Abstract
Sex differences in the human brain are of interest for many reasons: for example, there are sex differences in the observed prevalence of psychiatric disorders and in some psychological ...traits that brain differences might help to explain. We report the largest single-sample study of structural and functional sex differences in the human brain (2750 female, 2466 male participants; mean age 61.7 years, range 44-77 years). Males had higher raw volumes, raw surface areas, and white matter fractional anisotropy; females had higher raw cortical thickness and higher white matter tract complexity. There was considerable distributional overlap between the sexes. Subregional differences were not fully attributable to differences in total volume, total surface area, mean cortical thickness, or height. There was generally greater male variance across the raw structural measures. Functional connectome organization showed stronger connectivity for males in unimodal sensorimotor cortices, and stronger connectivity for females in the default mode network. This large-scale study provides a foundation for attempts to understand the causes and consequences of sex differences in adult brain structure and function.
Polybrominated diphenyl ethers (PBDEs) were measured in air (using PUF disk passive samplers) and soil samples taken at approximately monthly intervals over 1 year at 10 locations on a transect ...across the West Midlands of the UK. Concentrations in air are consistent with those detected elsewhere in Europe and the Great Lakes basin. Concentrations in soil fall within the range reported for rural woodland and grassland soils in the UK and Norway. In both air and soil, concentrations clearly decrease with increasing distance from the city center, supporting the existence of an urban "pulse", indicating the West Midlands conurbation to be a source of PBDEs to the wider environment. Examination of seasonal trends revealed no evidence of a "spring pulse" in concentrations in air, with no summer peak in concentrations in air observed for 70% of sites. The PBDE congener pattern in air differs from that in soil, with ratios of congeners 47:99 higher in air than in soil. It is hypothesized that PBDEs volatilize from treated products indoors, before ventilating outdoors, where congener 99 undergoes preferential atmospheric deposition and accumulation in soil.
γδ T cells are considered to be innate-like lymphocytes that respond rapidly to stress without clonal selection and differentiation. Here we use next-generation sequencing to probe how this paradigm ...relates to human Vδ2
T cells, implicated in responses to viral infection and cancer. The prevalent Vδ1 T cell receptor (TCR) repertoire is private and initially unfocused in cord blood, typically becoming strongly focused on a few high-frequency clonotypes by adulthood. Clonal expansions have differentiated from a naive to effector phenotype associated with CD27 downregulation, retaining proliferative capacity and TCR sensitivity, displaying increased cytotoxic markers and altered homing capabilities, and remaining relatively stable over time. Contrastingly, Vδ2
T cells express semi-invariant TCRs, which are present at birth and shared between individuals. Human Vδ1
T cells have therefore evolved a distinct biology from the Vδ2
subset, involving a central, personalized role for the γδ TCR in directing a highly adaptive yet unconventional form of immune surveillance.
Vδ2
T cells form the predominant human γδ T-cell population in peripheral blood and mediate T-cell receptor (TCR)-dependent anti-microbial and anti-tumour immunity. Here we show that the Vδ2
...compartment comprises both innate-like and adaptive subsets. Vγ9
Vδ2
T cells display semi-invariant TCR repertoires, featuring public Vγ9 TCR sequences equivalent in cord and adult blood. By contrast, we also identify a separate, Vγ9
Vδ2
T-cell subset that typically has a CD27
CCR7
CD28
IL-7Rα
naive-like phenotype and a diverse TCR repertoire, however in response to viral infection, undergoes clonal expansion and differentiation to a CD27
CD45RA
CX
CR1
granzymeA/B
effector phenotype. Consistent with a function in solid tissue immunosurveillance, we detect human intrahepatic Vγ9
Vδ2
T cells featuring dominant clonal expansions and an effector phenotype. These findings redefine human γδ T-cell subsets by delineating the Vδ2
T-cell compartment into innate-like (Vγ9
) and adaptive (Vγ9
) subsets, which have distinct functions in microbial immunosurveillance.
Mucosal-Associated Invariant T (MAIT) cells are innate-like T cells characterised by the invariant TCR-chain, Vα7.2-Jα33, and are restricted by MR1, which presents bacterial vitamin B metabolites. ...They are important for antibacterial immunity at mucosal sites; however, detailed characteristics of liver-infiltrating MAIT (LI-MAIT) and their role in biliary immune surveillance remain unexplored.
The phenotype and intrahepatic localisation of human LI-MAIT cells was examined in diseased and normal livers. MAIT cell activation in response to E. coli-exposed macrophages, biliary epithelial cells (BEC) and liver B cells was assessed with/without anti-MR1.
Intrahepatic MAIT cells predominantly localised to bile ducts in the portal tracts. Consistent with this distribution, they expressed biliary tropic chemokine receptors CCR6, CXCR6, and integrin αEβ7. LI-MAIT cells were also present in the hepatic sinusoids and possessed tissue-homing chemokine receptor CXCR3 and integrins LFA-1 and VLA-4, suggesting their recruitment via hepatic sinusoids. LI-MAIT cells were enriched in the parenchyma of acute liver failure livers compared to chronic diseased livers. LI-MAIT cells had an activated, effector memory phenotype, expressed α4β7 and receptors for IL-12, IL-18, and IL-23. Importantly, in response to E. coli-exposed macrophages, liver B cells and BEC, MAIT cells upregulated IFN-γ and CD40 Ligand and degranulated in an MR1-dependent, cytokine-independent manner. In addition, diseased liver MAIT cells expressed T-bet and RORγt and the cytokines IFN-γ, TNF-α, and IL-17.
Our findings provide the first evidence of an immune surveillance effector response for MAIT cells towards BEC in human liver; thus they could be manipulated for treatment of biliary disease in the future.
Concentrations and chiral signatures of polychlorinated biphenyls (PCBs) were measured in outdoor air (using polyurethane foam (PUF)--disk passive samplers) and surface soil samples taken at ...approximately monthly intervals over 1 year at 10 locations on a rural-urban transect across the West Midlands of the U.K. In both air and soil, concentrations clearly decrease with increasing distance from the city center, supporting the existence of an urban "pulse", that indicate the West Midlands conurbation to be a source of PCBs to the wider environment. Concentrations of PCBs in outdoor air samples in this study are well below those reported previously for indoor air in the West Midlands. This, combined with comparison of chiral signatures in outdoor air and soil with those in samples of indoor air taken in the West Midlands, suggest strongly that the principal contemporary source of PCBs in this conurbation is ventilation of indoor air and not volatilization from soil. Future reductions in PCB concentrations in outdoor air and ultimately human exposure appear best achieved by action to remove remaining sources of PCBs from existing structures.
Avian malaria caused by
species is a known cause of mortality in avifauna worldwide, however reports within New Zealand kiwi (
spp.) are scant. Postmortem reports from kiwi were obtained from the ...Massey University/Te Kunenga ki Pūrehuroa School of Veterinary Science Pathology Register from August 2010-August 2020. Gross lesions were described from postmortem reports, and archived H.E.-stained slides used for histological assessment. Nested PCR testing was performed on formalin-fixed paraffin-embedded tissue samples to assess the presence of
spp. and
DNA and cases with a PCR-positive result were sequenced to determine the lineage involved. Of 1005 postmortem reports, 23 cases of confirmed or suspected avian malaria were included in this study. The most consistent gross lesions included splenomegaly, hepatomegaly, and interstitial pneumonia with oedema. Histological lesions were characterised by severe interstitial pneumonia, pulmonary oedema, interstitial myocarditis, hepatic sinusoidal congestion and hypercellularity, and splenic macrophage hyperplasia and hyperaemia/congestion with numerous haemosiderophages. Cytoplasmic meronts were consistently found within endothelial cells of a variety of tissues, and within tissue macrophages of the liver, lung and spleen. A diagnosis of avian malaria was confirmed via PCR testing in 13 cases, with sequencing revealing
(LINN1) and
(GRW6) as the species involved. This is the largest case series describing the pathology of avian malaria as a cause of mortality in endemic New Zealand avifauna.
•Individualized psychosis risk predictions could feasibly become a clinical reality.•Neuroimaging biomarkers play a central role in many risk prediction models.•Ethically relevant benefits include ...early intervention and risk factor avoidance.•Ethically relevant risks include stigma, unequal access, and machine learning bias.•Ethical analysis should proceed alongside scientific advances in psychosis prediction.
Risk prediction for psychosis has advanced to the stage at which it could feasibly become a clinical reality. Neuroimaging biomarkers play a central role in many risk prediction models. Using such models to predict the likelihood of transition to psychosis in individuals known to be at high risk has the potential to meaningfully improve outcomes, principally through facilitating early intervention. However, this compelling benefit must be evaluated in light of the broader ethical ramifications of this prospective development in clinical practice. This paper advances ethical discussion in the field in two ways: firstly, through in-depth consideration of the distinctive implications of the clinical application of predictive tools; and, secondly, by evaluating the manner in which newer predictive models incorporating neuroimaging alter the ethical landscape. We outline the current state of the science of predictive testing for psychosis, with a particular focus on emerging neuroimaging biomarkers. We then proceed to ethical analysis employing the four principles of biomedical ethics as a conceptual framework. We conclude with a call for scientific advancement to proceed in tandem with ethical consideration, informed by empirical study of the views of high risk individuals and their families. This collaborative approach will help ensure that predictive testing progresses in an ethically acceptable manner that minimizes potential adverse effects and maximizes meaningful benefits for those at high risk of psychosis.
There is no effective treatment for autoimmune biliary diseases. Therefore, understanding their immunopathology is crucial. The biliary epithelial cells (BEC), expressing TLR-4, are constantly ...exposed to gut microbes and bacterial wall LPS, and in settings of inflammation, the immune infiltrate is dense within the peribiliary region of human liver. By dual immunohistochemistry, we affirm human intrahepatic T cell infiltrate includes CCR6
CD4
and AhR
CD4
T cells with potential for plasticity to Th17 phenotype. Mechanistically, we demonstrate that Th1 and Th17 inflammatory cytokines and LPS enhance human primary BEC release of the CCR6 ligand CCL20 and BEC secretion of Th17-polarizing cytokines IL-6 and IL-1β. Cell culture assays with human BEC secretome showed that secretome polarizes CD4 T cells toward a Th17 phenotype and supports the survival of Th17 cells. BEC secretome did not promote Th1 cell generation. Additionally, we give evidence for a mutually beneficial feedback of the type 17 cell infiltrate on BEC, showing that treatment with type 17 cytokines increases BEC proliferation, as monitored by Ki67 and activation of JAK2-STAT3 signaling. This study identifies human BEC as active players in determining the nature of the intrahepatic immune microenvironment. In settings of inflammation and/or infection, biliary epithelium establishes a prominent peribiliary type 17 infiltrate via recruitment and retention and enhances polarization of intrahepatic CD4 cells toward Th17 cells via type 17 cytokines, and, reciprocally, Th17 cells promote BEC proliferation for biliary regeneration. Altogether, we provide new insight into cross-talk between Th17 lymphocytes and human primary biliary epithelium in biliary regenerative pathologies.
Albatrosses are among the world's most imperiled vertebrates, with 73% of species threatened with extinction. Ingestion of plastic is a well‐recognized threat among three North Pacific species, but ...lesser known in the southern hemisphere, where it is considered a minor threat. As plastic entering the ocean is increasing while albatross populations decline, the threat of ocean plastic to albatross populations may be underestimated. We present case studies of 107 beach‐cast albatrosses of twelve species, received by wildlife hospitals in Australia and New Zealand, and estimate plastic ingestion and mortality rates for albatrosses in the southern hemisphere. Ingested plastic was present in 5.6% of individuals, and the cause of death in half of these cases. We estimate ingestion of plastic may cause 3.4–17.5% of nearshore mortalities and is worth consideration as a substantial threat to albatross populations. We provide clinical findings and “checklist” methodologies for identifying potential cases of foreign‐body gastrointestinal obstruction. We suggest practical policy responses, empowering decision makers to reduce albatross mortality from anthropogenic sources.
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