Biology subjects

Ahmed, T.

Publications and source records attributed to Ahmed, T..

45 records · Page 3Linked to original sources

bioRxiv2020

U2AF1 is a haplo-essential gene required for cancer cell survival

Somatic mutations in the spliceosome gene U2AF1 are common in patients with myelodysplastic syndromes. U2AF1 mutations that code for the most common amino acid substitutions are always heterozygous, and the retained wild-type allele is expressed, suggesting that mutant hematopoietic cells may require the residual wild-type allele to be viable and cause disease. We show that hematopoiesis and RNA splicing in U2af1 heterozygous knock-out mice was similar to control mice, but that deletion of the wild-type allele in U2AF1(S34F) heterozygous mutant expressing hematopoietic cells (i.e., hemizygous mutant) was lethal. These results confirm that U2AF1 mutant hematopoietic cells are dependent on the expression of wild-type U2AF1 for survival in vivo and that U2AF1 is a haplo-essential cancer gene. Mutant U2AF1 (S34F) expressing cells were also more sensitive to reduced, but not absent, expression of wild-type U2AF1 than non-mutant cells. Furthermore, mice transplanted with leukemia cells expressing mutant U2AF1 had significantly reduced tumor burden and improved survival after the wild-type U2af1 allele was deleted compared to when it was not deleted. These results suggest that selectively targeting the wild-type U2AF1 allele in heterozygous mutant cells could induce cancer cell death and be a therapeutic strategy for patients harboring U2AF1 mutations.

cancer biology↗

bioRxiv2020

An extensive computational approach to inhibit MSP-1 of P.vivax elucidates further horizon in the establishment next generation therapeutics against malaria

Malaria represents a life-threatening disease caused by the obligate intra-erythrocytic protozoa of the Plasmodium genus, exerting a sinister global health burden and accounting for approximately 660,000 deaths annually. Additionally, 219 million new cases are reported each year, most of which result from the growing issue of artemisinin resistance shown by the Plasmodium parasite. Much of the research done for the purpose of development of therapeutics against malaria has traditionally been focused on Plasmodium falciparum, which is responsible for majority of the cases of mortality due to malaria, Plasmodium vivax is also known to contribute greatly towards the malaria relate morbidities particularly in vivax endemic areas. In this study, we have used two different computational approaches aimed at establishing newer concepts towards the development of advanced therapeutics against vivax malaria by targeting the surface antigen, merozoite surface protein-1 (MSP-1). In-silico approach involving computational siRNA designing against MSP-1 resulted in a total of four candidate siRNAs being rationally validated following corroboration with a plethora of algorithms. Additionally, molecular docking analysis unraveled a total of three anti-parasitic peptides. These peptides namely: AP02283, AP02285 and AP00101 were found to exhibit considerable binding affinity with MSP-1 of P.vivax, thus providing an apparent indication of their anti-malarial property and affirming their potency to be used as novel molecules for development of next generation anti-malarials. However, irrespective of the prospective magnitude of these in-silico findings, the results require extensive validation by further rigorous laboratory experiments involving both in-vitro and in-vivo approaches.

bioinformatics↗

bioRxiv2020

Spatial Distribution of Discarded Vehicle Tires and Their Influence on Aedes albopictusand Culex quinquefasciatus Populations in New Orleans, Louisiana

