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Abstract The thymus is a rich source of regulatory T cells and plays a role in self-tolerance. Therefore, transplantation of a vascularized donor thymus may facilitate the induction of tolerance in recipients of a cotransplanted heart allograft. To investigate this hypothesis, we developed a new technique to procure the heart and thymus en bloc from juvenile donors and transplant the composite allograft into thymectomized recipients. Thymic function was monitored by serial biopsy and flow cytometry of peripheral blood. Heart-thymus en bloc transplantation resulted in immediate revascularization of the heart and donor thymus with maintenance of normal thymic architecture, even in biopsies taken months after transplantation. Heart-thymus en bloc transplantation requires minimal modification to current heart procurement techniques. Here, we describe the details of the preparation, procurement, transplantation, and postoperative monitoring for this model, with the intention that this technique could be implemented by other investigators to study the effects of heart and thymus cotransplantation. This method could ultimately offer a new approach to tolerance induction in children.

Abstract Introduction It is estimated that 1.3 billion people in the world have hypertension and a large proportion of them are unaware. Waist circumference has emerged as Potential predictor of Cardiovascular Diseases (CVD) risk; however, fewer studies in Tanzania have evaluated its role in screening for CVD risk. This study aimed to determine the role of waist circumference in screening for hypertension, a major risk for CVD. Methods An analytical cross-sectional study was conducted in Manzese ward, Dar es Salaam, from August to September 2023. Adults who attended a screening campaign were systematically randomly sampled. Data were collected using WHO STEPwise Approach to Chronic Disease Risk Factor Surveillance questionnaire. The relationship between waist circumference and hypertension was analyzed using a Modified Poisson regression model with robust standard errors. Results Among 561 participants screened, 70.4% were female, with a median age of 47 years (IQR: 34–58). The overall prevalence of hypertension was 45.8% (95% Confidence interval [CI]: 41.7–49.9). Those with elevated waist circumference had a 34% higher likelihood of hypertension (adjusted prevalence ratio [aPR] 1.34, 95% CI: 1.03–1.73, P = 0.027). Participants aged 35 and above were 160% more likely to be hypertensive (aPR 2.6, 95% CI: 1.79–3.78, P

Background Globally, the rate of antiretroviral therapy coverage for pregnant women living with human immunodeficiency virus (HIV) increased by 38% between 2010 and 2015 but only by 2% between 2016 and 2020. Objectives We aimed to determine the prevalence of vertical transmission of HIV among infants from mothers living with HIV and associated factors in the Eastern Lake Zone and Southern Highland of Tanzania from January to December 2022. Methods This retrospective cross-sectional study extracted data from the Open Laboratory Data Repository database collected from January to December 2022 at 93 health facilities. A total of 1,411 infants exposed to HIV from the Mbeya (851), Songwe (304), and Mara regions (256) were enrolled. Results The prevalence for vertical transmission of HIV was 2.48% (35/1411). We observed a non-significant difference in the prevalence of vertical transmission in children whose first test was done below six weeks of life (1.89%) and other age groups (2.52-2.62%) (p

Precision medicine can significantly improve outcomes for patients with cancer, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here, we describe somatic biallelic TET2 mutations in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine but acutely sensitive to 5′-azacitidine (5′-Aza) hypomethylating monotherapy, resulting in long-term morphological remission. Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5′-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5′-Aza compared with cells with monoallelic mutations. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first-line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for patients with cancer.

Genome wide association studies in cancer are used to understand the heritable genetic contribution to disease risk. Here, the authors perform a genome wide association study in European patients with acute myeloid leukemia and identify loci associated with risk of developing the disease.

