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Forest fragmentation and introduced pathogens are negatively impacting trees and forests globally, including the Carolinian forest of southern Ontario, Canada. Multiple species at risk live in this threatened but biodiverse forest, including the endangered Cornus florida (eastern flowering dogwood), which is now limited to fragmented woodlots, and has been decimated by the introduced fungal pathogen Discula destructiva (dogwood anthracnose). Ongoing management of C. florida in Canada is challenged by multiple knowledge gaps, two of which we aimed to address in this study. We first evaluated the association between anthracnose disease prevalence and a suite of ecological and environmental variables across 21 sites. Across our sites, larger trees tended to have the highest disease incidence, and trees on shallow slopes had the most crown dieback. We then quantified genetic diversity and gene flow, and found that genetic structure has not been substantially impacted by habitat fragmentation, although dispersal typically covers short distances. However, genetic diversity is relatively low in smaller populations and in younger trees. Localized dispersal and eroding genetic diversity may limit future adaptation and hence exacerbate population declines. We recommend that managers prioritize plantings in small populations, avoid shallow slopes, and track younger trees to evaluate age-related mortality.

Oxygenation during the Cambrian Radiation progressed via a series of short-lived pulses. However, the metazoan biotic response to this episodic oxygenation (and potentially productivity changes) has not been quantified, nor have the causal evolutionary processes been constrained. Here we present analyses of the dynamics of early Cambrian metazoan body size changes, habitat distribution, and ecological complexity on the Siberian Platform (525–510 Ma).First, we quantify high-resolution changes in species body size in archaeocyath sponges, hyolith lophophorates, and helcionelloid molluscs, and brachiopods. Archaeocyath, hyoliths, and helcionelloids, show dynamic and synchronous trends over million-year timescales, with peaks in body size during the latest Tommotian/early Atdabanian (~521–519 Ma) and late Atdabanian/early Botoman (~519–516.5 Ma), and notably small body sizes in the middle Atdabanian and after the Sinsk anoxic extinction event, starting ca. 513 Ma. These intervals of body size changes are also mirrored in individual species and correlate positively with increased rates of origination and broadly with total species diversity. Calcitic brachiopods (rhynchonelliformeans), however, show a general increase in body size following the increase in species diversity through this interval; phosphatic brachiopods (linguliformeans) show a body size decrease that negatively correlates with diversity. Both brachiopod groups show a rapid recovery at the Sinsk Event. The synchronous changes in these metrics in archaeocyaths, hyoliths and helcionelloids suggest the operation of external drivers through the early Cambrian, coincident with two oxic or productivity pulses. But the trends shown by brachiopods suggests a differing physiological response. Together, these dynamics created both the distinct evolutionary record of metazoan groups during the Cambrian Explosion and determined the nature of its termination.Second, during the oxic pulse at ~521–519 Ma, we quantify the expansion of archaeocyath sponge reef habitat coupled to an increase in reef size and metacommunity complexity, from individual within-community reactions to their local environment, to ecologically complex synchronous community-wide response, accompanied by an increase in rates of origination. Subsequently, reef and archaeocyath body size are reduced in association with increased rates of extinction due to inferred expanded marine anoxia (~519–516.5 Ma). The later oxic pulse at ~515 Ma shows further reef habitat expansion, increased archaeocyath body size and diversity, but weaker community-wide environmental responses.These metrics confirm that oxygenation events created temporary pulses of evolutionary diversification and enhanced ecosystem complexity, potentially via the expansion of habitable space, and increased archaeocyath individual and reef longevity in turn leading to niche differentiation. Most notably, we show that progression towards increasing biodiversity and ecosystem complexity was episodic and discontinuous, rather than linear, during the Cambrian Radiation.

This previously unpublished essay by the late author argues that male biographers of Williams have been unfair in their accounts of the women in Williams’s life and counters claims commonly made in previous Williams biographies concerning the nature of Williams’s relationship with specific female friends. Williams’s relationship to his wife, Florence Williams is also seen to be built on mutual understanding and loyalty despite published claims of infidelity which are directly refuted here by focusing in detail on the nature of Williams’s relationships with, in particular, Evelyn Scott, Nancy Cunard, Myra Marini, Kathleen Hoagland, Baroness Elsa von Freytag-Loringhoven and Marion Strobel. The use by Williams’s most recent biographer, Herbert Leibowitz, of poems as “biographical evidence” to support his claims is also countered through close readings of the same poems.

