Biology subjects

Islam, R.

Publications and source records attributed to Islam, R..

28 records · Page 2Linked to original sources

bioRxiv2020

SETD1B controls cognitive function via cell type specific regulation of neuronal identity genes

Histone-3-lysine-4-methylation (H3K4me) is mediated by six different lysine methyltransferases (KMTs). Amongst these enzymes SET domain containing 1b (SETD1B) has been linked to intellectual disability but its role in the adult brain has not been studied yet. Here we show that mice lacking Setd1b from excitatory neurons of the adult forebrain exhibit severe memory impairment. By combining neuron-specific ChIP-seq, RNA-seq and single cell RNA-seq approaches we show that Setd1b controls the expression of neuronal-identity genes with a broad H3K4me3 peak linked to learning and memory processes. Our data furthermore suggest that basal neuronal gene-expression is ensured by other H3K4 KMTs such as Kmt2a and Kmt2b while the additional presence of Setd1b at the single cell level provides transcriptional consistency to the expression of genes important for learning & memory.

neuroscience↗

bioRxiv2020

SMPD3-mediated extracellular vesicle biogenesis inhibits oligodendroglioma growth

Isocitrate dehydrogenase (IDH) mutant gliomas, including oligodendroglioma (IDH-O) and astrocytoma (IDH-A), have signature slow-growth rates that are poorly understood. Here, we reveal that SMPD3, a ceramide-producing sphingomyelinase implicated as a tumor suppressor gene and involved in extracellular vesicle biogenesis, suppresses IDH-mutant tumor growth via autocrine and paracrine actions. In patients with IDH-mutant gliomas, higher SMPD3 expression levels correlate with longer survival, consistent with ceramide acting as an anti-oncometabolite. SMPD3 knock-down in patient-derived IDH-O cells enhances proliferation cell-autonomously in 2D-culture and 3D-human cerebral organoids, and accelerates tumor growth in mouse orthotopic xenografts. Supporting paracrine actions, IDH-O-derived extracellular vesicles, enriched in ribosomal proteins, induce astrocytic death in vitro. Furthermore, non-neoplastic glia in IDH-O tumors proliferate abnormally yet undergo apoptosis, concomitant with the acquisition of a translation-enriched transcriptional signature by tumor-associated oligodendrocytes. SMPD3 thus suppresses IDH-mutant glioma growth cell-autonomously and phenotypically alters normal glia via extracellular vesicle biogenesis and paracrine actions.

cancer biology↗

bioRxiv2020

Analysis of Ten Microsecond simulation data of SARS-CoV-2 dimeric main protease

The dimeric main protease of SARS-CoV-2, has become a crucial target for inhibiting/modulating its catalytic activity. However, understanding of its conformational change, and atomistic flexibility, is very much lucrative for designing/developing small molecules. Fortunately, huge data has been revealed by a research group, performed about ten-microsecond molecular dynamics to paving the way for understanding the structural complexity of protease. Herein, we have done the basic structural analysis, advanced flexibility and conformational analysis like PCA, for revealing out the regions and residues, which are mostly flexible and likely to be responsible for different conformation of protease protein.

bioinformatics↗

bioRxiv2020

Segment-specific orientation of the dorsal and ventral roots for precise therapeutic targeting of human spinal cord

An understanding of spinal cord functional neuroanatomy is essential for diagnosis and treatment of multiple disorders including, chronic pain, movement disorders, and spinal cord injury. Till now, no information is available on segment-specific spinal roots orientation in humans. In this study we collected neuroanatomical measurements of the dorsal and ventral roots from C2-L5, as well as spinal cord and vertebral bone measurements from adult cadavers. Spatial orientation of dorsal and ventral roots were measured and correlated to the anatomical landmarks of the spinal cord and vertebral column. The results show less variability in rostral root angles compared to the caudal angles across all segments. Dorsal and ventral rootlets were oriented mostly perpendicular to the spinal cord at the cervical level and demonstrate more parallel orientation at the thoracic and lumbar segments. The number of rootlets was the highest in dorsal cervical and lumbar segments. Spinal cord transverse diameter and size of the dorsal columns were largest at cervical and lumbar segments. The strongest correlation was found between the length of intervertebral foramen to rostral rootlet and vertebral bone length. These results could be used to locate spinal roots and spinal cord landmarks based on bone marks on CT or X-rays. These results also provide background for future correlations between anatomy of spinal cord and spinal column structures that could improve stereotactic surgical procedures and electrode positioning for spinal cord neuromodulation. One Sentence SummaryThis is the first detailed analysis of the segment-specific dorsal and ventral spinal roots spatial orientation measured and correlated to the anatomical landmarks of the spinal cord and vertebral column for human.

