unlabeled elotuzumab significantly reduced (P < 0.05) uptake of [ Zr]DFO-elotuzumab in the bones. Importantly, while [ F]FDG demonstrated similar uptake in the bone and muscle, [ Zr]DFO-elotuzumab showed > 3-fold enhanced uptake in bones. These data demonstrate the feasibility of [ Zr]DFO-elotuzumab as a companion diagnostic for CS1-targeted therapies. These data demonstrate the feasibility of [89Zr]DFO-elotuzumab as a companion diagnostic for CS1-targeted therapies. This study aimed to evaluate the potential utility of [ Ga]Ga-FAPI-04 PET/CT for diagnosing primary and metastatic lesions in patients with liver cancer, as well as to compare it with contrast-enhanced CT (CE-CT), liver MRI, and [ F]-FDG PET/CT. We performed a single-center post hoc retrospective analysis of data obtained from a prospective parent study (NCT04416165). This study included 34 patients diagnosed with or suspected hepatic lesions who underwent concomitant [ Ga]Ga-FAPI-04 and [ F]-FDG/CT scans. Moreover, these patients underwent liver MRI (n = 34) and CE-CT (n = 25). Histopathologic (n = 62) or radiographic follow-up (n = 128) served as the reference standard for the final diagnosis. Among the 34 patients, 20, 12, and 2 patients presented with hepatocellular carcinomas, intrahepatic cholangiocarcinomas, and benign hepatic nodules, respectively. The sensitivities of CE-CT, MRI, [ Ga]Ga-FAPI-04, and [ F]-FDG/CT for detecting primary liver tumors were 96%, 100%, 96%, and 65%, respectively.
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  • In the present study a series of tetrahydroisoquinoline derivatives were synthesized and evaluated for their activity towards three ABC transporters, P-gp, MRP1 and BCRP. The compounds proved to be selective against P-gp. One of them, 8b, displayed activity in the nanomolar range (EC50 = 94 nM). Thus, compound 8b was tested for its ability to restore the cytotoxic activity of a well-known anti-cancer agent and P-gp substrate, doxorubicin, as first proof of concept. Moreover, compound 8b was also tested in an in vitro model of competent gastro-intestinal (GI) barrier (Caco-2 cells) for its ability to inhibit P-gp, present on luminal side, and increase the apical-to-basolateral transport of several structurally uncorrelated drugs, belonging to different therapeutic areas but actively excreted by P-gp. Notably the transport of the drugs across the GI barrier was increased by a concentration of 8b devoid of toxicity and of perturbing effects on barrier function. An in vitro simulated digestion process was set up interestingly the effect of 8b on the transport of digoxin was preserved also after the simulated digestion process. This result may suggest 8b as a safe and effective P-gp modulator that can increase the bioavailability of a wide spectrum of drugs administered per os, improving their transport across the GI barrier.Diuretics are the first-line therapy for widespread cardiovascular and non-cardiovascular diseases. Traditional diuretics are commonly prescribed for treatment in patients with hypertension, edema and heart failure, as well as with a number of kidney problems. They are diseases with high mortality, and the number of patients suffering from heart and kidney diseases is increasing year by year. The use of several classes of diuretics currently available for clinical use exhibits an overall favorable risk/benefit balance. However, they are not devoid of side effects. Hence, pharmaceutical researchers have been making efforts to develop new drugs with a better pharmacological profile. High-throughput screening, progress in protein structure analysis and modern methods of chemical modification have opened good possibilities for identification of new promising agents for preclinical and clinical testing. In this review, we provide an overview of the medicinal chemistry approaches toward the development of small molecule compounds showing diuretic activity that have been discovered over the past decade and are interesting drug candidates. We have discussed promising natriuretics/aquaretics/osmotic diuretics from such classes as vasopressin receptor antagonists, SGLT2 inhibitors, urea transporters inhibitors, aquaporin antagonists, adenosine receptor antagonists, natriuretic peptide receptor agonists, ROMK inhibitors, WNK-SPAK inhibitors, and pendrin inhibitors.
    Corona virus diseases 2019 (COVID-19) pandemic spread rapidly. Growing evidences that overweight and obesity which extent nearly a third of the world population were associated with severe COVID-19. This study aimed to explore the association and risk of increased BMI and obesity with composite poor outcome in COVID-19 adult patients.

    We conducted a systematic literature search from PubMed and Embase database. We included all original research articles in COVID-19 adult patients and obesity based on classification of Body Mass Index (BMI) and composite poor outcome which consist of ICU admission, ARDS, severe COVID-19, use of mechanical ventilation, hospital admission, and mortality.

    Sixteen studies were included in meta-analysis with 9 studies presented BMI as continuous outcome and 10 studies presented BMI as dichotomous outcome (cut-off ≥30kg/m
    ). COVID-19 patients with composite poor outcome had higher BMI with mean difference 1.12 (95% CI, 0.67-1.57, P<0.001). Meanwhile, obesity was associated with composite poor outcome with odds ratio (OR)=1.78 (95% CI, 1.25-2.54, P<0.001) Multivariate meta-regression showed the association between BMI and obesity on composite poor outcome were affected by age, gender, DM type 2, and hypertension.

    Obesity is a risk factor of composite poor outcome of COVID-19. On the other hand, COVID-19 patients with composite poor outcome have higher BMI. BMI is an important routine procedure that should always be assessed in the management of COVID-19 patients and special attention should be given to patients with obesity.
    Obesity is a risk factor of composite poor outcome of COVID-19. On the other hand, COVID-19 patients with composite poor outcome have higher BMI. BMI is an important routine procedure that should always be assessed in the management of COVID-19 patients and special attention should be given to patients with obesity.People believe repeated statements more compared to new statements - they show a truth by repetition effect. In three pre-registered experiments, we show that repetition may also increase perceptions that statements are used as fake news on social media, irrespective of the factual truth or falsehood of the statements (Experiment 1 & 2), but that repetition reduces perceptions of falsehood when the context of judgment is left unspecified (Experiment 3). On a theoretical level, the findings support an ecological account of repetition effects, as opposed to either a fluency-as-positivity or to an amplification account of these effects. On a practical level, they qualify the influence of repetition on the perception of fake news.Combining physical activity and academic content is a promising way to improve health and academic learning in schoolchildren. This paper examined the continuation of physically active lessons (PAL) in five Norwegian elementary schools, two years after a 10-month intervention period, which consisted of weekly minimum 2 x 45 min of PAL. Data were collected through semi-structured interviews with nine teachers and five school leaders. The Level of Use instrument was used to assess how the teachers integrated PAL into the school day. Two years after the intervention period, seven of nine teachers conducted PAL regularly, on average one lesson per week. Teachers' implementation progress varied from struggling with logistics, to stable routine and creative adaption. Perceived benefits for the children, active leadership, and ongoing implementation support seem important for continuation. https://www.selleckchem.com/products/mcc950-sodium-salt.html Introduction of PAL as a school development project, systematic planning from the onset and a gradual introduction of PAL, can be an effective strategy for continuation and long-term sustainability.
    In the present study a series of tetrahydroisoquinoline derivatives were synthesized and evaluated for their activity towards three ABC transporters, P-gp, MRP1 and BCRP. The compounds proved to be selective against P-gp. One of them, 8b, displayed activity in the nanomolar range (EC50 = 94 nM). Thus, compound 8b was tested for its ability to restore the cytotoxic activity of a well-known anti-cancer agent and P-gp substrate, doxorubicin, as first proof of concept. Moreover, compound 8b was also tested in an in vitro model of competent gastro-intestinal (GI) barrier (Caco-2 cells) for its ability to inhibit P-gp, present on luminal side, and increase the apical-to-basolateral transport of several structurally uncorrelated drugs, belonging to different therapeutic areas but actively excreted by P-gp. Notably the transport of the drugs across the GI barrier was increased by a concentration of 8b devoid of toxicity and of perturbing effects on barrier function. An in vitro simulated digestion process was set up interestingly the effect of 8b on the transport of digoxin was preserved also after the simulated digestion process. This result may suggest 8b as a safe and effective P-gp modulator that can increase the bioavailability of a wide spectrum of drugs administered per os, improving their transport across the GI barrier.Diuretics are the first-line therapy for widespread cardiovascular and non-cardiovascular diseases. Traditional diuretics are commonly prescribed for treatment in patients with hypertension, edema and heart failure, as well as with a number of kidney problems. They are diseases with high mortality, and the number of patients suffering from heart and kidney diseases is increasing year by year. The use of several classes of diuretics currently available for clinical use exhibits an overall favorable risk/benefit balance. However, they are not devoid of side effects. Hence, pharmaceutical researchers have been making efforts to develop new drugs with a better pharmacological profile. High-throughput screening, progress in protein structure analysis and modern methods of chemical modification have opened good possibilities for identification of new promising agents for preclinical and clinical testing. In this review, we provide an overview of the medicinal chemistry approaches toward the development of small molecule compounds showing diuretic activity that have been discovered over the past decade and are interesting drug candidates. We have discussed promising natriuretics/aquaretics/osmotic diuretics from such classes as vasopressin receptor antagonists, SGLT2 inhibitors, urea transporters inhibitors, aquaporin antagonists, adenosine receptor antagonists, natriuretic peptide receptor agonists, ROMK inhibitors, WNK-SPAK inhibitors, and pendrin inhibitors. Corona virus diseases 2019 (COVID-19) pandemic spread rapidly. Growing evidences that overweight and obesity which extent nearly a third of the world population were associated with severe COVID-19. This study aimed to explore the association and risk of increased BMI and obesity with composite poor outcome in COVID-19 adult patients. We conducted a systematic literature search from PubMed and Embase database. We included all original research articles in COVID-19 adult patients and obesity based on classification of Body Mass Index (BMI) and composite poor outcome which consist of ICU admission, ARDS, severe COVID-19, use of mechanical ventilation, hospital admission, and mortality. Sixteen studies were included in meta-analysis with 9 studies presented BMI as continuous outcome and 10 studies presented BMI as dichotomous outcome (cut-off ≥30kg/m ). COVID-19 patients with composite poor outcome had higher BMI with mean difference 1.12 (95% CI, 0.67-1.57, P<0.001). Meanwhile, obesity was associated with composite poor outcome with odds ratio (OR)=1.78 (95% CI, 1.25-2.54, P<0.001) Multivariate meta-regression showed the association between BMI and obesity on composite poor outcome were affected by age, gender, DM type 2, and hypertension. Obesity is a risk factor of composite poor outcome of COVID-19. On the other hand, COVID-19 patients with composite poor outcome have higher BMI. BMI is an important routine procedure that should always be assessed in the management of COVID-19 patients and special attention should be given to patients with obesity. Obesity is a risk factor of composite poor outcome of COVID-19. On the other hand, COVID-19 patients with composite poor outcome have higher BMI. BMI is an important routine procedure that should always be assessed in the management of COVID-19 patients and special attention should be given to patients with obesity.People believe repeated statements more compared to new statements - they show a truth by repetition effect. In three pre-registered experiments, we show that repetition may also increase perceptions that statements are used as fake news on social media, irrespective of the factual truth or falsehood of the statements (Experiment 1 & 2), but that repetition reduces perceptions of falsehood when the context of judgment is left unspecified (Experiment 3). On a theoretical level, the findings support an ecological account of repetition effects, as opposed to either a fluency-as-positivity or to an amplification account of these effects. On a practical level, they qualify the influence of repetition on the perception of fake news.Combining physical activity and academic content is a promising way to improve health and academic learning in schoolchildren. This paper examined the continuation of physically active lessons (PAL) in five Norwegian elementary schools, two years after a 10-month intervention period, which consisted of weekly minimum 2 x 45 min of PAL. Data were collected through semi-structured interviews with nine teachers and five school leaders. The Level of Use instrument was used to assess how the teachers integrated PAL into the school day. Two years after the intervention period, seven of nine teachers conducted PAL regularly, on average one lesson per week. Teachers' implementation progress varied from struggling with logistics, to stable routine and creative adaption. Perceived benefits for the children, active leadership, and ongoing implementation support seem important for continuation. https://www.selleckchem.com/products/mcc950-sodium-salt.html Introduction of PAL as a school development project, systematic planning from the onset and a gradual introduction of PAL, can be an effective strategy for continuation and long-term sustainability.
    0 Commentarii 0 Distribuiri 31 Views 0 previzualizare

