Biology subjects

Shahriar, S.

Publications and source records attributed to Shahriar, S..

4 recordsLinked to original sources

bioRxiv2023

Brain cell type specific proteomics approach to discover pathological mechanisms in the childhood CNS disorder mucolipidosis type IV

1 Mucolipidosis IV (MLIV) is an ultra-rare, recessively inherited lysosomal disorder resulting from inactivating mutations in MCOLN1, the gene encoding the lysosomal cation channel TRPML1. The disease primarily affects the central nervous system (CNS) and manifests in the first year with cognitive and motor developmental delay, followed by a gradual decline in neurological function across the second decade of life, blindness, and premature death in third or fourth decades. Brain pathology manifestations in MLIV are consistent with hypomyelinating leukodystrophy with brain iron accumulation. Presently, there are no approved or investigational therapies for MLIV, and pathogenic mechanisms remain largely unknown. The MLIV mouse model, Mcoln1-/- mice, recapitulates all major manifestations of the human disease. Here, to better understand the pathological mechanisms in the MLIV brain, we performed cell type specific LC-MS/MS proteomics analysis in the MLIV mouse model and reconstituted molecular signatures of the disease in either freshly isolated populations of neurons, astrocytes, oligodendrocytes, and neural stem cells, or whole tissue cortical homogenates from young adult symptomatic Mcoln1-/- mice. Our analysis confirmed on the molecular level major histopathological hallmarks of MLIV universally present in Mcoln1-/- tissue and brain cells, such as hypomyelination, lysosomal dysregulation, and impaired metabolism of lipids and polysaccharides. Importantly, pathway analysis in brain cells revealed mitochondria-related alterations in all Mcoln1-/- brain cells, except oligodendrocytes, that was not possible to resolve in whole tissue. We also report unique proteome signatures and dysregulated pathways for each brain cell population used in this study. These data shed new light on cell-intrinsic mechanisms of MLIV and provide new insights for biomarker discovery and validation to advance translational studies for this disease.

neuroscience↗

bioRxiv2022

Single-cell RNA sequencing implicates venous endothelial cells as a source of VEGF-mediated neo-angiogenesis in neuroinflammation

Histopathological studies of multiple sclerosis (MS), a demyelinating disease of the central nervous system (CNS), and its animal model, experimental autoimmune encephalomyelitis (EAE), have found newly formed leaky vessels in demyelinated acute and chronic plaques, in addition to blood-brain barrier (BBB) damage in existing vessels, that exacerbate disease pathology by increasing infiltration of immune cells. Which vessel subtypes and signaling pathways generate these aberrant vessels is poorly understood. Using single-cell RNA-sequencing and in vivo validation, we find that transcriptome signatures of neo-angiogenesis arise in venous endothelial cells in both acute and chronic EAE, and correlate with upregulation in VEGF-A signaling. These neo-angiogenic markers are also increased in acute and chronic MS lesions. Treatment with a VEGF-A blocking antibody diminishes neo-angiogenic transcriptomic signatures and vascular proliferation in vivo, but does not restore BBB function or ameliorate significantly EAE pathology. Therefore, anti-angiogenic therapies in combination with immunomodulatory therapies may benefit MS progression.

neuroscience↗

bioRxiv2022

Mural norrin/β-catenin signaling regulates Lama2 expression to promote neurovascular unit assembly