neuroscience↗

bioRxiv2019

Changes in spinal cord hemodynamic reflect modulation of spinal network with different parameters of epidural stimulation

In this study functional ultrasound (fUS) imaging has been implemented to explore the local hemodynamic response induced by electrical epidural stimulation and to study real-time in vivo functional changes of the spinal cord, taking advantage of the superior spatiotemporal resolution provided by fUS. By quantifying the hemodynamic and electromyographic response features, we tested the hypothesis that the transient hemodynamic response of the spinal cord to electrical epidural stimulation could reflect modulation of the spinal circuitry and accordingly respond to the changes in parameters of electrical stimulation. The results of this study for the first time demonstrate that the hemodynamic response to electrical stimulation could reflect functional organization of the spinal cord. Response in the dorsal areas to epidural stimulation was significantly higher and faster compared to the response in ventral spinal cord. Positive relation between the hemodynamic and the EMG responses was observed at the lower frequencies of epidural stimulation (20 and 40 Hz), which according to our previous findings can facilitate spinal circuitry after spinal cord injury, compared to higher frequencies (200 and 500 Hz). These findings suggest that different mechanisms could be involved in spinal cord hemodynamic changes during different parameters of electrical stimulation and for the first time provide the evidence that functional organization of the spinal cord circuitry could be related to specific organization of spinal cord vasculature and hemodynamic.\n\nSignificance StatementElectrical epidural stimulation (EES) has been successfully applied to control chronic refractory pain and was evolved to alleviate motor impairment after spinal cord injury, in Parkinsons disease, and other neurological conditions. The mechanisms underlying the EES remain unclear, and current methods for monitoring EES are limited in sensitivity and spatiotemporal resolutions to evaluate functional changes in response to EES. We tested the hypothesis that the transient hemodynamic response of the spinal cord to EES could reflect modulation of the spinal cord circuitry and accordingly respond to the changes in parameters of EES. The proposed methodology opens a new direction for quantitative evaluation of the spinal cord hemodynamic in understanding the mechanisms of spinal cord functional organization and effect of neuromodulation.

neuroscience↗

bioRxiv2019

Multifactorial motor behavior assessment for real-time evaluation of emerging therapeutics to treat neurologic impairments

Integrating multiple assessment parameters of motor behavior is critical for understanding neural activity dynamics during motor control in both intact and dysfunctional nervous systems. Here, we described a novel approach (termed Multifactorial Behavioral Assessment (MfBA)) to integrate, in real-time, electrophysiological and biomechanical properties of rodent spinal sensorimotor network activity with behavioral aspects of motor task performance. Specifically, the MfBA simultaneously records limb kinematics, multi-directional forces and electrophysiological metrics, such as high-fidelity chronic intramuscular electromyography synchronized in time to spinal stimulation in order to characterize spinal cord functional motor evoked potentials (fMEPs). Additionally, we designed the MfBA to incorporate a body weight support system to allow bipedal and quadrupedal stepping on a treadmill and in an open field environment to assess function in rodent models of neurologic disorders that impact motor activity This novel approach was validated using, a neurologically intact cohort, a cohort with unilateral Parkinsonian motor deficits due to midbrain lesioning, and a cohort with complete hind limb paralysis due to T8 spinal cord transection. In the SCI cohort, lumbosacral epidural electrical stimulation (EES) was applied, with and without administration of the serotonergic agonist Quipazine, to enable hind limb motor functions following paralysis. The results presented herein demonstrate the MfBA is capable of integrating multiple metrics of motor activity in order to characterize relationships between EES inputs that modulate mono- and polysynaptic outputs from spinal circuitry which in turn, can be used to elucidate underlying electrophysiologic mechanisms of motor behavior by synchronizing these datasets to metrics of movement and behavior. These results also demonstrate that proposed MfBA is an effective tool to integrate biomechanical and electrophysiology metrics, synchronized to therapeutic inputs such as EES or pharmacology, during body weight supported treadmill or open field motor activities, to target a high range of variations in motor behavior as a result of neurological deficit at the different levels of CNS.