  • In addition, 2-methoxystypandrone (5) triggered strong apoptosis that was mediated by the arrest of the G0/G1 phase of the cell cycle. Furthermore, 2-methoxystypandrone (5) downregulated p-IκB-α, p-NF-κB p65, Bcl2, and Bcl-xl and upregulated BAX proteins. Taken together, these findings revealed that 2-methoxystypandrone (5) isolated from RJH could potentially serve as an early lead compound for leukemia treatment involving intracellular signaling by increasing mitochondrial ROS and exerting anti-proliferative effects.Enzyme replacement therapy for lysosomal storage diseases usually requires recombinant enzymes containing mannose-6-phosphate (M6P) glycans for cellular uptake and lysosomal targeting. For the first time, a strategy is established here for the in vitro mannosyl-phosphorylation of high-mannose type N-glycans that utilizes a recombinant Mnn14 protein derived from Saccharomyces cerevisiae. Among a series of N-terminal- or C-terminal-deleted recombinant Mnn14 proteins expressed in Pichia pastoris, rMnn1477-935 with deletion of N-terminal 76 amino acids spanning the transmembrane domain (46 amino acids) and part of the stem region (30 amino acids), showed the highest level of mannosyl-phosphorylation activity. The optimum reaction conditions for rMnn1477-935 were determined through enzyme assays with a high-mannose type N-glycan (Man8GlcNAc2) as a substrate. In addition, rMnn1477-935 was shown to mannosyl-phosphorylate high-mannose type Nglycans (Man7-9GlcNAc2) on recombinant human lysosomal alpha-glucosidase (rhGAA) with remarkably high efficiency. Moreover, the majority of the resulting mannosyl-phosphorylated glycans were bis-form which can be converted to bis-phosphorylated M6P glycans having a superior lysosomal targeting capability. An in vitro N-glycan mannosyl-phosphorylation reaction using rMnn1477-935 will provide a flexible and straightforward method to increase the M6P glycan content for the generation of "Biobetter" therapeutic enzymes.Supplement of high-protein food plays an important role in improving the symptoms of malnutrition and the immune capacity of the body, but the association of high-protein diet and gut microbiota remained unaddressed. Here, we systematically analyzed the internal organs and gut microbiota in C57(WT) or PD-1H-depleted (KO) **** (T cells were activated) fed with pupae or feed for six weeks. We observed that the body weight gain in the **** fed with pupae increased less significantly than that of the feed group, while the villi and small intestine lengths in the pupa group were reduced compared with that of **** given feed. However, the average body weight of the KO **** increased compared with that of the WT **** fed with pupae or feed. Pupae increased the concentration of blood glucose in WT, but not in KO ****. Moreover, in the feed group, there was no difference in the weight of the internal organs between the WT and KO ****, but in the pupae-fed group, liver weight was decreased and spleen weight was increase findings provide evidence about the association among gut microbiota, T cell activation (for PD-1H depletion) and high-protein diet metabolism, have important theoretical significance for nutrition and health research.Organophosphorus nerve agents (OPNAs), including both G- and V-type nerve agents such as sarin, soman, tabun and VX, are extremely neurotoxic organophosphorus compounds. Catalytic bioscavengers capable of hydrolyzing OPNAs are under development because of the low protective effects and adverse side effects of chemical antidotes to OPNA poisoning. However, these bioscavengers have certain limitations for practical application, including low catalytic activity and narrow specificity. https://www.selleckchem.com/products/homoharringtonine.html In this study, we generated a fusion-hybrid form of engineered recombinant human paraoxonase 1 (rePON1) and bacterial organophosphorus hydrolase (OPH), referred to as GV-hybrids, using a flexible linker to develop more promising catalytic bioscavengers against a broad range of OPNAs. These GV-hybrids were able to synergistically hydrolyze both G-type OPNA analogs (paraoxon 1.7 ~ 193.7-fold, p-nitrophenyl diphenyl phosphate (PNPDPP) 2.3 ~ 33.0-fold and diisopropyl fluorophosphates (DFP) 1.4 ~ 22.8-fold) and V-type OPNA analogs (demeton-Smethyl (DSM) 1.9 ~ 34.6-fold and malathion 1.1 ~ 4.2-fold above) better than their individual enzyme forms. Among the GV-hybrid clones, the GV7 clone showed remarkable improvements in the catalytic activity toward both G-type OPNA analogs (kcat/Km (106 M-1 min-1) 59.8 ± 0.06 (paraoxon), 5.2 ± 0.02 (PNPDPP) and 47.0 ± 6.0 (DFP)) and V-type OPNA analogs (kcat/Km (M-1 min-1) 504.3 ± 48.5 (DSM) and 1324.0 ± 47.5 (malathion)). In conclusion, we developed GV-hybrid forms of rePON1 and bacterial OPH mutants as effective and suitable catalytic bioscavengers to hydrolyze a broad range of OPNA analogs.More and more available fungal genome sequence data reveal a large amount of secondary metabolite (SM) biosynthetic 'dark matter' to be discovered. Heterogeneous expression is one of the most effective approaches to exploit these novel natural products, but it is limited by having to clone entire biosynthetic gene clusters (****) without errors. So far, few effective technologies have been developed to manipulate the specific large DNA fragments in filamentous fungi. Here, we developed a fungal ****capturing system based on CRISPR/Cas9 cleavage in vitro. In our system, Cas9 protein was purified and CRISPR guide sequences in combination with in vivo yeast assembly were rationally designed. Using targeted cleavages of plasmid DNAs with linear (8.5 kb) or circular (8.5 kb and 28 kb) states, we were able to cleave the plasmids precisely, demonstrating the high efficiency of this system. Furthermore, we successfully captured the entire Nrc gene cluster from the genomic DNA of Neosartorya fischeri. Our results provide an easy and efficient approach to manipulate fungal genomic DNA based on the in vitro application of Cas9 endonuclease. Our methodology will lay a foundation for capturing entire groups of **** in filamentous fungi and accelerate fungal SMs mining.
    In addition, 2-methoxystypandrone (5) triggered strong apoptosis that was mediated by the arrest of the G0/G1 phase of the cell cycle. Furthermore, 2-methoxystypandrone (5) downregulated p-IκB-α, p-NF-κB p65, Bcl2, and Bcl-xl and upregulated BAX proteins. Taken together, these findings revealed that 2-methoxystypandrone (5) isolated from RJH could potentially serve as an early lead compound for leukemia treatment involving intracellular signaling by increasing mitochondrial ROS and exerting anti-proliferative effects.Enzyme replacement therapy for lysosomal storage diseases usually requires recombinant enzymes containing mannose-6-phosphate (M6P) glycans for cellular uptake and lysosomal targeting. For the first time, a strategy is established here for the in vitro mannosyl-phosphorylation of high-mannose type N-glycans that utilizes a recombinant Mnn14 protein derived from Saccharomyces cerevisiae. Among a series of N-terminal- or C-terminal-deleted recombinant Mnn14 proteins expressed in Pichia pastoris, rMnn1477-935 with deletion of N-terminal 76 amino acids spanning the transmembrane domain (46 amino acids) and part of the stem region (30 amino acids), showed the highest level of mannosyl-phosphorylation activity. The optimum reaction conditions for rMnn1477-935 were determined through enzyme assays with a high-mannose type N-glycan (Man8GlcNAc2) as a substrate. In addition, rMnn1477-935 was shown to mannosyl-phosphorylate high-mannose type Nglycans (Man7-9GlcNAc2) on recombinant human lysosomal alpha-glucosidase (rhGAA) with remarkably high efficiency. Moreover, the majority of the resulting mannosyl-phosphorylated glycans were bis-form which can be converted to bis-phosphorylated M6P glycans having a superior lysosomal targeting capability. An in vitro N-glycan mannosyl-phosphorylation reaction using rMnn1477-935 will provide a flexible and straightforward method to increase the M6P glycan content for the generation of "Biobetter" therapeutic enzymes.Supplement of high-protein food plays an important role in improving the symptoms of malnutrition and the immune capacity of the body, but the association of high-protein diet and gut microbiota remained unaddressed. Here, we systematically analyzed the internal organs and gut microbiota in C57(WT) or PD-1H-depleted (KO) mice (T cells were activated) fed with pupae or feed for six weeks. We observed that the body weight gain in the mice fed with pupae increased less significantly than that of the feed group, while the villi and small intestine lengths in the pupa group were reduced compared with that of mice given feed. However, the average body weight of the KO mice increased compared with that of the WT mice fed with pupae or feed. Pupae increased the concentration of blood glucose in WT, but not in KO mice. Moreover, in the feed group, there was no difference in the weight of the internal organs between the WT and KO mice, but in the pupae-fed group, liver weight was decreased and spleen weight was increase findings provide evidence about the association among gut microbiota, T cell activation (for PD-1H depletion) and high-protein diet metabolism, have important theoretical significance for nutrition and health research.Organophosphorus nerve agents (OPNAs), including both G- and V-type nerve agents such as sarin, soman, tabun and VX, are extremely neurotoxic organophosphorus compounds. Catalytic bioscavengers capable of hydrolyzing OPNAs are under development because of the low protective effects and adverse side effects of chemical antidotes to OPNA poisoning. However, these bioscavengers have certain limitations for practical application, including low catalytic activity and narrow specificity. https://www.selleckchem.com/products/homoharringtonine.html In this study, we generated a fusion-hybrid form of engineered recombinant human paraoxonase 1 (rePON1) and bacterial organophosphorus hydrolase (OPH), referred to as GV-hybrids, using a flexible linker to develop more promising catalytic bioscavengers against a broad range of OPNAs. These GV-hybrids were able to synergistically hydrolyze both G-type OPNA analogs (paraoxon 1.7 ~ 193.7-fold, p-nitrophenyl diphenyl phosphate (PNPDPP) 2.3 ~ 33.0-fold and diisopropyl fluorophosphates (DFP) 1.4 ~ 22.8-fold) and V-type OPNA analogs (demeton-Smethyl (DSM) 1.9 ~ 34.6-fold and malathion 1.1 ~ 4.2-fold above) better than their individual enzyme forms. Among the GV-hybrid clones, the GV7 clone showed remarkable improvements in the catalytic activity toward both G-type OPNA analogs (kcat/Km (106 M-1 min-1) 59.8 ± 0.06 (paraoxon), 5.2 ± 0.02 (PNPDPP) and 47.0 ± 6.0 (DFP)) and V-type OPNA analogs (kcat/Km (M-1 min-1) 504.3 ± 48.5 (DSM) and 1324.0 ± 47.5 (malathion)). In conclusion, we developed GV-hybrid forms of rePON1 and bacterial OPH mutants as effective and suitable catalytic bioscavengers to hydrolyze a broad range of OPNA analogs.More and more available fungal genome sequence data reveal a large amount of secondary metabolite (SM) biosynthetic 'dark matter' to be discovered. Heterogeneous expression is one of the most effective approaches to exploit these novel natural products, but it is limited by having to clone entire biosynthetic gene clusters (BGCs) without errors. So far, few effective technologies have been developed to manipulate the specific large DNA fragments in filamentous fungi. Here, we developed a fungal BGC-capturing system based on CRISPR/Cas9 cleavage in vitro. In our system, Cas9 protein was purified and CRISPR guide sequences in combination with in vivo yeast assembly were rationally designed. Using targeted cleavages of plasmid DNAs with linear (8.5 kb) or circular (8.5 kb and 28 kb) states, we were able to cleave the plasmids precisely, demonstrating the high efficiency of this system. Furthermore, we successfully captured the entire Nrc gene cluster from the genomic DNA of Neosartorya fischeri. Our results provide an easy and efficient approach to manipulate fungal genomic DNA based on the in vitro application of Cas9 endonuclease. Our methodology will lay a foundation for capturing entire groups of BGCs in filamentous fungi and accelerate fungal SMs mining.
    0 Commentarii 0 Distribuiri 26 Views 0 previzualizare