Allogeneic haematopoietic cell transplantation (HCT) replaces the stem cells responsible for blood production with those harvested from a donor, and is received by 40,000 patients worldwide each year. To quantify dynamics of long-term stem cell engraftment, we sequenced whole genomes of 2,824 single-cell-derived haematopoietic colonies from blood samples of 10 donor-recipient pairs taken 9-31 years after HLA-matched sibling HCT. With younger donors, 10,000–50,000 stem cells had engrafted and were still contributing to haematopoiesis at time of sampling, but estimates were 10-fold lower with older donors. Engrafted stem cells made multilineage contributions to myeloid, B-lymphoid and T-lymphoid populations, although individual clones often showed biases towards one or other mature cell type. Recipients had lower clonal diversity than matched donors, equivalent to ~10-15 years of additional ageing, arising from up to 25-fold greater expansion of stem cell clones. An HCT-related population bottleneck alone could not explain these differences: instead, phylogenetic trees evinced two distinct modes of HCT-specific selection. In ‘pruning selection’, cell divisions underpinning recipient-enriched clonal expansions had occurred in the donor, preceding transplant – their selective advantage derived from preferential mobilisation, harvest, survival ex vivo or initial homing. In ‘growth selection’, cell divisions underpinning clonal expansion occurred through proliferative advantage in the recipient’s marrow after homing – clones with multiple driver mutations especially demonstrated this pattern. Uprooting stem cells from their native environment and transplanting them to foreign soil exaggerates selective pressures, distorting and accelerating the loss of clonal diversity compared to the unperturbed haematopoiesis of donors.

Most children with developmental disabilities (DD), such as intellectual disabilities and autism, live in low- and middle-income countries (LMICs), where services are usually limited. Various governmental, non-governmental and research organisations in LMICs have developed awareness-raising campaigns and training and education resources on DD in childhood relevant to LMICs. This study aimed to comprehensively search and review freely available materials in the academic and grey literature, aimed at awareness raising, training and education on DD among non-specialist professionals and community members in LMICs. We consulted 183 experts, conducted key-word searches in five academic databases, four grey-literature databases and seventeen customised Google search engines. Following initial screening we manually searched relevant systematic reviews, lists of resources and conducted forwards and backwards citation checks of included articles. We identified 7327 articles and resources after deduplication. We then used a rigorous multi-step screening process to select 78 training resources on DD relevant to LMICs, of which 43 aimed at informing and/or raising awareness DD, 16 highlighted specific strategies for staff in health settings and 19 in education settings. Our mapping analysis revealed that a wealth of materials is available for both global and local use, including comics, children’s books, flyers, posters, fact sheets, blogs, videos, websites pages, social media channels, handbooks and self-education guides, and training programmes or sessions. Twelve resources were developed for cross-continental or global use in LMICs, 19 were developed for and/or used in Africa, 23 in Asia, 24 in Latin America. Most resources were developed within the context where they were intended to be used. Identified gaps included a limited range of resources on intellectual disabilities, manuals for actively delivering training to staff in education settings and resources targeted at eastern European LMICs. Beyond identifying these gaps, the value of the review lies in the compilation of summary tables of information on all freely available resources found, to support their selection and use in wider contexts. Information on the resource content, country of original development and copyright is provided to facilitate resource sharing and uptake.

Background: The current healthcare environment is filled with numerous team caring models, which are often used interchangeably, but ultimately mean different levels of collaboration among HCPs, and between HCPs and patients: multiprofessional collaboration, transprofessional collaboration, and interprofessional patient-centered collaborative (IPCC) care. Furthermore, the labels for these care models are not patient-friendly, portraying that only HCP ‘professionals’ comprise the team membership. Clarity is required around the terminology and labeling of these caring models to ensure enhanced patient involvement within interprofessional teams. Discussion: The definitions of the three team care models are provided with an explanation of how these models of care connect to the 55year-old patient’s case and impact on the relationship between HCPs and patient. Conclusion: While IPCC care is considered as the gold standard for the collaboration between a variety of HCP professional groups and the patient, work needs to be done on the label applied to this caring model. Future research should explore, from patients’ perspectives, the labels used in IPCC care and propose an alternative title that is more inclusive of patients as team members.