Raptors are emblematic of the global biodiversity crisis because one out of five species are threatened with extinction and over half have declining populations due to human threats. Yet our understanding of where these “threats” impact raptor species is limited across terrestrial Earth. This is concerning because raptors, as apex predators, are critically positioned in ecological food webs, and their declining populations can undermine important ecosystem services ranging from pest control to disease regulation. Here, we map the distribution of 15 threats within the known ranges of 172 threatened and near threatened raptor species globally as declared by the International Union for the Conservation of Nature. We analyze the proportion of each raptor range that is exposed to threats, identify global hotspots of impacted raptor richness, and investigate how human impacts on raptors vary based on several intrinsic (species traits) and extrinsic factors. We find that humans are potentially negatively affecting at least one threatened raptor species across three quarters of Earth’s terrestrial area (78%; 113 million km2). Our results also show that raptors have 66% of their range potentially impacted by threats on average (range 2.7–100%). Alarmingly, critically endangered species have 90% of their range impacted by threats on average. We also highlight 57 species (33%) of particular concern that have > 90% of their ranges potentially impacted. Without immediate conservation intervention, these 57 species, including the most heavily impacted Forest Owlet (Athene blewitti), the Madagascar Serpent-eagle (Eutriorchis astur), and the Rufous Fishing-owl (Scotopelia ussheri), will likely face extinction in the near future. Global “hotspots” of impacted raptor richness are ubiquitous, with core areas of threat in parts of the Sahel and East Africa where 92% of the assessed raptors are potentially impacted per grid cell (10 species on average), and in Northern India where nearly 100% of raptors are potentially impacted per grid cell (11 species). Additionally, “coolspots” of unimpacted richness that represent refuges from threats occur in Greenland and Canada, where 98 and 58% of raptors are potentially unimpacted per grid cell, respectively (nearly one species on average), Saharan Africa, where 21% of raptors are potentially unimpacted per grid cell (one species on average), and parts of the Amazon, where 12% of raptors are potentially unimpacted per grid cell (0.6 species on average). The results provide essential information to guide conservation planning and action for the world’s imperiled raptors.

Allograft failure remains a major barrier in the field of lung transplantation and results primarily from acute and chronic rejection. To date, standard-of-care immunosuppressive regimens have proven unsuccessful in achieving acceptable long-term graft and patient survival. Recent insights into the unique immunologic properties of lung allografts provide an opportunity to develop more effective immunosuppressive strategies. Here we describe advances in our understanding of the mechanisms driving lung allograft rejection and highlight recent progress in the development of novel, lung-specific strategies aimed at promoting long-term allograft survival, including tolerance.

The clinical course of chronic lymphocytic leukaemia (CLL) is variable and difficult to predict. Here, the authors conduct a genome wide association study meta-analysis for time to first treatment in CLL patients and report two loci associating with progressive disease.

The effectiveness of protected areas depends not only on whether they are intact, but also on whether they are mutually connected. Here the authors examine the structural connectivity of terrestrial protected areas globally, finding that less than 10% of the protected network can be considered connected.

Multiple languages being spoken within a species’ distribution can impede communication among conservation stakeholders, the compilation of scientific information, and the development of effective conservation actions. Here, we investigate the number of official languages spoken within the distributions of 10,863 bird species to identify which species might be particularly affected by consequences of language barriers. We show that 1587 species have 10 languages or more spoken within their distributions. Threatened and migratory species have significantly more languages spoken within their distributions, when controlling for range size. Particularly high numbers of species with many languages within their distribution are found in Eastern Europe, Russia and central and western Asia. Global conservation efforts would benefit from implementing guidelines to overcome language barriers, especially in regions with high species and language diversity.

The definition of regulatory landscape at chronic lymphocytic leukaemia (CLL) risk loci is limited. Here, the authors perform an epigenomic characterisation of 42 known risk loci in CLL and normal B cells at different developmental stages and show active chromatin and target genes in the risk loci.

A key obstacle to wildlife conservation is a scarcity of funding. A recent paper [Courchamp, F., Jaric, I., Albert, C., Meinard, Y., Ripple, W. J., and Chapron, G. (2018). The paradoxical extinction of the most charismatic animals. PLoS Biol. 16:e2003997. doi: 10.1371/journal.pbio.2003997] illustrates how for-profit businesses' widespread use of threatened wildlife imagery could create complacency in the public about their conservation. A wildlife imagery royalty, whereby businesses that use threatened wildlife in their marketing pay a small percentage of their sales to the conservation of those species could be revolutionary for conservation funding. However, businesses are not currently compelled to support the protection of the species espoused in their products. We build upon the arguments presented by recent publications [Good, C., Burnham, D., and Macdonald, D. W. (2017). A cultural conscience for conservation. Animals 7:52. doi: 10.3390/ani7070052; Courchamp, F., Jaric, I., Albert, C., Meinard, Y., Ripple, W. J., and Chapron, G. (2018). The paradoxical extinction of the most charismatic animals. PLoS Biol. 16:e2003997. doi: 10.1371/journal.pbio.2003997] to explore limitations and a number of key pathways that may help bring a wildlife imagery royalty to fruition.

