Publications by authors named "Jahan Salma"

10 Publications

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Tropism of SARS-CoV-2 for Developing Human Cortical Astrocytes.

bioRxiv 2021 Jan 18. Epub 2021 Jan 18.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) readily infects a variety of cell types impacting the function of vital organ systems, with particularly severe impact on respiratory function. It proves fatal for one percent of those infected. Neurological symptoms, which range in severity, accompany a significant proportion of COVID-19 cases, indicating a potential vulnerability of neural cell types. To assess whether human cortical cells can be directly infected by SARS-CoV-2, we utilized primary human cortical tissue and stem cell-derived cortical organoids. We find significant and predominant infection in cortical astrocytes in both primary and organoid cultures, with minimal infection of other cortical populations. Infected astrocytes had a corresponding increase in reactivity characteristics, growth factor signaling, and cellular stress. Although human cortical cells, including astrocytes, have minimal ACE2 expression, we find high levels of alternative coronavirus receptors in infected astrocytes, including DPP4 and CD147. Inhibition of DPP4 reduced infection and decreased expression of the cell stress marker, ARCN1. We find tropism of SARS-CoV-2 for human astrocytes mediated by DPP4, resulting in reactive gliosis-type injury.
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http://dx.doi.org/10.1101/2021.01.17.427024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814814PMC
January 2021

Cell stress in cortical organoids impairs molecular subtype specification.

Nature 2020 02 29;578(7793):142-148. Epub 2020 Jan 29.

Department of Neurology, University of California, San Francisco (UCSF), San Francisco, CA, USA.

Cortical organoids are self-organizing three-dimensional cultures that model features of the developing human cerebral cortex. However, the fidelity of organoid models remains unclear. Here we analyse the transcriptomes of individual primary human cortical cells from different developmental periods and cortical areas. We find that cortical development is characterized by progenitor maturation trajectories, the emergence of diverse cell subtypes and areal specification of newborn neurons. By contrast, organoids contain broad cell classes, but do not recapitulate distinct cellular subtype identities and appropriate progenitor maturation. Although the molecular signatures of cortical areas emerge in organoid neurons, they are not spatially segregated. Organoids also ectopically activate cellular stress pathways, which impairs cell-type specification. However, organoid stress and subtype defects are alleviated by transplantation into the mouse cortex. Together, these datasets and analytical tools provide a framework for evaluating and improving the accuracy of cortical organoids as models of human brain development.
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http://dx.doi.org/10.1038/s41586-020-1962-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433012PMC
February 2020

NRXN1 Deletion and Exposure to Methylmercury Increase Astrocyte Differentiation by Different Notch-Dependent Transcriptional Mechanisms.

Front Genet 2019 21;10:593. Epub 2019 Jun 21.

Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Controversial evidence points to a possible involvement of methylmercury (MeHg) in the etiopathogenesis of autism spectrum disorders (ASD). In the present study, we used human neuroepithelial stem cells from healthy donors and from an autistic patient bearing a bi-allelic deletion in the gene encoding for to evaluate whether MeHg would induce cellular changes comparable to those seen in cells derived from the ASD patient. In healthy cells, a subcytotoxic concentration of MeHg enhanced astroglial differentiation similarly to what observed in the diseased cells (N1), as shown by the number of GFAP positive cells and immunofluorescence signal intensity. In both healthy MeHg-treated and N1 untreated cells, aberrations in Notch pathway activity seemed to play a critical role in promoting the differentiation toward glia. Accordingly, treatment with the established Notch inhibitor DAPT reversed the altered differentiation. Although our data are not conclusive since only one of the genes involved in ASD is considered, the results provide novel evidence suggesting that developmental exposure to MeHg, even at subcytotoxic concentrations, induces alterations in astroglial differentiation similar to those observed in ASD.
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http://dx.doi.org/10.3389/fgene.2019.00593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610538PMC
June 2019

Krüppel-like factor 6 (KLF6) promotes cell proliferation in skeletal myoblasts in response to TGFβ/Smad3 signaling.

Skelet Muscle 2013 Apr 2;3(1). Epub 2013 Apr 2.

Department of Biology, York University; York University, 4700 Keele St, Toronto, ON, M3J 1P3, Canada.

Background: Krüppel-like factor 6 (KLF6) has been recently identified as a MEF2D target gene involved in neuronal cell survival. In addition, KLF6 and TGFβ have been shown to regulate each other's expression in non-myogenic cell types. Since MEF2D and TGFβ also fulfill crucial roles in skeletal myogenesis, we wanted to identify whether KLF6 functions in a myogenic context.

Methods: KLF6 protein expression levels and promoter activity were analyzed using standard cellular and molecular techniques in cell culture.