neuroscience↗

bioRxiv2019

Evaluation of liver protective activity of Moringa oleifera bark extract in paracetamol induced hepatotoxicity in rats.

BackgroundMoringa oleifera has been used in folk medicine to alleviate several diseases. In the present study, ethanolic extract of Moringa oleifera bark has been investigated to study its potential on paracetamol induced hepatotoxicity on model rats.\n\nMethodsRats (150-200 gm) were divided into 5 groups containing 6 animals each. Acute hepatotoxicity was induced by paracetamol (600 mg/kg body weight) administered once daily for one week whereas the extract of investigated plant was given orally throughout the whole experiment at 250 and 500mg/kg body weight. Silymarin (100mg/kg body weight) was given orally as standard hepatoprotective drug. The level of hepatic injury recovery was determined by the estimation of liver enzymes like SGPT, SGOT, ALP, Bilirubin, Total protein and Albumin.\n\nResultsTreatment with MO extract as well as standard hepatoprotective agent silymarin ameliorated the increased plasma levels of these hepatic enzymes and indicated the hepatoprotective potential of the extract.\n\nConclusionThe biochemical parameters provide evidence that the ethanolic extract of of Moringa oleifera bark has shown hepatoprotective activity.

pharmacology and toxicology↗

bioRxiv2018

Different features of cholera in malnourished and non-malnourised children: analysis of 10-year surveillance data from a large diarrheal disease hospital in urban Bangladesh

Background: Malnourished children are more prone to infectious diseases including severe diarrhea compared to non-malnourished children. Understanding of the differences in the presentation of severe diarrhea such as cholera in children with varying nutritional status may help in the early identification and management these children. However, data are scarce on differences in the presentation in such children. Thus, we aimed to identify the clinical differentials among children with cholera with or without malnutrition.\n\nMethods: Data were extracted from diarrheal disease surveillance system (DDSS) of the Dhaka Hospital of icddr,b for the period, January 2008 to December 2017. Among under-five children, cholera positive (culture confirmed) and malnourished children (weight-for-age, weight-for-length or height-for-age Z score (WAZ, WHZ or HAZ) <-2) were considered as the cases (n=305) and children with cholera but non-malnourished (WAZ, HAZ, and WHZ [≥]-2.00 to [≤]+2.00) were the controls (n=276).\n\nResults: A total of 14,403 under-five children were enrolled in the surveillance system during the study period. After adjusting for potential covariates such as maternal illiteracy and slum dwelling, it was revealed that under-five malnourished children with cholera significantly more often presented to the hospital during evening hours (6 pm to 12 mid-night) (OR=1.64, 95% CI=1.16-2.31, P<0.05), had fathers who were illiterate (OR=1.70, 95% CI=1.11-2.62, P<0.05), presented with history of cough within last 7 days (OR=1.64, 95% CI=1.10-2.43, P<0.05), dehydrating diarrhea (OR=1.70, 95% CI=1.15-2.53, P<0.05), and had longer hospitalization (OR=1.50, 95% CI=1.05-2.14, P<0.05).\n\nConclusions: The study results underscore the importance of understanding of the basic differences in the presentation of severe cholera in malnourished children for prompt identification and the subsequent management of these children. These observations may help policy makers in formulating better case management strategy.\n\nAuthor SummaryMalnourished children are more vulnerable to infectious diseases including cholera in comparison to the non-malnourished children. They often have suboptimal immune function, though there is no precise information on whether there is any difference in associated factor(s) or clinical course of cholera in under-five children with varying nutritional status. Therefore, this study was conducted to elucidate these insights by using the surveillance data of the Dhaka hospital of icddr,b. Among all the under-five children with cholera, 305 malnourished (WAZ or WLZ or HAZ <-2) children constituted as the cases (malnourished), and another 276 non-malnourished (WAZ, HAZ, and WHZ [≥]-2.00GtoG[≤]+2.00) cholera children formed the comparison group.\n\nIn this study we revealed that care seeking at evening time was more common in the malnourished children with cholera compared to those without malnutrition. Dehydrating diarrhea was about two folds higher and prolonged hospitalization was frequent in malnourished children with cholera than their counterparts. These key findings may help policy makers in formulating better case management strategy in the near future.