Background. In kidney transplantation, long-term allograft acceptance in cynomolgus macaques was achieved using a mixed-chimerism protocol based on the clinically available reagents, rabbit anti-thymocyte globulin (ATG), and belatacept. Here, we have tested the same protocol in cynomolgus macaques transplanted with fully allogeneic lung grafts. Methods. Five cynomolgus macaques underwent left orthotopic lung transplantation. Initial immunosuppression included equine ATG and anti-IL6RmAb induction, followed by triple-drug immunosuppression for 4 mo. Post-transplant, a nonmyeloablative conditioning regimen was applied, including total body and thymic irradiation. Rabbit ATG, belatacept, anti-IL6RmAb, and donor bone marrow transplantation (DBMT) were given, in addition to a 28-d course of cyclosporine. All immunosuppressant drugs were stopped on day 29 after DBMT. Results. One monkey rejected its lung before DBMT due to AMR, after developing donor-specific antibodies. Two monkeys developed fatal post-transplant lymphoproliferative disorder, and both monkeys had signs of cellular rejection in their allografts upon autopsy. The remaining 2 monkeys showed severe cellular rejection on days 42 and 70 post-DBMT. Cytokine analysis suggested higher levels of pro-inflammatory markers in the lung transplant cohort, as compared to kidney recipients. Conclusion. Although the clinically applicable protocol showed success in kidney transplantation, the study did not show long-term survival in a lung transplant model, highlighting the organ-specific differences in tolerance induction.

Abstract Systematic conservation planning identifies priority areas to cost‐effectively meet conservation targets. Yet, these tools rarely guide wholesale declaration of reserve systems in a single time step due to financial and implementation constraints. Rather, incremental scheduling of actions to progressively build reserve networks is required. To ensure this incremental action is guided by the original plan, and thus builds a reserve network that meets all conservation targets, strategic scheduling, and iterative planning is needed. We explore the issue of scheduling conservation actions using the national scale conservation plan for Papua New Guinea (PNG), commissioned by the PNG Conservation and Environment Protection Authority that identifies a comprehensive set of priority areas that meet conservation targets in both the land and sea. As part of the planning process a subset of areas were identified in collaboration as priorities for immediate action—termed areas of interest (AOIs). However, the extent to which targets are met if action stopped after implementing the AOIs is unknown. We test three possible implementation scenarios based on these priority areas to measure target achievement and shortfalls. We then consider how iterative planning would interact with scheduling actions to identify new long‐term priorities that will meet missing targets. Our results show that while a large number of conservation targets are met within the AOIs there are shortfalls for protecting threatened and range restricted endemic species. Meeting targets for these would require an updated set of national priorities and an additional 13% of land area compared with if all areas identified in the original assessment were protected in a single time step. This provides important insights into the benefits of strategic scheduling of implementation, as well as the need for capacity to monitor action and update priorities as implementation proceeds.

Abstract We assess the magnitude and the extent of recent change of significant human footprint within protected areas, key biodiversity areas and the habitat range of 308 lowland forest specialist birds in Sundaland, a global hotspot of biodiversity in Southeast Asia. Using the most recent human footprint dataset, we find that 70% of Sundaland has been heavily modified by humans. This represents a 55% increase in areas under intense human pressure since 1993. Areas under intense human pressure covered on average 50% of the extent of key biodiversity areas, 78% of each protected area and 38% of the range of lowland forest specialist birds. The results imply that the actual level of protection by protected areas is only one‐third to half of that on paper once human footprint is accounted for. While all protected areas were impacted by human pressures, those managed strictly for biodiversity conservation presented the largest increases. These results highlight an exceptionally high human footprint across Sundaland and an impending further deepening of the biodiversity crisis across the region.

The United Nation’s Strategic Plan for Biodiversity 2011-2020 calls for reducing species extinctions, as it is increasingly clear that human activities threaten to drive species to decline. Yet despite considerable scientific evidence pointing to the detrimental effects of interacting threats on biodiversity, many species lack information on their exposure to cumulative human pressures. Using the most comprehensive global dataset on cumulative human footprint, we assess the extent of intense human pressures across 20,529 terrestrial vertebrate species’ geographic ranges. We consider intense human pressure as areas where landscapes start to be significantly modified (a summed Human Footprint value at or above three on the index), which is where land uses such as pastureland appear. This threshold has been correlated with extinction risk for many species. We show that 85% (17,517) of the terrestrial vertebrate species assessed have >half of their range exposed to intense human pressure, with 16% (3328) of the species assessed being entirely exposed to this degree of pressure. Threatened terrestrial vertebrates and species with small ranges are disproportionately exposed to intense human pressure. Our analysis also suggests that there are at least 2478 species considered ‘least concern’ that have considerable portions of their range overlapping with these pressures, which may indicate their risk of decline. These results point to the utility of assessing cumulative human pressure data across species ranges, which may be a useful first step for measuring species vulnerability. Keywords: Human footprint, Extinction risk, Biodiversity conservation, Species threats, Overexploitation, Land use change, Urbanization, Land clearing