  • Green chemistry-based non-isocyanate polyurethanes (NIPU) are synthesized and 3D-printed via rapid, projection photopolymerization into compliant mechanisms of 3D structure with spatially-localized material properties. Trimethylolpropane allyl ether-cyclic carbonate is used to couple the unique properties of two types of reaction chemistry (1) primary diamine-cyclic carbonate ring-opening conjugation for supplanting conventional isocyanate-polyol reactions in creating urethane groups, with the additional advantage of enabling modular segment interchangeability within the diurethane prepolymers; and (2) thiol-ene (click) conjugation for non-telechelic, low monodispersity, quasi-crystalline-capable, and alternating step-growth co-photopolymerization. Fourier Transform Infrared Spectroscopy is used to monitor the functional group transformation in reactions, and to confirm these process-associated molecular products. The extent of how these processes utilize molecular tunability to affect material properties were investigated through measurement-based comparison of the various polymer compositions frequency-related dynamic mechanical analysis, tension-related elastic-deformation mechanical analysis, and material swelling analysis. Stained murine myoblasts cultured on NIPU slabs were evaluated via fluorescent microscopy for "green-chemistry" affects on cytocompatibility and cell adhesion to assess potential biofouling resistance. 3D multi-material structures with micro-features were printed, thus demonstrating the capability to spatially pattern different NIPU materials in a controlled manner and build compliant mechanisms.
    Malunited proximal radius fractures causing dislocation of the radio-capitellar joint are rare. We present a case of a two-year-old female patient with such an injury who was treated with a proximal radius osteotomy with good long-term outcomes.

    Case study of a single patient with a malunited proximal radius fracture which was identified as causing radio-capitellar dislocation who underwent corrective osteotomy with a good result.

    Our opinion is that a corrective osteotomy for a malunited proximal radius fracture causing radio-capitellar dislocation is a sound treatment option and that no supplementary soft tissue reconstruction such as annular ligament exploration/reconstruction is necessary.
    Our opinion is that a corrective osteotomy for a malunited proximal radius fracture causing radio-capitellar dislocation is a sound treatment option and that no supplementary soft tissue reconstruction such as annular ligament exploration/reconstruction is necessary.
    Total elbow arthroplasty (TEA) is the established treatment for end-stage rheumatoid arthritis but improved surgical techniques have resulted in expanded indications. The aim of this study is to review the literature to evaluate the evolution of surgical indications for TEA.

    A systematic review of PubMed and EMBASE databases was conducted. Case series and comparative studies reporting results after three types of primary TEA were eligible for inclusion.

    Forty-nine eligible studies were identified (
     = 1995). The number of TEA cases published annually increased from 6 cases in 1980 to 135 cases in 2008. The commonest indication for TEA throughout the review period was rheumatoid arthritis but its annual proportion reduced from 77% to 50%. The mean Mayo Elbow Performance Score significantly improved for all indications. Three comparative studies reported statistically improved functional outcomes in rheumatoid arthritis over the trauma sequelae group. Complication and revision rates varied; rheumatoid arthritis 5.2-30.9% and 11-13%, acute fracture 0-50% and 10-11%, trauma sequelae 14.2-50% and 0-30%, osteoarthritis 50% and 11%, respectively.

    TEA can provide functional improvements in inflammatory arthritis, acute fractures, trauma sequelae and miscellaneous indications. https://www.selleckchem.com/products/Sunitinib-Malate-(Sutent).html Long-term TEA survivorship appears satisfactory in rheumatoid arthritis and fracture cases; however, further research into alternative surgical indications is still required.
    TEA can provide functional improvements in inflammatory arthritis, acute fractures, trauma sequelae and miscellaneous indications. Long-term TEA survivorship appears satisfactory in rheumatoid arthritis and fracture cases; however, further research into alternative surgical indications is still required.We report a rare case of atypical Mycobacterium intracellulare infection encountered in a left sternoclavicular joint of an immunocompetent patient. The 34-year-old female patient presented with a one-year history of left sternoclavicular joint pain and swelling. The patient had multiple radiological investigations, which were suspicious for an infective cause. The patient had a biopsy of the joint, which returned showing acid-fast bacilli. The patient consequently received a prolonged course of medical treatment for M. intracellulare.The SARS-CoV-2 pandemic has changed the way we work, and health care services have to adapt. The use of personal protective equipment (PPE) and the delay of non-urgent procedures were the immediate measures adopted by Gastrointestinal (GI) Endoscopy Units at the time of crisis. As the peak has now passed in most countries, GI facilities are facing the next challenge of this pandemic service providers must adapt their routine work to a 'new normal'. Routine casework must resume, and waiting lists must be addressed all in the awareness of the ongoing potential risks of COVID-19, and the threat of a second wave. In this review, we discuss strategies to manage the workload by improving procedure appropriateness and prioritization, whilst maintaining a 'COVID-free' environment. This includes monitoring of an adequate stock of PPE and the implications for the staff's workload, and the GI trainees' need of training.
    Functional sugar alcohols have been widely used in the food, medicine, and pharmaceutical industries for their unique properties. Among these, erythritol is a zero calories sweetener produced by the yeast
    . However, in wild-type strains, erythritol is produced with low productivity and yield and only under high osmotic pressure together with other undesired polyols, such as mannitol or d-arabitol. The yeast is also able to catabolize erythritol in non-stressing conditions.

    Herein,
    has been metabolically engineered to increase erythritol production titer, yield, and productivity from glucose. This consisted of the disruption of anabolic pathways for mannitol and d-arabitol together with the erythritol catabolic pathway. Genes
    and
    encoding, respectively, glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase were also constitutively expressed in regenerating the NADPH
    consumed during erythritol synthesis. Finally, the gene
    gene from
    encoding ubiquitin ligase was overexpressed to improve cell thermoresistance.
    Green chemistry-based non-isocyanate polyurethanes (NIPU) are synthesized and 3D-printed via rapid, projection photopolymerization into compliant mechanisms of 3D structure with spatially-localized material properties. Trimethylolpropane allyl ether-cyclic carbonate is used to couple the unique properties of two types of reaction chemistry (1) primary diamine-cyclic carbonate ring-opening conjugation for supplanting conventional isocyanate-polyol reactions in creating urethane groups, with the additional advantage of enabling modular segment interchangeability within the diurethane prepolymers; and (2) thiol-ene (click) conjugation for non-telechelic, low monodispersity, quasi-crystalline-capable, and alternating step-growth co-photopolymerization. Fourier Transform Infrared Spectroscopy is used to monitor the functional group transformation in reactions, and to confirm these process-associated molecular products. The extent of how these processes utilize molecular tunability to affect material properties were investigated through measurement-based comparison of the various polymer compositions frequency-related dynamic mechanical analysis, tension-related elastic-deformation mechanical analysis, and material swelling analysis. Stained murine myoblasts cultured on NIPU slabs were evaluated via fluorescent microscopy for "green-chemistry" affects on cytocompatibility and cell adhesion to assess potential biofouling resistance. 3D multi-material structures with micro-features were printed, thus demonstrating the capability to spatially pattern different NIPU materials in a controlled manner and build compliant mechanisms. Malunited proximal radius fractures causing dislocation of the radio-capitellar joint are rare. We present a case of a two-year-old female patient with such an injury who was treated with a proximal radius osteotomy with good long-term outcomes. Case study of a single patient with a malunited proximal radius fracture which was identified as causing radio-capitellar dislocation who underwent corrective osteotomy with a good result. Our opinion is that a corrective osteotomy for a malunited proximal radius fracture causing radio-capitellar dislocation is a sound treatment option and that no supplementary soft tissue reconstruction such as annular ligament exploration/reconstruction is necessary. Our opinion is that a corrective osteotomy for a malunited proximal radius fracture causing radio-capitellar dislocation is a sound treatment option and that no supplementary soft tissue reconstruction such as annular ligament exploration/reconstruction is necessary. Total elbow arthroplasty (TEA) is the established treatment for end-stage rheumatoid arthritis but improved surgical techniques have resulted in expanded indications. The aim of this study is to review the literature to evaluate the evolution of surgical indications for TEA. A systematic review of PubMed and EMBASE databases was conducted. Case series and comparative studies reporting results after three types of primary TEA were eligible for inclusion. Forty-nine eligible studies were identified (  = 1995). The number of TEA cases published annually increased from 6 cases in 1980 to 135 cases in 2008. The commonest indication for TEA throughout the review period was rheumatoid arthritis but its annual proportion reduced from 77% to 50%. The mean Mayo Elbow Performance Score significantly improved for all indications. Three comparative studies reported statistically improved functional outcomes in rheumatoid arthritis over the trauma sequelae group. Complication and revision rates varied; rheumatoid arthritis 5.2-30.9% and 11-13%, acute fracture 0-50% and 10-11%, trauma sequelae 14.2-50% and 0-30%, osteoarthritis 50% and 11%, respectively. TEA can provide functional improvements in inflammatory arthritis, acute fractures, trauma sequelae and miscellaneous indications. https://www.selleckchem.com/products/Sunitinib-Malate-(Sutent).html Long-term TEA survivorship appears satisfactory in rheumatoid arthritis and fracture cases; however, further research into alternative surgical indications is still required. TEA can provide functional improvements in inflammatory arthritis, acute fractures, trauma sequelae and miscellaneous indications. Long-term TEA survivorship appears satisfactory in rheumatoid arthritis and fracture cases; however, further research into alternative surgical indications is still required.We report a rare case of atypical Mycobacterium intracellulare infection encountered in a left sternoclavicular joint of an immunocompetent patient. The 34-year-old female patient presented with a one-year history of left sternoclavicular joint pain and swelling. The patient had multiple radiological investigations, which were suspicious for an infective cause. The patient had a biopsy of the joint, which returned showing acid-fast bacilli. The patient consequently received a prolonged course of medical treatment for M. intracellulare.The SARS-CoV-2 pandemic has changed the way we work, and health care services have to adapt. The use of personal protective equipment (PPE) and the delay of non-urgent procedures were the immediate measures adopted by Gastrointestinal (GI) Endoscopy Units at the time of crisis. As the peak has now passed in most countries, GI facilities are facing the next challenge of this pandemic service providers must adapt their routine work to a 'new normal'. Routine casework must resume, and waiting lists must be addressed all in the awareness of the ongoing potential risks of COVID-19, and the threat of a second wave. In this review, we discuss strategies to manage the workload by improving procedure appropriateness and prioritization, whilst maintaining a 'COVID-free' environment. This includes monitoring of an adequate stock of PPE and the implications for the staff's workload, and the GI trainees' need of training. Functional sugar alcohols have been widely used in the food, medicine, and pharmaceutical industries for their unique properties. Among these, erythritol is a zero calories sweetener produced by the yeast . However, in wild-type strains, erythritol is produced with low productivity and yield and only under high osmotic pressure together with other undesired polyols, such as mannitol or d-arabitol. The yeast is also able to catabolize erythritol in non-stressing conditions. Herein, has been metabolically engineered to increase erythritol production titer, yield, and productivity from glucose. This consisted of the disruption of anabolic pathways for mannitol and d-arabitol together with the erythritol catabolic pathway. Genes and encoding, respectively, glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase were also constitutively expressed in regenerating the NADPH consumed during erythritol synthesis. Finally, the gene gene from encoding ubiquitin ligase was overexpressed to improve cell thermoresistance.
    0 Commentarii 0 Distribuiri 39 Views 0 previzualizare

