Search

Abstract The expansion of wildlife ranching has been broadly linked to conservation benefits, job creation, and economic contributions. However, a more nuanced understanding of the socioeconomic contributions of wildlife ranching accounting for the enterprise diversity in the sector remains a major limitation to assessing its potential to contribute to sustainable development. We assessed several important socioeconomic contributions of diverse wildlife‐based business models, defined by their main revenue‐generating activities, within the South African wildlife ranching industry, and the financial viability of these models. Owners and managers of privately‐owned wildlife ranches and conventional agricultural farms (for comparative purposes) were interviewed in the Eastern Cape (112 ranches; 24 farms) and Limpopo provinces (152 ranches; 4 farms). We used a hierarchical clustering analysis to delineate six wildlife ranching business models. These included three more specialized models: ecotourism, trophy hunting, and wildlife breeding, and three more mixed models: mixed hunting (i.e., both meat and trophy hunting), mixed wildlife‐agriculture, and trophy hunting‐game meat. In general, ecotourism‐focused ranches employed more people in total and per hectare (median = 23 jobs; 0.008/ha), and a higher proportion of women and skilled employees (41% and 45% of employees, respectively) than the other ranching models (median = 7–21 jobs; 0.002–0.005/ha) and conventional agriculture (median = 12 jobs; 0.004/ha). Trophy hunting‐focused ranches employed the second highest number of people per hectare (0.006) although on average, a third of these jobs were seasonal. Trophy hunting ranches tended to be more profitable (median profit margin = 33%) than ecotourism (−10%), wildlife breeding (0%) and mixed‐hunting (12%) ranches, though ecotourism ranches showed very high variability (interquartile range = −32% to 14%). These findings advance our understanding of the distinct socioeconomic contributions of diverse wildlife ranches, which benefits policy discourse and implementation surrounding the industry, promoting improved industry sustainability and inclusive growth.

Abstract Sub-Saharan Africa is under-represented in global biodiversity datasets, particularly regarding the impact of land use on species’ population abundances. Drawing on recent advances in expert elicitation to ensure data consistency, 200 experts were convened using a modified-Delphi process to estimate ‘intactness scores’: the remaining proportion of an ‘intact’ reference population of a species group in a particular land use, on a scale from 0 (no remaining individuals) to 1 (same abundance as the reference) and, in rare cases, to 2 (populations that thrive in human-modified landscapes). The resulting bii4africa dataset contains intactness scores representing terrestrial vertebrates (tetrapods: ±5,400 amphibians, reptiles, birds, mammals) and vascular plants (±45,000 forbs, graminoids, trees, shrubs) in sub-Saharan Africa across the region’s major land uses (urban, cropland, rangeland, plantation, protected, etc.) and intensities (e.g., large-scale vs smallholder cropland). This dataset was co-produced as part of the Biodiversity Intactness Index for Africa Project. Additional uses include assessing ecosystem condition; rectifying geographic/taxonomic biases in global biodiversity indicators and maps; and informing the Red List of Ecosystems.

Abstract Background Youth swimming performance is determined by several physiological, biomechanical and anthropometric characteristics. This review aimed to identify physical performance determinants of youth swimming performance, assessing strength, power, anaerobic, aerobic and body composition measures. ̇ Methods Searches were conducted in electronic databases (PubMed and Web of Science) using keywords relating to swimming and physiological measures, supplemented by citation searching of similar reviews. A total of 843 studies were identified in the initial search. The following inclusion criteria were used: participants were competitive/trained swimmers; swimming time-trial or event was conducted; data was provided on one or more physiological parameters; study was published in English and peer-reviewed. A total of 43 studies met the inclusion criteria. Risk of bias was assessed using Joanna Briggs Institute (JBI) checklist. Results Cross-sectional studies scored between 4–8 and randomised-controlled trials scored 8–9 on their respective JBI checklists. Youth swimming performance was determined by muscle strength, muscle power, lean body mass, anaerobic and aerobic metabolism measures in most studies, where improved performance values of these variables were conducive to swimming performance. Body fat percentage did not have a clear relationship in youth swimming performance. Conclusions Findings of this review suggest that greater levels of muscle strength, muscle power and lean body mass are favourable in swimming performance, with muscle strength and muscle power particularly beneficial for start and turn performance. Anaerobic and aerobic metabolism measures were good determinants of swimming performance, with middle- and long-distance events more influenced by the latter. Body fat percentage has a nuanced relationship with swimming performance, where further investigation is required. Findings were inconsistent across studies, potentially due to unidentified confounding factors. Key points • Greater muscular strength and power qualities, anaerobic and aerobic capacities, and lean body mass are conducive to swimming performance. • Body fat percentage has a nuanced relationship with swimming performance. • Practitioners should consider general strength and power training as a useful tool to enhance performance in their youth competitors.

Background Despite improvements in survival over time, the mortality rate for infants with single‐ventricle heart disease remains high. Infants of low socioeconomic status (SES) are particularly vulnerable. We sought to determine whether use of a novel remote monitoring program, the Cardiac High Acuity Monitoring Program, mitigates differences in outcomes by SES. Methods and Results Within the Cardiac High Acuity Monitoring Program, we identified 610 infants across 11 centers from 2014 to 2021. All enrolled families had access to a mobile application allowing for near‐instantaneous transfer of patient information to the care team. Patients were divided into SES tertiles on the basis of 6 variables relating to SES. Hierarchical logistic regression, adjusted for potential confounding characteristics, was used to determine the association between SES and death or transplant listing during the interstage period. Of 610 infants, 39 (6.4%) died or were listed for transplant. In unadjusted analysis, the rate of reaching the primary outcome between SES tertiles was similar (P=0.24). Even after multivariable adjustment, the odds of death or transplant listing were no different for those in the middle (odds ratio, 1.7 [95% CI, 0.73–3.94) or highest (odds ratio, 0.997 [95% CI, 0.30, 3.36]) SES tertile compared with patients in the lowest (overall P value 0.4). Conclusions In a large multicenter cohort of infants with single‐ventricle heart disease enrolled in a digital remote monitoring program during the interstage period, we found no difference in outcomes based on SES. Our study suggests that this novel technology could help mitigate differences in outcomes for this fragile population of patients.