To assess the feasibility of applying machine-learning (ML) methods to imputation in the Medical Expenditure Panel Survey (MEPS).All data come from the 2016-2017 MEPS.Currently, expenditures for medical encounters in the MEPS are imputed with a predictive mean matching (PMM) algorithm in which a linear regression model is used to predict expenditures for events with (donors) and without (recipients) data. Recipient events and donor events are then matched based on the smallest distance between predicted expenditures, and the donor event's expenditures are used as the recipient event's imputation. We replace linear regression algorithm in the PMM framework with ML methods to predict expenditures. We examine five alternatives to linear regression: Gradient Boosting, Random Forests, Extreme Random Forests, Deep Neural Networks, and a Stacked Ensemble approach. Additionally, we introduce an alternative matching scheme which matches on a vector of predicted expenditures by sources of payment instead of a single total expenditure prediction to generate potentially superior matches.Study data is derived from a large federal survey.ML algorithms perform better at both prediction and matching imputation than Ordinary Least Squares (OLS), the most common prediction algorithm used in PMM. On average, the Stacked Ensemble approach that combines all the ML algorithms performs best, improving expenditure prediction RMachine learning algorithms and an alternative matching scheme improve the overall quality of expenditure PMM imputation in the MEPS. These methods may have additional value in other national surveys that currently rely on PMM or similar methods for imputation. This article is protected by copyright. All rights reserved.

Funder: Wellcome Clinical PhD fellowship, Funder: Wellcome PhD Studentship, Funder: Jean Shank/Pathological Society Intermediate Fellowship, Mutation accumulation in somatic cells contributes to cancer development and is proposed as a cause of aging. DNA polymerases Pol ε and Pol δ replicate DNA during cell division. However, in some cancers, defective proofreading due to acquired POLE/POLD1 exonuclease domain mutations causes markedly elevated somatic mutation burdens with distinctive mutational signatures. Germline POLE/POLD1 mutations cause familial cancer predisposition. Here, we sequenced normal tissue and tumor DNA from individuals with germline POLE/POLD1 mutations. Increased mutation burdens with characteristic mutational signatures were found in normal adult somatic cell types, during early embryogenesis and in sperm. Thus human physiology can tolerate ubiquitously elevated mutation burdens. Except for increased cancer risk, individuals with germline POLE/POLD1 mutations do not exhibit overt features of premature aging. These results do not support a model in which all features of aging are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life.

The ontogeny of the human haematopoietic system during fetal development has previously been characterized mainly through careful microscopic observations1. Here we reconstruct a phylogenetic tree of blood development using whole-genome sequencing of 511 single-cell-derived haematopoietic colonies from healthy human fetuses at 8 and 18 weeks after conception, coupled with deep targeted sequencing of tissues of known embryonic origin. We found that, in healthy fetuses, individual haematopoietic progenitors acquire tens of somatic mutations by 18 weeks after conception. We used these mutations as barcodes and timed the divergence of embryonic and extra-embryonic tissues during development, and estimated the number of blood antecedents at different stages of embryonic development. Our data support a hypoblast origin of the extra-embryonic mesoderm and primitive blood in humans. Whole-genome sequencing of haematopoietic colonies from human fetuses reveals the somatic mutations acquired by individual progenitors, which are used as barcodes to construct a phylogenetic tree of blood development.

Funder: European Research Council, Clonal expansions driven by somatic mutations become pervasive across human tissues with age, including in the haematopoietic system, where the phenomenon is termed clonal haematopoiesis1-4. The understanding of how and when clonal haematopoiesis develops, the factors that govern its behaviour, how it interacts with ageing and how these variables relate to malignant progression remains limited5,6. Here we track 697 clonal haematopoiesis clones from 385 individuals 55 years of age or older over a median of 13 years. We find that 92.4% of clones expanded at a stable exponential rate over the study period, with different mutations driving substantially different growth rates, ranging from 5% (DNMT3A and TP53) to more than 50% per year (SRSF2P95H). Growth rates of clones with the same mutation differed by approximately ±5% per year, proportionately affecting slow drivers more substantially. By combining our time-series data with phylogenetic analysis of 1,731 whole-genome sequences of haematopoietic colonies from 7 individuals from an older age group, we reveal distinct patterns of lifelong clonal behaviour. DNMT3A-mutant clones preferentially expanded early in life and displayed slower growth in old age, in the context of an increasingly competitive oligoclonal landscape. By contrast, splicing gene mutations drove expansion only later in life, whereas TET2-mutant clones emerged across all ages. Finally, we show that mutations driving faster clonal growth carry a higher risk of malignant progression. Our findings characterize the lifelong natural history of clonal haematopoiesis and give fundamental insights into the interactions between somatic mutation, ageing and clonal selection.