  • This article is part of the theme issue 'Integrative research perspectives on marine conservation'.Recent decades have seen an explosion in the amount of data available on all aspects of biodiversity, which has led to data-driven approaches to understand how and why diversity varies in time and space. Global repositories facilitate access to various classes of species-level data including biogeography, genetics and conservation status, which are in turn required to study different dimensions of diversity. Ensuring that these different data sources are interoperable is a challenge as we aim to create synthetic data products to monitor the state of the world's biodiversity. One way to approach this is to link data of different classes, and to inventory the availability of data across multiple sources. Here, we use a comprehensive list of more than 200 000 marine animal species, and quantify the availability of data on geographical occurrences, genetic sequences, conservation assessments and DNA barcodes across all phyla and broad functional groups. This reveals a very uneven picture 44% of species are represented by no record other than their taxonomy, but some species are rich in data. Although these data-rich species are concentrated into a few taxonomic and functional groups, especially vertebrates, data are spread widely across marine animals, with members of all 32 phyla represented in at least one database. By highlighting gaps in current knowledge, our census of marine diversity data helps to prioritize future data collection activities, as well as emphasizing the importance of ongoing sustained observations and archiving of existing data into global repositories. This article is part of the theme issue 'Integrative research perspectives on marine conservation'.Temperature variability and extremes can have profound impacts on populations and ecological communities. Predicting impacts of thermal variability poses a challenge, because it has both direct physiological effects and indirect effects through species interactions. In addition, differences in thermal performance between predators and prey and nonlinear averaging of temperature-dependent performance can result in complex and counterintuitive population dynamics in response to climate change. Yet the combined consequences of these effects remain underexplored. Here, modelling temperature-dependent predator-prey dynamics, we study how changes in temperature variability affect population size, collapse and stable coexistence of both predator and prey, relative to under constant environments or warming alone. We find that the effects of temperature variation on interacting species can lead to a diversity of outcomes, from predator collapse to stable coexistence, depending on interaction strengths and differences in species' thermal performance. Temperature variability also alters predictions about population collapse-in some cases allowing predators to persist for longer than predicted when considering warming alone, and in others accelerating collapse. To inform management responses that are robust to future climates with increasing temperature variability and extremes, we need to incorporate the consequences of temperature variation in complex ecosystems. This article is part of the theme issue 'Integrative research perspectives on marine conservation'.An accurate identification of species and communities is a prerequisite for analysing and recording biodiversity and community shifts. In the context of marine biodiversity conservation and management, this review outlines past, present and forward-looking perspectives on identifying and recording planktonic diversity by illustrating the transition from traditional species identification based on morphological diagnostic characters to full molecular genetic identification of marine assemblages. In this process, the article presents the methodological advancements by discussing progress and critical aspects of the crossover from traditional to novel and future molecular genetic identifications and it outlines the advantages of integrative approaches using the strengths of both morphological and molecular techniques to identify species and assemblages. We demonstrate this process of identifying and recording marine biodiversity on pelagic copepods as model taxon. Copepods are known for their high taxonomic and ecological diversity and comprise a huge variety of behaviours, forms and life histories, making them a highly interesting and well-studied group in terms of biodiversity and ecosystem functioning. Furthermore, their short life cycles and rapid responses to changing environments make them good indicators and core research components for ecosystem health and status in the light of environmental change. This article is part of the theme issue 'Integrative research perspectives on marine conservation'.Understanding food web responses to global warming, and their consequences for conservation and management, requires knowledge on how responses vary both among and within species. https://www.selleckchem.com/products/mdv3100.html Warming can reduce both species richness and biomass production. However, warming responses observed at different levels of biological organization may seem contradictory. For example, higher temperatures commonly lead to faster individual body growth but can decrease biomass production of fishes. Here we show that the key to resolve this contradiction is intraspecific variation, because (i) community dynamics emerge from interactions among individuals, and (ii) ecological interactions, physiological processes and warming effects often vary over life history. By combining insights from temperature-dependent dynamic models of simple food webs, observations over large temperature gradients and findings from short-term mesocosm and multi-decadal whole-ecosystem warming experiments, we resolve mechanisms by which warming waters can affect food webs via individual-level responses and review their empirical support. We identify a need for warming experiments on food webs manipulating population size structures to test these mechanisms. We stress that within-species variation in both body size, temperature responses and ecological interactions are key for accurate predictions and appropriate conservation efforts for fish production and food web function under a warming climate. This article is part of the theme issue 'Integrative research perspectives on marine conservation'.
    This article is part of the theme issue 'Integrative research perspectives on marine conservation'.Recent decades have seen an explosion in the amount of data available on all aspects of biodiversity, which has led to data-driven approaches to understand how and why diversity varies in time and space. Global repositories facilitate access to various classes of species-level data including biogeography, genetics and conservation status, which are in turn required to study different dimensions of diversity. Ensuring that these different data sources are interoperable is a challenge as we aim to create synthetic data products to monitor the state of the world's biodiversity. One way to approach this is to link data of different classes, and to inventory the availability of data across multiple sources. Here, we use a comprehensive list of more than 200 000 marine animal species, and quantify the availability of data on geographical occurrences, genetic sequences, conservation assessments and DNA barcodes across all phyla and broad functional groups. This reveals a very uneven picture 44% of species are represented by no record other than their taxonomy, but some species are rich in data. Although these data-rich species are concentrated into a few taxonomic and functional groups, especially vertebrates, data are spread widely across marine animals, with members of all 32 phyla represented in at least one database. By highlighting gaps in current knowledge, our census of marine diversity data helps to prioritize future data collection activities, as well as emphasizing the importance of ongoing sustained observations and archiving of existing data into global repositories. This article is part of the theme issue 'Integrative research perspectives on marine conservation'.Temperature variability and extremes can have profound impacts on populations and ecological communities. Predicting impacts of thermal variability poses a challenge, because it has both direct physiological effects and indirect effects through species interactions. In addition, differences in thermal performance between predators and prey and nonlinear averaging of temperature-dependent performance can result in complex and counterintuitive population dynamics in response to climate change. Yet the combined consequences of these effects remain underexplored. Here, modelling temperature-dependent predator-prey dynamics, we study how changes in temperature variability affect population size, collapse and stable coexistence of both predator and prey, relative to under constant environments or warming alone. We find that the effects of temperature variation on interacting species can lead to a diversity of outcomes, from predator collapse to stable coexistence, depending on interaction strengths and differences in species' thermal performance. Temperature variability also alters predictions about population collapse-in some cases allowing predators to persist for longer than predicted when considering warming alone, and in others accelerating collapse. To inform management responses that are robust to future climates with increasing temperature variability and extremes, we need to incorporate the consequences of temperature variation in complex ecosystems. This article is part of the theme issue 'Integrative research perspectives on marine conservation'.An accurate identification of species and communities is a prerequisite for analysing and recording biodiversity and community shifts. In the context of marine biodiversity conservation and management, this review outlines past, present and forward-looking perspectives on identifying and recording planktonic diversity by illustrating the transition from traditional species identification based on morphological diagnostic characters to full molecular genetic identification of marine assemblages. In this process, the article presents the methodological advancements by discussing progress and critical aspects of the crossover from traditional to novel and future molecular genetic identifications and it outlines the advantages of integrative approaches using the strengths of both morphological and molecular techniques to identify species and assemblages. We demonstrate this process of identifying and recording marine biodiversity on pelagic copepods as model taxon. Copepods are known for their high taxonomic and ecological diversity and comprise a huge variety of behaviours, forms and life histories, making them a highly interesting and well-studied group in terms of biodiversity and ecosystem functioning. Furthermore, their short life cycles and rapid responses to changing environments make them good indicators and core research components for ecosystem health and status in the light of environmental change. This article is part of the theme issue 'Integrative research perspectives on marine conservation'.Understanding food web responses to global warming, and their consequences for conservation and management, requires knowledge on how responses vary both among and within species. https://www.selleckchem.com/products/mdv3100.html Warming can reduce both species richness and biomass production. However, warming responses observed at different levels of biological organization may seem contradictory. For example, higher temperatures commonly lead to faster individual body growth but can decrease biomass production of fishes. Here we show that the key to resolve this contradiction is intraspecific variation, because (i) community dynamics emerge from interactions among individuals, and (ii) ecological interactions, physiological processes and warming effects often vary over life history. By combining insights from temperature-dependent dynamic models of simple food webs, observations over large temperature gradients and findings from short-term mesocosm and multi-decadal whole-ecosystem warming experiments, we resolve mechanisms by which warming waters can affect food webs via individual-level responses and review their empirical support. We identify a need for warming experiments on food webs manipulating population size structures to test these mechanisms. We stress that within-species variation in both body size, temperature responses and ecological interactions are key for accurate predictions and appropriate conservation efforts for fish production and food web function under a warming climate. This article is part of the theme issue 'Integrative research perspectives on marine conservation'.
    0 Commentarii 0 Distribuiri 26 Views 0 previzualizare

  • 043) was higher in infected cats. This finding may suggest an association between infection by L. infantum and feline kidney disease.Provitamin A biofortified maize is promoted in developing country to curb vitamin A deficiency. To determine the provitamin A carotenoid content of fresh and stored biofortified maize requires analytical techniques that are affordable by the targeted population. In this study color parameters (L∗, a∗, b∗) individually or in combination were used to estimate carotenoid content in high carotenoid biofortified maize. There was an increase in L∗ value with storage indicating grains were becoming lighter while a∗ and b∗ values did not change significantly. Almost all storage bags induced total color change (ΔE∗) greater than 2 which is perceivable by consumers as a deviation from original quality. The coefficient of determination (R2) between carotenoid content and color parameters were high and significant for most color parameters suggesting that they could be used to estimate carotenoid content in biofortified maize. While change of color is indicative of carotenoid degradation, our study found that ΔE∗ is a poor estimator of carotenoids lost during post-harvest storage of biofortified maize. Hue (h∗), L∗ and a∗ gave consistently and significantly higher R2 (p less then 0.05) for almost all carotenoids analyzed suggesting that they could be used to generate predictive models for estimating carotenoid content in stored biofortified maize.
    Advanced triple negative breast cancer (ATNBC) is defined by a lack of expression of hormones receptors as well as HER2/neu and its high probability of visceral metastasis. This pathology is associated with a poor prognosis. Previously, we found that T2, an

    -arylsubstituted thiosemicarbazone (

    -TSC), had cytotoxic effect on human breast cancer cells lines. Hence, in this study, we investigated the anti-metastasic action of T2 on ATNBC.

