Stepping Stones: A Leadership Development Program to Inspire and Promote Reflection Among Women Faculty and Staff

Women frequently benefit from focused faculty development opportunities not because they need to be “fixed,” but rather it is a means to demonstrate that success, even in chilly environments, is possible. The Stepping Stones program uses a unique design to provide participants with inspiration, time for reflection, and strategies for how to navigate one's career, through hearing about the journeys of successful women. In this article, we describe the program and evaluation results. Post‐event and longitudinal follow‐up surveys indicate that the program and its unique narrative format help to debunk the superwoman myth and leave participants with a sense of optimism about their future careers

230 Th normalization: new insights on an essential tool for quantifying sedimentary fluxes in the modern and quaternary ocean

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Costa, K. M., Hayes, C. T., Anderson, R. F., Pavia, F. J., Bausch, A., Deng, F., Dutay, J., Geibert, W., Heinze, C., Henderson, G., Hillaire-Marcel, C., Hoffmann, S., Jaccard, S. L., Jacobel, A. W., Kienast, S. S., Kipp, L., Lerner, P., Lippold, J., Lund, D., Marcantonio, F., McGee, D., McManus, J. F., Mekik, F., Middleton, J. L., Missiaen, L., Not, C., Pichat, S., Robinson, L. F., Rowland, G. H., Roy-Barman, M., Alessandro, Torfstein, A., Winckler, G., & Zhou, Y. 230 Th normalization: new insights on an essential tool for quantifying sedimentary fluxes in the modern and quaternary ocean. Paleoceanography and Paleoclimatology, 35(2), (2020): e2019PA003820, doi:10.1029/2019PA003820.230Th normalization is a valuable paleoceanographic tool for reconstructing high‐resolution sediment fluxes during the late Pleistocene (last ~500,000 years). As its application has expanded to ever more diverse marine environments, the nuances of 230Th systematics, with regard to particle type, particle size, lateral advective/diffusive redistribution, and other processes, have emerged. We synthesized over 1000 sedimentary records of 230Th from across the global ocean at two time slices, the late Holocene (0–5,000 years ago, or 0–5 ka) and the Last Glacial Maximum (18.5–23.5 ka), and investigated the spatial structure of 230Th‐normalized mass fluxes. On a global scale, sedimentary mass fluxes were significantly higher during the Last Glacial Maximum (1.79–2.17 g/cm2kyr, 95% confidence) relative to the Holocene (1.48–1.68 g/cm2kyr, 95% confidence). We then examined the potential confounding influences of boundary scavenging, nepheloid layers, hydrothermal scavenging, size‐dependent sediment fractionation, and carbonate dissolution on the efficacy of 230Th as a constant flux proxy. Anomalous 230Th behavior is sometimes observed proximal to hydrothermal ridges and in continental margins where high particle fluxes and steep continental slopes can lead to the combined effects of boundary scavenging and nepheloid interference. Notwithstanding these limitations, we found that 230Th normalization is a robust tool for determining sediment mass accumulation rates in the majority of pelagic marine settings (>1,000 m water depth).We thank Zanna Chase and one anonymous reviewer for valuable feedback. K. M. C. was supported by a Postdoctoral Scholarship at WHOI. L. M. acknowledges funding from the Australian Research Council grant DP180100048. The contribution of C. T. H., J. F. M., and R. F. A. were supported in part by the U.S. National Science Foundation (US‐NSF). G. H. R. was supported by the Natural Environment Research Council (grant NE/L002434/1). S. L. J. acknowledges support from the Swiss National Science Foundation (grants PP002P2_144811 and PP00P2_172915). This study was supported by the Past Global Changes (PAGES) project, which in turn received support from the Swiss Academy of Sciences and the US‐NSF. This work grew out of a 2018 workshop in Aix‐Marseille, France, funded by PAGES, GEOTRACES, SCOR, US‐NSF, Aix‐Marseille Université, and John Cantle Scientific. All data are publicly available as supporting information to this document and on the National Center for Environmental Information (NCEI) at https://www.ncdc.noaa.gov/paleo/study/28791

Engaging stakeholders to inform national implementation of critical time intervention in a program serving homeless-experienced Veterans

The Veterans Affairs (VA) Grant and Per Diem Case Management “Aftercare” program provides 6 months of case management for homeless-experienced Veterans (HEVs) transitioning to permanent housing, with the aim of decreasing returns to homelessness. Implementing Critical Time Intervention (CTI)—an evidence-based case management practice—would standardize care across the 128 community-based agencies that provide Aftercare services. To prepare for national CTI implementation in Aftercare, guided by Replicating Effective Programs (REP), we conducted a four-site pilot in which we adapted a CTI implementation package (training, technical assistance, and external facilitation); characterized stakeholder perspectives regarding the acceptability and appropriateness of this package; and identified contextual factors that affected CTI implementation. We engaged a stakeholder workgroup to tailor existing CTI training and technical assistance materials for Aftercare. To provide tailored support for providers and leaders to adopt and incorporate evidence-based practices (EBPs) into routine care, we also developed external facilitation materials and processes. Over 9 months, we implemented this package at four sites. We conducted semi-structured interviews at pre-implementation, mid-implementation, and 6 months post-implementation, with HEVs (n = 37), case managers (n = 16), supervisors (n = 10), and VA leaders (n = 4); these data were integrated with templated reflection notes from the project facilitator. We used rapid qualitative analysis and targeted coding to assess the acceptability and appropriateness of CTI and our implementation package and identify factors influencing CTI implementation. Stakeholders generally found CTI acceptable and appropriate; there was consensus that components of CTI were useful and compatible for this setting. To adapt our implementation package for scale-up, this pilot highlighted the value of robust and tangible CTI training and technical assistance—grounded in real-world cases—that highlights the congruence of CTI with relevant performance metrics. Variations in agency-level contextual factors may necessitate more intense and tailored supports to implement and sustain complex EBPs like CTI. Processes used in this pilot are relevant for implementing other EBPs in organizations that serve vulnerable populations. EBP scale-up and sustainment can be enhanced by engaging stakeholders to tailor EBPs for specific contexts; pilot testing and refining implementation packages for scale-up; and using qualitative methods to characterize contextual factors that affect EBP implementation

The secreted triose phosphate isomerase of Brugia malayi is required to sustain microfilaria production in vivo

Human lymphatic filariasis is a major tropical disease transmitted through mosquito vectors which take up microfilarial larvae from the blood of infected subjects. Microfilariae are produced by long-lived adult parasites, which also release a suite of excretory-secretory products that have recently been subject to in-depth proteomic analysis. Surprisingly, the most abundant secreted protein of adult Brugia malayi is triose phosphate isomerase (TPI), a glycolytic enzyme usually associated with the cytosol. We now show that while TPI is a prominent target of the antibody response to infection, there is little antibody-mediated inhibition of catalytic activity by polyclonal sera. We generated a panel of twenty-three anti-TPI monoclonal antibodies and found only two were able to block TPI enzymatic activity. Immunisation of jirds with B. malayi TPI, or mice with the homologous protein from the rodent filaria Litomosoides sigmodontis, failed to induce neutralising antibodies or protective immunity. In contrast, passive transfer of neutralising monoclonal antibody to mice prior to implantation with adult B. malayi resulted in 60–70% reductions in microfilarial levels in vivo and both oocyte and microfilarial production by individual adult females. The loss of fecundity was accompanied by reduced IFNγ expression by CD4+ T cells and a higher proportion of macrophages at the site of infection. Thus, enzymatically active TPI plays an important role in the transmission cycle of B. malayi filarial parasites and is identified as a potential target for immunological and pharmacological intervention against filarial infections

No Remdesivir Resistance Observed in the Phase 3 Severe and Moderate COVID-19 SIMPLE Trials

Remdesivir (RDV) is a broad-spectrum nucleotide analog prodrug approved for the treatment of COVID-19 in hospitalized and non-hospitalized patients with clinical benefit demonstrated in multiple Phase 3 trials. Here we present SARS-CoV-2 resistance analyses from the Phase 3 SIMPLE clinical studies evaluating RDV in hospitalized participants with severe or moderate COVID-19 disease. The severe and moderate studies enrolled participants with radiologic evidence of pneumonia and a room-air oxygen saturation of ≤94% or >94%, respectively. Virology sample collection was optional in the study protocols. Sequencing and related viral load data were obtained retrospectively from participants at a subset of study sites with local sequencing capabilities (10 of 183 sites) at timepoints with detectable viral load. Among participants with both baseline and post-baseline sequencing data treated with RDV, emergent Nsp12 substitutions were observed in 4 of 19 (21%) participants in the severe study and none of the 2 participants in the moderate study. The following 5 substitutions emerged: T76I, A526V, A554V, E665K, and C697F. The substitutions T76I, A526V, A554V, and C697F had an EC50 fold change of ≤1.5 relative to the wildtype reference using a SARS-CoV-2 subgenomic replicon system, indicating no significant change in the susceptibility to RDV. The phenotyping of E665K could not be determined due to a lack of replication. These data reveal no evidence of relevant resistance emergence and further confirm the established efficacy profile of RDV with a high resistance barrier in COVID-19 patients

Specific and social fears in children and adolescents: separating normative fears from problem indicators and phobias

Objective: To distinguish normative fears from problematic fears and phobias. Methods: We investigated 2,512 children and adolescents from a large community school-based study, the High Risk Study for Psychiatric Disorders. Parent reports of 18 fears and psychiatric diagnosis were investigated. We used two analytical approaches: confirmatory factor analysis (CFA)/item response theory (IRT) and nonparametric receiver operating characteristic (ROC) curve. Results: According to IRT and ROC analyses, social fears are more likely to indicate problems and phobias than specific fears. Most specific fears were normative when mild; all specific fears indicate problems when pervasive. In addition, the situational fear of toilets and people who look unusual were highly indicative of specific phobia. Among social fears, those not restricted to performance and fear of writing in front of others indicate problems when mild. All social fears indicate problems and are highly indicative of social phobia when pervasive. Conclusion: These preliminary findings provide guidance for clinicians and researchers to determine the boundaries that separate normative fears from problem indicators in children and adolescents, and indicate a differential severity threshold for specific and social fears

Geographical limits to species-range shifts are suggested by climate velocity

The reorganization of patterns of species diversity driven by anthropogenic climate change, and the consequences for humans, are not yet fully understood or appreciated. Nevertheless, changes in climate conditions are useful for predicting shifts in species distributions at global and local scales. Here we use the velocity of climate change to derive spatial trajectories for climatic niches from 1960 to 2009 (ref. 7) and from 2006 to 2100, and use the properties of these trajectories to infer changes in species distributions. Coastlines act as barriers and locally cooler areas act as attractors for trajectories, creating source and sink areas for local climatic conditions. Climate source areas indicate where locally novel conditions are not connected to areas where similar climates previously occurred, and are thereby inaccessible to climate migrants tracking isotherms: 16% of global surface area for 1960 to 2009, and 34% of ocean for the \u27business as usual\u27 climate scenario (representative concentration pathway (RCP) 8.5)8 representing continued use of fossil fuels without mitigation. Climate sink areas are where climate conditions locally disappear, potentially blocking the movement of climate migrants. Sink areas comprise 1.0% of ocean area and 3.6% of land and are prevalent on coasts and high ground. Using this approach to infer shifts in species distributions gives global and regional maps of the expected direction and rate of shifts of climate migrants, and suggests areas of potential loss of species richness

Induction of Protective CD4+ T Cell-Mediated Immunity by a Leishmania Peptide Delivered in Recombinant Influenza Viruses

The available evidence suggests that protective immunity to Leishmania is achieved by priming the CD4+ Th1 response. Therefore, we utilised a reverse genetics strategy to generate influenza A viruses to deliver an immunogenic Leishmania peptide. The single, immunodominant Leishmania-specific LACK158–173 CD4+ peptide was engineered into the neuraminidase stalk of H1N1 and H3N2 influenza A viruses. These recombinant viruses were used to vaccinate susceptible BALB/c mice to determine whether the resultant LACK158–173-specific CD4+ T cell responses protected against live L. major infection. We show that vaccination with influenza-LACK158–173 triggers LACK158–173-specific Th1-biased CD4+ T cell responses within an appropriate cytokine milieu (IFN-γ, IL-12), essential for the magnitude and quality of the Th1 response. A single intraperitoneal exposure (non-replicative route of immunisation) to recombinant influenza delivers immunogenic peptides, leading to a marked reduction (2–4 log) in parasite burden, albeit without reduction in lesion size. This correlated with increased numbers of IFN-γ-producing CD4+ T cells in vaccinated mice compared to controls. Importantly, the subsequent prime-boost approach with a serologically distinct strain of influenza (H1N1->H3N2) expressing LACK158–173 led to a marked reduction in both lesion size and parasite burdens in vaccination trials. This protection correlated with high levels of IFN-γ producing cells in the spleen, which were maintained for 6 weeks post-challenge indicating the longevity of this protective effector response. Thus, these experiments show that Leishmania-derived peptides delivered in the context of recombinant influenza viruses are immunogenic in vivo, and warrant investigation of similar vaccine strategies to generate parasite-specific immunity

Autophagy Interplay with Apoptosis and Cell Cycle Regulation in the Growth Inhibiting Effect of Resveratrol in Glioma Cells

Prognosis of patients with glioblastoma (GBM) remains very poor, thus making the development of new drugs urgent. Resveratrol (Rsv) is a natural compound that has several beneficial effects such as neuroprotection and cytotoxicity for several GBM cell lines. Here we evaluated the mechanism of action of Rsv on human GBM cell lines, focusing on the role of autophagy and its crosstalk with apoptosis and cell cycle control. We further evaluated the role of autophagy and the effect of Rsv on GBM Cancer Stem Cells (gCSCs), involved in GBM resistance and recurrence. Glioma cells treated with Rsv was tested for autophagy, apoptosis, necrosis, cell cycle and phosphorylation or expression levels of key players of these processes. Rsv induced the formation of autophagosomes in three human GBM cell lines, accompanied by an upregulation of autophagy proteins Atg5, beclin-1 and LC3-II. Inhibition of Rsv-induced autophagy triggered apoptosis, with an increase in Bax and cleavage of caspase-3. While inhibition of apoptosis or autophagy alone did not revert Rsv-induced toxicity, inhibition of both processes blocked this toxicity. Rsv also induced a S-G2/M phase arrest, accompanied by an increase on levels of pCdc2(Y15), cyclin A, E and B, and pRb (S807/811) and a decrease of cyclin D1. Interestingly, this arrest was dependent on the induction of autophagy, since inhibition of Rsv-induced autophagy abolishes cell cycle arrest and returns the phosphorylation of Cdc2(Y15) and Rb(S807/811), and levels of cyclin A, and B to control levels. Finally, inhibition of autophagy or treatment with Rsv decreased the sphere formation and the percentage of CD133 and OCT4-positive cells, markers of gCSCs. In conclusion, the crosstalk among autophagy, cell cycle and apoptosis, together with the biology of gCSCs, has to be considered in tailoring pharmacological interventions aimed to reduce glioma growth using compounds with multiple targets such as Rsv

Guidelines for Genome-Scale Analysis of Biological Rhythms

Genome biology approaches have made enormous contributions to our understanding of biological rhythms, particularly in identifying outputs of the clock, including RNAs, proteins, and metabolites, whose abundance oscillates throughout the day. These methods hold significant promise for future discovery, particularly when combined with computational modeling. However, genome-scale experiments are costly and laborious, yielding “big data” that are conceptually and statistically difficult to analyze. There is no obvious consensus regarding design or analysis. Here we discuss the relevant technical considerations to generate reproducible, statistically sound, and broadly useful genome-scale data. Rather than suggest a set of rigid rules, we aim to codify principles by which investigators, reviewers, and readers of the primary literature can evaluate the suitability of different experimental designs for measuring different aspects of biological rhythms. We introduce CircaInSilico, a web-based application for generating synthetic genome biology data to benchmark statistical methods for studying biological rhythms. Finally, we discuss several unmet analytical needs, including applications to clinical medicine, and suggest productive avenues to address them