Guy Beiner’s Forgetful Remembrance (2018) offers an investigation into historical events, and what happens when communities affected by or related to the event attempt to either remember or forget....

Academic work and care work are deeply entangled modes of labor. For parent-academics, these entanglements are particularly knotted during the postpartum period, when care work responsibilities intensify, increasingly under precarious labor conditions. Postpartum care work—whether conducted by oneself or by someone else—both encroaches upon and makes possible academic work, resulting in blurred spatiotemporal divisions between the two. This article draws on autoethnography and participant observation to map out a postpartum geography of care work and academic work in academia. It does so by examining three key sites in/of the university where care work and academic work intersect—bathrooms, campus daycare centers, and the internet—and by considering three kinds of work that happen there—milk-work, childcare work, and connection-work. In these three sites in particular, I argue, the intellectual work and the care work that sustain the university spill over into one another. Furthermore, each of these geographic sites can manifest as sites of care, access, labor, and surveillance, often simultaneously and always depending on the gendered, raced, classed, and dis/abled positionality of those moving in and through them. By advancing an understanding of (postpartum) reproductive rights as workers’ rights, this paper also envisions more intersectional and coalitional feminist labor solidarities across campus.

Mutations in cancer-associated genes drive tumour outgrowth, but our knowledge of the timing of driver mutations and subsequent clonal dynamics is limited1-3. Here, using whole-genome sequencing of 1,013 clonal haematopoietic colonies from 12 patients with myeloproliferative neoplasms, we identified 580,133 somatic mutations to reconstruct haematopoietic phylogenies and determine clonal histories. Driver mutations were estimated to occur early in life, including the in utero period. JAK2V617F was estimated to have been acquired by 33 weeks of gestation to 10.8 years of age in 5 patients in whom JAK2V617F was the first event. DNMT3A mutations were acquired by 8 weeks of gestation to 7.6 years of age in 4 patients, and a PPM1D mutation was acquired by 5.8 years of age. Additional genomic events occurred before or following JAK2V617F acquisition and as independent clonal expansions. Sequential driver mutation acquisition was separated by decades across life, often outcompeting ancestral clones. The mean latency between JAK2V617F acquisition and diagnosis was 30 years (range 11-54 years). Estimated historical rates of clonal expansion varied substantially (3% to 190% per year), increased with additional driver mutations, and predicted latency to diagnosis. Our study suggests that early driver mutation acquisition and life-long growth and evolution underlie adult myeloproliferative neoplasms, raising opportunities for earlier intervention and a new model for cancer development.

Properly folded, functional proteins are essential for cell health. Cells sustain protein homeostasis, or proteostasis, via protein quality control (PQC) mechanisms. It is currently hypothesized that a breakdown in proteostasis during ageing leads to the accumulation of protein aggregates in the cell and disease. Sequestration of misfolded proteins into PQC compartments represents one branch of the PQC network. In neurodegenerative diseases, certain proteins form abnormal protein deposits. Which PQC compartments house misfolded proteins associated with neurodegenerative diseases is still being investigated. It remains unclear if sequestration of these misfolded proteins is toxic or protective to the cell. Here, we review the current knowledge on various PQC compartments that form in the cell, the kinds of protein aggregates found in neurodegenerative diseases, and what is known about their sequestration. Understanding how protein sequestration occurs can shed light on why aggregates are toxic to the cell and are linked to neurodegenerative diseases like Huntington's, Alzheimer's, and Parkinson's diseases.