    In order to deepen T2 action mode on ATNBC, we first confirmed T2 cytotoxicity on a panel of TNBC cells and then continued studying T2 effects
    an
    on the syngeneic 4T1 mouse model.

    We found that T2 had a cytotoxic effect comparable to chemotherapeutics used in present treatment schemes for ATNBC. T2 treatment not only induced apoptosis, but it also down-modulated 4T1 invasive and metastatic-associated capacities, such as clonogenicity, migration and metallo-proteases activity. Moreover, this agent reduced the number of 4T1 cancer stem cells. Finally, T2 treatment induced a more differentiated cell phenotype and the overexpression of the metastasis suppressor gene NDRG-1.
    assays showed that T2 reduced tumor burden, down modulated local tumor invasion and significantly reduced the number of lung metastases in the 4T1 advanced TNBC murine model, while the compound did not exhibit intolerable toxicity.

    This study provided evidence that T2 not only exerted an anti-tumor activity but it also showed anti-invasive and anti-metastatic actions on ATNBC
    and
    , suggesting that T2 could be considered as a promising therapy that deserves further analysis.
    This study provided evidence that T2 not only exerted an anti-tumor activity but it also showed anti-invasive and anti-metastatic actions on ATNBC in vivo and in vitro, suggesting that T2 could be considered as a promising therapy that deserves further analysis.This paper aims to provide a critical review of the studies dealing with Educational Robotics for children with Neurodevelopmental Disorders. We aimed to investigate whether in the literature there is a sound evidence that activities with robots improve the abilities and performances of children with special needs. This paper explores the methodological aspects as well as the outcomes of the selected studies to provide a clear picture of the state-of-the-art on this topic. After a systematic search in the online database via keyword searches, 15 scientific papers were included in this review. We applied strict selection criteria limiting our review only to papers reporting educational robotics activities with children (from 3 up to 19 years old) with a diagnosis of neurodevelopmental disorders, in which the children had the opportunity to somehow program the behaviours of real robots. The majority of experiences showed improvements in the participants' performance or abilities, their engagement and involvement, communication/interaction with peers, during robotics sessions. Some studies reported mixed results, calling for the need to carefully design the objective and the related activities of each experience.Our previous reports showed that 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) has antiproliferative actions in endothelial cells stably expressing viral G protein-coupled receptor (vGPCR) associated with the pathogenesis of Kaposi's sarcoma. It has been reported that COX-2 enzyme, involved in the tumorigenesis of many types of cancers, is induced by vGPCR. Therefore, we investigated whether COX-2 down-regulation is part of the growth inhibitory effects of 1α,25(OH)2D3. Proliferation was measured in presence of COX-2 inhibitor Celecoxib (10-20 μM) revealing a decreased in vGPCR cell number, displaying typically apoptotic features in a dose dependent manner similarly to 1α,25(OH)2D3. In addition, the reduced cell viability observed with 20 μM Celecoxib was enhanced in presence of 1α,25(OH)2D3. Remarkably, although COX-2 mRNA and protein levels were up-regulated after 1α,25(OH)2D3 treatment, COX-2 enzymatic activity was reduced in a VDR-dependent manner. Furthermore, an interaction between COX-2 and VDR was revealed through GST pull-down and computational analysis. Additionally, high-affinity prostanoid receptors (EP3 and EP4) were found down-regulated by 1α,25(OH)2D3. Altogether, these results suggest a down-regulation of COX-2 activity and of prostanoid receptors as part of the antineoplastic mechanism of 1α,25(OH)2D3 in endothelial cells transformed by vGPCR.Facial appearance has essential consequences in various social interactions. Previous studies have shown that although people can perceive a variety of impressions from a face, these impressions may form from a relatively small number of core dimensions in the psychological impression space (e.g., valence and dominance). However, few studies have thus far examined which facial shape features contribute to perceptions of the core trait impression dimensions for Asian female faces. This study aimed to identify the commonalities between various facial impressions of Japanese female faces and determine the facial shape components associated with such impressions by applying geometric morphometric (GMM) analysis. https://www.selleckchem.com/products/BIBF1120.html In Experiment 1 (Modeling study), Japanese female faces were evaluated in terms of 18 trait adjectives that are frequently used to describe facial appearance in daily life. We found that Japanese female facial appearance is indeed evaluated mainly on the valence and dominance dimensions. In Experiment 2 (Validation study), we confirmed that all the trait impressions were quantitatively manipulated by transforming the facial shape features associated with valence and dominance.
    043) was higher in infected cats. This finding may suggest an association between infection by L. infantum and feline kidney disease.Provitamin A biofortified maize is promoted in developing country to curb vitamin A deficiency. To determine the provitamin A carotenoid content of fresh and stored biofortified maize requires analytical techniques that are affordable by the targeted population. In this study color parameters (L∗, a∗, b∗) individually or in combination were used to estimate carotenoid content in high carotenoid biofortified maize. There was an increase in L∗ value with storage indicating grains were becoming lighter while a∗ and b∗ values did not change significantly. Almost all storage bags induced total color change (ΔE∗) greater than 2 which is perceivable by consumers as a deviation from original quality. The coefficient of determination (R2) between carotenoid content and color parameters were high and significant for most color parameters suggesting that they could be used to estimate carotenoid content in biofortified maize. While change of color is indicative of carotenoid degradation, our study found that ΔE∗ is a poor estimator of carotenoids lost during post-harvest storage of biofortified maize. Hue (h∗), L∗ and a∗ gave consistently and significantly higher R2 (p less then 0.05) for almost all carotenoids analyzed suggesting that they could be used to generate predictive models for estimating carotenoid content in stored biofortified maize. Advanced triple negative breast cancer (ATNBC) is defined by a lack of expression of hormones receptors as well as HER2/neu and its high probability of visceral metastasis. This pathology is associated with a poor prognosis. Previously, we found that T2, an -arylsubstituted thiosemicarbazone ( -TSC), had cytotoxic effect on human breast cancer cells lines. Hence, in this study, we investigated the anti-metastasic action of T2 on ATNBC. In order to deepen T2 action mode on ATNBC, we first confirmed T2 cytotoxicity on a panel of TNBC cells and then continued studying T2 effects an on the syngeneic 4T1 mouse model. We found that T2 had a cytotoxic effect comparable to chemotherapeutics used in present treatment schemes for ATNBC. T2 treatment not only induced apoptosis, but it also down-modulated 4T1 invasive and metastatic-associated capacities, such as clonogenicity, migration and metallo-proteases activity. Moreover, this agent reduced the number of 4T1 cancer stem cells. Finally, T2 treatment induced a more differentiated cell phenotype and the overexpression of the metastasis suppressor gene NDRG-1. assays showed that T2 reduced tumor burden, down modulated local tumor invasion and significantly reduced the number of lung metastases in the 4T1 advanced TNBC murine model, while the compound did not exhibit intolerable toxicity. This study provided evidence that T2 not only exerted an anti-tumor activity but it also showed anti-invasive and anti-metastatic actions on ATNBC and , suggesting that T2 could be considered as a promising therapy that deserves further analysis. This study provided evidence that T2 not only exerted an anti-tumor activity but it also showed anti-invasive and anti-metastatic actions on ATNBC in vivo and in vitro, suggesting that T2 could be considered as a promising therapy that deserves further analysis.This paper aims to provide a critical review of the studies dealing with Educational Robotics for children with Neurodevelopmental Disorders. We aimed to investigate whether in the literature there is a sound evidence that activities with robots improve the abilities and performances of children with special needs. This paper explores the methodological aspects as well as the outcomes of the selected studies to provide a clear picture of the state-of-the-art on this topic. After a systematic search in the online database via keyword searches, 15 scientific papers were included in this review. We applied strict selection criteria limiting our review only to papers reporting educational robotics activities with children (from 3 up to 19 years old) with a diagnosis of neurodevelopmental disorders, in which the children had the opportunity to somehow program the behaviours of real robots. The majority of experiences showed improvements in the participants' performance or abilities, their engagement and involvement, communication/interaction with peers, during robotics sessions. Some studies reported mixed results, calling for the need to carefully design the objective and the related activities of each experience.Our previous reports showed that 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) has antiproliferative actions in endothelial cells stably expressing viral G protein-coupled receptor (vGPCR) associated with the pathogenesis of Kaposi's sarcoma. It has been reported that COX-2 enzyme, involved in the tumorigenesis of many types of cancers, is induced by vGPCR. Therefore, we investigated whether COX-2 down-regulation is part of the growth inhibitory effects of 1α,25(OH)2D3. Proliferation was measured in presence of COX-2 inhibitor Celecoxib (10-20 μM) revealing a decreased in vGPCR cell number, displaying typically apoptotic features in a dose dependent manner similarly to 1α,25(OH)2D3. In addition, the reduced cell viability observed with 20 μM Celecoxib was enhanced in presence of 1α,25(OH)2D3. Remarkably, although COX-2 mRNA and protein levels were up-regulated after 1α,25(OH)2D3 treatment, COX-2 enzymatic activity was reduced in a VDR-dependent manner. Furthermore, an interaction between COX-2 and VDR was revealed through GST pull-down and computational analysis. Additionally, high-affinity prostanoid receptors (EP3 and EP4) were found down-regulated by 1α,25(OH)2D3. Altogether, these results suggest a down-regulation of COX-2 activity and of prostanoid receptors as part of the antineoplastic mechanism of 1α,25(OH)2D3 in endothelial cells transformed by vGPCR.Facial appearance has essential consequences in various social interactions. Previous studies have shown that although people can perceive a variety of impressions from a face, these impressions may form from a relatively small number of core dimensions in the psychological impression space (e.g., valence and dominance). However, few studies have thus far examined which facial shape features contribute to perceptions of the core trait impression dimensions for Asian female faces. This study aimed to identify the commonalities between various facial impressions of Japanese female faces and determine the facial shape components associated with such impressions by applying geometric morphometric (GMM) analysis. https://www.selleckchem.com/products/BIBF1120.html In Experiment 1 (Modeling study), Japanese female faces were evaluated in terms of 18 trait adjectives that are frequently used to describe facial appearance in daily life. We found that Japanese female facial appearance is indeed evaluated mainly on the valence and dominance dimensions. In Experiment 2 (Validation study), we confirmed that all the trait impressions were quantitatively manipulated by transforming the facial shape features associated with valence and dominance.
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  • Microendoscopic spinal surgery has demonstrated efficacy and is increasingly utilized as a minimally invasive approach to neural decompression, but there is a theoretical concern that bleeding and postoperative epidural hematoma (PEH) may occur with increased frequency in a contained small surgical field. Hemostatic agents, such as topical gelatin-thrombin matrix sealant (TGTMS), are routinely used in spine surgery procedures, yet there has been no data on whether PEH is suppressed by these agents when administered in microendoscopic spine surgery.