Results: We found that KLF6 and MEF2D are co-localized in the nuclei of mononucleated but not multinucleated myogenic cells and, that the MEF2 cis element is a key component of the KLF6 promoter region. In addition, TGFβ potently enhanced KLF6 protein levels and this effect was repressed by pharmacological inhibition of Smad3. Interestingly, pharmacological inhibition of MEK/ERK (1/2) signaling resulted in re-activation of the differentiation program in myoblasts treated with TGFβ, which is ordinarily repressed by TGFβ treatment. Conversely, MEK/ERK (1/2) inhibition had no effect on TGFβ-induced KLF6 expression whereas Smad3 inhibition negated this effect, together supporting the existence of two separable arms of TGFβ signaling in myogenic cells. Loss of function analysis using siRNA-mediated KLF6 depletion resulted in enhanced myogenic differentiation whereas TGFβ stimulation of myoblast proliferation was reduced in KLF6 depleted cells.

Conclusions: Collectively these data implicate KLF6 in myoblast proliferation and survival in response to TGFβ with consequences for our understanding of muscle development and a variety of muscle pathologies.
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http://dx.doi.org/10.1186/2044-5040-3-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669038PMC
April 2013

Suppression of a MEF2-KLF6 survival pathway by PKA signaling promotes apoptosis in embryonic hippocampal neurons.

J Neurosci 2012 Feb;32(8):2790-803

Department of Biology, York University, Toronto, Ontario, Canada.

In the mammalian nervous system, regulation of transcription factor activity is a crucial determinant of neuronal cell survival, differentiation, and death. The myocyte enhancer factor 2 (MEF2) transcription factors have been implicated in cellular processes underlying neuronal survival and differentiation. A core component of the MEF2 complex is the MEF2D subunit. Recently, we reported that cAMP-dependent protein kinase (cAMP/PKA) signaling negatively regulates MEF2D function in myogenic cells. Here, we assessed whether cAMP signaling converges on the prosurvival role of MEF2D in Sprague Dawley rat embryonic (E18) hippocampal neurons. Initially, we observed that experimental induction of cAMP/PKA signaling promotes apoptosis in primary hippocampal neurons as indicated by TUNEL and FACS analysis. Luciferase reporter gene assays revealed that PKA potently represses MEF2D trans-activation properties in neurons. This effect was largely reversed by engineered neutralizing mutations of PKA phospho-acceptor sites on MEF2D (S121/190A). Krüppel-like factor 6 (KLF6) was identified as a key transcriptional target of MEF2 in hippocampal neurons, and siRNA-mediated knockdown of KLF6 expression promotes neuronal cell death and also antagonizes the prosurvival role of MEF2D. These observations have important implications for understanding the pathways controlling cell survival and death in the mammalian nervous system.
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http://dx.doi.org/10.1523/JNEUROSCI.3609-11.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6621893PMC
February 2012

Protein kinase A-regulated assembly of a MEF2{middle dot}HDAC4 repressor complex controls c-Jun expression in vascular smooth muscle cells.

J Biol Chem 2009 Jul 23;284(28):19027-42. Epub 2009 Apr 23.

Department of Biology, York University, Toronto, Ontario M3J 1P3, Canada.

Vascular smooth muscle cells (VSMCs) maintain the ability to modulate their phenotype in response to changing environmental stimuli. This phenotype modulation plays a critical role in the development of most vascular disease states. In these studies, stimulation of cultured vascular smooth muscle cells with platelet-derived growth factor resulted in marked induction of c-jun expression, which was attenuated by protein kinase Cdelta and calcium/calmodulin-dependent protein kinase inhibition. Given that these signaling pathways have been shown to relieve the repressive effects of class II histone deacetylases (HDACs) on myocyte enhancer factor (MEF) 2 proteins, we ectopically expressed HDAC4 and observed repression of c-jun expression. Congruently, suppression of HDAC4 by RNA interference resulted in enhanced c-jun expression. Consistent with these findings, mutation of the MEF2 cis-element in the c-jun promoter resulted in promoter activation during quiescent conditions, suggesting that the MEF2 cis-element functions as a repressor in this context. Furthermore, we demonstrate that protein kinase A attenuates c-Jun expression by promoting the formation of a MEF2.HDAC4 repressor complex by inhibiting salt-inducible kinase 1. Finally, we document a physical interaction between c-Jun and myocardin, and we document that forced expression of c-Jun represses the ability of myocardin to activate smooth muscle gene expression. Thus, MEF2 and HDAC4 act to repress c-Jun expression in quiescent VSMCs, protein kinase A enhances this repression, and platelet-derived growth factor derepresses c-Jun expression through calcium/calmodulin-dependent protein kinases and novel protein kinase Cs. Regulation of this molecular "switch" on the c-jun promoter may thus prove critical for toggling between the activated and quiescent VSMC phenotypes.
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http://dx.doi.org/10.1074/jbc.M109.000539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2707197PMC
July 2009

Spot urinary protein/osmolality ratio as a predictor for proteinuria of nephrotic range.