Abstract: The ataxia telangiectasia and Rad3-related (ATR) protein kinase promotes cancer cell survival by signaling stalled replication forks generated by replication stress, a common feature of many cancers including acute myeloid leukemia (AML). Here we show that the antileukemic activity of the chemotherapeutic nucleoside analogs hydroxyurea and gemcitabine was significantly potentiated by ATR inhibition via a mechanism involving ribonucleotide reductase (RNR) abrogation and inhibition of replication fork progression. When administered in combination with gemcitabine, an inhibitor of the M1 RNR subunit, the ATR inhibitor VX-970, eradicated disseminated leukemia in an orthotopic mouse model, eliciting long-term survival and effective cure. These data identify a synergistic interaction between ATR inhibition and RNR loss that will inform the deployment of small molecule inhibitors for the treatment of AML and other hematologic malignancies.

While GWAS have uncovered susceptibility loci for B-cell precursor acute lymphoblastic leukemia (BCP-ALL), much of the heritable risk remains undiscovered. Here, the authors perform a meta-analysis of two existing BCP-ALL GWAS together with an unpublished GWAS to identify risk loci at 8q24.21 and 2q22.3.

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Research with nonhuman primates (NHPs) – monkeys for the most part – has led to critical health advances that have saved or improved millions of human lives. While NHPs account for just one-half of one percent of animals in current medical research, it is no exaggeration to say they are essential to our ability to find cures for cancer, AIDS, Alzheimer’s, Parkinson’s, obesity/diabetes, and dozens of other diseases that cause human suffering and death.

Chronic lymphocytic leukaemia has a hereditary component, much of which remains to be identified. Here, the authors perform a genome-wide association study and find new risk loci for the disease, which are associated with genes involved in immune function.

The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.

[This corrects the article DOI: 10.1371/journal.pbio.3000158.].

Conserving threatened species requires identifying where across their range they are being impacted by threats, yet this remains unresolved across most of Earth. Here, we present a global analysis of cumulative human impacts on threatened species by using a spatial framework that jointly considers the co-occurrence of eight threatening processes and the distribution of 5,457 terrestrial vertebrates. We show that impacts to species are widespread, occurring across 84% of Earth's surface, and identify hotspots of impacted species richness and coolspots of unimpacted species richness. Almost one-quarter of assessed species are impacted across >90% of their distribution, and approximately 7% are impacted across their entire range. These results foreshadow localised extirpations and potential extinctions without conservation action. The spatial framework developed here offers a tool for defining strategies to directly mitigate the threats driving species' declines, providing essential information for future national and global conservation agendas.

Habitat loss and urbanization are primary components of human impact on the environment. Here, Venter et al.use global data on infrastructure, agriculture, and urbanization to show that the human footprint is growing slower than the human population, but footprints are increasing in biodiverse regions.

Chronic lymphocytic leukemia (CLL) is an adult B cell malignancy. Genome-wide association studies show that variation at 15q15.1 influences CLL risk. We deciphered the causal variant at 15q15.1 and the mechanism by which it influences tumorigenesis. We imputed all possible genotypes across the locus and then mapped highly associated SNPs to areas of chromatin accessibility, evolutionary conservation, and transcription factor binding. SNP rs539846 C>A, the most highly associated variant (p = 1.42 × 10−13, odds ratio = 1.35), localizes to a super-enhancer defined by extensive histone H3 lysine 27 acetylation in intron 3 of B cell lymphoma 2 (BCL2)-modifying factor (BMF). The rs539846-A risk allele alters a conserved RELA-binding motif, disrupts RELA binding, and is associated with decreased BMF expression in CLL. These findings are consistent with rs539846 influencing CLL susceptibility through differential RELA binding, with direct modulation of BMF expression impacting on anti-apoptotic BCL2, a hallmark of oncogenic dependency in CLL.