    The purpose of this study was to investigate the effect of TGTMS on bleeding and PEH formation in lumbar micoroendoscopic surgery.

    This is a randomized controlled trial (RCT) with additional prospective observational cohort.

    Patients were registered from July 2017 to September 2018 and a hundred and three patients undergoing microendoscopic laminectomy for lumbar spinal stenosis at a single institution were enrolled in this study.

    The primary outcome was inal stenosis did not demonstrate any difference in postoperative bleeding or PEH. Nonetheless, for patients that had active bleeding that required the use of TGTMS, there was no evidence of difference in postoperative clinical outcomes relative to controls.
    Impact factor, citation rate, and other traditional measures of scholarly impact do not account for the role that social media has in the dissemination of research. The Altmetric Attention Score (AAS) quantifies the active online presence of individual articles on various platforms (eg, Twitter, Facebook).

    We sought to better understand the factors associated with greater online attention and AAS in seven spine journals.

    Cross-sectional study.

    No patients were included in this study. We analyzed 380 articles in seven major spine journals.

    Extracted manuscript characteristics included AAS; number of Twitter, Facebook, and news outlet mentions; number of citations, references, academic institutions, and authors; and sample size, geographic region, subject of study, and level of evidence.

    All original scientific manuscripts published in the official January, February, and March 2017 issues of Spine, The Spine Journal, Spine Deformity, Journal of Neurosurgery-Spine, Clinical Spine Surgery, Global SpinS. We believe these findings may be useful to authors seeking ways to maximize the impact of their research.
    Our analysis of seven spine journals revealed a weak, positive correlation between AAS and number of citations. Number of references was associated with higher AAS. We believe these findings may be useful to authors seeking ways to maximize the impact of their research.Brucellosis is a zoonotic disease caused by certain species of Brucella. Each species has its preferred host animal, though it can infect other animals too. For a longer period, only six classical species were recognized in the genus Brucella. No vaccine is available for human brucellosis. Therefore, human brucellosis can be controlled only by controlling brucellosis in animals. The genus is now expanding with the newly isolated atypical strains from various animals, including marine mammals. Presently, 12 species of Brucella have been recognized. The first genome of Brucella was released in 2002, and today, we have more than 1500 genomes of Brucella spp. https://www.selleckchem.com/products/sodium-phenylbutyrate.html isolated worldwide. Multiple genome sequences are available for the major zoonotic species, B. abortus, B. melitensis, and B. suis. The Brucella genome has two chromosomes with the approximate sizes of 2.1 and 1.2 Mbp. The genome of Brucella is highly conserved across all the species at the nucleotide level. One of the unanswered questions is what makes host preference in different species of Brucella. Here, I summarize the recent advancements in the Brucella genomics research.
    To characterize patients with neurotrophic keratopathy (NK) and describe treatment outcomes.

    Setting Two institutional tertiary cornea clinics.

    Medical record review of 37 consecutive patients (37 eyes) with NK.

    Management of NK.

    Best-corrected visual acuity (BCVA), epithelial defects (ED), re-epithelialization time, number of perforations, need for penetrating keratoplasty and tarsorrhaphy.

    Average age was 64.4±15.0 years, with 59.5% male patients. Average follow up time was 20.8±32.6 months. Moderate to severe NK (Mackie Stage) was present in 62.1% of patients. Herpetic, neurosurgical and pars plana vitrectomy were the top three causes in each Mackie Stage. 72.9% used topical steroids to treat inflammatory ocular disease. Mean number of EDs was 1.6 per patient averaging 85 days to heal. Persistent EDs affected 56.7%. Corneal perforation (18.9%) was more likely with advanced age, herpetic cause and Stage 3 presentation. Tarsorrhaphy was performed in 35% of patients and were more likely with Stagesk factors for corneal perforation.The present study evaluates the effect of molecular mobility and molecular interactions in the physical stability of rivaroxaban (RIV) - soluplus® (SOL) amorphous solid dispersions (ASDs). Initially, the use of Adam-Gibbs approach revealed that RIV's molecular mobility (below its glass transition temperature) is significantly reduced in the presence of SOL, while the use of ATR-FTIR spectroscopy showed the formation of hydrogen bonds (HBs) between the two ASD components, indicating that these two mechanisms can be considered as responsible for system's physical stability. Contrary to previously published reports, the utilization of ATR-FTIR spectroscopy in the present study was able to clarify, for the first time, the type of intermolecular interactions formed within the examined ASD system, while the presence of a separate drug-rich amorphous phase (significantly increasing as the content of the drug increases) was also identified. Furthermore, in order to gain an insight into the intermolecular interactions responsible for drug's amorphous phase separation, molecular dynamics (MD) simulation models were utilized as realistic representations of the actual systems. Analysis of the obtained trajectories showed that the formation of strong intermolecular HBs between RIV's secondary amide proton and its three carbonyl oxygens (originating from the οxazolidone, oxomorpholin and carboxamide part of the drug molecule) as well as the significant reduction of the available HB acceptors in SOL due to copolymer's chain shrinkage, were responsible for the formation of a separate drug-rich amorphous phase within the ASD.
    Microendoscopic spinal surgery has demonstrated efficacy and is increasingly utilized as a minimally invasive approach to neural decompression, but there is a theoretical concern that bleeding and postoperative epidural hematoma (PEH) may occur with increased frequency in a contained small surgical field. Hemostatic agents, such as topical gelatin-thrombin matrix sealant (TGTMS), are routinely used in spine surgery procedures, yet there has been no data on whether PEH is suppressed by these agents when administered in microendoscopic spine surgery. The purpose of this study was to investigate the effect of TGTMS on bleeding and PEH formation in lumbar micoroendoscopic surgery. This is a randomized controlled trial (RCT) with additional prospective observational cohort. Patients were registered from July 2017 to September 2018 and a hundred and three patients undergoing microendoscopic laminectomy for lumbar spinal stenosis at a single institution were enrolled in this study. The primary outcome was inal stenosis did not demonstrate any difference in postoperative bleeding or PEH. Nonetheless, for patients that had active bleeding that required the use of TGTMS, there was no evidence of difference in postoperative clinical outcomes relative to controls. Impact factor, citation rate, and other traditional measures of scholarly impact do not account for the role that social media has in the dissemination of research. The Altmetric Attention Score (AAS) quantifies the active online presence of individual articles on various platforms (eg, Twitter, Facebook). We sought to better understand the factors associated with greater online attention and AAS in seven spine journals. Cross-sectional study. No patients were included in this study. We analyzed 380 articles in seven major spine journals. Extracted manuscript characteristics included AAS; number of Twitter, Facebook, and news outlet mentions; number of citations, references, academic institutions, and authors; and sample size, geographic region, subject of study, and level of evidence. All original scientific manuscripts published in the official January, February, and March 2017 issues of Spine, The Spine Journal, Spine Deformity, Journal of Neurosurgery-Spine, Clinical Spine Surgery, Global SpinS. We believe these findings may be useful to authors seeking ways to maximize the impact of their research. Our analysis of seven spine journals revealed a weak, positive correlation between AAS and number of citations. Number of references was associated with higher AAS. We believe these findings may be useful to authors seeking ways to maximize the impact of their research.Brucellosis is a zoonotic disease caused by certain species of Brucella. Each species has its preferred host animal, though it can infect other animals too. For a longer period, only six classical species were recognized in the genus Brucella. No vaccine is available for human brucellosis. Therefore, human brucellosis can be controlled only by controlling brucellosis in animals. The genus is now expanding with the newly isolated atypical strains from various animals, including marine mammals. Presently, 12 species of Brucella have been recognized. The first genome of Brucella was released in 2002, and today, we have more than 1500 genomes of Brucella spp. https://www.selleckchem.com/products/sodium-phenylbutyrate.html isolated worldwide. Multiple genome sequences are available for the major zoonotic species, B. abortus, B. melitensis, and B. suis. The Brucella genome has two chromosomes with the approximate sizes of 2.1 and 1.2 Mbp. The genome of Brucella is highly conserved across all the species at the nucleotide level. One of the unanswered questions is what makes host preference in different species of Brucella. Here, I summarize the recent advancements in the Brucella genomics research. To characterize patients with neurotrophic keratopathy (NK) and describe treatment outcomes. Setting Two institutional tertiary cornea clinics. Medical record review of 37 consecutive patients (37 eyes) with NK. Management of NK. Best-corrected visual acuity (BCVA), epithelial defects (ED), re-epithelialization time, number of perforations, need for penetrating keratoplasty and tarsorrhaphy. Average age was 64.4±15.0 years, with 59.5% male patients. Average follow up time was 20.8±32.6 months. Moderate to severe NK (Mackie Stage) was present in 62.1% of patients. Herpetic, neurosurgical and pars plana vitrectomy were the top three causes in each Mackie Stage. 72.9% used topical steroids to treat inflammatory ocular disease. Mean number of EDs was 1.6 per patient averaging 85 days to heal. Persistent EDs affected 56.7%. Corneal perforation (18.9%) was more likely with advanced age, herpetic cause and Stage 3 presentation. Tarsorrhaphy was performed in 35% of patients and were more likely with Stagesk factors for corneal perforation.The present study evaluates the effect of molecular mobility and molecular interactions in the physical stability of rivaroxaban (RIV) - soluplus® (SOL) amorphous solid dispersions (ASDs). Initially, the use of Adam-Gibbs approach revealed that RIV's molecular mobility (below its glass transition temperature) is significantly reduced in the presence of SOL, while the use of ATR-FTIR spectroscopy showed the formation of hydrogen bonds (HBs) between the two ASD components, indicating that these two mechanisms can be considered as responsible for system's physical stability. Contrary to previously published reports, the utilization of ATR-FTIR spectroscopy in the present study was able to clarify, for the first time, the type of intermolecular interactions formed within the examined ASD system, while the presence of a separate drug-rich amorphous phase (significantly increasing as the content of the drug increases) was also identified. Furthermore, in order to gain an insight into the intermolecular interactions responsible for drug's amorphous phase separation, molecular dynamics (MD) simulation models were utilized as realistic representations of the actual systems. Analysis of the obtained trajectories showed that the formation of strong intermolecular HBs between RIV's secondary amide proton and its three carbonyl oxygens (originating from the οxazolidone, oxomorpholin and carboxamide part of the drug molecule) as well as the significant reduction of the available HB acceptors in SOL due to copolymer's chain shrinkage, were responsible for the formation of a separate drug-rich amorphous phase within the ASD.
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  • The accumulation of oxidative stress, neuroinflammation and abnormal aggregation of amyloid β-peptide (Aβ) have been shown to induce synaptic dysfunction and memory deficits in Alzheimer's disease (AD). Cellular depletion of the major endogenous antioxidant Glutathione (GSH) has been linked to cognitive decline and the development of AD pathology. Supplementation with γ-glutamylcysteine (γ-GC), the immediate precursor and the limiting substrate for GSH biosynthesis, can transiently augment cellular GSH levels by bypassing the regulation of GSH homeostasis.