Neurovascular unit (NVU) assembly and barrier maturation rely on vascular basement membrane (vBM) composition. Laminins, a major vBM component, are critical for these processes, yet which signaling pathway(s) regulate their expression remains unknown. Here we show that mural cells have active Norrin/{beta}-catenin signaling during central nervous system development. Bulk RNA sequencing and validation using P10 and P14 wild-type versus Apcdd1-/- retinas reveal that Lama2 (Laminin-2 chain) mRNA and protein levels are increased in mutant vasculature undergoing higher Norrin/{beta}-catenin signaling. Mural cells are the main source of Lama2, and {beta}-catenin activation induces Lama2 expression in mural cells in vitro. Markers of mature astrocytes including Aquaporin-4 (a water channel in astrocyte endfeet) and Integrin-6 (a laminin receptor) are upregulated in Apcdd1-/- retinas following higher Lama2 vBM deposition. Thus, the Norrin/{beta}-catenin pathway regulates Lama2 expression in mural cells to promote NVU assembly and neurovascular barrier maturation. SUMMARYBiswas et al., demonstrate that Norrin/{beta}-catenin signaling is active in CNS mural cells and regulates Lama2 deposition in the vascular basement membrane, promoting neurovascular unit assembly and blood-CNS barrier maturation.

developmental biology↗

bioRxiv2020

Effect of sanitation improvements on soil-transmitted helminth eggs in courtyard soil from rural Bangladesh: Evidence from a cluster-randomized controlled trial

Improved sanitation has been hypothesized to reduce soil-transmitted helminth (STH) infections by reducing the prevalence and abundance of STH eggs/larvae in soil. We evaluated the effect of a randomized sanitation program (providing households with an improved dual-pit latrine, tools for child/animal feces management, and behavioral messaging) on reducing STH eggs in soil from household courtyards. We collected soil samples from 1405 households enrolled in the sanitation intervention (n=419) and control (n=914) groups of a cluster-randomized controlled trial (WASH Benefits) in rural Bangladesh approximately 2 years after the initiation of the interventions. We analyzed samples for Ascaris lumbricoides, Trichuris trichiura, and hookworm eggs by microscopy. We estimated prevalence ratios (PR) and relative egg count reductions (ECR) to compare the prevalence of any STH eggs and arithmetic and geometric mean egg counts for any STH per gram of soil between the sanitation and control arms. Among intervention households, latrines achieved high and sustained user uptake by adults while child open defecation remained common and most households did not dispose of child feces hygienically. In courtyard soil from control households, the prevalence of any STH eggs was 75.7% and the prevalence of any larvated STH eggs was 67.3%. A. lumbricoides was detected in 63.0% of control samples and T. trichiura in 55.7% of control samples; hookworm was not detected in any sample. The arithmetic mean egg count for any STH was 3.96 eggs/dry gram, while the geometric mean was 1.58 eggs/dry gram. There was no difference between the intervention and control groups in the prevalence of any STH eggs (PR=0.98 (95% CI: 0.91-1.05)) or mean egg counts (ECR=0.08 (95% CI: -0.10, 0.26) for geometric mean and 0.07 (95% CI: -0.22, 0.37) for arithmetic mean). Adjusted models gave similar results. A compound-level sanitation intervention that provided improved latrines and tools for disposal of child and animal feces did not have an impact on environmental reservoirs of STH eggs. In order to effectively reduce the prevalence and abundance of STH eggs in the environment, sustained, widespread use of sanitation strategies to isolate and hygienically dispose of child and animal feces may need to complement traditional strategies for containment of adult human feces. Author summaryImproved sanitation has been hypothesized to reduce soil-transmitted helminth (STH) infections by reducing the prevalence and abundance of STH eggs/larvae in soil. We evaluated the effect of a randomized sanitation program (providing households with an improved dual-pit latrine, tools for child/animal feces management, and behavioral messaging) on reducing STH eggs in soil from household courtyards. We collected soil samples from 1405 households enrolled in the control and sanitation groups of a cluster-randomized controlled trial (WASH Benefits) in rural Bangladesh approximately 2 years after the initiation of the interventions. We analyzed samples for Ascaris lumbricoides, Trichuris trichiura and hookworm eggs by microscopy. We found no effect of the sanitation intervention on STH eggs in soil. In order to effectively reduce the prevalence and abundance of STH eggs in the environment, sustained, widespread use of sanitation strategies to isolate and hygienically dispose of child and animal feces may need to complement traditional strategies for containment of adult human feces.

ecology↗