ObjectiveTo determine sex differences in the neurochemical concentrations measured by in vivo proton magnetic resonance spectroscopy (1H MRS) of healthy mice on a genetic background commonly used for neurodegenerative disease models.Methods1H MRS data collected from wild type mice with C57BL/6 or related genetic backgrounds in seven prior studies were used in this retrospective analysis. To be included, data had to be collected at 9.4 tesla magnetic field using advanced 1H MRS protocols, with isoflurane anesthesia and similar animal handling protocols, and a similar number of datasets from male and female mice had to be available for the brain regions analyzed. Overall, 155 spectra from female mice and 166 spectra from male mice (321 in total), collected from six brain regions (brainstem, cerebellum, cortex, hippocampus, hypothalamus, and striatum) at various ages were included.ResultsConcentrations of taurine, total creatine (creatine + phosphocreatine), ascorbate, glucose and glutamate were consistently higher in male vs. female mice in most brain regions. Striatum was an exception with similar total creatine in male and female mice. The sex difference pattern in the hypothalamus was notably different from other regions. Interaction between sex and age was significant for total creatine and taurine in the cerebellum and hippocampus.ConclusionSex differences in regional neurochemical levels are small but significant and age-dependent, with consistent male–female differences across most brain regions. The neuroendocrine region hypothalamus displays a different pattern of sex differences in neurochemical levels. Differences in energy metabolism and cellular density may underlie the differences, with higher metabolic rates in females and higher osmoregulatory and antioxidant capacity in males.

Physical activity (PA) in the form of aerobic exercise (AE) preserves and improves neurocognitive function across the lifespan. However, a mechanistic understanding of the pathways by which aerobic exercise impacts brain health is still lacking, particularly with respect to stress-related pathways. One mechanistic hypothesis is that AE improves neurocognitive health in part by modifying circulating levels of stress-related hormones and signaling factors associated with the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS), as commonly measured by the biomarkers cortisol (CORT) and salivary α-amylase (sAA). Thus, this hypothesis predicts that changes in stress biomarkers, such as CORT and sAA, are possible explanatory pathways mediating the positive effects of AE on neurocognitive health. In the present review article, we provide a summary of available studies examining the possibility that exercise-induced changes to stress biomarkers could partly account for exercise-related improvements in neurocognitive health. Our review indicates that despite the intuitive appeal of this hypothesis, there is insufficient evidence available to conclude that chronic and habitual AE affects neurocognitive health by altering stress biomarker pathways. The cross-sectional nature of the majority of reviewed studies highlights the need for well-controlled studies to adequately test this hypothesis.

Social-ecological systems (SES) research has emerged as an important area of sustainability science, informing and supporting pressing issues of transformation towards more sustainable, just and equitable futures. To date, much SES research has been done in or from the Global North, where the challenges and contexts for supporting sustainability transformations are substantially different from the Global South. This paper synthesises emerging insights on SES dynamics that can inform actions and advance research to support sustainability transformations specifically in the southern African context. The paper draws on work linked to members of the Southern African Program on Ecosystem Change and Society (SAPECS), a leading SES research network in the region, synthesizing key insights with respect to the five core themes of SAPECS: (i) transdisciplinary and engaged research, (ii) ecosystem services and human well-being, (iii) governance institutions and management practices, (iv) spatial relationships and cross-scale connections, and (v) regime shifts, traps and transformations. For each theme, we focus on insights that are particularly novel, interesting or important in the southern African context, and reflect on key research gaps and emerging frontiers for SES research in the region going forward. Such place-based insights are important for understanding the variation in SES dynamics around the world, and are crucial for informing a context-sensitive global agenda to foster sustainability transformations at local to global scales.

This study compared hematocrit measured with the EPOC and i-STAT Alinity v point-of-care analyzers and manual measurement of packed cell volume in managed African savanna elephants (Loxodonta africana) and southern white rhinoceros (Ceratotherium simum simum). Biochemical analytes were also measured with the EPOC, i-STAT Alinity v, and a veterinary diagnostic laboratory in the same animals. Analytes assessed included blood urea nitrogen, chloride, creatinine, glucose, ionized calcium, potassium, and sodium. There were no differences for hematocrit values for African savanna elephants or southern white rhinoceros (p ≤ 0.05). In African savanna elephants, there were no differences between the EPOC and i-STAT Alinity v analyzers for any measured analytes except ionized calcium. When compared to a veterinary diagnostic laboratory, there were differences for a majority of the biochemical analytes measured on the EPOC and i-STAT Alinity v analyzers in African savanna elephants. In southern white rhinoceros, there were differences for a majority of analytes among all three analyzers. While differences existed among the portable analyzers and a veterinary diagnostic laboratory for biochemical analytes in both species, these numerically small differences are unlikely to be clinically significant. For routine health care of African savanna elephants and southern white rhinoceros, these point-of-care analyzers may be a useful alternative to commercial analyzers for the parameters evaluated.

To understand fatty acid status and the potential impact of sample storage, dried blood spot (DBS) samples were collected from fourteen green turtles and ten Kemp’s ridleys undergoing rehabilitation. Half the DBS samples from each animal species were collected in 2021 and sent for immediate analysis while the other half were collected in 2017 from different animals and stored at −80 °C for 4 years before analysis. The blood fatty acid profiles in both species during rehabilitation differed visually from prior wild turtle data. Essential fatty acids linoleic (18:2w6) and linolenic acid (18:3w3) were higher in green turtles than in Kemp’s ridleys but both were approximately half of the percentage previously found in wild turtles. No difference in arachidonic acid between species in rehabilitation were found but percentages were approximately 10% of wild representatives. Sea turtle diets in rehabilitation management may need to be evaluated to ensure species-specific fatty acid balance. Twenty-eight of the 36 individual fatty acids tested were found and all seven fatty acid groupings were detected. When analyzed by storage time, 11 individual fatty acids and four fatty acid groups differed (p = 0.05). When compared by species, 14 individual fatty acids and three groups differed. Current data suggest DBS samples may be best utilized when analyzed immediately.

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease caused by a CAG repeat expansion in the ATXN3 gene. Though the ATXN3 protein is expressed ubiquitously throughout the CNS, regional pathology in SCA3 patients is observed within select neuronal populations and more recently within oligodendrocyte-rich white matter tracts. We have previously recapitulated these white matter abnormalities in an overexpression mouse model of SCA3 and demonstrated that oligodendrocyte maturation impairments are one of the earliest and most progressive changes in SCA3 pathogenesis. Disease-associated oligodendrocyte signatures have recently emerged as significant contributors to several other neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease, but their role in regional vulnerability and disease progression remains unexplored. Here, we are the first to comparatively assess myelination in human tissue in a region-dependent manner. Translating these findings to SCA3 mouse models of disease, we confirmed endogenous expression of mutant Atxn3 leads to regional transcriptional dysregulation of oligodendrocyte maturation markers in Knock-In models of SCA3. We then investigated the spatiotemporal progression of mature oligodendrocyte transcriptional dysregulation in an overexpression SCA3 mouse model and how it relates to the onset of motor impairment. We further determined that regional reduction in mature oligodendrocyte cell counts in SCA3 mice over time parallels the onset and progression of brain atrophy in SCA3 patients. This work emphasizes the prospective contributions of disease-associated oligodendrocyte signatures to regional vulnerability and could inform timepoints and target regions imperative for biomarker assessment and therapeutic intervention in several neurodegenerative diseases.

BackgroundLesbian, gay, bisexual, transgender, and other LGBTQIA cancer patients experience significant disparities in cancer-related outcomes. Their relationships may not be acknowledged in care systems designed to serve primarily heterosexual and cisgender (H/C) patients, and resources for partners and caregivers of H/C patients may not address the needs of LGBTQIA caregivers. Tailored interventions are needed to address disparities in LGBTQIA patients and caregivers.MethodsTo address this gap, researchers from Karmanos Cancer Institute in Detroit, MI and Wilmot Cancer Institute in Rochester, NY worked with a cancer action council (CAC) of LGBTQIA stakeholders with lived experience of cancer in a community-academic partnership. This group used the ADAPT-ITT model to guide their process of assessing needs in this community, identifying evidence-based interventions that could be adapted to meet those needs, and beginning the process of adapting an existing intervention to meet the needs of a new population.ResultsIn the Assessment phase of the model, CAC members shared their own experiences and concerns related to cancer and identified cancer caregiving as a priority area for intervention. In the Decision-Making phase of the model, researchers and CAC members performed a review of the literature on interventions that reported outcomes for cancer caregiver, identifying 13 promising interventions. Each of these interventions was evaluated over a series of meetings using a scoring rubric. Based on this rubric, the FOCUS intervention was established as an appropriate target for adaptation to the LGBTQIA population. In the first stage of the Adaptation phase, CAC members reacted to the intervention content and identified principal components for adaptation.ConclusionWhile the FOCUS intervention adaptation is still in process, this manuscript can serve as a guide for others establishing community-academic partnerships to adapt interventions, as well as those developing interventions and resources for LGBTQIA persons coping with cancer.

ObjectiveOverweight and obesity [body mass index (BMI) ≥ 25 kg/m2] are associated with poorer prognosis among women with breast cancer, and weight gain is common during treatment. Symptoms of depression and anxiety are also highly prevalent in women with breast cancer and may be exacerbated by post-diagnosis weight gain. Altered brain function may underlie psychological distress. Thus, this secondary analysis examined the relationship between BMI, psychological health, and resting state functional connectivity (rsFC) among women with breast cancer.MethodsThe sample included 34 post-menopausal women newly diagnosed with Stage 0-IIa breast cancer (Mage = 63.59 ± 5.73) who were enrolled in a 6-month randomized controlled trial of aerobic exercise vs. usual care. At baseline prior to randomization, whole-brain analyses were conducted to evaluate the relationship between BMI and seed-to-voxel rsFC of the hippocampus and amygdala. Connectivity values from significant clusters were then extracted and examined as predictors of self-reported depression and anxiety.ResultsMean BMI was in the obese range (M = 31.83 ± 6.62). For both seeds examined, higher BMI was associated with lower rsFC with regions of prefrontal cortex (PFC), including ventrolateral PFC (vlPFC), dorsolateral PFC, and superior frontal gyrus (z range = 2.85–4.26). Hippocampal connectivity with the vlPFC was negatively correlated with self-reported anxiety (β = 0.47, p < 0.01).ConclusionHigher BMI was associated with lower hippocampal and amygdala connectivity to regions of PFC implicated in cognitive control and emotion regulation. BMI-related differences in hippocampal and amygdala connectivity following a recent breast cancer diagnosis may relate to future worsening of psychological functioning during treatment and remission. Additional longitudinal research exploring this hypothesis is warranted.

Human studies, in combination with animal and cellular models, support glial cells as both major contributors to neurodegenerative diseases and promising therapeutic targets. Among glial cells, oligodendrocytes and Schwann cells are the myelinating glial cells of the central and peripheral nervous system, respectively. In this review, we discuss the contributions of these central and peripheral myelinating glia to the pathomechanisms of polyglutamine (polyQ) spinocerebellar ataxia (SCA) types 1, 2, 3, 6, 7, and 17. First, we highlight the function of oligodendrocytes in healthy conditions and how they are disrupted in polyQ SCA patients and diseased model systems. We then cover the role of Schwann cells in peripheral nerve function and repair as well as their possible role in peripheral neuropathy in polyQ SCAs. Finally, we discuss potential polyQ SCA therapeutic interventions in myelinating glial.

There is increasing interest in the potential of private land conservation areas (PLCAs) as a complementary biodiversity conservation strategy to state-owned protected areas. However, there is limited understanding of how the diverse social-ecological contexts of PLCAs influence their effectiveness in conserving biodiversity. Here, we investigated how the effectiveness of South African PLCAs in conserving biodiversity varied across social-ecological contexts, using natural land cover as a proxy. Social-ecological contexts were represented by biophysical and legal factors (distance to towns and roads, elevation, slope, terrain ruggedness, rainfall, PLCA size, distance to state-owned national parks, and presence of legal protection) and, for a subset of commercially-operated PLCAs, management factors (adopted business model, and profitability). Biophysical and legal contextual factors had low explanatory power in the best model for the nationwide analysis (n = 5121 PLCAs). For a subset of PLCAs (n = 72) we found that effectiveness depended on the strategy they adopted to generate an income, as opposed to the amount of income itself. PLCAs that attracted high volumes of visitors to small properties to view charismatic “Big 5” wildlife were less effective in conserving natural land cover than larger, more exclusive “Big 5” PLCAs and those focused on hunting. Overall, site-specific management factors were better at explaining the effectiveness of PLCAs than biophysical factors. Our findings indicate that conservation practitioners and policy makers need to recognise the diverse goals, motivations and management models of PLCAs when considering how to support them in conserving biodiversity. Future studies could explore whether these trends hold for other proxies of biodiversity conservation, beyond land cover change.

Racial disparities in cancer incidence and outcomes are well-documented in the US, with Black people having higher incidence rates and worse outcomes than White people. In this review, we present a summary of almost 30 years of research conducted by investigators at the Karmanos Cancer Institute’s (KCI’s) Population Studies and Disparities Research (PSDR) Program focusing on Black-White disparities in cancer incidence, care, and outcomes. The studies in the review focus on individuals diagnosed with cancer from the Detroit Metropolitan area, but also includes individuals included in national databases. Using an organizational framework of three generations of studies on racial disparities, this review describes racial disparities by primary cancer site, disparities associated with the presence or absence of comorbid medical conditions, disparities in treatment, and disparities in physician-patient communication, all of which contribute to poorer outcomes for Black cancer patients. While socio-demographic and clinical differences account for some of the noted disparities, further work is needed to unravel the influence of systemic effects of racism against Black people, which is argued to be the major contributor to disparate outcomes between Black and White patients with cancer. This review highlights evidence-based strategies that have the potential to help mitigate disparities, improve care for vulnerable populations, and build an equitable healthcare system. Lessons learned can also inform a more equitable response to other health conditions and crises.

The ability to finely control our movement is key to achieving many of the educational milestones and life-skills we develop throughout our lives. Despite the centrality of coordination to early development, there is a vast gap in our understanding of the underlying biology. Like most complex traits, both genetics and environment influence motor coordination, however, the specific genes, early environmental risk factors and molecular pathways are unknown. Previous studies have shown that about 5% of school-age children experience unexplained difficulties with motor coordination. These children are said to have Developmental Coordination Disorder (DCD). For children with DCD, these motor coordination difficulties significantly impact their everyday life and learning. DCD is associated with poorer academic achievement, reduced quality of life, it can constrain career opportunities and increase the risk of mental health issues in adulthood. Despite the high prevalence of coordination difficulties, many children remain undiagnosed by healthcare professionals. Compounding under-diagnosis in the clinic, research into the etiology of DCD is severely underrepresented in the literature. Here we present the first genome-wide association study to examine the genetic basis of early motor coordination in the context of motor difficulties. Using data from the Avon Longitudinal Study of Parents and Children we generate a derived measure of motor coordination from four components of the Movement Assessment Battery for Children, providing an overall measure of coordination across the full range of ability. We perform the first genome-wide association analysis focused on motor coordination (N = 4542). No single nucleotide polymorphisms (SNPs) met the threshold for genome-wide significance, however, 59 SNPs showed suggestive associations. Three regions contained multiple suggestively associated SNPs, within five preliminary candidate genes: IQSEC1, LRCC1, SYNJ2B2, ADAM20, and ADAM21. Association to the gene IQSEC1 suggests a potential link to axon guidance and dendritic projection processes as a potential underlying mechanism of motor coordination difficulties. This represents an interesting potential mechanism, and whilst further validation is essential, it generates a direct window into the biology of motor coordination difficulties. This research has identified potential biological drivers of DCD, a first step towards understanding this common, yet neglected neurodevelopmental disorder.

Abstract Background Niemann–Pick disease type C is a fatal and progressive neurodegenerative disorder characterized by the accumulation of unesterified cholesterol in late endosomes and lysosomes. We sought to develop new therapeutics for this disorder by harnessing the body’s endogenous cholesterol scavenging particle, high-density lipoprotein (HDL). Methods Here we design, optimize, and define the mechanism of action of synthetic HDL (sHDL) nanoparticles. Results We demonstrate a dose-dependent rescue of cholesterol storage that is sensitive to sHDL lipid and peptide composition, enabling the identification of compounds with a range of therapeutic potency. Peripheral administration of sHDL to Npc1 I1061T homozygous mice mobilizes cholesterol, reduces serum bilirubin, reduces liver macrophage size, and corrects body weight deficits. Additionally, a single intraventricular injection into adult Npc1 I1061T brains significantly reduces cholesterol storage in Purkinje neurons. Since endogenous HDL is also a carrier of sphingomyelin, we tested the same sHDL formulation in the sphingomyelin storage disease Niemann–Pick type A. Utilizing stimulated Raman scattering microscopy to detect endogenous unlabeled lipids, we show significant rescue of Niemann–Pick type A lipid storage. Conclusions Together, our data establish that sHDL nanoparticles are a potential new therapeutic avenue for Niemann–Pick diseases.

Background: Robinson Crusoe Island is a geographically and socially isolated settlement located over 600 km west of the Port of Valparíso, Chile. An unusually high incidence (30%) of the Chilean equivalent of developmental language disorder (in Spanish, trastorno especifico de lenguaje (TEL)), has been reported in Islander children, with 90% of these affected children found to be direct descendants of a pair of original founder-brothers, therefore strongly suggesting a shared genetic basis. Aim: This study reports a comprehensive examination of 34 genes that have been previously directly implicated in language-related mechanisms. It utilises whole-genome sequencing to investigate potential underlying variants in seven TEL affected and 10 unaffected islanders. The aim was to identify the underlying genetic cause of the TEL phenotype under two inheritance model paradigms; Mendelian monogenic and complex susceptibility. Subjects and methods: A targeted candidate gene approach was used to look for rare, shared variants that may underlie the diagnosis of TEL in a Mendelian genetic model. This study tested whether an overall burden of rare variants is enriched in individuals affected by TEL or with Islanders related to the founder-brother lineage. It further examined if any variants segregate with affection status or with founder-brother-related status and, therefore, may increase risk of developing a language disorder as part of a complex model. Finally, gene-based tests were performed to evaluate relationships between combined variation across candidate genes and TEL affection status. Results: No single pathogenic rare variant segregated with either affection or founder-related status within the 34 candidate genes. Additionally, no evidence was found of an overall increased variant burden in TEL individuals compared to those with TLD. Gene-based analysis found no clear association between the combined effects of variants across the 34 genes and affection status or founder-brother-relatedness. Conclusion: The high prevalence of language disorders found on Robinson Crusoe Island is not caused by either a shared high-impact variant, or an increased burden of variants within candidate genes previously implicated in language disorders. We have comprehensively tested for ‘low hanging fruit’ in genes implicated in language disorders. Therefore, the underlying cause of TEL on Robinson Crusoe lies outside of these known language disorder genes, or within a complex susceptibility model.

Emerging evidence has implicated non-neuronal cells, particularly oligodendrocytes, in the pathophysiology of many neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease and Spinocerebellar ataxia type 3 (SCA3). We recently demonstrated that cell-autonomous dysfunction of oligodendrocyte maturation is one of the of the earliest and most robust changes in vulnerable regions of the SCA3 mouse brain. However, the cell- and disease-specific mechanisms that underlie oligodendrocyte dysfunction remain poorly understood and are difficult to isolate in vivo. In this study, we used primary oligodendrocyte cultures to determine how known pathogenic SCA3 mechanisms affect this cell type. We isolated oligodendrocyte progenitor cells from 5- to 7-day-old mice that overexpress human mutant ATXN3 or lack mouse ATXN3 and differentiated them for up to 5 days in vitro. Utilizing immunocytochemistry, we characterized the contributions of ATXN3 toxic gain-of-function and loss-of-function in oligodendrocyte maturation, protein quality pathways, DNA damage signaling, and methylation status. We illustrate the utility of primary oligodendrocyte culture for elucidating cell-specific pathway dysregulation relevant to SCA3. Given recent work demonstrating disease-associated oligodendrocyte signatures in other neurodegenerative diseases, this novel model has broad applicability in revealing mechanistic insights of oligodendrocyte contribution to pathogenesis.

Language disorders are highly heritable and are influenced by complex interactions between genetic and environmental factors. Despite more than twenty years of research, we still lack critical understanding of the biological underpinnings of language. This review provides an overview of the genetic landscape of developmental language disorders (DLD), with an emphasis on the importance of defining the specific features (the phenotype) of DLD to inform gene discovery. We review the specific phenotype of DLD in the genetic literature, and the influence of historic variation in diagnostic inclusion criteria on researchers’ ability to compare and replicate genotype–phenotype studies. This review provides an overview of the recently identified gene pathways in populations with DLD and explores current state-of-the-art approaches to genetic analysis based on the hypothesised architecture of DLD. We will show how recent global efforts to unify diagnostic criteria have vastly increased sample size and allow for large multi-cohort metanalyses, leading the identification of a growing number of contributory loci. We emphasise the important role of estimating the genetic architecture of DLD to decipher underlying genetic associations. Finally, we explore the potential for epigenetics and environmental interactions to further unravel the biological basis of language disorders.

Abstract Private land conservation areas (PLCAs) have become critical for achieving global conservation goals, but we lack understanding of how and when these areas respond to global pressures and opportunities. In southern Africa, where many PLCAs rely on trophy hunting as an income‐generating strategy, a potential ban on trophy hunting locally or abroad holds unknown consequences for the future conservation of these lands. In this study, we investigate the consequences of a potential trophy hunting ban in PLCAs in two biodiversity hotspots in South Africa's Eastern and Western Cape provinces. We used semistructured interviews with PLCA managers and owners to elicit perceived impacts of an internationally imposed trophy hunting ban on conservation activities in PLCAs, and to probe alternative viable land uses. The majority of interviewees believed that both the economic viability of their PLCA and biodiversity would be lost following a hunting ban. Owners would primarily consider transitioning to ecotourism or livestock farming, but these options were constrained by the social‐ecological context of their PLCA (e.g., competition with other PLCAs, ecological viability of farming). Our results suggest that a trophy hunting ban may have many unintended consequences for biodiversity conservation, national economies, and the livelihoods of PLCA owners and employees. Along with similar social‐ecological studies in other areas and contexts, our work can inform policy decisions around global trophy hunting regulation.

Private land conservation areas (PLCAs) are increasingly looked to for meeting the deficit left by state-owned protected areas in reaching global conservation targets. However, despite the increasing extent and recognition of PLCAs as a complementary conservation strategy, little research has been done to quantify their effectiveness; a critical consideration if they are to be counted towards international biodiversity conservation targets. The long history of PLCAs in South Africa provides an interesting case study to address this knowledge gap. Here, we quantified the effectiveness of South African PLCAs by comparing losses in natural land cover and biodiversity intactness within PLCAs with different levels of protection to that of unprotected control points. Points within PLCAs were matched with unprotected control points to test the prediction that if PLCAs offer effective protection, losses in natural land cover and biodiversity intactness would be significantly lower within their boundaries in comparison to unprotected controls exposed to similar conditions. Consequences of natural land cover loss on biodiversity intactness were thus assessed, thus advancing standard approaches for quantifying effectiveness. Between 1990 and 2013, PLCAs lost significantly less natural land cover (3%) and biodiversity intactness (2%) than matched unprotected areas (6% and 4%, respectively). Of the natural land cover lost within PLCAs, most was converted to cultivated land. Farms can support more species than other land uses (e.g. mines), a likely explanation for why losses in biodiversity intactness were less than losses in natural land cover. Contrary to the predicted pattern, effectiveness did not increase with level of protection; informal PLCAs with no legal protection had comparable natural land cover and biodiversity intactness retention to strictly protected PLCAs, with most losses recorded among PLCAs with moderate protection. This study provides the first national-scale evidence that PLCAs can be an effective mechanism for conserving natural land cover and biodiversity intactness, which is highly relevant given current discussions around their likely long-term biodiversity conservation capacity.

Studies examining genetic conditions common in Latin America are highly underrepresented in the scientific literature. Understanding of the population structure is limited, particularly Chile, in part due to the lack of available population specific data. An important first-step in elucidating disease mechanisms in Latin America countries is to understand the genetic structure of isolated populations. Robinson Crusoe Island (RCI) is a small land mass off the coast of Chile. The current population of over 900 inhabitants are primarily descended from a small number of founders who colonized the island in the late 1800s. Extensive genealogical records can trace the ancestry of almost the entire population. We perform a comprehensive genetic analysis to investigate the ancestry of the island population, examining ancestral mitochondrial and Y chromosome haplogroups, as well as autosomal admixture. Mitochondrial and Y chromosome haplogroups indicated a substantial European genetic contribution to the current RCI population. Analysis of the mitochondrial haplogroups found in the present-day population revealed that 79.1% of islanders carried European haplogroups, compared to 60.0% of the mainland Chilean controls from Santiago. Both groups showed a substantially lower contribution of indigenous haplogroups than expected. Analysis of the Y chromosome haplogroups also showed predominantly European haplogroups detected in 92.3% of male islanders and 86.7% of mainland Chilean controls. Using the near-complete genealogical data collected from the RCI population, we successfully inferred the ancestral haplogroups of 16/23 founder individuals, revealing genetic ancestry from Northern and Southern Europe. As mitochondrial and Y investigations only provide information for direct maternal and paternal lineages, we expanded this to investigate genetic admixture using the autosomes. Admixture analysis identified substantial indigenous genetic admixture in the RCI population (46.9%), higher than that found in the Santiago mainland Chilean controls (43.4%), but lower than a more representative Chilean population (Chile_GRU) (49.1%). Our study revealed the Robinson Crusoe Island population show a substantial genetic contribution for indigenous Chileans, similar to the level reported in mainland Chileans. However, direct maternal and paternal haplogroup analysis revealed strong European genetic contributions consistent with the history of the Island.

Tandem repeat diseases include the neurodegenerative disorders known as polyglutamine (polyQ) diseases, caused by CAG repeat expansions in the coding regions of the respective disease genes. The nine known polyQ disease include Huntington’s disease (HD), dentatorubral–pallidoluysian atrophy (DRPLA), spinal bulbar muscular atrophy (SBMA), and six spinocerebellar ataxias (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17). The underlying disease mechanism in the polyQ diseases is thought principally to reflect dominant toxic properties of the disease proteins which, when harboring a polyQ expansion, differentially interact with protein partners and are prone to aggregate. Among the polyQ diseases, SCA3 is the most common SCA, and second to HD in prevalence worldwide. Here we summarize current understanding of SCA3 disease mechanisms within the broader context of the broader polyQ disease field. We emphasize properties of the disease protein, ATXN3, and new discoveries regarding three potential pathogenic mechanisms: 1) altered protein homeostasis; 2) DNA damage and dysfunctional DNA repair; and 3) nonneuronal contributions to disease. We conclude with an overview of the therapeutic implications of recent mechanistic insights.

Objective The purpose of this study was to examine the state of smartphone applications for cancer intended for the general public with a focus on interactive features, content sources, and application developer affiliations. The level of health provider involvement in screening or appraising application content was also assessed. Methods A total of 123 apps were identified for analysis from two major mobile application marketplaces (Apple iTunes = 40; Google Play = 83). Application characteristics were collected, analyzed, and reported. These included the mobile platform, cost, application developer affiliation, date of last update, purpose of application, content sources, and interactive features. Results In the study sample, 50% of the applications focused on general information for cancer (62/123). Next, this was followed by applications for breast cancer (15%, 19/123) and skin cancer (7%, 8/123). Only 10% of application descriptions (12/123) identified sources for application content. Interactive features included the ability to monitor symptoms, side effects, treatments, and chronic pain (20%, 25/123). Only 3% of the applications (4/123) stated content had been evaluated by health providers. Conclusions This study contributes an updated analysis of applications for cancer available in the digital health marketplace. The findings have implications for information quality and supportive resources for cancer care. More transparent information about content sources, organizational affiliations, and level of health provider oversight in screening application content is warranted. Recommendations for improving the quality of cancer applications are also offered.

Abstract: High expression of the α chain of the interleukin-3 receptor (IL-3Rα; CD123) is a hallmark of acute myeloid leukemia (AML) leukemic stem cells (LSCs). Elevated CD123 expression is part of the diagnostic immunophenotyping of myeloid leukemia, and higher expression is associated with poor prognosis. However, the biological basis of the poorer prognosis is unclear, and may include heightened IL-3 signaling and non–cell autonomous interactions with the bone marrow (BM) microenvironment. We used TF-1 cells expressing different levels of CD123 and found elevated CD123 levels amplified the proliferative response to exogenous IL-3 and maintained viability in reducing IL-3 concentrations. This was associated with stronger activation of STAT5, Akt, and extracellular signal-regulated kinase 1/2 in vitro. Surprisingly, in vivo e14.5 fetal liver cells transduced with retroviral constructs to express high CD123 failed to engraft in syngeneic recipients. In exploring the underlying mechanism for this, we found that CXCR4, a key molecule involved in LSC/BM interactions, was specifically downregulated in CD123 overexpressing cells in a manner dependent on IL-3 signaling. CXCR4 downregulation was sufficient to alter the chemotactic response of hematopoietic cells to stromal derived factor-1 (SDF-1). Thus, we propose that the overexpression of CD123 in AML LSC dictates their location by altering CXCR4/SDF-1 interaction in the BM, raising the possibility that this mechanism underpins the egress of BM AML LSC and more mature cells into the circulation.

Abstract Background The BDNF gene codes for brain-derived neurotrophic factor, a growth factor involved in neural development, cell differentiation, and synaptic plasticity. Present in both the brain and periphery, BDNF plays critical roles throughout the body and is essential for placental and fetal development. Rodent studies show that early life stress, including prenatal stress, broadly alters BDNF methylation, with presumed changes in gene expression. No studies have assessed prenatal exposure to maternal traumatic stress and BDNF methylation in humans. This study examined associations of prenatal exposure to maternal stress and BDNF methylation at CpG sites across the BDNF gene. Results Among 24 mothers and newborns in the eastern Democratic Republic of Congo, a region with extreme conflict and violence to women, maternal experiences of war trauma and chronic stress were associated with BDNF methylation in umbilical cord blood, placental tissue, and maternal venous blood. Associations of maternal stress and BDNF methylation showed high tissue specificity. The majority of significant associations were observed in putative transcription factor binding regions. Conclusions This is the first study in humans to examine BDNF methylation in relation to prenatal exposure to maternal stress in three tissues simultaneously and the first in any mammalian species to report associations of prenatal stress and BDNF methylation in placental tissue. The findings add to the growing body of evidence highlighting the importance of considering epigenetic effects when examining the impacts of trauma and stress, not only for adults but also for offspring exposed via effects transmitted before birth.

The most common dominantly inherited ataxia, spinocerebellar ataxia type 3 (SCA3), is an incurable neurodegenerative disorder caused by a CAG repeat expansion in the ATXN3 gene that encodes an abnormally long polyglutamine tract in the disease protein, ATXN3. Mice lacking ATXN3 are phenotypically normal; hence, disease gene suppression offers a compelling approach to slow the neurodegenerative cascade in SCA3. Here we tested antisense oligonucleotides (ASOs) that target human ATXN3 in two complementary mouse models of SCA3: yeast artificial chromosome (YAC) MJD-Q84.2 (Q84) mice expressing the full-length human ATXN3 gene and cytomegalovirus (CMV) MJD-Q135 (Q135) mice expressing a human ATXN3 cDNA. Intracerebroventricular injection of ASOs resulted in widespread delivery to the most vulnerable brain regions in SCA3. In treated Q84 mice, three of five tested ASOs reduced disease protein levels by >50% in the diencephalon, cerebellum, and cervical spinal cord. Two ASOs also significantly reduced mutant ATXN3 in the mouse forebrain and resulted in no signs of astrogliosis or microgliosis. In Q135 mice expressing a single ATXN3 isoform via a cDNA transgene, ASOs did not result in similar robust ATXN3 silencing. Our results indicate that ASOs targeting full-length human ATXN3 would likely be well tolerated and could lead to a preventative therapy for SCA3.

Abstract Views that protected area (PA) expansion relies predominantly on land purchased by government are increasingly being challenged. The inclusion of privately owned PAs (PPAs) in national conservation strategies is now commonplace, but little is known about their long‐term persistence and how it compares to that of state‐owned PAs. We undertook the first long‐term assessment of the dynamics of a national system of terrestrial PPAs, assessing its growth, as well as its resilience to downgrading, downsizing, and degazettement (PADDD). Between 1926 and 2018, 6.2% of all private nature reserves established in South Africa were degazetted, compared to 2.2% of state‐owned nature reserves. Privately owned PA growth exceeded that of state‐owned PAs. Trends in PA establishment differed between privately owned and state‐owned PAs, reflecting different legislative, political, and economic events. Our findings highlight the value of enabling legislative environments to facilitate PPA establishment, and demonstrate the potential of PPAs as a long‐term conservation strategy.

Spinocerebellar ataxia type 3 (SCA3) is a fatal, late-onset neurodegenerative disorder characterized by selective neuropathology in the brainstem, cerebellum, spinal cord, and substantia nigra. Here we report the first NIH-approved human embryonic stem cell (hESC) line derived from an embryo harboring the SCA3 mutation. Referred to as SCA3-hESC, this line is heterozygous for the mutant polyglutamine-encoding CAG repeat expansion in the ATXN3 gene. We observed relevant molecular hallmarks of the human disease at all differentiation stages from stem cells to cortical neurons, including robust ATXN3 aggregation and altered expression of key components of the protein quality control machinery. In addition, SCA3-hESCs exhibit nuclear accumulation of mutant ATXN3 and form p62-positive aggresomes. Finally, antisense oligonucleotide-mediated reduction of ATXN3 markedly suppressed aggresome formation. The SCA3-hESC line offers a unique and highly relevant human disease model that holds strong potential to advance understanding of SCA3 disease mechanisms and facilitate the evaluation of candidate therapies for SCA3. Keywords: Aggresome, Antisense oligonucleotide, Ataxin-3, Machado-Joseph disease, Neurodegeneration, Polyglutamine disease

Hydrates are technologically important and ubiquitous yet they remain a poorly understood and understudied class of molecular crystals. In this work, we attempt to rationalize propensity towards hydrate formation through crystallization studies of molecules that lack strong hydrogen-bond donor groups. A Cambridge Structural Database (CSD) survey indicates that the statistical occurrence of hydrates in 124 molecules that contain five- and six-membered N-heterocyclic aromatic moieties is 18.5%. However, hydrate screening experiments on a library of 11 N-heterocyclic aromatic compounds with at least two acceptor moieties and no competing hydrogen-bond donors or acceptors reveals that over 70% of this group form hydrates, suggesting that extrapolation from CSD statistics might, at least in some cases, be deceiving. Slurrying in water and exposure to humidity were found to be the most effective discovery methods. Electrostatic potential maps and/or analysis of the crystal packing in anhydrate structures was used to rationalize why certain molecules did not readily form hydrates.

Platelets express negatively charged phosphatidylserine (PS) on their plasma membrane when propagating coagulation within a developing thrombus. Here the authors show that an adaptor protein 14-3-3 regulates mitochondrial function and PS exposure and thus platelet procoagulant activity, promising a new therapy to reduce thrombosis.

Spinocerebellar ataxia type 3 (SCA3) is a dominantly inherited neurodegenerative disorder caused by a polyglutamine-encoding CAG repeat expansion in the ATXN3 gene which encodes the deubiquitinating enzyme, ATXN3. Several mechanisms have been proposed to explain the pathogenic role of mutant, polyQ-expanded ATXN3 in SCA3 including disease protein aggregation, impairment of ubiquitin-proteasomal degradation and transcriptional dysregulation. A better understanding of the normal functions of this protein may shed light on SCA3 disease pathogenesis. To assess the potential normal role of ATXN3 in regulating gene expression, we compared transcriptional profiles in WT versus Atxn3 null mouse embryonic fibroblasts. Differentially expressed genes in the absence of ATXN3 contribute to multiple signal transduction pathways, suggesting a status switch of signaling pathways including depressed Wnt and BMP4 pathways and elevated growth factor pathways such as Prolactin, TGF-β, and Ephrin pathways. The Eph receptor A3 (Efna3), a receptor protein-tyrosine kinase in the Ephrin pathway that is highly expressed in the nervous system, was the most differentially upregulated gene in Atxn3 null MEFs. This increased expression of Efna3 was recapitulated in Atxn3 knockout mouse brainstem, a selectively vulnerable brain region in SCA3. Overexpression of normal or expanded ATXN3 was sufficient to repress Efna3 expression, supporting a role for ATXN3 in regulating Ephrin signaling. We further show that, in the absence of ATXN3, Efna3 upregulation is associated with hyperacetylation of histones H3 and H4 at the Efna3 promoter, which in turn is induced by decreased levels of HDAC3 and NCoR in ATXN3 null cells. Together, these results reveal a normal role for ATXN3 in transcriptional regulation of multiple signaling pathways of potential relevance to disease processes in SCA3.