    In the present study, we investigated the effect of dietary supplementation of γ-GC on oxidative stress and Aβ pathology in the brains of APP/PS1 ****. The APP/PS1 **** were fed γ-GC from 3 months of age with biomarkers of apoptosis and cell death, oxidative stress, neuroinflammation and Aβ load being assessed at 6 months of age.

    Our data showed that supplementation with γ-GC lowered the levels of brain lipid peroxidation, protein carbonyls and apoptoent and neurodegeneration.Major depressive disorder (MDD) is a prevalent psychiatric disorder that brings great harm and burden to both patients and society. This study aimed to examine the effects of whole-body vibration (WBV) training on a chronic restraint stress (CRS) induced depression rat model and provide an initial understanding of related molecular mechanisms. Adult Sprague-Dawley male rats were randomly divided into the following three groups a) control group, b) depressive disorder group, and c) depression with WBV training treatment group. Daily food intake, body weight, sucrose preference test, open field test, elevated plus maze, forced swimming test, and Barnes maze task tests were performed. Immunofluorescence staining and ELISA analysis were used to assess neuronal damage, synaptic proteins, glial cells, and trophic factors. The data of behavioral tests and related biochemical indicators were statistically analyzed and compared between groups. Rats undergoing CRS showed increased anxiety-like behavior and memory impairment, along with synaptic atrophy and neuronal degeneration. WBV could reverse behavioral dysfunction, inhibit the degeneration of neurons, alleviate the damage of neurons and the pathological changes of glial cells, enhance trophic factor expression, and ameliorate the downregulation of dendritic and synaptic proteins after CRS. The effect of WBV in rats may be mediated via the reduction of hippocampal neuronal degeneration and by improving expression of synaptic proteins. WBV training exerts multifactorial benefits on MDD that supports its use as a promising new therapeutic option for improving depression-like behaviors in the depressive and/or potentially depressive.
    The clinical significance of myocardial bridging (MB) on the left anterior descending artery (LAD) is debated. We aimed to assess the association between MB and LAD plaque volumes/compositions in a case-control set up.

    In our retrospective analysis we investigated 50 cases with incidentally recognized LAD MB and 50 matched controls without LAD MB on coronary computed tomography angiography. We quantified plaque volumes proximal to the MB and beneath it in patients with MB and in the corresponding coronary segments in patients without MB.

    In total, we have included 100 patients (mean age 60.6±10.8years, males 80%). Plaque volume was similar in the LAD segments proximal to the MB in cases vs. controls (150.0mm
    [IQR 90.7-194.5mm
    ] vs. 132.8mm
    [IQR 94.2-184.3mm
    ], respectively; p=0.95) while the plaque volume was smaller beneath LAD MB vs. control segment (16.2mm
    [IQR 12.6-25.8mm
    ] vs. 21.1mm
    [IQR 14.0-42.4mm
    ], respectively; p=0.002). No significant differences were found regarding different plaque components in segments proximal to the MB while fatty plaque and necrotic core volumes were smaller or negligible in coronary segment beneath MB than in controls (0.07mm
    [IQR 0.005-0.27mm
    ] vs. 12.7mm
    [IQR 7.4-24.4mm
    ] and 0.00mm
    [IQR 0.00-0.04mm
    ] vs. 0.06mm
    [IQR 0.03-2.8mm
    ], respectively (p<0.001).

    Comparing patients with MB vs. https://www.selleckchem.com/products/Staurosporine.html matched controls without it, MB was not associated with increased plaque volumes in LAD segment proximal to MB and plaque quantity was smaller in the MB segment. Our data are supportive of benign nature of incidentally recognized LAD MB.
    Comparing patients with MB vs. matched controls without it, MB was not associated with increased plaque volumes in LAD segment proximal to MB and plaque quantity was smaller in the MB segment. Our data are supportive of benign nature of incidentally recognized LAD MB.
    Irrespective of initial treatment for congenital heart disease (CHD) in childhood, CHD is a lifelong condition, leaving patients at risk for complications. To support uninterrupted, age- and development-based care for young persons with CHD, guidelines and consensus papers emphasise the need for formal transition programmes, including transfer to adult CHD (ACHD) clinics. Here, we surveyed existing transfer and transition programmes in European ACHD centres. Our aims were to provide a contemporary view of transitional care for patients with CHD and to evaluate progress over the last decade.

    We conducted a descriptive, cross-sectional survey in 96 ACHD centres in Europe. A specific survey form was developed that sampled the practices of transfer and/or transition. We used a transfer-transition index to quantify adherence to quality indicators of successful transfer and transition.

    Of the 96 ACHD centres, 40 (41.7%) offered a formal transition, and 85 (88.5%) had structured transfer from paediatric to ACHD care. Although 31% of the centres performed at a 'good' level on the transfer-transition index, only 4 (4.2%) satisfied all criteria. Most centres with a transition programme offered education and support through a dedicated transition specialist, who was a master's-prepared nurse in most centres. A minority of the ACHD centres offered a flexible transition process, starting at least two years before transfer.