Discarded vehicle tires play an important role in the colonization of container mosquito populations, particularly their geographic expansion. We assessed the spatial distribution of illegally discarded tires and their response to land use-land cover (LULC), and demographic factors using geospatial analysis and generalized regression. Multiple stepwise regressions were used to evaluate the response of the Container Index (CI) of colonized Aedes albopictus (Skuse), and Culex quinquefasciatus Say to macro- and microhabitats variables. The illegally discarded tires were distributed over 11 planning districts with clustering distribution for tires frequency and overdispersed distribution for tires number. Out of 1,137 ([~]37.08%) water-holding tires, 598 ([~]52.64%) tires at 65 ([~]38.46%) sites were positive for colonized mosquito populations. A total of 13 mosquito species were identified, with the highest CI of Ae. albopictus (44.19%) and Cx. quinquefasciatus (22.18%). Aedes albopictus colonized all 65 sample sites and Cx. quinquefasciatus found at 32 sites. The Container Index (CI) of colonized mosquito was clustered in seven planning districts for Ae. albopictus and five planning districts for Cx. quinquefasciatus. Microhabitat (muddy water) rather than macrohabitats variables predicted both species colonization, especially Ae. albopictus. The contribution of macro- and microhabitat characteristics in predicting colonized mosquito in water-holding tires was discussed.

ecology↗

bioRxiv2019

Breeding behaviour and productivity of Black-necked crane (Grus nigricolis) in Ladakh, Indian Trans-Himalaya

A long-term study was conducted to understand some aspects of breeding biology of Black-necked crane (Grus nigricollis) in Changthang, Ladakh. Data on aspects such as the breeding season, courtship, mating, egg laying and incubation period, nest site fidelity, egg morphometry, breeding productivity and recruitment rate were collected between 2003 and 2012. Black-necked crane started arriving from last week of March to first half of April and showed fidelity at ten nesting sites. Courtship and mating peaked early morning (0700 hours), around noon (1100 hours) and in late evening (0600 hours) while the nest building at evening (1600 hours). The egg laying period initiated in May and extended up to July. The average incubation period was 33.88{+/-}0.3 days. Hatching success, nest survival rate and fledgling increment rate of the bird were 73.3%, 0.55 {+/-} 0.03 and 0.41 {+/-} 0.02 respectively with an overall breeding productivity of 0.73. The present population of Black-necked crane in Changthang, Ladakh seems to stable with an average recruitment rate of 15.7{+/-}1.4.

ecology↗

bioRxiv2019

ENVELOPED VIRUS-LIKE PARTICLES (eVLPs) EXPRESSING MODIFIED FORMS OF ZIKA VIRUS PROTEINS E AND NS1 PROTECT MICE FROM ZIKA VIRUS INFECTION

While Zika virus (ZIKV) infection induces mild disease in the majority of cases, it has been identified as responsible for microcephaly and severe neurological disorders in recent 2015-2016 outbreaks in South America and the Caribbean. Since then, several prophylactic vaccine strategies have been studied. Here, we describe the development of a ZIKV candidate vaccine consisting of bivalent enveloped virus-like particles (eVLPs) expressing a modified form of E and truncated NS1 (EG/NS1) proteins. In EG/NS1, the E transmembrane/cytoplasmic tail has been replaced with those domains from the VSV G protein and a {beta}-domain of NS1 was fused in-frame to Gag from Moloney murine leukemia virus (MLV). Immunization of BALB/C mice demonstrated that bivalent EG/NS1 and monovalent EG eVLPs induced comparable levels of antibody (Ab) titers but that EG/NS1 induced much higher neutralizing activity, comparable to naturally acquired anti-ZIKV immunity. In contrast, monovalent NS1 eVLPs did not induce a significant anti-NS1 Ab response but promoted strong T cell immunity that was also elicited with EG/NS1 eVLPs. ZIKV challenge studies in C57BL/6-IFNR-/- mice demonstrated that EG/NS1 eVLPs conferred 100% protection against clinical disease after ZIKV challenge compared to 80% protection after EG eVLP vaccination, with protection against challenge correlating with neutralizing antibody titers and overt signs of infection.\n\nAuthor SummaryZika virus has caused rapidly spreading epidemics with potentially severe neurological symptoms including microcephaly in new born babies. Rapid progress has been made with several candidate vaccines under clinical evaluation but no vaccine or treatment is yet available. In this context, we have produced and tested recombinant virus-like particles that incorporate one or two Zika virus proteins, E and NS1 that have been modified for optimal efficacy. Our immunogenicity studies in mice showed a synergistic effect of both proteins in the bivalent vaccine. NS1 induced a strong T cell response enhancing the neutralizing antibody production induced by the E protein. In challenge experiments, the bivalent vaccine protected 100% of mice from clinical signs of Zika virus infection. These products could be further used to explore Zika virus correlates of protection and evaluated as vaccine candidates.

