Exploring Species Limits in Two Closely Related Chinese Oaks

Background. The species status of two closely related Chinese oaks, Quercus liaotungensis and Q. mongolica, has been called into question. The objective of this study was to investigate the species status and to estimate the degree of introgression between the two taxa using different approaches. [br/] Methodology/Principal Findings. Using SSR (simple sequence repeat) and AFLP (amplified fragment length polymorphism) markers, we found that interspecific genetic differentiation is significant and higher than the differentiation among populations within taxa. Bayesian clusters, principal coordinate analysis and population genetic distance trees all classified the oaks into two main groups consistent with the morphological differentiation of the two taxa rather than with geographic locations using both types of markers. Nevertheless, a few individuals in Northeast China and many individuals in North China have hybrid ancestry according to Bayesian assignment. One SSR locus and five AFLPs are significant outliers against neutral expectations in the interspecific FST simulation analysis, suggesting a role for divergent selection in differentiating species.[br/] Main Conclusions/Significance. All results based on SSRs and AFLPs reached the same conclusion: Q. liaotungensis and Q. mongolica maintain distinct gene pools in most areas of sympatry. They should therefore be considered as discrete taxonomic units. Yet, the degree of introgression varies between the two species in different contact zones, which might be caused by different population history or by local environmental factors

Pemphigus autoimmunity: Hypotheses and realities

The goal of contemporary research in pemphigus vulgaris and pemphigus foliaceus is to achieve and maintain clinical remission without corticosteroids. Recent advances of knowledge on pemphigus autoimmunity scrutinize old dogmas, resolve controversies, and open novel perspectives for treatment. Elucidation of intimate mechanisms of keratinocyte detachment and death in pemphigus has challenged the monopathogenic explanation of disease immunopathology. Over 50 organ-specific and non-organ-specific antigens can be targeted by pemphigus autoimmunity, including desmosomal cadherins and other adhesion molecules, PERP cholinergic and other cell membrane (CM) receptors, and mitochondrial proteins. The initial insult is sustained by the autoantibodies to the cell membrane receptor antigens triggering the intracellular signaling by Src, epidermal growth factor receptor kinase, protein kinases A and C, phospholipase C, mTOR, p38 MAPK, JNK, other tyrosine kinases, and calmodulin that cause basal cell shrinkage and ripping desmosomes off the CM. Autoantibodies synergize with effectors of apoptotic and oncotic pathways, serine proteases, and inflammatory cytokines to overcome the natural resistance and activate the cell death program in keratinocytes. The process of keratinocyte shrinkage/detachment and death via apoptosis/oncosis has been termed apoptolysis to emphasize that it is triggered by the same signal effectors and mediated by the same cell death enzymes. The natural course of pemphigus has improved due to a substantial progress in developing of the steroid-sparing therapies combining the immunosuppressive and direct anti-acantholytic effects. Further elucidation of the molecular mechanisms mediating immune dysregulation and apoptolysis in pemphigus should improve our understanding of disease pathogenesis and facilitate development of steroid-free treatment of patients

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

The search for translational pain outcomes to refine analgesic development: Where did we come from and where are we going?

Pain measures traditionally used in rodents record mere reflexes evoked by sensory stimuli; the results thus may not fully reflect the human pain phenotype. Alterations in physical and emotional functioning, pain-depressed behaviors and facial pain expressions were recently proposed as additional pain outcomes to provide a more accurate measure of clinical pain in rodents, and hence to potentially enhance analgesic drug development. We aimed to review how preclinical pain assessment has evolved since the development of the tail flick test in 1941, with a particular focus on a critical analysis of some nonstandard pain outcomes, and a consideration of how sex differences may affect the performance of these pain surrogates. We tracked original research articles in Medline for the following periods: 1973-1977, 1983-1987, 1993-1997, 2003-2007, and 2014-2018. We identified 606 research articles about alternative surrogate pain measures, 473 of which were published between 2014 and 2018. This indicates that preclinical pain assessment is moving toward the use of these measures, which may soon become standard procedures in preclinical pain laboratories.FPU grant from the Spanish Ministry of Education, Culture and SportsSpanish Ministry of Economy and Competitiveness (MINECO, grant SAF2016-80540-R)Ramón Areces FoundationJunta de Andalucía (grant CTS 109)Esteve PharmaceuticalsEuropean Regional Development Fund (ERDF

Interventions outside the workplace for reducing sedentary behaviour in adults under 60 years of age