    Nearly half of the included ACHD centres offered a formal transition programme, and almost 90% offered structured transfer. Despite some improvements since 2009, most of the programmes lacked an age- and development-based approach.
    Nearly half of the included ACHD centres offered a formal transition programme, and almost 90% offered structured transfer. Despite some improvements since 2009, most of the programmes lacked an age- and development-based approach.
    The accumulation of oxidative stress, neuroinflammation and abnormal aggregation of amyloid β-peptide (Aβ) have been shown to induce synaptic dysfunction and memory deficits in Alzheimer's disease (AD). Cellular depletion of the major endogenous antioxidant Glutathione (GSH) has been linked to cognitive decline and the development of AD pathology. Supplementation with γ-glutamylcysteine (γ-GC), the immediate precursor and the limiting substrate for GSH biosynthesis, can transiently augment cellular GSH levels by bypassing the regulation of GSH homeostasis. In the present study, we investigated the effect of dietary supplementation of γ-GC on oxidative stress and Aβ pathology in the brains of APP/PS1 mice. The APP/PS1 mice were fed γ-GC from 3 months of age with biomarkers of apoptosis and cell death, oxidative stress, neuroinflammation and Aβ load being assessed at 6 months of age. Our data showed that supplementation with γ-GC lowered the levels of brain lipid peroxidation, protein carbonyls and apoptoent and neurodegeneration.Major depressive disorder (MDD) is a prevalent psychiatric disorder that brings great harm and burden to both patients and society. This study aimed to examine the effects of whole-body vibration (WBV) training on a chronic restraint stress (CRS) induced depression rat model and provide an initial understanding of related molecular mechanisms. Adult Sprague-Dawley male rats were randomly divided into the following three groups a) control group, b) depressive disorder group, and c) depression with WBV training treatment group. Daily food intake, body weight, sucrose preference test, open field test, elevated plus maze, forced swimming test, and Barnes maze task tests were performed. Immunofluorescence staining and ELISA analysis were used to assess neuronal damage, synaptic proteins, glial cells, and trophic factors. The data of behavioral tests and related biochemical indicators were statistically analyzed and compared between groups. Rats undergoing CRS showed increased anxiety-like behavior and memory impairment, along with synaptic atrophy and neuronal degeneration. WBV could reverse behavioral dysfunction, inhibit the degeneration of neurons, alleviate the damage of neurons and the pathological changes of glial cells, enhance trophic factor expression, and ameliorate the downregulation of dendritic and synaptic proteins after CRS. The effect of WBV in rats may be mediated via the reduction of hippocampal neuronal degeneration and by improving expression of synaptic proteins. WBV training exerts multifactorial benefits on MDD that supports its use as a promising new therapeutic option for improving depression-like behaviors in the depressive and/or potentially depressive. The clinical significance of myocardial bridging (MB) on the left anterior descending artery (LAD) is debated. We aimed to assess the association between MB and LAD plaque volumes/compositions in a case-control set up. In our retrospective analysis we investigated 50 cases with incidentally recognized LAD MB and 50 matched controls without LAD MB on coronary computed tomography angiography. We quantified plaque volumes proximal to the MB and beneath it in patients with MB and in the corresponding coronary segments in patients without MB. In total, we have included 100 patients (mean age 60.6±10.8years, males 80%). Plaque volume was similar in the LAD segments proximal to the MB in cases vs. controls (150.0mm [IQR 90.7-194.5mm ] vs. 132.8mm [IQR 94.2-184.3mm ], respectively; p=0.95) while the plaque volume was smaller beneath LAD MB vs. control segment (16.2mm [IQR 12.6-25.8mm ] vs. 21.1mm [IQR 14.0-42.4mm ], respectively; p=0.002). No significant differences were found regarding different plaque components in segments proximal to the MB while fatty plaque and necrotic core volumes were smaller or negligible in coronary segment beneath MB than in controls (0.07mm [IQR 0.005-0.27mm ] vs. 12.7mm [IQR 7.4-24.4mm ] and 0.00mm [IQR 0.00-0.04mm ] vs. 0.06mm [IQR 0.03-2.8mm ], respectively (p<0.001). Comparing patients with MB vs. https://www.selleckchem.com/products/Staurosporine.html matched controls without it, MB was not associated with increased plaque volumes in LAD segment proximal to MB and plaque quantity was smaller in the MB segment. Our data are supportive of benign nature of incidentally recognized LAD MB. Comparing patients with MB vs. matched controls without it, MB was not associated with increased plaque volumes in LAD segment proximal to MB and plaque quantity was smaller in the MB segment. Our data are supportive of benign nature of incidentally recognized LAD MB. Irrespective of initial treatment for congenital heart disease (CHD) in childhood, CHD is a lifelong condition, leaving patients at risk for complications. To support uninterrupted, age- and development-based care for young persons with CHD, guidelines and consensus papers emphasise the need for formal transition programmes, including transfer to adult CHD (ACHD) clinics. Here, we surveyed existing transfer and transition programmes in European ACHD centres. Our aims were to provide a contemporary view of transitional care for patients with CHD and to evaluate progress over the last decade. We conducted a descriptive, cross-sectional survey in 96 ACHD centres in Europe. A specific survey form was developed that sampled the practices of transfer and/or transition. We used a transfer-transition index to quantify adherence to quality indicators of successful transfer and transition. Of the 96 ACHD centres, 40 (41.7%) offered a formal transition, and 85 (88.5%) had structured transfer from paediatric to ACHD care. Although 31% of the centres performed at a 'good' level on the transfer-transition index, only 4 (4.2%) satisfied all criteria. Most centres with a transition programme offered education and support through a dedicated transition specialist, who was a master's-prepared nurse in most centres. A minority of the ACHD centres offered a flexible transition process, starting at least two years before transfer. Nearly half of the included ACHD centres offered a formal transition programme, and almost 90% offered structured transfer. Despite some improvements since 2009, most of the programmes lacked an age- and development-based approach. Nearly half of the included ACHD centres offered a formal transition programme, and almost 90% offered structured transfer. Despite some improvements since 2009, most of the programmes lacked an age- and development-based approach.
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  • Being composed of small cells may carry energetic costs related to maintaining ionic gradients across cell membranes as well as benefits related to diffusive oxygen uptake. Here, we test the hypothesis that these costs and benefits of cell size in ectotherms are temperature dependent. To study the consequences of cell size for whole-organism metabolic rate, we compared diploid and triploid zebrafish larvae differing in cell size. A fully factorial design was applied combining three different rearing and test temperatures that allowed us to distinguish acute from acclimated thermal effects. Individual oxygen consumption rates of diploid and triploid larvae across declining levels of oxygen availability were measured. We found that both acute and acclimated thermal effects affected the metabolic response. In comparison with triploids, diploids responded more strongly to acute temperatures, especially when reared at the highest temperature. These observations support the hypothesis that animals composed of smaller cells (i.e. diploids) are less vulnerable to oxygen limitation in warm aquatic habitats. Furthermore, we found slightly improved hypoxia tolerance in diploids. By contrast, warm-reared triploids had higher metabolic rates when they were tested at acute cold temperature, suggesting that being composed of larger cells may provide metabolic advantages in the cold. We offer two mechanisms as a potential explanation of this result, related to homeoviscous adaptation of membrane function and the mitigation of developmental noise. Our results suggest that being composed of larger cells provides metabolic advantages in cold water, while being composed of smaller cells provides metabolic advantages in warm water.The control of a predator's locomotion is critical to its ability to capture prey. Flying animals adjust their heading continuously with control similar to guided missiles. However, many animals do not move with rapid continuous motion, but rather interrupt their progress with frequent pauses. https://www.selleckchem.com/products/rsl3.html To understand how such intermittent locomotion may be controlled during predation, we examined the kinematics of zebrafish (Danio rerio) as they pursued larval prey of the same species. Like many fishes, zebrafish move with discrete burst-and-coast swimming. We found that the change in heading and tail excursion during the burst phase was linearly related to the prey's bearing. These results suggest a strategy, which we call intermittent pure pursuit, that offers advantages in sensing and control. This control strategy is similar to perception and path-planning algorithms required in the design of some autonomous robots and may be common to a diversity of animals.The immune system undergoes marked changes during aging characterized by a state of chronic, low-grade inflammation, so called inflammaging. Domestic dogs are the most morphological and physiological diverse group of mammals, with the widest range in body masses for a single species. Additionally, smaller dogs tend to live significantly longer than larger dogs across all breeds. Body mass is intricately linked to mass-specific metabolism and aging rates, thus, dogs are exemplary for studies in inflammaging. Dermal fibroblasts cells play an important role in skin inflammation, and as such, are a good cell type to determine inflammatory patterns in dogs. Here, we examine aerobic and glycolytic cellular metabolism, and IL-6 concentrations in primary fibroblast cells isolated from small and large, young and old dogs when treated with lipopolysaccharide (LPS) from Escherichia coli to stimulate an inflammatory phenotype. We found no differences in cellular metabolism of any group when treated with LPS. Unlike **** and humans, there was a less drastic amplification of IL-6 concentration after LPS treatment in the geriatric population of dogs compared with puppies. We also found evidence that large breed puppies have significantly less background or control IL-6 concentrations compared with small breed puppies. This implies that the patterns of inflammaging in dogs may be distinct and different from other mammals commonly studied.Invasive species exert negative impacts on biodiversity and ecosystems on a global scale, which may be enhanced in the future by climate change. Knowledge of how invasive species respond physiologically and behaviorally to novel and changing environments can improve our understanding of which traits enable the ecological success of these species, and potentially facilitate mitigation efforts. We examined the effects of acclimation to temperatures ranging from 5 to 28°C on aerobic metabolic rates, upper temperature tolerance (critical thermal maximum, CTmax), as well as temperature preference (Tpref) and avoidance (Tavoid) of the round goby (Neogobius melanostomus), one of the most impactful invasive species in the world. We show that round goby maintained a high aerobic scope from 15 to 28°C; that is, the capacity to increase its aerobic metabolic rate above that of its maintenance metabolism remained high across a broad thermal range. Although CTmax increased relatively little with acclimation temperature compared with other species, Tpref and Tavoid were not affected by acclimation temperature at all, meaning that round goby maintained a large thermal safety margin (CTmax-Tavoid) across acclimation temperatures, indicating a high level of thermal resilience in this species. The unperturbed physiological performance and high thermal resilience were probably facilitated by high levels of phenotypic buffering, which can make species readily adaptable and ecologically competitive in novel and changing environments. We suggest that these physiological and behavioral traits could be common for invasive species, which would only increase their success under continued climate change.**** of our understanding of in vivo skeletal muscle properties is based on studies performed under maximal activation, which is problematic because muscles are rarely activated maximally during movements such as walking. Currently, force-length properties of the human triceps surae at submaximal voluntary muscle activity levels are not characterized. We therefore evaluated plantar flexor torque- and force-ankle angle, and torque- and force-fascicle length properties of the soleus and lateral gastrocnemius muscles during voluntary contractions at three activity levels 100, 30 and 22% of maximal voluntary contraction. Soleus activity levels were controlled by participants via real-time electromyography feedback and contractions were performed at ankle angles ranging from 10 deg plantar flexion to 35 deg dorsiflexion. Using dynamometry and ultrasound imaging, torque-fascicle length curves of the soleus and lateral gastrocnemius muscles were constructed. The results indicate that small muscle activity reductions shift the torque- and force-angle, and torque- and force-fascicle length curves of these muscles to more dorsiflexed ankle angles and longer fascicle lengths (from 3 to 20% optimal fascicle length, depending on ankle angle).
    Being composed of small cells may carry energetic costs related to maintaining ionic gradients across cell membranes as well as benefits related to diffusive oxygen uptake. Here, we test the hypothesis that these costs and benefits of cell size in ectotherms are temperature dependent. To study the consequences of cell size for whole-organism metabolic rate, we compared diploid and triploid zebrafish larvae differing in cell size. A fully factorial design was applied combining three different rearing and test temperatures that allowed us to distinguish acute from acclimated thermal effects. Individual oxygen consumption rates of diploid and triploid larvae across declining levels of oxygen availability were measured. We found that both acute and acclimated thermal effects affected the metabolic response. In comparison with triploids, diploids responded more strongly to acute temperatures, especially when reared at the highest temperature. These observations support the hypothesis that animals composed of smaller cells (i.e. diploids) are less vulnerable to oxygen limitation in warm aquatic habitats. Furthermore, we found slightly improved hypoxia tolerance in diploids. By contrast, warm-reared triploids had higher metabolic rates when they were tested at acute cold temperature, suggesting that being composed of larger cells may provide metabolic advantages in the cold. We offer two mechanisms as a potential explanation of this result, related to homeoviscous adaptation of membrane function and the mitigation of developmental noise. Our results suggest that being composed of larger cells provides metabolic advantages in cold water, while being composed of smaller cells provides metabolic advantages in warm water.The control of a predator's locomotion is critical to its ability to capture prey. Flying animals adjust their heading continuously with control similar to guided missiles. However, many animals do not move with rapid continuous motion, but rather interrupt their progress with frequent pauses. https://www.selleckchem.com/products/rsl3.html To understand how such intermittent locomotion may be controlled during predation, we examined the kinematics of zebrafish (Danio rerio) as they pursued larval prey of the same species. Like many fishes, zebrafish move with discrete burst-and-coast swimming. We found that the change in heading and tail excursion during the burst phase was linearly related to the prey's bearing. These results suggest a strategy, which we call intermittent pure pursuit, that offers advantages in sensing and control. This control strategy is similar to perception and path-planning algorithms required in the design of some autonomous robots and may be common to a diversity of animals.The immune system undergoes marked changes during aging characterized by a state of chronic, low-grade inflammation, so called inflammaging. Domestic dogs are the most morphological and physiological diverse group of mammals, with the widest range in body masses for a single species. Additionally, smaller dogs tend to live significantly longer than larger dogs across all breeds. Body mass is intricately linked to mass-specific metabolism and aging rates, thus, dogs are exemplary for studies in inflammaging. Dermal fibroblasts cells play an important role in skin inflammation, and as such, are a good cell type to determine inflammatory patterns in dogs. Here, we examine aerobic and glycolytic cellular metabolism, and IL-6 concentrations in primary fibroblast cells isolated from small and large, young and old dogs when treated with lipopolysaccharide (LPS) from Escherichia coli to stimulate an inflammatory phenotype. We found no differences in cellular metabolism of any group when treated with LPS. Unlike mice and humans, there was a less drastic amplification of IL-6 concentration after LPS treatment in the geriatric population of dogs compared with puppies. We also found evidence that large breed puppies have significantly less background or control IL-6 concentrations compared with small breed puppies. This implies that the patterns of inflammaging in dogs may be distinct and different from other mammals commonly studied.Invasive species exert negative impacts on biodiversity and ecosystems on a global scale, which may be enhanced in the future by climate change. Knowledge of how invasive species respond physiologically and behaviorally to novel and changing environments can improve our understanding of which traits enable the ecological success of these species, and potentially facilitate mitigation efforts. We examined the effects of acclimation to temperatures ranging from 5 to 28°C on aerobic metabolic rates, upper temperature tolerance (critical thermal maximum, CTmax), as well as temperature preference (Tpref) and avoidance (Tavoid) of the round goby (Neogobius melanostomus), one of the most impactful invasive species in the world. We show that round goby maintained a high aerobic scope from 15 to 28°C; that is, the capacity to increase its aerobic metabolic rate above that of its maintenance metabolism remained high across a broad thermal range. Although CTmax increased relatively little with acclimation temperature compared with other species, Tpref and Tavoid were not affected by acclimation temperature at all, meaning that round goby maintained a large thermal safety margin (CTmax-Tavoid) across acclimation temperatures, indicating a high level of thermal resilience in this species. The unperturbed physiological performance and high thermal resilience were probably facilitated by high levels of phenotypic buffering, which can make species readily adaptable and ecologically competitive in novel and changing environments. We suggest that these physiological and behavioral traits could be common for invasive species, which would only increase their success under continued climate change.Much of our understanding of in vivo skeletal muscle properties is based on studies performed under maximal activation, which is problematic because muscles are rarely activated maximally during movements such as walking. Currently, force-length properties of the human triceps surae at submaximal voluntary muscle activity levels are not characterized. We therefore evaluated plantar flexor torque- and force-ankle angle, and torque- and force-fascicle length properties of the soleus and lateral gastrocnemius muscles during voluntary contractions at three activity levels 100, 30 and 22% of maximal voluntary contraction. Soleus activity levels were controlled by participants via real-time electromyography feedback and contractions were performed at ankle angles ranging from 10 deg plantar flexion to 35 deg dorsiflexion. Using dynamometry and ultrasound imaging, torque-fascicle length curves of the soleus and lateral gastrocnemius muscles were constructed. The results indicate that small muscle activity reductions shift the torque- and force-angle, and torque- and force-fascicle length curves of these muscles to more dorsiflexed ankle angles and longer fascicle lengths (from 3 to 20% optimal fascicle length, depending on ankle angle).
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