immunology↗

bioRxiv2019

Tubewell use protects against rotavirus infection during the monsoons in an urban setting

Rotavirus, a diarrheal pathogen spread via fecal-oral transmission, is typically characterized by a winter incidence peak in most countries. Unlike for cholera and other water-borne infections, the role of environmental and socioeconomic factors on the spatial variation of rotavirus seasonality remains unclear. Here, we analyze their association with rotavirus seasonality, specifically the odds of monsoon cases, across 46 locations from 2001 to 2012 in Dhaka. Drinking water from tubewells, compared to other sources, has a clear protective effect against cases during the monsoon, when flooding and water contamination are more likely. This finding supports a significant environmental component of transmission.

epidemiology↗

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

AMP-activated protein kinase is essential for the maintenance of energy levels during synaptic activation

While accounting for 2% of the total body mass, the brain is the organ that consumes the most energy. Although it is widely acknowledged that neuronal energy metabolism is tightly regulated, the mechanism how neurons meet their energy demand to sustain synaptic transmission remains poorly studied. Here we provide substantial evidence that the AMP-activated protein kinase (AMPK) plays a leading role in this process. Our results show that following synaptic activation, AMPK activation is required to sustain neuronal energy levels particularly through mitochondrial respiration. Further, our studies revealed that this metabolic plasticity regulated by AMPK is required for the expression of immediate early genes, synaptic plasticity and memory formation. These findings are important in the context of neurodegenerative disorders, as AMPK deregulation as it is observed in Alzheimers disease, impairs the metabolic response to synaptic activation. Altogether, our data provides the proof of concept that AMPK is an essential player in the regulation of neuroenergetic metabolism plasticity induced in response to synaptic activation.

neuroscience↗

bioRxiv2018

Non-Canonical Activation of CREB Mediates Neuroprotection in a C. elegans Model of Excitotoxic Necrosis

Excitotoxicity, caused by exaggerated neuronal stimulation by Glutamate (Glu), is a major cause of neurodegeneration in brain ischemia. While we know that neurodegeneration is triggered by overstimulation of Glu-Receptors (GluRs), the subsequent mechanisms that lead to cellular demise remain controversial. Surprisingly, signaling downstream of GluRs can also activate neuroprotective pathways. The strongest evidence involves activation of the transcription factor cAMP Response Element Binding-protein (CREB), widely recognized for its importance in synaptic plasticity. Canonical views describe CREB as a phosphorylation-triggered transcription factor, where transcriptional activation involves CREB phosphorylation and association with CREB Binding Protein (CBP). However, given CREBs ubiquitous cross-tissue expression, the multitude of cascades leading to CREB phosphorylation, and its ability to regulate thousands of genes, it remains unclear how CREB exerts closely-tailored, differential neuroprotective responses in excitotoxicity. A non-canonical, alternative cascade for activation of CREB-mediated transcription involves the CREB co-factor cAMP-regulated transcriptional co-activator (CRTC), and may be independent of CREB phosphorylation. To identify cascades that activate CREB in excitotoxicity we use a C. elegans model of neurodegeneration by excitotoxic necrosis. We demonstrate that CREBs neuroprotective effect is conserved, and seems most effective in neurons with moderate Glu exposure. We find that factors mediating canonical CREB activation are not involved. Instead, phosphorylation-independent CREB activation in nematode excitotoxic necrosis hinges on CRTC. CREB-mediated transcription that depends on CRTC, but not on CREB phosphorylation, might lead to expression of a specific subset of neuroprotective genes. Elucidating conserved mechanisms of excitotoxicity-specific CREB activation can help us focus on core neuroprotective programs in excitotoxicity.

neuroscience↗