Rare hematopoietic stem and progenitor cell (HSPC) pools outside the bone marrow (BM) contribute to blood production in stress and disease but remain ill-defined. Although nonmobilized peripheral blood (PB) is routinely sampled for clinical management, the diagnosis and monitoring potential of PB HSPCs remain untapped, as no healthy PB HSPC baseline has been reported. Here we comprehensively delineate human extramedullary HSPC compartments comparing spleen, PB, and mobilized PB to BM using single-cell RNA-sequencing and/or functional assays. We uncovered HSPC features shared by extramedullary tissues and others unique to PB. First, in contrast to actively dividing BM HSPCs, we found no evidence of substantial ongoing hematopoiesis in extramedullary tissues at steady state but report increased splenic HSPC proliferative output during stress erythropoiesis. Second, extramedullary hematopoietic stem cells/multipotent progenitors (HSCs/MPPs) from spleen, PB, and mobilized PB share a common transcriptional signature and increased abundance of lineage-primed subsets compared with BM. Third, healthy PB HSPCs display a unique bias toward erythroid-megakaryocytic differentiation. At the HSC/MPP level, this is functionally imparted by a subset of phenotypic CD71+ HSCs/MPPs, exclusively producing erythrocytes and megakaryocytes, highly abundant in PB but rare in other adult tissues. Finally, the unique erythroid-megakaryocytic–skewing of PB is perturbed with age in essential thrombocythemia and β-thalassemia. Collectively, we identify extramedullary lineage-primed HSPC reservoirs that are nonproliferative in situ and report involvement of splenic HSPCs during demand-adapted hematopoiesis. Our data also establish aberrant composition and function of circulating HSPCs as potential clinical indicators of BM dysfunction.

Background: COVID-19 vaccine hesitancy remains problematic and is particularly prevalent in minority and underserved communities. Aim and Scope: The development and initial efficacy of a single-session Vaccine Hesitancy-focused Telehealth Group at a Veterans hospital in the Bronx, NY are described. This single-session telehealth group integrated motivational interviewing, psychoeducation, and a “vaccine positive” peer with the goal of addressing COVID-19 vaccine hesitancy and improving vaccination rates. Methods: This project was approved by the quality assurance and improvement team at the James J. Peters VA Medical Center in the Bronx, NY. From the vaccine-hesitant Veteran referrals received from providers, eight vaccine hesitancy groups, averaging 3.5 participants per session, were conducted. Thirty Veterans total participated in the telehealth group. Results: Two-thirds of the participants have received the COVID-19 vaccine, with the vast majority of participants receiving the vaccine after the group. About half of the participants (n=14) were more willing to get the vaccine following the intervention and none experienced an increase in hesitancy. Conclusions: Preliminary results suggest this may be one intervention to increase vaccine acceptability and COVID-19 vaccination rates. Program strengths, limitations, and suggestions are discussed.

The Gastroparesis Clinical Research Consortium is a multicenter coalition created and funded by the National Institutes of Diabetes and Digestive and Kidney Disorders, with a mission to advance understanding of the pathophysiology of gastroparesis and develop an effective treatment for patients with symptomatic gastroparesis. In this review, we summarize the results of the published Gastroparesis Clinical Research Consortium studies as a ready and convenient resource for gastroenterologists and others to provide a clear understanding of the consortium's experience and perspective on gastroparesis and related disorders.

Purpose There are over 1.3 million colorectal cancer (CRC) survivors in the USA, many of whom report lower health-related quality of life (HRQoL) years after treatment. This study aimed to explore the effect of digital health tools on HRQoL in CRC survivors. Methods We conducted a two-arm, randomized controlled trial of 42 subjects who had completed treatment for CRC. Participants in the intervention arm received a Fitbit Flex™ and daily text messages for 12 weeks. HRQoL was assessed as a secondary endpoint in both arms at enrollment and 12 weeks using the Medical Outcomes Study Short Form Survey (SF-36) and the Functional Assessment of Cancer Therapy–Colorectal (FACT-C). Survey score changes from enrollment to 12 weeks were compared between the two arms using independent t tests, and scores at enrollment and 12 weeks were compared using paired t tests. Results An increase in the FACT-C functional well-being subscale was observed in individuals in the intervention arm pre- to post-intervention (median difference, 2; interquartile range (IQR), 1, 4; P = .02). Although the between-group comparison was not statistically significant, no change in the functional well-being subscale was observed in the control arm (median difference, 0; IQR, 1, 1; P = .71). No other measures of HRQoL appeared to differ within arm across time points or between arms. Conclusion A 12-week digital physical activity intervention may improve functional well-being among CRC survivors. Larger randomized studies are needed to determine if digital health tools improve functional well-being among CRC survivors and if this improvement can be sustained over time. Trial registration NCT02966054; registration date, November 17, 2016