Background Adults spend a majority of their time outside the workplace being sedentary. Large amounts of sedentary behaviour increase the risk of type 2 diabetes, cardiovascular disease, and both all‐cause and cardiovascular disease mortality. Objectives Primary • To assess effects on sedentary time of non‐occupational interventions for reducing sedentary behaviour in adults under 60 years of age Secondary • To describe other health effects and adverse events or unintended consequences of these interventions • To determine whether specific components of interventions are associated with changes in sedentary behaviour • To identify if there are any differential effects of interventions based on health inequalities (e.g. age, sex, income, employment) Search methods We searched CENTRAL, MEDLINE, Embase, Cochrane Database of Systematic Reviews, CINAHL, PsycINFO, SportDiscus, and ClinicalTrials.gov on 14 April 2020. We checked references of included studies, conducted forward citation searching, and contacted authors in the field to identify additional studies. Selection criteria We included randomised controlled trials (RCTs) and cluster RCTs of interventions outside the workplace for community‐dwelling adults aged 18 to 59 years. We included studies only when the intervention had a specific aim or component to change sedentary behaviour. Data collection and analysis Two review authors independently screened titles/abstracts and full‐text articles for study eligibility. Two review authors independently extracted data and assessed risk of bias. We contacted trial authors for additional information or data when required. We examined the following primary outcomes: device‐measured sedentary time, self‐report sitting time, self‐report TV viewing time, and breaks in sedentary time. Main results We included 13 trials involving 1770 participants, all undertaken in high‐income countries. Ten were RCTs and three were cluster RCTs. The mean age of study participants ranged from 20 to 41 years. A majority of participants were female. All interventions were delivered at the individual level. Intervention components included personal monitoring devices, information or education, counselling, and prompts to reduce sedentary behaviour. We judged no study to be at low risk of bias across all domains. Seven studies were at high risk of bias for blinding of outcome assessment due to use of self‐report outcomes measures. Primary outcomes Interventions outside the workplace probably show little or no difference in device‐measured sedentary time in the short term (mean difference (MD) ‐8.36 min/d, 95% confidence interval (CI) ‐27.12 to 10.40; 4 studies; I² = 0%; moderate‐certainty evidence). We are uncertain whether interventions reduce device‐measured sedentary time in the medium term (MD ‐51.37 min/d, 95% CI ‐126.34 to 23.59; 3 studies; I² = 84%; very low‐certainty evidence) We are uncertain whether interventions outside the workplace reduce self‐report sitting time in the short term (MD ‐64.12 min/d, 95% CI ‐260.91 to 132.67; I² = 86%; very low‐certainty evidence). Interventions outside the workplace may show little or no difference in self‐report TV viewing time in the medium term (MD ‐12.45 min/d, 95% CI ‐50.40 to 25.49; 2 studies; I² = 86%; low‐certainty evidence) or in the long term (MD 0.30 min/d, 95% CI ‐0.63 to 1.23; 2 studies; I² = 0%; low‐certainty evidence). It was not possible to pool the five studies that reported breaks in sedentary time given the variation in definitions used. Secondary outcomes Interventions outside the workplace probably have little or no difference on body mass index in the medium term (MD ‐0.25 kg/m², 95% CI ‐0.48 to ‐0.01; 3 studies; I² = 0%; moderate‐certainty evidence). Interventions may have little or no difference in waist circumference in the medium term (MD ‐2.04 cm, 95% CI ‐9.06 to 4.98; 2 studies; I² = 65%; low‐certainty evidence). Interventions probably have little or no difference on glucose in the short term (MD ‐0.18 mmol/L, 95% CI ‐0.30 to ‐0.06; 2 studies; I² = 0%; moderate‐certainty evidence) and medium term (MD ‐0.08 mmol/L, 95% CI ‐0.21 to 0.05; 2 studies, I² = 0%; moderate‐certainty evidence) Interventions outside the workplace may have little or no difference in device‐measured MVPA in the short term (MD 1.99 min/d, 95% CI ‐4.27 to 8.25; 4 studies; I² = 23%; low‐certainty evidence). We are uncertain whether interventions improve device‐measured MVPA in the medium term (MD 6.59 min/d, 95% CI ‐7.35 to 20.53; 3 studies; I² = 70%; very low‐certainty evidence). We are uncertain whether interventions outside the workplace improve self‐reported light‐intensity PA in the short‐term (MD 156.32 min/d, 95% CI 34.34 to 278.31; 2 studies; I² = 79%; very low‐certainty evidence). Interventions may have little or no difference on step count in the short‐term (MD 226.90 steps/day, 95% CI ‐519.78 to 973.59; 3 studies; I² = 0%; low‐certainty evidence) No data on adverse events or symptoms were reported in the included studies. Authors' conclusions Interventions outside the workplace to reduce sedentary behaviour probably lead to little or no difference in device‐measured sedentary time in the short term, and we are uncertain if they reduce device‐measured sedentary time in the medium term. We are uncertain whether interventions outside the workplace reduce self‐reported sitting time in the short term. Interventions outside the workplace may result in little or no difference in self‐report TV viewing time in the medium or long term. The certainty of evidence is moderate to very low, mainly due to concerns about risk of bias, inconsistent findings, and imprecise results. Future studies should be of longer duration; should recruit participants from varying age, socioeconomic, or ethnic groups; and should gather quality of life, cost‐effectiveness, and adverse event data. We strongly recommend that standard methods of data preparation and analysis are adopted to allow comparison of the effects of interventions to reduce sedentary behaviour

Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts