One of the main objectives of ecological research is to enhance our understanding of the processes that lead to species extinction. A potentially crucial extinction pattern is the dependence of contemporary biodiversity dynamics on past climates, also known as “climate legacy”. However, the general impact of climate legacy on extinction dynamics is unknown. Here, we conduct a systematic review to summarize the effect of climate legacies on extinction dynamics. We find that few works studying the relationship between extinction dynamics and climate include the potential impact of climate legacies (10%), with even fewer studies reaching beyond merely discussing them (3%). Among the studies that quantified climate legacies, six out of seven reported an improved fit of models to extinction dynamics, with most also describing substantial impacts of legacy effects on extinction risk. These include an increase in extinction risk of up to 40% when temperature changes add to a long-term trend in the same direction, as well as substantial effects on species’ adaptations, population dynamics and juvenile recruitment. Various ecological processes have been identified in the literature as potential ways in which climate legacies could affect the vulnerability of modern ecosystems to anthropogenic climate change, including niche conservatism, physiological thresholds, time lags and cascading effects. Overall, we find high agreement that climate legacy is a crucial process shaping extinction dynamics. Incorporating climate legacies in biodiversity assessments could be a key step toward a better understanding of the ecological consequences arising from climate change.

Large European arms companies increasingly own and control subsidiaries in other parts of the world. These subsidiaries operate hundreds of production sites used to manufacture and export weapons for the benefit of the parent company. Yet, they are bound by the legal framework in host countries. An important case study of this phenomenon is South Africa, which is now the site for numerous subsidiaries of large European arms manufacturers, including Rheinmetall and Hensoldt. Between 2018 and 2021, a Rheinmetall subsidiary in South Africa continued to export weapons to Saudi Arabia despite a German prohibition. This article uses South Africa as a case study to examine the potential consequences of the practice of offshoring in the context of weaknesses in South Africa’s arms export control framework and provides recommendations on how to improve scrutiny and reporting in South Africa’s system to better guard against this type of conduct.

Arrangements of feature sets that have been proposed to represent qualitative and quantitative variation among objects are shown to generate identical sets of set-symmetric distances. The set-symmetric distances for these feature arrangements can be represented by path lengths in an additive linear tree. Imperfect versions of these feature arrangements are proposed, which also are indistinguishable by the set-symmetric distance model. The distances for the imperfect versions can be represented by path lengths in an additive imperfectly linear tree. When dissimilarities are defined by the more general contrast model and a constant may be added to proximity data, then for both the perfect and imperfect arrangements an additive tree analysis obtains a perfect fit with an imperfectly linear tree. However, in the case of the contrast model also the distinction between the perfect and imperfect arrangements disappears in that also for the perfect arrangements the resulting tree need no longer be linear.

Mental health apps (MHAs) are increasingly popular in India due to rising mental health awareness and app accessibility. Despite their benefits, like mood tracking, sleep tools and virtual therapy, MHAs lack regulatory oversight. India's framework, including the Central Drugs Standard Control Organization (CDSCO) and Medical Device Rules 2017, does not cover standalone health apps, raising concerns about data privacy and accuracy. Establishing a centralised regulatory body with guidelines for MHAs is essential for user safety and efficacy. This paper examines the current regulatory landscape, compares international approaches and proposes a tiered regulatory framework to foster responsible innovation while safeguarding user interests in digital mental health services.

The modern marine megafauna is known to play important ecological roles and includes many charismatic species that have drawn the attention of both the scientific community and the public. However, the extinct marine megafauna has never been assessed as a whole, nor has it been defined in deep time. Here, we review the literature to define and list the species that constitute the extinct marine megafauna, and to explore biological and ecological patterns throughout the Phanerozoic. We propose a size cut-off of 1 m of length to define the extinct marine megafauna. Based on this definition, we list 706 taxa belonging to eight main groups. We found that the extinct marine megafauna was conspicuous over the Phanerozoic and ubiquitous across all geological eras and periods, with the Mesozoic, especially the Cretaceous, having the greatest number of taxa. Marine reptiles include the largest size recorded (21 m; Shonisaurus sikanniensis) and contain the highest number of extinct marine megafaunal taxa. This contrasts with today’s assemblage, where marine animals achieve sizes of >30 m. The extinct marine megafaunal taxa were found to be well-represented in the Paleobiology Database, but not better sampled than their smaller counterparts. Among the extinct marine megafauna, there appears to be an overall increase in body size through time. Most extinct megafaunal taxa were inferred to be macropredators preferentially living in coastal environments. Across the Phanerozoic, megafaunal species had similar extinction risks as smaller species, in stark contrast to modern oceans where the large species are most affected by human perturbations. Our work represents a first step towards a better understanding of the marine megafauna that lived in the geological past. However, more work is required to expand our list of taxa and their traits so that we can obtain a more complete picture of their ecology and evolution.

Multistate methodology proves effective in analyzing hospitalized coronavirus disease 2019 (COVID-19) patients with emerging variants in real time. An analysis of 2,548 admissions in Freiburg, Germany, showed reduced severity over time in terms of shorter hospital stays and higher discharge rates when comparing more recent phases with earlier phases of the pandemic.

OBJECTIVES/GOALS: Phagocytes, diverse cells that ingest material, are the primary cell type infected by Mycobacterium tuberculosis (Mtb) and the executors of protective mechanisms. T cells play a critical role by helping phagocytes control the infection. Understanding the precise T cell-dependent mechanisms by which phagocytic cell types contain Mtb is critical. METHODS/STUDY POPULATION: To determine the impact T cells have on different phagocyte cell populations’ host defense mechanisms, groups of wild–type and T cell deficient TCRa-/- mice were infected with an Mtb strain expressing fluorescent mScarlet protein. At four weeks post-infection, a time when T cell help contributes to control of Mtb, lungs were homogenized and cells sorted based on detection of mScarlet, indicating Mtb-infected cells. Cell suspensions from each mouse background were underwent single-cell RNA sequencing analysis to reveal the heterogenous cellular transcriptional response of different phagocyte populations. RESULTS/ANTICIPATED RESULTS: We found that Mtb-infected phagocytes from wild-type and TCRa-/- mouse lungs contain the same dominant cell phenotypic clusters, but these have different patterns of gene expression. Without T cells, phagocytes are prone to a more inflammatory phenotype. DISCUSSION/SIGNIFICANCE: This will translate fundamental biological data to test the hypothesis that Mtb encounters different environmental stresses exerted by different phagocytic cell types. This work could reveal host intracellular niches that enable bacterial persistence and elucidate new pathways that could be targeted for traditional antibiotic therapies for TB.

The earliest monumentality in Western Europe is associated with megalithic structures, but where did the builders of these monuments live? Here, the authors focus on west-central France, one of the earliest centres of megalithic building in Atlantic Europe, commencing in the mid fifth millennium BC. They report on an enclosure at Le Peu (Charente), dated to the Middle Neolithic (c. 4400 BC), and defined by a ditch with two ‘crab claw’ entrances and a double timber palisade flanked by two timber structures—possibly defensive bastions. Inside, timber buildings—currently the earliest known in the region—were possibly home to the builders of the nearby Tusson long mounds.

The National Center for Advancing Translational Science (NCATS) seeks to improve upon the translational process to advance research and treatment across all diseases and conditions and bring these interventions to all who need them. Addressing the racial/ethnic health disparities and health inequities that persist in screening, diagnosis, treatment, and health outcomes (e.g., morbidity, mortality) is central to NCATS’ mission to deliver more interventions to all people more quickly. Working toward this goal will require enhancing diversity, equity, inclusion, and accessibility (DEIA) in the translational workforce and in research conducted across the translational continuum, to support health equity. This paper discusses how aspects of DEIA are integral to the mission of translational science (TS). It describes recent NIH and NCATS efforts to advance DEIA in the TS workforce and in the research we support. Additionally, NCATS is developing approaches to apply a lens of DEIA in its activities and research – with relevance to the activities of the TS community – and will elucidate these approaches through related examples of NCATS-led, partnered, and supported activities, working toward the Center’s goal of bringing more treatments to all people more quickly.

Conservation scientists are increasingly recognizing the need to evaluate the effectiveness of interventions to improve human–wildlife coexistence across different contexts. Here we assessed the long-term efficacy of the Long Shields Community Guardians programme in Zimbabwe. This community-based programme seeks to protect livestock and prevent depredation by lions Panthera leo through non-lethal means, with the ultimate aim of promoting human–lion coexistence. Using a quasi-experimental approach, we measured temporal trends in livestock depredation by lions and the prevalence of retaliatory killing of lions by farmers and wildlife managers. Farmers that were part of the Long Shields programme experienced a significant reduction in livestock loss to lions, and the annual number of lions subject to retaliatory killing by farmers dropped by 41% since the start of the programme in 2013, compared to 2008–2012, before the programme was initiated. Our findings demonstrate the Long Shields programme can be a potential model for limiting livestock depredation by lions. More broadly, our study demonstrates the effectiveness of community-based interventions to engage community members, improve livestock protection and ameliorate levels of retaliatory killing, thereby reducing human–lion conflict.

Since the NAD+-dependent histone deacetylases sirtuin-1 (SIRT1) and sirtuin-2 (SIRT2) are critically involved in epigenetics, endocrinology and immunology and affect the longevity in model organisms, we investigated their expression in brains of 3-month-old and 14–15 months old rat model of depression Flinders Sensitive Line (FSL) and control Flinders Resistant Line (FRL) rats. In view of the dysregulated NPY system in depression, we also studied NPY in young and old FSL to explore the temporal trajectory of depressive-like–ageing interaction. Sirt1, Sirt2 and Npy mRNA were determined using qRT-PCR in prefrontal cortex (PFC) from young and old FSL and FRL, and in hippocampi from young FSL and FRL. PFC: Sirt1 expression was decreased in FSL (p = 0.001). An interaction between age and genotype was found (p = 0.032); young FSL had lower Sirt1 with respect to both age (p = 0.026) and genotype (p = 0.001). Sirt2 was lower in FSL (p = 0.003). Npy mRNA was downregulated in FSL (p = 0.001) but did not differ between the young and old rat groups. Hippocampus: Sirt1 was reduced in young FSL compared to young FRL (p = 0.005). There was no difference in Sirt2 between FSL and FRL. Npy levels were decreased in hippocampus of young FSL compared to young FRL (p = 0.003). Effects of ageing could not be investigated due to loss of samples. To conclude, i this is the first demonstration that SIRT1 and SIRT2 are changed in brain of FSL, a rat model of depression; ii the changes are age-dependent; iii sirtuins are potential targets for treatment of age-related neurodegenerative diseases.

*MDD is the predominant cause of “Years of life lived with disability” and “Years of life lost because of premature death” as a consequence of the disorder per se, comorbidities (cardiovascular, diabetes) and the high suicide rate. The problem is increasing due to higher depression frequency with age and growing life-longevity. One third of patients do not respond adequately to conventional therapies and “more of the same” drugs will not solve the problem. Consequently, there exists a crucial need to develop treatments with different modes of action. *Neuropeptide Y (NPY) and neuropeptide S (NPS) have been mapped in brain of MDD and PTSD rodent models. NPY is reduced in genetic and environmental depression models and in PTSD and can be reversed by antidepressants. These findings are parallel to the decreased NPY in humans diagnosed with MDD and PTSD. *NPS found in locus caeruleus regulates anxiety and stress–related behaviors and intranasal administration is anxiolytic in rat. The intranasal effects in humans are being explored. *Based on known biology and our findings, we hypothesized that NPY could be a target for MDD and PTSD, the reasoning being analogous to insulin treatment in insulin deficient diabetes, and conducted - the first ever - double blind, placebo controlled trials of insufflated NPY in MDD and PTSD (Sayed et al 2018, Mathé et al 2020). In conclusion, intranasal NPY is opening a promising new avenue for efficient, fast acting treatment of MDD and PTSD. Support:The Swedish MRC #10414; Center Psychiatry Research-KI, The Torsten Söderbergs Stiftelse

ABSTRACT IMPACT: This work describes, for the first time, the methylome in patients with T-LGLL, focusing on the IL-15 promoter, and clearly demonstrates that 5-azacytidine decreases IL-15 production leading to T-LGLL cell death. These results form the basis a translational clinical trial in T-LGLL that will begin accrual in 2021 OBJECTIVES/GOALS: T-LGLL is an incurable leukemia with few treatment options driven by overexpression of IL-15. Our objective is to characterize the methylation status of the IL-15 promoter in T-LGLL patients and evaluate the potential use of 5-azacytidine (5-aza) in a translational trial by studying the effect of 5-aza in vitro on IL-15 levels, and the IL-15 promoter. METHODS/STUDY POPULATION: We sorted T-LGLL patient (n=3) and normal donor (ND) samples (n=3) for CD3+/CD8+/CD5-/dim for T-LGLL immunophenotype. We analyzed DNA methylation and gene expression profiling using reduced representation bisulfite and RNA sequencing and determined differential methylation and gene expression using 1-way ANOVA analysis. To determine the functional significance of differential methylation, we evaluated MOTN-1 T-LGLL cell viability in vitro with 5-aza at increasing concentrations. Next, we evaluated IL-15 gene expression in MOTN-1 cells treated with 5-Aza versus MOTN-1 with control using western immunoblot. Finally, we exposed MOTN-1 cells to a novel IL-15 inhibitor, IBI-15, and compared cell viability against MOTN-1 cells exposed to an inactive control. RESULTS/ANTICIPATED RESULTS: There was significant differential methylation (P= 0.0178) and expression (P =0.0059) in T-LGLL patients vs ND. These data revealed significant differential hypermethylation of gene promoters, including an increase in DNA methylation of the IL-15 promoter in T-LGLL cells vs ND. In MOTN-1 cells treated in vitro with 5-Aza at 24 and 48 hours, a dose-dependent decrease in the viability of T-LGLL cells was observed, from 100% to 49.5%, p=0.037. Further, a marked decrease in IL-15 expression was observed at all concentrations of 5-aza compared to control (p=0.0001). Finally, a decrease in cell viability was observed utilizing the IL-15 inhibitor IBI-15 vs control. These results confirm that 5-aza leads to decreased transcription of the IL-15 gene, possibly due to hypomethylation of the IL-15 promoter. DISCUSSION/SIGNIFICANCE OF FINDINGS: Hypermethylation of the IL-15 promoter and subsequent increase in IL-15 is critical to the pathogenesis of T-LGLL. Inhibition of the IL-15 promoter by 5-aza leads to down-regulation of the IL-15 gene transcript, which is sufficient to induce T-LGLL cell death. Based on these results, a phase I trial will be conducted using CC-486 (oral 5-Aza) in T-LGLL.