Bangladesh Med Res Counc Bull 2007 Aug;33(2):65-8

Department of Pediatrics Nephrology, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh.

A prospective study was carried out on 50 patients (age 1-15 years) with nephrotic range of proteinuria to determine the correlation of 24-hour urinary total protein with spot urinary protein/creatinine ratio and urinary protein/osmolality ratio. Another 50 patients having no proteinuria grouped as control. Twenty-four hours urine and spot urine were collected from each child and were analyzed for total volume, total protein, creatinine and osmolality level. The average 24-hour urinary total proteins in nephritic patient were 2148.6 +/- 808.7 mg and the spot urinary protein/creatinine and spot urinary protein/osmolality were 3.2332 +/- 0.4293 mg/mg and 3.2418 +/- 0.4393 mg/mOsm respectively. There was a strong positive correlation of the 24-hour urinary total protein with spot urinary protein/creatinine and protein/osmolality ratios (r=0.9846 and 0.9870, p= <0.001). But in control group, these ratios did not show any correlation with 24-hour urinary total protein. These results suggest that in pediatric patients with nephrotic range of proteinuria, the spot urinary protein/osmolality ratio can predict the 24-hour urinary total protein excretion like that of spot urinary protein/creatinine ratios.
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http://dx.doi.org/10.3329/bmrcb.v33i2.1207DOI Listing
August 2007

Protein kinase A represses skeletal myogenesis by targeting myocyte enhancer factor 2D.

Mol Cell Biol 2008 May 25;28(9):2952-70. Epub 2008 Feb 25.

Department of Biology, York University, 4700 Keele Street, Toronto M3J 1P3, Ontario, Canada.

Activation of protein kinase A (PKA) by elevation of the intracellular cyclic AMP (cAMP) level inhibits skeletal myogenesis. Previously, an indirect modulation of the myogenic regulatory factors (MRFs) was implicated as the mechanism. Because myocyte enhancer factor 2 (MEF2) proteins are key regulators of myogenesis and obligatory partners for the MRFs, here we assessed whether these proteins could be involved in PKA-mediated myogenic repression. Initially, in silico analysis revealed several consensus PKA phosphoacceptor sites on MEF2, and subsequent analysis by in vitro kinase assays indicated that PKA directly and efficiently phosphorylates MEF2D. Using mass spectrometric determination of phosphorylated residues, we document that MEF2D serine 121 and serine 190 are targeted by PKA. Transcriptional reporter gene assays to assess MEF2D function revealed that PKA potently represses the transactivation properties of MEF2D. Furthermore, engineered mutation of MEF2D PKA phosphoacceptor sites (serines 121 and 190 to alanine) rendered a PKA-resistant MEF2D protein, which efficiently rescues myogenesis from PKA-mediated repression. Concomitantly, increased intracellular cAMP-mediated PKA activation also resulted in an enhanced nuclear accumulation of histone deacetylase 4 (HDAC4) and a subsequent increase in the MEF2D-HDAC4 repressor complex. Collectively, these data identify MEF2D as a primary target of PKA signaling in myoblasts that leads to inhibition of the skeletal muscle differentiation program.
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http://dx.doi.org/10.1128/MCB.00248-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2293079PMC
May 2008

Phylogeny of the corticotropin-releasing factor family of peptides in the metazoa.

Gen Comp Endocrinol 2006 Mar 10;146(1):1-8. Epub 2006 Feb 10.

Department of Zoology, University of Toronto, Toronto, Ont., Canada L4A 1K6.

The corticotropin-releasing factor (CRF) family of peptides consists of four distinct paralogs found on separate chromosomes in vertebrates. Among invertebrates, the family has been relatively well characterized in the insects where at least 2 or 3 paralogs, a CRF-binding protein ortholog and a CRF receptor variant have been found. The conservation of structure and function of this system in insects imply that the CRF system evolved in ancestral species well before the Precambrian explosion. The CRF family peptides association with diuresis and feeding may have developed early in its evolution. However, CRF's role in the hypothalamo-pituitary-adrenal axis and regulation of the glucocorticoids in association with energy metabolism appears to have developed in the chordate lineage.
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http://dx.doi.org/10.1016/j.ygcen.2005.11.019DOI Listing
March 2006