Biology subjects

Gilani, A.

Publications and source records attributed to Gilani, A..

5 recordsLinked to original sources

bioRxiv2024

C3aR1 on β cells enhances β cell function and survival

Pancreatic {beta} cell dysfunction is critical to the development of type 2 diabetes (T2D). We show that the complement receptor C3aR1 on {beta} cells plays an essential role in maintaining {beta} cell homeostasis, especially under the metabolic duress of obesity and T2D. Mice with {beta} cell specific deletion of C3ar1 have worse glucose tolerance, lower insulin levels, and decreased {beta} cell mass. Islets from {beta} cell specific C3ar1 knockout ({beta}-C3aR1 KO) mice demonstrate impaired insulin secretion. Disruption of C3ar1 on {beta} cells ablates the insulin secretory response to C3a, establishing a signaling axis between C3a and {beta} cell-derived C3aR1. Markers of {beta} cell identity were decreased while stress markers were increased in {beta}-C3aR1 KO mice. Islets from {beta}-C3aR1 KO also exhibit increased {beta} cell death to lipotoxicity. Finally, we show that C3AR1 is positively correlated with insulin secretion in human islets. These findings indicate that C3aR1 expression on {beta} cells is necessary to maintain optimal {beta} cell function and preserve {beta} cell mass in T2D.

physiology↗

bioRxiv2023

Determinants of cerebral blood flow and arterial transit time in healthy older adults

Cerebral blood flow (CBF) and arterial transit time (ATT), markers of brain vascular health, worsen with age. The primary aim of this cross-sectional study was to identify modifiable determinants of CBF and ATT in healthy older adults (n=78, aged 60-81 yrs). Associations between cardiorespiratory fitness and CBF or ATT were of particular interest as the impact of cardiorespiratory fitness is not clear in existing literature. Secondly, this study assessed whether CBF or ATT relate to cognitive function in older adults. Results from multiple linear regressions found higher BMI was associated with lower global CBF ({beta}=-0.35, P=0.008) and a longer global ATT ({beta}=0.30, P=0.017), global ATT lengthened with increasing age ({beta}=0.43, P=0.004), and higher cardiorespiratory fitness was associated with longer ATT in parietal ({beta}=0.44, P=0.004) and occipital ({beta}=0.45, P=0.003) regions. Global or regional CBF or ATT were not associated with processing speed, working memory, or attention. In conclusion, preventing excessive weight gain may help attenuate age-related declines in brain vascular health. ATT may be more sensitive to age-related decline than CBF, and therefore useful for early detection and management of cerebrovascular impairment. Finally, cardiorespiratory fitness appears to have little effect on CBF but may induce longer ATT in specific regions.

physiology↗

bioRxiv2023

Lifestyle and brain health determinants of word-finding failures in healthy ageing

Cognitive decline associated with healthy ageing is multifactorial: brain-based and lifestyle factors uniquely and jointly contribute to distinct neurocognitive trajectories of ageing. To evaluate existing models of neurocognitive ageing such as compensation, maintenance, or reserve, we explore how various known brain-based and cardiorespiratory fitness factors intersect to better understand cognitive decline. In a pre-registered study (https://osf.io/6fqg7), we tested 73 healthy older adults aged 60--81 (M = 65.51, SD = 4.94) and collected neuroimaging (functional, structural, and perfusion MRI), cardiorespiratory fitness, and cognitive data to investigate a prominent challenge for older adults: word-finding failures. fMRI signal was recorded while participants responded to a definition-based tip-of-the-tongue task, T1-weighted imaging estimated grey matter volume, and cerebral blood flow was indexed using multi-delay pseudo-continuous arterial spin labelling. Commonality analyses were used to analyse these multi-domain data (neuroimaging, cardiorespiratory fitness, language skills, demographic characteristics) and uncover associations between predictors in explaining age-related tip-of-the-tongue rates. Commonality analyses revealed that functional activation of language networks associated with tip-of-the-tongue states is in part linked with age and, interestingly, cardiorespiratory fitness: the combination of higher cardiorespiratory fitness and functional recruitment in some older adults offsets part of the age-related variance in tip-of-the-tongues. Moreover, age-associated atrophy and perfusion in regions other than those showing functional differences accounted for variance in tip-of-the-tongues. Our findings can be interpreted in the context of the classic models of neurocognitive ageing, suggesting compensation. Brain health indices in concordance with cardiorespiratory fitness can provide a more holistic explanation of individual differences in age-related cognitive decline. HighlightsO_LIWord-finding problems are linked to brain health and cardiorespiratory fitness (CRF) C_LIO_LIBrain activity linked to word-finding failures is modulated by CRF and age C_LIO_LIDistinct contribution of structure and perfusion also associated with word-finding C_LIO_LILinking brain and CRF factors provides better account of age-related cognitive decline C_LI

