The Cynomolgus Macaque Intestinal Mycobiome Is Dominated by the Kazachstania Genus and K. pintolopesii Species

The cynomolgus macaque, Macaca fascicularis, is a non-human primate (NHP) widely used in biomedical research as its genetics, immunology and physiology are similar to those of humans. They may also be a useful model of the intestinal microbiome as their prokaryome resembles that of humans. However, beyond the prokaryome relatively little is known about other constituents of the macaque intestinal microbiome including the mycobiome. Here, we conducted a region-by-region taxonomic survey of the cynomolgus intestinal mycobiota, from duodenum to distal colon, of sixteen captive animals of differing age (from young to old). Using a high-throughput ITS1 amplicon sequencing-based approach, the cynomolgus gut mycobiome was dominated by fungi from the Ascomycota phylum. The budding yeast genus Kazachstania was most abundant, with the thermotolerant species K. pintolopesii highly prevalent, and the predominant species in both the small and large intestines. This is in marked contrast to humans, in which the intestinal mycobiota is characterised by other fungal genera including Candida and Saccharomyces, and Candida albicans. This study provides a comprehensive insight into the fungal communities present within the captive cynomolgus gut, and for the first time identifies K. pintolopesii as a candidate primate gut commensal

Multidecadal variability in Atlas cedar growth in northwest Africa during the last 850 years: implications for dieback and conservation of an endangered species

Widespread forest dieback is a phenomenon of global concern that requires an improved understanding of the relationship between tree growth and climate to support conservation efforts. One priority for conservation is the Atlas cedar (Cedrus atlantica), an endangered species exhibiting dieback throughout its North African range. In this study, we evaluate the long-term context for recent dieback and develop a projection of future C. atlantica growth by exploring the periodic variability of its growth through time. First, we present a new C. atlantica tree- ring chronology (1150–2013 CE) from the Middle Atlas mountains, Morocco. We then compare the new chronology to existing C. atlantica chronologies in Morocco and use principal components analysis (PCA) to isolate the common periodic signal from the seven longest available records (PCA7, 1271–1984 CE) in the Middle and High Atlas portions of the C. atlantica range. PCA7 captures 55.7% of the variance and contains significant multidecadal ( ̃95yr, ̃57yr, ̃21yr) periodic components, revealed through spectral and wavelet analyses. Parallel analyses of historical climate data (1901–2016 CE) suggests that the multidecadal growth signal ori- ginates primarily in growing season (spring and summer) precipitation variability, compounded by slow- changing components of summer and winter temperatures. Finally, we model the long-term growth patterns between 1271–1984 CE using a small number (three to four) of harmonic components, illustrating that sup- pressed growth since the 1970s – a factor implicated in the dieback of this species – is consistent with recurrent climatically-driven growth declines. Forward projection of this model suggests two climatically-favourable periods for growth in the 21st century that may enhance current conservation actions for the long-term survival of the C. atlantica in the Middle and High Atlas mountains

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The effects of neoadjuvant chemoradiotherapy and an in-hospital exercise training programme on physical fitness and quality of life in locally advanced rectal cancer patients (The EMPOWER Trial): Study protocol for a randomised controlled trial

Background: The standard treatment pathway for locally advanced rectal cancer is neoadjuvant chemoradiotherapy (CRT) followed by surgery. Neoadjuvant CRT has been shown to decrease physical fitness, and this decrease is associated with increased post-operative morbidity. Exercise training can stimulate skeletal muscle adaptations such as increased mitochondrial content and improved oxygen uptake capacity, both of which are contributors to physical fitness. The aims of the EMPOWER trial are to assess the effects of neoadjuvant CRT and an in-hospital exercise training programme on physical fitness, health-related quality of life (HRQoL), and physical activity levels, as well as post-operative morbidity and cancer staging. Methods/Design: The EMPOWER Trial is a randomised controlled trial with a planned recruitment of 46 patients with locally advanced rectal cancer and who are undergoing neoadjuvant CRT and surgery. Following completion of the neoadjuvant CRT (week 0) prior to surgery, patients are randomised to an in-hospital exercise training programme (aerobic interval training for 6 to 9 weeks) or a usual care control group (usual care and no formal exercise training). The primary endpoint is oxygen uptake at lactate threshold ( V · o 2 at δ L ) measured using cardiopulmonary exercise testing assessed over several time points throughout the study. Secondary endpoints include HRQoL, assessed using semi-structured interviews and questionnaires, and physical activity levels assessed using activity monitors. Exploratory endpoints include post-operative morbidity, assessed using the Post-Operative Morbidity Survey (POMS), and cancer staging, assessed by using magnetic resonance tumour regression grading. Discussion: The EMPOWER trial is the first randomised controlled trial comparing an in-hospital exercise training group with a usual care control group in patients with locally advanced rectal cancer. This trial will allow us to determine whether exercise training following neoadjuvant CRT can improve physical fitness and activity levels, as well as other important clinical outcome measures such as HRQoL and post-operative morbidity. These results will aid the design of a large, multi-centre trial to determine whether an increase in physical fitness improves clinically relevant post-operative outcomes

Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening

AbstractThe identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis. Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery.</jats:p

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome