The role of species ecology in predicting Toxoplasma gondii prevalence in wild and domesticated mammals globally.

Macroecological approaches can provide valuable insight into the epidemiology of globally distributed, multi-host pathogens. Toxoplasma gondii is a protozoan that infects any warm-blooded animal, including humans, in almost every habitat worldwide. Toxoplasma gondii infects its hosts through oocysts in the environment, carnivory of tissue cysts within intermediate host prey and vertical transmission. These routes of infection enable specific predictions regarding the ecological and life history traits that should predispose specific taxa to higher exposure and, thus infection rates of T. gondii. Using T. gondii prevalence data compiled from 485 studies representing 533 free-ranging wild mammalian species, we examined how ecological (habitat type, trophic level) and life history (longevity, vagility, gestation duration and torpor) traits influence T. gondii infection globally. We also compared T. gondii prevalence between wild and domesticated species from the same taxonomic families using data compiled from 540 studies of domestic cattle, sheep, and pigs. Across free-ranging wildlife, we found the average T. gondii prevalence was 22%, which is comparable to the global human estimate. Among ecological guilds, terrestrial species had lower T. gondii prevalence than aquatic species, with freshwater aquatic taxa having an increased prevalence compared to marine aquatic species. Dietary niches were also influential, with carnivores having an increased risk compared to other trophic feeding groups that have reduced tissue cyst exposure in their diet. With respect to influential life history traits, we found that more vagile wildlife species had higher T. gondii infection rates, perhaps because of the higher cumulative risk of infection during movement through areas with varying T. gondii environmental loads. Domestic farmed species had a higher T. gondii prevalence compared to free-ranging confamilial wildlife species. Through a macroecological approach, we determined the relative significance of transmission routes of a generalist pathogen, demonstrating an increased infection risk for aquatic and carnivorous species and highlighting the importance of preventing pathogen pollution into aquatic environments. Toxoplasma gondii is increasingly understood to be primarily an anthropogenically-associated pathogen whose dissemination is enhanced by ecosystem degradation and human subsidisation of free-roaming domestic cats. Adopting an ecosystem restoration approach to reduce one of the world's most common parasites would synergistically contribute to other initiatives in conservation, feline and wildlife welfare, climate change, food security and public health.

Body mass index stratified meta-analysis of genome-wide association studies of polycystic ovary syndrome in women of European ancestry.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex multifactorial disorder with a substantial genetic component. However, the clinical manifestations of PCOS are heterogeneous with notable differences between lean and obese women, implying a different pathophysiology manifesting in differential body mass index (BMI). We performed a meta-analysis of genome-wide association study (GWAS) data from six well-characterised cohorts, using a case-control study design stratified by BMI, aiming to identify genetic variants associated with lean and overweight/obese PCOS subtypes. RESULTS: The study comprised 254,588 women (5,937 cases and 248,651 controls) from individual studies performed in Australia, Estonia, Finland, the Netherlands and United States of America, and separated according to three BMI stratifications (lean, overweight and obese). Genome-wide association analyses were performed for each stratification within each cohort, with the data for each BMI group meta-analysed using METAL software. Almost half of the total study population (47%, n = 119,584) were of lean BMI (≤ 25 kg/m2). Two genome-wide significant loci were identified for lean PCOS, led by rs12000707 within DENND1A (P = 1.55 × 10-12) and rs2228260 within XBP1 (P = 3.68 × 10-8). One additional locus, LINC02905, was highlighted as significantly associated with lean PCOS through gene-based analyses (P = 1.76 × 10-6). There were no significant loci observed for the overweight or obese sub-strata when analysed separately, however, when these strata were combined, an association signal led by rs569675099 within DENND1A reached genome-wide significance (P = 3.22 × 10-9) and a gene-based association was identified with ERBB4 (P = 1.59 × 10-6). Nineteen of 28 signals identified in previous GWAS, were replicated with consistent allelic effect in the lean stratum. There were less replicated signals in the overweight and obese groups, and only 4 SNPs were replicated in each of the three BMI strata. CONCLUSIONS: Genetic variation at the XBP1, LINC02905 and ERBB4 loci were associated with PCOS within unique BMI strata, while DENND1A demonstrated associations across multiple strata, providing evidence of both distinct and shared genetic features between lean and overweight/obese PCOS-affected women. This study demonstrated that PCOS-affected women with contrasting body weight are not only phenotypically distinct but also show variation in genetic architecture; lean PCOS women typically display elevated gonadotrophin ratios, lower insulin resistance, higher androgen levels, including adrenal androgens, and more favourable lipid profiles. Overall, these findings add to the growing body of evidence supporting a genetic basis for PCOS as well as differences in genetic patterns relevant to PCOS BMI-subtype.

APOL1 Nephropathy Risk Variants Through the Life Course: A Review.

Two variant alleles of the gene apolipoprotein L1 (APOL1), known as risk variants (RVs), are a major contributor to kidney disease burden in those of African descent. The APOL1 protein contributes to innate immunity and may protect against Trypanosoma, HIV, Salmonella, and leishmaniasis. However, the effects of carrying 1 or more RVs contribute to a variety of disease processes starting as early as in utero and can be exacerbated by other factors (or "second hits"). Indeed, these genetic variations interact with environmental exposures, infections, and systemic disease to modify health outcomes across the life span. This review focuses on APOL1-associated diseases through the life-course perspective and discusses how early exposure to second hits can impact long-term outcomes. APOL1-related kidney disease typically presents in adolescents to young adults, and individuals harboring RVs are more likely to progress to kidney failure than are those with kidney disease who lack APOL-1 RVs. Ongoing research is aimed at elucidating the association of APOL1 RV effects with adverse donor and recipient kidney transplant outcomes. Unfortunately, there is currently no established treatment for APOL1-associated nephropathy. Long-term research is needed to evaluate the risk and protective factors associated with APOL1 RVs at different stages of life.

Substituting space for time: Bird responses to forest loss in space provide a general picture of responses over time.

The practice of space-for-time substitution assumes that the responses of species or communities to land-use change over space represents how they will respond to that same change over time. Space-for-time substitution is commonly used in both ecology and conservation, but whether the assumption produces reliable insights remains inconclusive. Here, we tested space-for-time substitution using data from the North American Breeding Bird Survey (BBS) and Global Forest Change (GFC) to compare the effects of landscape-scale forest cover on bird richness and abundance over time and space, for 25 space-time comparisons. Each comparison consisted of a landscape that experienced at least 20% forest loss over 19 years (temporal site) and a set of 15-19 landscapes (spatial sites) that represented the same forest cover gradient over space in 2019 as experienced over time in their corresponding temporal site. Across the 25 comparisons, the observed responses of forest and open-habitat birds to forest cover over time generally aligned with their responses to forest cover over space, but with comparatively higher variability in the magnitude and direction of effect across the 25 temporal slopes than across the 25 spatial slopes. On average, the mean differences between the spatial and temporal slopes across the 25 space-time comparisons frequently overlapped with zero, suggesting that the spatial slopes are generally informative of the temporal slopes. However, we observed high variability around these mean differences, indicating that a single spatial slope is not strongly predictive of its corresponding temporal slope. We suggest that our results may be explained by annual variability in other relevant environmental factors that combine to produce complex effects on population abundances over time that are not easily captured by snapshots in space. While not being a 1:1 proxy, measuring bird responses to changes in habitat amount in space provides an idea on how birds might be expected to eventually equilibrate to similar changes in habitat amount over time. Further, analyses such as this could be potentially used to screen for cases of regional space-time mismatches where population-limiting factors other than habitat could be playing a more important role in the population trends observed there.

Local and regional-scale effects of hedgerows on grassland- and forest-associated bird populations within agroecosystems.

Linear woody features (LWFs), like hedgerows along field edges, provide wildlife habitat and support biodiversity in agroecosystems. Assessments of LWFs usually focus on community-level indices, such as species richness. However, effective conservation actions need to balance the contrasting habitat preferences of different wildlife species, necessitating a focus on population-level effects in working landscapes. We assessed associations between LWFs and abundance for 45 bird species within an intensive agroecosystem in eastern Ontario, Canada. We used distance- and removal-sampling methods across 4 years (2016-2019) to estimate local bird abundance in habitats representing a range of LWF densities. We also predicted abundance across a subset of the study region with and without LWFs to understand their contribution to regional population density. Associations between local bird abundance and LWFs were variable among species, but overall community effects were clearly positive, particularly for forest and shrubland species. At the site level, 20/45 species (44%) had higher densities associated with greater LWF presence on average, compared to 5/45 (11%) with negative associations. At the regional scale, LWFs had predicted benefits on total abundance for 31 species (69%), contributing to an estimated 20% increase on average. Positive effects were most pronounced in areas with greater agricultural land use (primarily field crops), suggesting LWFs may provide crucial habitat in heavily modified landscapes but have little to no additional benefit for the avian community in areas with greater existing heterogeneity and habitat retention. Species that responded negatively tended to be at risk with strong habitat preferences for intact forests or large, open grasslands and, thus, greater sensitivity to potential edge effects. With rapidly declining songbird populations and a global need for food security, conservation strategies that amplify biodiversity and enhance agricultural productivity through ecosystem services such as pest control, pollination, and water regulation are vital. We demonstrate the benefits of habitat heterogeneity in agroecosystems on songbird densities and highlight the need to integrate local and landscape-level assessments in conservation planning. An effective, balanced strategy includes concentrating LWFs in areas of extensive arable crops, with habitat retention patches where possible, while maintaining heterogeneity through mixtures of natural habitats and pastoral farming in less intensive regions.

Les caractéristiques d'emboisement linéaires (CEL), tels que les haies en bordure de champs, fournissent un habitat à la faune et à la flore et favorisent la biodiversité dans les agroécosystèmes. Les évaluations des caractéristiques d'emboisement linéaires se concentrent généralement sur des indices au niveau de la communauté, tels que la richesse des espèces. Cependant, pour être efficaces, les actions de conservation doivent équilibrer les préférences variables des différentes espèces sauvages en matière d'habitat, ce qui nécessite de se concentrer sur les effets au niveau de la population dans les paysages exploités. Nous avons évalué les associations entre les CEL et l'abondance de 45 espèces d'oiseaux dans un agroécosystème intensif de l'est de l'Ontario, au Canada. Nous avons utilisé des méthodes d'échantillonnage par distance et par enlèvement sur quatre ans (2016­2019) pour estimer l'abondance locale des oiseaux dans des habitats représentant une gamme de densités de CEL. Nous avons également prédit l'abondance dans un sous­ensemble de la région étudiée avec et sans CEL pour comprendre leur contribution à la densité de la population régionale. Les associations entre l'abondance des oiseaux locaux et les CEL étaient variables d'une espèce à l'autre, mais les effets globaux sur les communautés étaient clairement positifs, en particulier pour les espèces des forêts et des zones arbustives. Au niveau du site, 20/45 espèces (44%) avaient des densités plus élevées associées à une plus grande présence de CEL en moyenne, contre 5/45 (11%) avec des associations négatives. À l'échelle régionale, les CEL ont eu des effets bénéfiques sur l'abondance totale de 31 espèces (69%), contribuant à une augmentation estimée à 20% en moyenne. Les effets positifs étaient plus prononcés dans les zones où l'utilisation des terres agricoles était plus importante (principalement les grandes cultures), ce qui suggère que les CEL peuvent fournir un habitat crucial dans les paysages fortement modifiés, mais qu'elles ont peu ou pas d'avantages supplémentaires pour la communauté aviaire dans les zones où l'hétérogénéité existante et la conservation de l'habitat sont plus importantes. Les espèces qui ont répondu négativement avaient tendance à être en danger, avec de fortes préférences d'habitat pour les forêts intactes ou les grandes prairies ouvertes, et donc une plus grande sensibilité aux effets de lisière potentiels. Avec le déclin rapide des populations d'oiseaux chanteurs et le besoin mondial de sécurité alimentaire, les stratégies de conservation qui amplifient la biodiversité et améliorent la productivité agricole grâce aux services écosystémiques tels que la lutte contre les ravageurs, la pollinisation et la régulation de l'eau sont vitales. Nous démontrons les avantages de l'hétérogénéité de l'habitat dans les agroécosystèmes sur les densités de passereaux et soulignons la nécessité d'intégrer les évaluations locales et au niveau du paysage dans la planification de la conservation. Une stratégie efficace et équilibrée consiste à concentrer les CEL dans les zones de cultures arables extensives, avec des parcelles de conservation de l'habitat là où c'est possible, tout en maintenant l'hétérogénéité grâce à des mélanges d'habitats naturels et à l'agriculture pastorale dans les régions moins intensives.

Disruption of Endosomal Sorting in Schwann Cells Leads to Defective Myelination and Endosomal Abnormalities Observed in Charcot-Marie-Tooth Disease.

Endosomal sorting plays a fundamental role in directing neural development. By altering the temporal and spatial distribution of membrane receptors, endosomes regulate signaling pathways that control the differentiation and function of neural cells. Several genes linked to inherited demyelinating peripheral neuropathies, known as Charcot-Marie-Tooth (CMT) disease, encode proteins that directly interact with components of the endosomal sorting complex required for transport (ESCRT). Our previous studies demonstrated that a point mutation in the ESCRT component hepatocyte growth-factor-regulated tyrosine kinase substrate (HGS), an endosomal scaffolding protein that identifies internalized cargo to be sorted by the endosome, causes a peripheral neuropathy in the neurodevelopmentally impaired teetering mice. Here, we constructed a Schwann cell-specific deletion of Hgs to determine the role of endosomal sorting during myelination. Inactivation of HGS in Schwann cells resulted in motor and sensory deficits, slowed nerve conduction velocities, delayed myelination and hypomyelinated axons, all of which occur in demyelinating forms of CMT. Consistent with a delay in Schwann cell maturation, HGS-deficient sciatic nerves displayed increased mRNA levels for several promyelinating genes and decreased mRNA levels for genes that serve as markers of myelinating Schwann cells. Loss of HGS also altered the abundance and activation of the ERBB2/3 receptors, which are essential for Schwann cell development. We therefore hypothesize that HGS plays a critical role in endosomal sorting of the ERBB2/3 receptors during Schwann cell maturation, which further implicates endosomal dysfunction in inherited peripheral neuropathies.SIGNIFICANCE STATEMENT Schwann cells myelinate peripheral axons, and defects in Schwann cell function cause inherited demyelinating peripheral neuropathies known as CMT. Although many CMT-linked mutations are in genes that encode putative endosomal proteins, little is known about the requirements of endosomal sorting during myelination. In this study, we demonstrate that loss of HGS disrupts the endosomal sorting pathway in Schwann cells, resulting in hypomyelination, aberrant myelin sheaths, and impairment of the ERBB2/3 receptor pathway. These findings suggest that defective endosomal trafficking of internalized cell surface receptors may be a common mechanism contributing to demyelinating CMT.

Shared genetics and causal relationships between migraine and thyroid function traits.

BACKGROUND: Epidemiological studies have reported a comorbid relationship between migraine and thyroid dysfunction. METHODS: We investigated the genetic relationship between migraine and thyroid function traits using genome-wide association study (GWAS) data. RESULTS: We found a significant genetic correlation (rg) with migraine for hypothyroidism (rg = 0.0608), secondary hypothyroidism (rg = 0.195), free thyroxine (fT4) (rg = 0.0772), and hyperthyroidism (rg = -0.1046), but not thyroid stimulating hormone (TSH). Pairwise GWAS analysis revealed two shared loci with TSH and 11 shared loci with fT4. Cross-trait GWAS meta-analysis of migraine identified novel genome-wide significant loci: 17 with hypothyroidism, one with hyperthyroidism, five with secondary hypothyroidism, eight with TSH, and 15 with fT4. Of the genes at these loci, six (RERE, TGFB2, APLF, SLC9B1, SGTB, BTBD16; migraine + hypothyroidism), three (GADD45A, PFDN1, RSPH6A; migraine + TSH), and three (SSBP3, BRD3, TEF; migraine + fT4) were significant in our gene-based analysis (pFisher's combined P-value < 2.04 × 10-6). In addition, causal analyses suggested a negative causal relationship between migraine and hyperthyroidism (p = 8.90 × 10-3) and a positive causal relationship between migraine and secondary hypothyroidism (p = 1.30 × 10-3). CONCLUSION: These findings provide strong evidence for genetic correlation and suggest complex causal relationships between migraine and thyroid traits.

Protected area planning to conserve biodiversity in an uncertain future.

Protected areas are a key instrument for conservation. Despite this, they are vulnerable to risks associated with weak governance, land-use intensification, and climate change. We used a novel hierarchical optimization approach to identify priority areas for expanding the global protected area system that explicitly accounted for such risks while maximizing protection of all known terrestrial vertebrate species. To incorporate risk categories, we built on the minimum set problem, where the objective is to reach species distribution protection targets while accounting for 1 constraint, such as land cost or area. We expanded this approach to include multiple objectives accounting for risk in the problem formulation by treating each risk layer as a separate objective in the problem formulation. Reducing exposure to these risks required expanding the area of the global protected area system by 1.6% while still meeting conservation targets. Incorporating risks from weak governance drove the greatest changes in spatial priorities for protection, and incorporating risks from climate change required the largest increase (2.52%) in global protected area. Conserving wide-ranging species required countries with relatively strong governance to protect more land when they bordered nations with comparatively weak governance. Our results underscore the need for cross-jurisdictional coordination and demonstrate how risk can be efficiently incorporated into conservation planning. Planeación de las áreas protegidas para conservar la biodiversidad en un futuro incierto.

Aunque las áreas protegidas son un instrumento clave para la conservación, no dejan de ser vulnerables a los riesgos asociados a una gestión pobre, la intensificación del uso de suelo y al cambio climático. Usamos una estrategia novedosa de optimización jerárquica para identificar las áreas prioritarias para la expansión del sistema global de áreas protegidas. La estrategia consideró de manera explícita los riesgos mencionados y también maximizó la protección de todas las especies conocidas de vertebrados terrestres. Para incorporar a las categorías de riesgo partimos del mínimo problema establecido, en donde el objetivo es lograr los objetivos de protección de la distribución de especies mientras se considera sólo una restricción, como el costo o área del suelo. Expandimos esta estrategia para que incluyera varios objetivos que consideraran el riesgo desde la formulación del problema mediante el manejo de cada nivel de riesgo como un objetivo aparte durante la formulación del problema. La reducción de la exposición a estos riesgos requirió que se expandiera el área total del sistema global de áreas protegidas en un 1.6% y así todavía cumplir con los objetivos de conservación. La incorporación de riesgos a partir de una gestión pobre fue el principal impulsor de cambios en las prioridades espaciales para la protección, mientras que la incorporación de riesgos a partir del cambio climático requirió el mayor incremento (2.52%) del área protegida a nivel mundial. La conservación de especies con distribución amplia requirió que los países con una gestión relativamente fuerte protegieran más suelo al tener fronteras con países con una gestión pobre en comparación son la suya. Nuestros resultados destacan la necesidad de una coordinación entre jurisdicciones y demuestran cómo puede incorporarse el riesgo de manera exitosa a la planeación de la conservación.

Renal physiology and kidney injury during intense (CrossFit®) exercise.

BACKGROUND: High-intensity training (HIT) programmes are popularly associated with improvements in exercise efficiency and body composition, although, at extremes, have been accompanied by concerns of secondary rhabdomyolysis and severe acute kidney injury (AKI). Beyond the anecdotal, robust literature on the physiological impact of HIT on renal function is currently limited. AIMS: To investigate the acute impact of high-intensity (CrossFit®) training on renal function, and to evaluate the incidence of AKI by Risk, Injury, Failure, Loss, End-stage renal disease (RIFLE) criteria following CrossFit® training. METHODS: Clinical and biochemical parameters were measured in 22 healthy adults before and after two CrossFit® workouts: 'Fran' (12 men, 10 women) and 'Macho Man' (9 men, 4 women). RESULTS: Serum creatinine increased by 16 ± 10 µmol/L following Fran and 18 ± 12 µmol/L following Macho Man (P < 0.05). Cystatin C did not change significantly following Fran and increased by 0.06 ± 0.06 mg/L (P < 0.05) following Macho Man. AKI, as defined by RIFLE 'Risk' criteria, was observed in 5/22 (23%) participants following Fran and 5/13 (38%) participants following Macho Man. Urinary albumin/creatinine ratio rose by 18.7 ± 18.3 and 5.2 ± 6.0 mg/mmol following Fran and Macho Man respectively off non-albuminuric baselines (P < 0.05). CONCLUSIONS: Intense (CrossFit®) exercise is associated with significant metabolic demands and alterations in parameters of renal physiology and function. The observed rise in both conventional and novel biomarkers of renal function following the workout Macho Man specifically might indicate a degree of transient subclinical functional impairment with CrossFit®-type training.

Quantifying phenology and migratory behaviours of hummingbirds using single-site dynamics and mark-detection analyses.

Nuanced understanding of seasonal movements of partially migratory birds is paramount to species and habitat conservation. Using nascent statistical methods, we identified migratory strategies of birds outfitted with radio-frequency identification (RFID) tags detected at RFID feeders in two sites in California, USA. We quantified proportions of migrants and residents and the seasonal phenology for each movement strategy in Allen's and Anna's hummingbirds; we also validated our methodology by fitting our model to obligate migratory black-chinned hummingbirds. Allen's and Anna's hummingbirds exhibited characteristics of facultative migratory behaviour. We also quantified apparent annual survival for each migratory strategy and found that residents had significantly higher probabilities of apparent survival. Low survival estimates for migrants suggest that a high proportion of birds in the migrant group permanently emigrated from our study sites. Considered together, our analyses suggest that hummingbirds in both northern and southern California sites partake in diverse and highly plastic migratory behaviours. Our assessment elucidates the dynamics underlying idiosyncratic migratory behaviours of two species of hummingbirds, in addition to describing a framework for similar assessments of migratory behaviours using the multi-state open robust design with state uncertainty model and single-site dynamics.

Diabetes and restenosis.

Restenosis, defined as the re-narrowing of an arterial lumen after revascularization, represents an increasingly important issue in clinical practice. Indeed, as the number of stent placements has risen to an estimate that exceeds 3 million annually worldwide, revascularization procedures have become much more common. Several investigators have demonstrated that vessels in patients with diabetes mellitus have an increased risk restenosis. Here we present a systematic overview of the effects of diabetes on in-stent restenosis. Current classification and updated epidemiology of restenosis are discussed, alongside the main mechanisms underlying the pathophysiology of this event. Then, we summarize the clinical presentation of restenosis, emphasizing the importance of glycemic control in diabetic patients. Indeed, in diabetic patients who underwent revascularization procedures a proper glycemic control remains imperative.

Community modeling reveals the importance of elevation and land cover in shaping migratory bird abundance in the Andes.

The tropical Andes are characterized by extreme topographic and climatic complexity, which has likely contributed to their outstanding current species diversity, composed of many range-restricted species. However, little is known about how the distribution and abundance of highly mobile organisms, like long-distance migratory birds, varies across different land covers, elevations, and climatic conditions within the Andes. We conducted 1,606 distance-sampling point counts across the Colombian Andes, spanning elevations from 253 to 3,708 m, a range of precipitation regimes and representative land covers. We then employed a novel application of a multispecies hierarchical modeling approach to evaluate how elevation, local land cover, aboveground woody biomass, cloud cover, precipitation, and seasonality in precipitation shape the abundance of the migratory land bird community in the Andes. We detected 1,824 individuals of 29 species of migratory land birds, six of which were considered incidental in our study region. We modeled the abundance of the remaining 23 species, while considering observer and time of day effects on detectability. We found that both elevation and land cover had an overriding influence on the abundance of migratory species across the Andes, with strong evidence for a mid-elevation peak in abundance, and species-specific responses to both variables. As a community, migratory birds had the highest mean abundance in shade coffee plantations, secondary forest, and mature forest. Aboveground woody biomass did not affect the abundance of all species as a group, but a few showed strong responses to this variable. Contrary to predictions of a positive correlation between abundance and precipitation, we found no evidence for community-level responses to precipitation, aside for a weak tendency for birds to select areas with intermediate levels of precipitation. This novel use of a multispecies model sheds new light on the mechanisms shaping the winter distribution of migratory birds and highlights the importance of elevation and land cover types over climatic variables in the context of the Colombian Andes.

Decreased Immunoglobulin G Core Fucosylation, A Player in Antibody-dependent Cell-mediated Cytotoxicity, is Associated with Autoimmune Thyroid Diseases.

Autoimmune thyroid diseases (AITD) are the most common group of autoimmune diseases, associated with lymphocyte infiltration and the production of thyroid autoantibodies, like thyroid peroxidase antibodies (TPOAb), in the thyroid gland. Immunoglobulins and cell-surface receptors are glycoproteins with distinctive glycosylation patterns that play a structural role in maintaining and modulating their functions. We investigated associations of total circulating IgG and peripheral blood mononuclear cells glycosylation with AITD and the influence of genetic background in a case-control study with several independent cohorts and over 3,000 individuals in total. The study revealed an inverse association of IgG core fucosylation with TPOAb and AITD, as well as decreased peripheral blood mononuclear cells antennary α1,2 fucosylation in AITD, but no shared genetic variance between AITD and glycosylation. These data suggest that the decreased level of IgG core fucosylation is a risk factor for AITD that promotes antibody-dependent cell-mediated cytotoxicity previously associated with TPOAb levels.

Frequency and risk factors for cognitive dysfunction in peritoneal dialysis patients.

OBJECTIVE: There is limited data on cognition in patients undergoing peritoneal dialysis (PD). We assessed prevalence and associated risk factors of neurocognitive impairment (NCI) in PD patients. DESIGN AND METHODS: A cross-sectional cohort study of 149 PD patients at a single centre between 2016 and 2020 who underwent neurocognitive screening at defined intervals by Addenbrooke's Cognitive Examination - Revised (ACE-R) with incorporated Mini-Mental State Examination (MMSE). Paired-sample t-test was used to compare cognitive performance to the general population and compare cohorts for dichotomous risk factors. Residual renal function (RRF) and clearance kinetics were evaluated using local regression models. Sub-analysis was performed in patients with cerebrovascular disease (CVD). RESULTS: Patients on PD performed poorly in ACE-R screening compared to population norms, with discrepancy in all cognitive domains. In patients without CVD, attention and language domains were comparable to norms. The MMSE detected cognitive impairment in 2% of studied patients, significantly fewer than when the ACE-R was applied (32%). Age, gender, diabetic status and depression were associated with lower neurocognitive screening performance (p < .05). Dialysis vintage beyond 12 months conferred poorer cognitive performance. RRF correlated with cognitive performance. CONCLUSION: Patients on PD have higher prevalence of NCI than the general population, primarily with impairments in memory, fluency and visuospatial reasoning. CVD confers poorer performance in attention and language domains. The MMSE is ineffective in detecting subtle NCI in this population compared with ACE-R. Risk factors for NCI include age, gender, diabetic status, depression and vintage beyond 12 months. Protective factors include RRF.

Correction: Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria.

[This corrects the article DOI: 10.1371/journal.pgen.1007813.].

Examination of genetic and pharmacological tools to study the proteasomal deubiquitinating enzyme ubiquitin-specific protease 14 in the nervous system.

Strategies for enhancing protein degradation have been proposed for treating neurological diseases associated with a decline in proteasome activity. A proteasomal deubiquitinating enzyme that controls substrate entry into proteasomes, ubiquitin-specific protease 14 (USP14), is an attractive candidate for therapies that modulate proteasome activity. This report tests the validity of genetic and pharmacological tools to study USP14's role in regulating protein abundance. Although previous studies implicated USP14 in the degradation of microtubule associate protein tau, tar DNA binding protein, and prion protein, the levels of these proteins were similar in our neurons cultured from wild type and USP14-deficient mice. Neither loss nor over-expression of USP14 affected the levels of these proteins in mice, implying that modifying the amount of USP14 is not sufficient to alter their steady-state levels. However, neuronal over-expression of a catalytic mutant of USP14 showed that manipulating USP14's ubiquitin-hydrolase activity altered the levels of specific proteins in vivo. Although pharmacological inhibitors of USP14's ubiquitin-hydrolase activity reduced microtubule associate protein tau, tar DNA binding protein, and prion protein in culture, the effect was similar in wild type and USP14-deficient neurons, thus impacting their use for specifically evaluating USP14 in a therapeutic manner. While examining how targeting USP14 may affect other proteins in vivo, this report showed that fatty acid synthase, v-rel reticuloendotheliosis viral oncogene homolog, CTNNB1, and synaptosome associated protein 23 are reduced in USP14-deficient mice; however, loss of USP14 differentially altered the levels of these proteins in the liver and brain. As such, it is critical to more thoroughly examine how inhibiting USP14 alters protein abundance to determine if targeting USP14 will be a beneficial strategy for treating neurodegenerative diseases.

Human density is associated with the increased prevalence of a generalist zoonotic parasite in mammalian wildlife.

Macroecological approaches can provide valuable insight into the epidemiology of globally distributed, multi-host pathogens. Toxoplasma gondii is a zoonotic protozoan that infects any warm-blooded animal, including humans, in almost every ecosystem worldwide. There is substantial geographical variation in T. gondii prevalence in wildlife populations and the mechanisms driving this variation are poorly understood. We implemented Bayesian phylogenetic mixed models to determine the association between species' ecology, phylogeny and climatic and anthropogenic factors on T. gondii prevalence. Toxoplasma gondii prevalence data were compiled for free-ranging wild mammal species from 202 published studies, encompassing 45 079 individuals from 54 taxonomic families and 238 species. We found that T. gondii prevalence was positively associated with human population density and warmer temperatures at the sampling location. Terrestrial species had a lower overall prevalence, but there were no consistent patterns between trophic level and prevalence. The relationship between human density and T. gondii prevalence is probably mediated by higher domestic cat abundance and landscape degradation leading to increased environmental oocyst contamination. Landscape restoration and limiting free-roaming in domestic cats could synergistically increase the resiliency of wildlife populations and reduce wildlife and human infection risks from one of the world's most common parasitic infections.

HRP2 and HRP3 cross-reactivity and implications for HRP2-based RDT use in regions with Plasmodium falciparum hrp2 gene deletions.

BACKGROUND: The Plasmodium falciparum antigen histidine rich protein 2 (HRP2) is a preferred target for malaria rapid diagnostic tests (RDTs) because of its abundant production by the parasite and thermal stability. As a result, a majority of RDTs procured globally target this antigen. However, previous reports from South America and recent reports from sub-Saharan Africa and Asia indicate that certain P. falciparum parasites have deletions of the gene coding for HRP2. The HRP2 antigen is paralogous to another P. falciparum antigen HRP3 and some antibodies to HRP2 cross-react with HRP3. Multiple parasites have been described with deletions of one or both hrp2 and hrp3 genes. It is unclear how the various combinations of hrp2 and hrp3 deletion genotypes affect clinical sensitivity of HRP2-based RDTs. METHODS: Cross-reactivity between HRP2 and HRP3 was tested on malaria RDTs using culture-adapted P. falciparum parasites with both hrp2 and hrp3 intact or with one or both genes deleted. Ten-fold serial dilutions of four culture-adapted P. falciparum parasites [3D7 (hrp2+/hrp3+), Dd2 (hrp2-/hrp3+), HB3 (hrp2+/hrp3-) and 3BD5 (hrp2-/hrp3-)] ranging from 100,000 to 0.01 parasites/µL were prepared. HRP2, Plasmodium lactate dehydrogenase (pLDH) and aldolase concentrations were determined for the diluted samples using a multiplex bead assay. The samples were subsequently tested on three RDT products designed to detect P. falciparum by HRP2 alone or in combination with pLDH. RESULTS: At parasite densities of approximately 1000 parasites/µL, parasites that expressed either hrp2 or hrp3 were detected by all three RDTs. Multiplex based antigen measurement using HRP2- conjugated beads demonstrated higher antigen concentration when both hrp2 and hrp3 genes were intact (3D7 parasites, 47.9 ng/ml) compared to HB3 (3.02 ng/mL) and Dd2 (0.20 ng/mL) strains that had one gene deleted. 3D7 at 10 parasites/µL (0.45 ng/mL) was reactive on all three RDT products whereas none of the other parasites were reactive at that density. CONCLUSIONS: Above a certain antigen threshold, HRP3 cross-reactivity on HRP2-based RDTs is sufficient to mask the effects of deletions of hrp2 only. Studies of hrp2 deletion and its effects on HRP2-based RDTs must be studied alongside hrp3 deletions and include clinical sample reactivity on HRP2-based tests.

Purification of native histidine-rich protein 2 (nHRP2) from Plasmodium falciparum culture supernatant, infected RBCs, and parasite lysate.

BACKGROUND: Despite the widespread use of histidine-rich protein 2 (HRP2)-based rapid diagnostic tests (RDTs), purified native HRP2 antigen is not standardly used in research applications or assessment of RDTs used in the field. METHODS: This report describes the purification of native HRP2 (nHRP2) from the HB3 Plasmodium falciparum culture strain. As this culture strain lacks pfhrp3 from its genome, it is an excellent source of HRP2 protein only and does not produce the closely-related HRP3. The nHRP2 protein was isolated from culture supernatant, infected red blood cells (iRBCs), and whole parasite lysate using nickel-metal chelate chromatography. Biochemical characterization of nHRP2 from HB3 culture was conducted by SDS-PAGE and western blotting, and nHRP2 was assayed by RDT, ELISA, and bead-based immunoassay. RESULTS: Purified nHRP2 was identified by SDS-PAGE and western blot as a - 60 kDa protein that bound anti-HRP-2 monoclonal antibodies. Mouse anti-HRP2 monoclonal antibody was found to produce high optical density readings between dilutions of 1:100 and 1:3,200 by ELISA with assay signal observed up to a 1:200,000 dilution. nHRP2 yield from HB3 culture by bead-based immunoassay revealed that both culture supernatant and iRBC lysate were practical sources of large quantities of this antigen, producing a total yield of 292.4 µg of nHRP2 from two pooled culture preparations. Assessment of nHRP2 recognition by RDTs revealed that Carestart Pf HRP2 and HRP2/pLDH RDTs detected purified nHRP2 when applied at concentrations between 20.6 and 2060 ng/mL, performing within a log-fold dilution of commercially-available recombinant HRP2. The band intensity observed for the nHRP2 dilutions was equivalent to that observed for P. falciparum culture strain dilutions of 3D7 and US06 F Nigeria XII between 12.5 and 1000 parasites/µL. CONCLUSIONS: Purified nHRP2 could be a valuable reagent for laboratory applications as well as assessment of new and existing RDTs prior to their use in clinical settings. These results establish that it is possible to extract microgram quantities of the native HRP2 antigen from HB3 culture and that this purified protein is well recognized by existing monoclonal antibody lines and RDTs.

Revision of the Australian guidelines to reduce health risks from drinking alcohol.

INTRODUCTION: The Australian guidelines to reduce health risks from drinking alcohol were released in 2020 by the National Health and Medical Research Council. Based on the latest evidence, the guidelines provide advice on how to keep the risk of harm from alcohol low. They refer to an Australian standard drink (10 g ethanol). RECOMMENDATIONS: •Guideline 1: To reduce the risk of harm from alcohol-related disease or injury, healthy men and women should drink no more than ten standard drinks a week and no more than four standard drinks on any one day. The less you drink, the lower your risk of harm from alcohol. •Guideline 2: To reduce the risk of injury and other harms to health, children and people under 18 years of age should not drink alcohol. •Guideline 3: To prevent harm from alcohol to their unborn child, women who are pregnant or planning a pregnancy should not drink alcohol. For women who are breastfeeding, not drinking alcohol is safest for their baby. CHANGES AS RESULT OF THE GUIDELINE: The recommended limit for healthy adults changed from two standard drinks per day (effectively 14 per week) to ten per week. The new guideline states that the less you drink, the lower your risk of harm from alcohol. The recommended maximum on any one day remains four drinks (clarified from previously "per drinking occasion"). Guidance is clearer for pregnancy and breastfeeding, and for people aged less than 18 years, recommending not drinking.