neuroscience↗

bioRxiv2022

Alternative Complement Pathway Regulates Thermogenic Fat Function via Adipsin and Adipocyte-derived C3aR1 in a Sex-dependent Fashion

Thermogenesis in beige/brown adipose tissues can be leveraged to combat metabolic disorders such as type 2 diabetes and obesity. The complement system plays pleiotropic roles in metabolic homeostasis and organismal energy balance with canonical effects on immune cells and non-canonical effects on non-immune cells. The adipsin/C3a/C3aR1 pathway stimulates insulin secretion and sustains pancreatic beta cell mass. However, its role in adipose thermogenesis has not been defined. Here, we show that Adipsin knockout mice exhibit increased energy expenditure and white adipose tissue (WAT) browning. C3a, a downstream product of adipsin, is generated from complement component 3 and decreases Ucp1 expression in subcutaneous adipocytes. In addition, adipocyte-specific C3aR1 knockout male mice show enhanced WAT thermogenesis and increased respiration. In stark contrast, adipocyte-specific C3aR1 knockout female mice display decreased brown fat thermogenesis and are cold intolerant. Female mice express lower levels of Adipsin in thermogenic adipocytes and adipose tissues than males. C3aR1 is also lower in female subcutaneous adipose tissue than males. Collectively, these results reveal sexual dimorphism in the adipsin/C3a/C3aR1 axis in regulating adipose thermogenesis. Our findings establish a newly discovered role of the alternative complement pathway in adipose thermogenesis and highlight sex-specific considerations in potential therapeutic targets for metabolic diseases.

cell biology↗

bioRxiv2020

Super elongation complex as a targetable dependency in diffuse midline glioma

Mutations in the histone 3 gene (H3K27M) are the eponymous drivers in diffuse intrinsic pontine gliomas (DIPGs) and other diffuse midline gliomas (DMGs), aggressive pediatric brain cancers for which no curative therapy currently exists. The salient molecular consequence of these recurrent oncohistones is a global loss of repressive H3K27me3 residues and broad epigenetic dysregulation. In order to identify specific, therapeutically targetable epigenetic dependencies within this disease context, we performed an shRNA screen targeting 408 genes classified as epigenetic/chromatin-associated molecules in patient-derived DMG cultures. This approach identified AFF4, the scaffold protein of the super elongation complex (SEC), as a previously-undescribed dependency in DMG. Interrogation of SEC function demonstrated a key role for maintaining DMG cell viability and clonogenic potential while promoting self-renewal of DMG tumor stem cells. Small-molecule inhibition of the SEC with the highly-specific, clinically relevant CDK9 inhibitors atuveciclib and AZD4573 restores regulatory RNA polymerase II pausing, promotes cellular differentiation, and leads to potent anti-tumor effect both in vitro and in patient-derived xenograft models. These studies present a biologic rationale for translational exploration of CDK9 inhibition as a promising therapeutic approach in a disease which currently has no effective medical therapies.

cancer biology↗