microbiology↗

bioRxiv2018

Calcium activation of frequency dependent temporally phasic, localized, and dense population of cortical neurons by continuous electrical stimulation

Electrical stimulation of the brain has become a mainstay of fundamental neuroscience research and an increasingly prevalent clinical therapy. Despite decades of use in basic neuroscience research and the growing prevalence of neuromodulation therapies, gaps in knowledge regarding activation or inactivation of neural elements over time have limited its ability to adequately interpret evoked downstream responses or fine-tune stimulation parameters to focus on desired responses. In this work, in vivo two-photon microscopy was used to image neuronal calcium activity in layer 2/3 neurons of somatosensory cortex (S1) in male C57BL/6J-Tg(Thy1-GCaMP6s)GP4.3Dkim/J mice during 30 s of continuous electrical stimulation at varying frequencies. We show frequency-dependent differences in spatial and temporal somatic responses during continuous stimulation. Our results elucidate conflicting results from prior studies reporting either dense spherical activation of somas biased towards those near the electrode, or sparse activation of somas at a distance via axons near the electrode. These findings indicate that the neural element specific temporal response local to the stimulating electrode changes as a function of applied charge density and frequency. These temporal responses need to be considered to properly interpret downstream circuit responses or determining mechanisms of action in basic science experiments or clinical therapeutic applications.\n\nSignificance StatementMicrostimulation of small populations of neurons has the potential to ameliorate symptoms associated with several neurological disorders. However, the specific mechanisms by which microstimulation elicits therapeutic responses are unclear. This work examines the effects of continuous microstimulation on the local population of neurons surrounding the implanted electrode. Stimulation was found to elicit spatiotemporal neuronal responses in a frequency dependent manner. These findings suggest that stimulation frequency may be an important consideration for applications in research or therapy. Further research aimed at understanding these neuronal activation properties may provide insight into the mechanistic mode of action of continuous microstimulation.

neuroscience↗

bioRxiv2017

Consequences Of NMDA Receptor Deficiency Can Be Rescued In The Adult Brain

N-methyl-D-aspartate receptors (NMDARs) are required to shape activity-dependent connections in the developing and adult brain. Impaired NMDAR signaling through genetic or environmental insults causes a constellation of neurodevelopmental disorders that manifest as intellectual disability, epilepsy, autism, or schizophrenia. It is not clear whether the developmental impacts of NMDAR dysfunction can be overcome by interventions in adulthood. This question is paramount for neurodevelopmental disorders arising from mutations that occur in the GRIN genes, which encode NMDAR subunits, and the broader set of mutations that disrupt NMDAR function. We developed a mouse model where a congenital loss-of-function allele of Grin1 is restored to wildtype by gene editing with Cre recombinase. Rescue of NMDARs in adult mice yields surprisingly robust improvements in cognitive behaviors, including those that are refractory to treatment with current medications. These results suggest that neurodevelopmental disorders arising from NMDAR deficiency can be effectively treated in adults.

neuroscience↗