Does habitat stability structure intraspecific genetic diversity? It’s complicated...

Regional phylogeographic studies have long been conducted in the southeastern United States for a variety of species. With some exceptions, many of these studies focus on single species or single clades of organisms, and those considering multiple species tend to focus on deep historical breaks causing differentiation. However, in many species more recent factors may be influencing genetic diversity. To understand the roles of historic and contemporary processes in structuring genetic diversity, we reanalyzed existing genetic data from Southeast of North America using approaches gleaned from phylogeographic and landscape genetic literature that were implemented across species including AMOVAs, PCoAs, Species Distribution Modelling, and tests of isolation by distance, environment, and habitat instability. Genetic variance was significantly partitioned by ecoregions, watersheds, and across phylogeographic breaks in the majority of species. Similarly, genetic variation was significantly associated with some combination of geographic or environmental distance or habitat instability in most species. Patterns of genetic variation were largely idiosyncratic across species. While habitat instability over time is significantly correlated with genetic diversity in some species, it appears generally less important than isolation by geographic or environmental distance. Our results suggest that many factors, both historical and contemporary, impact genetic diversity within a species, and more so, that these patterns aren’t always similar in closely related species. This supports the importance of species- specific factors and cautions against assumptions that closely related species will respond to historical and contemporary forces in similar ways

Experimental Observation of a New Attenuation Mechanism in <i>hcp</i>‐Metals That May Operate in the Earth's Inner Core

AbstractSeismic observations show the Earth's inner core has significant and unexplained variation in seismic attenuation with position, depth and direction. Interpreting these observations is difficult without knowledge of the visco‐ or anelastic dissipation processes active in iron under inner core conditions. Here, a previously unconsidered attenuation mechanism is observed in zinc, a low pressure analog of hcp‐iron, during small strain sinusoidal deformation experiments. The experiments were performed in a deformation‐DIA combined with X‐radiography, at seismic frequencies (∼0.003–0.1 Hz), high pressure and temperatures up to ∼80% of melting temperature. Significant dissipation (0.077 ≤ Q−1(ω) ≤ 0.488) is observed along with frequency dependent softening of zinc's Young's modulus and an extremely small activation energy for creep (⩽7 kJ mol−1). In addition, during sinusoidal deformation the original microstructure is replaced by one with a reduced dislocation density and small, uniform, grain size. This combination of behavior collectively reflects a mode of deformation called “internal stress superplasticity”; this deformation mechanism is unique to anisotropic materials and activated by cyclic loading generating large internal stresses. Here we observe a new form of internal stress superplasticity, which we name as “elastic strain mismatch superplasticity.” In it the large stresses are caused by the compressional anisotropy. If this mechanism is also active in hcp‐iron and the Earth's inner‐core it will be a contributor to inner‐core observed seismic attenuation and constrain the maximum inner‐core grain‐size to ≲10 km.</jats:p

Living Alone, Patient Sex and Mortality After Acute Myocardial Infarction

BACKGROUND: Psychosocial factors, including social support, affect outcomes of cardiovascular disease, but can be difficult to measure. Whether these factors have different effects on mortality post-acute myocardial infarction (AMI) in men and women is not clear. OBJECTIVE: To examine the association between living alone, a proxy for social support, and mortality postdischarge AMI and to explore whether this association is modified by patient sex. DESIGN: Historical cohort study. PARTICIPANTS/SETTING: All patients discharged with a primary diagnosis of AMI in a major urban center during the 1998–1999 fiscal year. MEASUREMENTS: Patients’ sociodemographic and clinical characteristics were obtained by standardized chart review and linked to vital statistics data through December 2001. RESULTS: Of 880 patients, 164 (18.6%) were living alone at admission and they were significantly more likely to be older and female than those living with others. Living alone was independently associated with mortality [adjusted hazard ratio (HR) 1.6, 95% confidence interval (CI) 1.0–2.5], but interacted with patient sex. Men living alone had the highest mortality risk (adjusted HR 2.0, 95% CI 1.1–3.7), followed by women living alone (adjusted HR 1.2, 95% CI 0.7–2.2), men living with others (reference, HR 1.0), and women living with others (adjusted HR 0.9, 95% CI 0.5–1.5). CONCLUSIONS: Living alone, an easily measured psychosocial factor, is associated with significantly increased longer-term mortality for men following AMI. Further prospective studies are needed to confirm the usefulness of living alone as a prognostic factor and to identify the potentially modifiable mechanisms underlying this increased risk

A Src-Tks5 Pathway Is Required for Neural Crest Cell Migration during Embryonic Development

In the adult organism, cell migration is required for physiological processes such as angiogenesis and immune surveillance, as well as pathological events such as tumor metastasis. The adaptor protein and Src substrate Tks5 is necessary for cancer cell migration through extracellular matrix in vitro and tumorigenicity in vivo. However, a role for Tks5 during embryonic development, where cell migration is essential, has not been examined. We used morpholinos to reduce Tks5 expression in zebrafish embryos, and observed developmental defects, most prominently in neural crest-derived tissues such as craniofacial structures and pigmentation. The Tks5 morphant phenotype was rescued by expression of mammalian Tks5, but not by a variant of Tks5 in which the Src phosphorylation sites have been mutated. We further evaluated the role of Tks5 in neural crest cells and neural crest-derived tissues and found that loss of Tks5 impaired their ventral migration. Inhibition of Src family kinases also led to abnormal ventral patterning of neural crest cells and their derivatives. We confirmed that these effects were likely to be cell autonomous by shRNA-mediated knockdown of Tks5 in a murine neural crest stem cell line. Tks5 was required for neural crest cell migration in vitro, and both Src and Tks5 were required for the formation of actin-rich structures with similarity to podosomes. Additionally, we observed that neural crest cells formed Src-Tks5-dependent cell protrusions in 3-D culture conditions and in vivo. These results reveal an important and novel role for the Src-Tks5 pathway in neural crest cell migration during embryonic development. Furthermore, our data suggests that this pathway regulates neural crest cell migration through the generation of actin-rich pro-migratory structures, implying that similar mechanisms are used to control cell migration during embryogenesis and cancer metastasis

The Genome of Mycobacterium Africanum West African 2 Reveals a Lineage-Specific Locus and Genome Erosion Common to the M. tuberculosis Complex

Mycobacterium africanum, a close relative of M. tuberculosis, is studied for the following reasons: M. africanum is commonly isolated from West African patients with tuberculosis yet has not spread beyond this region, it is more common in HIV infected patients, and it is less likely to lead to tuberculosis after one is exposed to an infectious case. Understanding this organism's unique biology gets a boost from the decoding of its genome, reported in this issue. For example, genome analysis reveals that M. africanum contains a region shared with “ancient” lineages in the M. tuberculosis complex and other mycobacterial species, which was lost independently from both M. tuberculosis and M. bovis. This region encodes a protein involved in transmembrane transport. Furthermore, M. africanum has lost genes, including a known virulence gene and genes for vitamin synthesis, in addition to an intact copy of a gene that may increase its susceptibility to antibiotics that are insufficiently active against M. tuberculosis. Finally, the genome sequence and analysis reported here will aid in the development of new diagnostics and vaccines against tuberculosis, which need to take into account the differences between M. africanum and other species in order to be effective worldwide

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707