Biology subjects

Delaney, A.

Publications and source records attributed to Delaney, A..

4 recordsLinked to original sources

bioRxiv2026

Sex Differences in Human Subcortical Anatomy are Robust and Replicable in Adulthood, Already Evident Prepubertally, and Aligned with Sex Chromosomal and Gonadal Influences

The existence and mechanistic bases of sex effects on human subcortical anatomy remain unclear. To address these gaps, we combined structural neuroimaging of sex differences in subcortical volume and shape across three independent cohorts (combined N=2,886) with neuroimaging maps of sex chromosomal and endocrine effects from three clinical cohorts (combined N=313, including sex chromosome aneuploidies and isolated gonadotropin-releasing hormone deficiency). We found that human subcortical anatomy shows focal sex differences of moderate-strong effect size during young adulthood (male-biased surface area overlying lateral/ventral putamen and pallidum, nucleus accumbens, ventral posterior complex of thalamus, anterior hippocampus, and medial and central nuclei of amygdala; female-biased surface area overlying caudate head, posterior/dorsal pallidum, mediodorsal, lateral dorsal, lateral geniculate, and medial geniculate nuclei of thalamus, posterior hippocampus, and basolateral and lateral nuclei of amygdala). These regional sex differences show strong within-sample reproducibility at modest sample sizes (N[≥]200) and are replicable in a fully independent mid-adulthood cohort. Adult subcortical sex differences are already evident in nascent form by pre/early puberty (age 9 years), and the same holds for cortical sex differences. Comparison with neuroimaging data from rare disorder cohorts reveals a statistically significant spatial and directional congruence of subcortical sex differences with the anatomical effects of X-chromosome dosage in the striatum and effects of testicular hormones in the amygdala. Our findings provide a reference map for the fine-grained spatial patterning of sex differences in adult subcortical shape, demonstrating its replicability, establishment before pubertal progression, and spatial concordance with potentially causal sex chromosomal and gonadal effects.

neuroscience↗

bioRxiv2025

Fractionation of sex differences in human cortical anatomy

Humans show reproducible sex differences in regional cortical volume (CV), but it remains unclear how these arise from underlying sex-biases in the two biologically dissociable determinants of CV: surface area (SA) and cortical thickness (CT). Moreover, limited access to experimental methods in humans has hindered direct studies of the causal drivers of regional sex differences in the human cortex, although rodent models have argued for both chromosomal and gonadal contributions to sex-biased mammalian cortical development. Here, we first use structural neuroimaging data in two independent human cohorts (combined N=1,754; 967 females) to quantify and spatially resolve the differential contributions of SA and CT to observed sex differences in CV. These dissociable facets of sex-biased cortical organization are highly reproducible and align with distinct functional networks and histo-molecular signatures. We then leverage complementary neuroimaging data in clinical case-control cohorts (combined N=313) featuring variations in X and Y chromosome dosage (sex chromosome aneuploidies) and testicular hormone production (isolated GnRH deficiency) to establish that regions of sex-biased CV, SA and CT in humans are enriched for congruent anatomical effects of X-chromosome dosage (e.g., primary sensory and insular cortices) and gonadal hormones (e.g. dorsomedial frontal and temporo-parietal-occipital regions). Taken together, these findings substantially advance both the breadth and granularity of our understanding regarding sex-biased cortical organization in humans - disambiguating sex effects on regional CV, SA and CT and nominating their potential genetic and endocrine causes.

neuroscience↗

bioRxiv2025

Palmitoleate Protects against Zika virus infection-induced Endoplasmic Reticulum Stress and Apoptosis in Neurons

Zika virus (ZIKV) infection during pregnancy is associated with the development of fetal complications such as microcephaly. We have recently demonstrated that palmitoleate protects against ZIKV-induced apoptosis in placental trophoblasts. In the present study, we hypothesize that palmitoleate prevents ZIKV infection-induced endoplasmic reticulum (ER) stress and apoptosis in neurons. Neurons were infected with 0.1-1 multiplicity of infection of recombinant MR766 or PRVABC59 strains of ZIKV for an hour followed by treatment of palmitoleate (100 {micro}M-200 {micro}M) for different post-infection time points. Apoptosis was measured by nuclear morphological changes, caspase 3/7 activity, and immunoblot analysis of pro-apoptotic mediators. Activation of ER stress markers and viral envelope levels were detected using qRT-PCR and immunoblot analysis. Infectious virus particles were measured by using plaque assay. ZIKV infection to neuronal cells showed increased levels of pro-apoptotic markers like cleaved-PARP, cleaved caspase-3, Bim, and Puma, whereas decreased levels of anti-apoptotic markers such as Mcl-1, Bcl-1, and Bcl-xL. Further, we observed activation of three arms of ER stress namely: inositol requiring enzyme 1 alpha (IRE1), protein kinase-like ER kinase (PERK), and activating transcription factor (ATF6) pathways with ZIKV infection. Treatment of palmitoleate dramatically decreased ZIKV infection-induced increase in percent apoptotic nuclei and caspase 3/7 activity. Further, treatment of palmitoleate decreased cleaved PARP and PUMA protein expressions. Treatment of palmitoleate reduced ZIKV-induced ER stress activation as evidenced by decreased levels of phosphorylated forms of IRE1 and eukaryotic initiation factor 2 alpha; decreased expressions of cleaved ATF6, spliced X-box associated protein 1 and C/EBP homologous protein compared to ZIKV infection alone. Further, treatment of palmitoleate attenuated ZIKV envelope levels and infectious titer in SH-SY5Y and primary fetal cortical neurons isolated from humanized STAT2 knockin mice. These data suggest that palmitoleate supplementation protects against ZIKV-induced neuronal ER stress, apoptosis and decreases Zika viral load thereby mitigates neuronal damage.

microbiology↗

bioRxiv2021

Protein and substrate flexibility contribute to enzymatic specificity in human and bacterial methionine adenosyltransferases

Protein conformational change can facilitate the binding of non-cognate substrates and underlie promiscuous activities. However, the contribution of substrate conformational dynamics to this process is comparatively poorly understood. Here we analyse human (hMAT2A) and Escherichia coli (eMAT) methionine adenosyltransferases that have identical active sites but different substrate specificity. In the promiscuous hMAT2A, non-cognate substrates bind in a stable conformation to allow catalysis. In contrast, non-cognate substrates rarely sample stable productive binding modes in eMAT owing to altered mobility in the enzyme active site. Different cellular concentrations of substrate likely drove the evolutionary divergence of substrate specificity in these orthologs. The observation of catalytic promiscuity in hMAT2A led to the detection of a new human metabolite, methyl thioguanosine, that is produced at elevated level in a cancer cell line. This work establishes that identical active sites can result in different substrate specificity owing to the effects of substrate and enzyme dynamics.

biochemistry↗