Evidence on current, national physical activity (PA) and sedentary behaviour (SB) policies is limited. We, therefore, analysed availability, comprehensiveness, implementation, and effectiveness of PA and SB policies internationally. In this cross-sectional study, Global Observatory for Physical Activity (GoPA!) Country Contacts from 173 countries were asked to provide data on their national PA and SB policies by completing GoPA! Policy Inventory. Data were collected for 76 countries (response rate = 44%). Formal written policies for PA and SB were found in 92% (95% confidence interval [CI] 86, 98) and 62% (95% CI 50, 75) of countries, respectively. Sixty-two percent (95% CI 51, 73) of countries have national PA guidelines, while 40% (95% CI 29, 52) have SB guidelines. Fifty-two (95% CI 40, 64) and 11% (95% CI 3, 19) of countries have quantifiable national targets for PA and SB, respectively. The most represented ministries/departments involved in the promotion of more PA and/or less SB were in the sport regions. More investment is needed in development and implementation of comprehensive and effective PA and SB policies, particularly in low- and lower-middle-income countries. Most of the included countries have PA policies, but their comprehensiveness, implementation, and effectiveness are generally low-to-moderate. SB policies are less available, comprehensive, implemented, and effective than PA policies. PA and SB policies are better developed in high-income countries, compared with low- and lower-middle-income countries, and in countries of European and Western-Pacific regions, compared with other world regions. More investment is needed in development and implementation of comprehensive and effective PA and SB policies, particularly in low- and lower-middle-income countries. Hormone receptor positive (HR+) breast cancer (BCa) is the most frequently diagnosed subtype. Acquired and intrinsic resistance to conventional endocrine therapy (ET) commonly occurs and prompts incurable metastatic disease. Hence, ET-resistant (ET-R) HR+ BCa presents a therapeutic challenge. Previous studies show elevated androgen receptor (AR) that supports resistance to ET tamoxifen and correlates with HR+ BCa metastasis. Yet surprisingly, studies with AR-blocker enzalutamide (Enz) in ET-R HR+ BCa present conflicting results. We now report that a constitutively active, unique from canonical Enz-targeted, AR accumulates in endocrine resistant HR+ BCa cells. AR protein profiles in acquired and intrinsic ET-R HR + -BCa were defined with cell-free modification tests, in-house in-vivo SUMOylation assays, and PLA imaging. Genomic activity of native AR and modified-AR mimetic was tested with reporter assays and limited transcriptome analysis. Spheroid growth and migration studies were used to evaluate inhibitory actions of Enz and combinatorial therapy. Sustained higher molecular weight SUMO-modified AR (SUMO-AR) persists in acquired and intrinsic ET-R BCa cell lines. Concurrently, SUMO isoforms and global SUMO-modified proteome also accumulates in the same cell lines. We identified AR as a novel substrate for the SUMO-E3 ligase HSPB1/Hsp27. Independent of ligand, SUMO-AR is resilient to ubiquitin-mediated proteasomal degradation, enriched in the nucleus, readily chromatin-bound, and transcriptionally active. Constitutive SUMO-AR initiates a gene-expression profile that favors epithelial-mesenchymal transition. https://www.selleckchem.com/products/azd9291.html Enz combined with a SUMO inhibitor attenuates migration and metastatic phenotype of ET-R HR+ BCa. Targeting both unmodified and SUMO-modified AR prevents the metastatic progression of HR+ BCa with ET-R. Video abstract. Targeting both unmodified and SUMO-modified AR prevents the metastatic progression of HR+ BCa with ET-R. Video abstract.Despite available treatments, a prophylactic HCV vaccine is needed to achieve elimination targets. HCV vaccine development has faltered largely because the extreme diversity of the virus limits the protective breadth of vaccine elicited antibodies. It is believed that the principle neutralizing epitope in natural infection, HVR1, which is the most variable epitope in HCV, mediates humoral immune escape. So far, efforts to circumvent HVR1 interference in the induction and function of conserved targeting Ab have failed. Efforts to understand factors contributing to cross-neutralization of HVR1 variants have also been limited. Here, following mouse immunizations with two patient-derived HVR1 peptides, we observe cross-genotype neutralization of variants differing at 15/21 positions. Surprisingly, sequence similarity was not associated with cross-neutralization. It appeared neutralization sensitivity was an intrinsic feature of each variant, rather than emergent from the immunogen specific Ab response. These findings provide novel insight into HVR1-mediated immune evasion, with important implications for HCV vaccine design. Single nucleotide variants account for approximately 90% of all known pathogenic variants responsible for human diseases. Recently discovered CRISPR/Cas9 base editors can correct individual nucleotides without cutting DNA and inducing double-stranded breaks. We aimed to find all possible pathogenic variants which can be efficiently targeted by any of the currently described base editors and to present them for further selection and development of targeted therapies. ClinVar database (GRCh37_clinvar_20171203) was used to search and select mutations available for current single-base editing systems. We included only pathogenic and likely pathogenic variants for further analysis. For every potentially editable mutation we checked the presence of PAM. If a PAM was found, we analyzed the sequence to find possibility to edit only one nucleotide without changing neighboring nucleotides. The code of the script to search Clinvar database and to analyze the sequences was written in R and is available in the appendix. We analyzed 21 editing system currently reported in 9 publications. Every system has different working characteristics such as the editing window and PAM sequence. C > T base editors can precisely target 3196 mutations (46% of all pathogenic T > C variants), and A > G editors - 6900 mutations (34% of all pathogenic G > A variants). Protein engineering helps to develop new enzymes with a narrower window of base editors as well as using new Cas9 enzymes with different PAM sequences. But, even now the list of mutations which can be targeted with currently available systems is huge enough to choose and develop new targeted therapies. Protein engineering helps to develop new enzymes with a narrower window of base editors as well as using new Cas9 enzymes with different PAM sequences. But, even now the list of mutations which can be targeted with currently available systems is huge enough to choose and develop new targeted therapies.