Background. Abdominal pain during pregnancy has a broad differential diagnosis which includes spontaneous adrenal hemorrhage (SAH). There is scant literature available on optimal mode of delivery in stable patients. Cases. Patient 1 was a 35-year-old nullipara who presented at 36 weeks of gestation with left flank pain. Patient 2 was a 27-year-old multipara at 38 weeks who presented with left upper quadrant pain. Diagnosis of SAH was made by CT scan and both were managed with pain control, serial hemoglobin assessments, and abdominal exams resulting in uncomplicated vaginal deliveries. Conclusion. SAH, although rare, is an important consideration when evaluating abdominal and flank pain in pregnancy. Management options vary from conservative management to surgical intervention depending on the stability of the patient.

We report herein on five new Fe(II) complexes of general formula [Fe(L)2(NCCH3)2](BF4)2•xCH3CN (L = substituted 2-pyridylimine-based ligands). The influence of proximally located electron withdrawing groups (e.g., NO2, CN, CF3, Cl, Br) bound to coordinated pyridylimine ligands has been studied for the effect on spin crossover in their Fe(II) complexes. Variable-temperature UV-visible spectroscopic studies performed on complexes with more strongly electronegative ligand substituents revealed spin crossover (SCO) in the solution, and thermodynamic parameters associated with the spin crossover were estimated.

Nature Communications 7: Article number: 12862 (2016); Published: 27 September 2016; Updated: 30 August 2017 In Supplementary Fig. 7 of this Article, graphs presenting 6-PFK kinetics in panel d were inadvertently duplicated from those in panel c. The correct version of Supplementary Fig. 7 appears below as Fig.

There is a growing recognition of the contribution that privately-owned land makes to conservation efforts, and governments are increasingly counting privately protected areas (PPAs) towards their international conservation commitments. The public availability of spatial data on countries’ conservation estates is important for broad-scale conservation planning and monitoring and for evaluating progress towards targets. Yet there has been limited consideration of how PPA data is reported to national and international protected area databases, particularly whether such reporting is transparent and fair (i.e., equitable) to the landholders involved. Here we consider PPA reporting procedures from three countries with high numbers of PPAs—Australia, South Africa, and the United States—illustrating the diversity within and between countries regarding what data is reported and the transparency with which it is reported. Noting a potential tension between landholder preferences for privacy and security of their property information and the benefit of sharing this information for broader conservation efforts, we identify the need to consider equity in PPA reporting processes. Unpacking potential considerations and tensions into distributional, procedural, and recognitional dimensions of equity, we propose a series of broad principles to foster transparent and fair reporting. Our approach for navigating the complexity and context-dependency of equity considerations will help strengthen PPA reporting and facilitate the transparent integration of PPAs into broader conservation efforts.

The prognosis of older patients with acute myelogenous leukemia is generally poor. The interleukin-3 receptor α-chain (CD123) is highly expressed on the surface of acute leukemia cells compared with normal hematopoietic stem cells. CSL362 is a fully humanized, CD123-neutralizing monoclonal antibody containing a modified Fc structure, which enhances human natural killer cell antibody-dependent cell-mediated cytotoxicity. Six continuous acute myelogenous leukemia xenografts established from patient explants and characterized by cell and molecular criteria, produced progressively lethal disease 42-202 days after transplantation. CSL362 alone reduced engraftment of one of four and three of four acute myelogenous leukemia xenografts in the bone marrow and peripheral organs, respectively. A cytarabine and daunorubicin regimen was optimized using this model to identify potentially synergistic interactions with CSL362. Cytarabine/daunorubicin improved the survival of mice engrafted with four of four acute myelogenous leukemia xenografts by 31–41 days. Moreover, CSL362 extended the survival of cytarabine/daunorubicin-treated mice for two of two acute myelogenous leukemia xenografts, while augmentation of natural killer cell-deficient NSG mice with adoptively transferred human natural killer cells improved survival against a single xenograft. Interestingly, this enhanced CSL362 efficacy was lost in the absence of chemotherapy. This study shows that acute myelogenous leukemia xenografts provide a platform for the evaluation of new therapeutics, simulating complex in vivo interactions, and that the in vivo efficacy of CSL362 supports continued clinical development of this drug.

Broad-scale models describing predator prey preferences serve as useful departure points for understanding predator-prey interactions at finer scales. Previous analyses used a subjective approach to identify prey weight preferences of the five large African carnivores, hence their accuracy is questionable. This study uses a segmented model of prey weight versus prey preference to objectively quantify the prey weight preferences of the five large African carnivores. Based on simulations of known predator prey preference, for prey species sample sizes above 32 the segmented model approach detects up to four known changes in prey weight preference (represented by model break-points) with high rates of detection (75% to 100% of simulations, depending on number of break-points) and accuracy (within 1.3±4.0 to 2.7±4.4 of known break-point). When applied to the five large African carnivores, using carnivore diet information from across Africa, the model detected weight ranges of prey that are preferred, killed relative to their abundance, and avoided by each carnivore. Prey in the weight ranges preferred and killed relative to their abundance are together termed "accessible prey". Accessible prey weight ranges were found to be 14-135 kg for cheetah Acinonyx jubatus, 1-45 kg for leopard Panthera pardus, 32-632 kg for lion Panthera leo, 15-1600 kg for spotted hyaena Crocuta crocuta and 10-289 kg for wild dog Lycaon pictus. An assessment of carnivore diets throughout Africa found these accessible prey weight ranges include 88±2% (cheetah), 82±3% (leopard), 81±2% (lion), 97±2% (spotted hyaena) and 96±2% (wild dog) of kills. These descriptions of prey weight preferences therefore contribute to our understanding of the diet spectrum of the five large African carnivores. Where datasets meet the minimum sample size requirements, the segmented model approach provides a means of determining, and comparing, the prey weight range preferences of any carnivore species.