Biology subjects

Ahmad, F.

Publications and source records attributed to Ahmad, F..

30 records · Page 2Linked to original sources

bioRxiv2020

Elevated Neurokinin 1-Receptor Expression in uterine products of conception is associated with first trimester Miscarriages

BackgroundMiscarriage is a common complication of early pregnancy, mostly occurring in first trimester. However, the etiological factors, prognostic and diagnostic biomarkers are not well known. Neurokinin-1 Receptor (NK-1R) is a receptor of tachykinin peptide, Substance P (SP) and has a role in various pathological conditions, cancers but its association with miscarriages and significance as a clinicopathological parameter is not studied. Accordingly, the present study aimed to clarify the localization and expression for NK-1R in human retained products of conception. Role of NK-1R is not known in miscarriages. Materials and MethodsNK-1R expression was assessed in products of conception by immunohistochemistry. Protein expression was evaluated using the nuclear labelling index (%). ResultsTen human products of conception tissues were studied by immunohistochemistry to demonstrate the localization of NK-1R. The expression of NK-1R protein was high in all the cases of POCs. NK-1R expression showed no notable differences among different cases of miscarriages irrespective of the mothers age and gestational age at which the event occurred. ConclusionsExpression of NK-1R was similar in all the cases and it was intense. It shows that dysregulation of NK-1R along with its ligand Substance P might be involved in miscarriages. Our results provide fundamental data regarding this anti-NK-1R strategy. Thus, the present study recommends that SP/NK1R system might, therefore, be considered as an emerging and promising diagnostic and therapeutic strategy against miscarriages. Hence, we report for the first time, the expression and localization of NK-1R in products of conception. We suggest NK-1R antagonist in addition to the Immunoglobulins and Human chorionic gonadotropin, to diagnose and treat spontaneous miscarriages.

pathology↗

bioRxiv2020

Prognostic significance of Substance P/ Neurokinin 1 receptor and its association with hormonal receptors in breast carcinoma

To evaluate the expression and Immunolocalization of Substance P (SP)/ Neurokinin-1 Receptor (NK-1R) in Breast Carcinoma (BC) patients and its association with routine proliferative markers (ER, PR, HER2/ neu and Ki-67). MethodsA cross-sectional study was performed on 34 cases of BC. There were 23 cases of group A (Grade III), 8 of group B (Grade II) and only 3 cases of group C (Grade I). Age range comprised of patients from 20-80 years and the mean age of patients was 45.74 years. HE, ER, PR, HER2 and Ki-67 staining was performed as routine biomarkers. Samples were then processed for immunomarkers study of Substance P and NK-1R immunohistochemistry was performed for few cases. Results14/23 cases (61%) of group A, 7/8 cases (88%) of group B and 2/3 (67%) cases of group C were SP positive. Overall, strong staining ([≥] 10% tumors cells), labeled as "3+", was observed in 9/14 (64.2%) cases of group A and 1/8 (12.5%) case of group B. Moderate staining labelled as "2+" (in [≥] 10% tumor cells) was observed in 3/14 (21.4%) cases of group A, 4/8 (50%) cases of group B. weak positive staining "1+" was observed in only 2/14 (14.28%) cases of group A, 2/8 (25%) cases of group B and all 2/2 (100%) cases of group C. ConclusionsSP and NK-1R is overexpressed in breast carcinomas and there is significant association between grade of tumor and their overexpression. It may serve as a novel biomarker for grading of BC. We also suggest that NK-1R antagonists as a potential therapeutic strategy to inhibit and manage BC. Key PointsO_LIImmunohistochemical expression of Substance P and Neurokinin 1 Receptor in breast carcinoma tissue was evaluated C_LIO_LIIt was strongly expressed in grade III, with maximum intensity C_LIO_LIIt may be investigated further for its role as prognostic and diagnostic marker C_LIO_LITherapeutic potential of Neurokinin-1 Receptor antagonists must be explored C_LI

pathology↗

bioRxiv2020

Modeling heterogeneity of Triple-Negative Breast Cancer highlights potency of WEE1 and BCL-XL targeting

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterized by a remarkable molecular heterogeneity. Currently, there are no effective druggable targets and advanced preclinical models of the human disease. Here, we generated a unique mouse model (MMTV-R26Met mice) of mammary tumors driven by a subtle increase in the expression of the wild-type MET receptor. MMTV-R26Met mice develop spontaneous, exclusive TNBC tumors, recapitulating primary resistance to treatment of patients. Proteomic profiling of MMTV-R26Met tumors and machine learning approach showed that the model faithfully recapitulates inter-tumoral heterogeneity of human TNBC. Further signaling network analysis highlighted potential druggable targets, of which co-targeting of WEE1 and BCL-XL synergistically killed TNBC cells and efficiently induced tumor regression. Mechanistically, BCL-XL inhibition exacerbates the dependency of TNBC cells on WEE1 function, leading to Histone H3 and phosphoS33RPA32 upregulation, RRM2 downregulation, cell cycle perturbation, mitotic catastrophe and apoptosis. Our study introduces a unique, powerful mouse model for studying TNBC formation and evolution, its heterogeneity, and for identifying efficient therapeutic targets.

cancer biology↗

bioRxiv2020

Identification and characterization of long noncoding RNAs and their association with acquisition of blood meal in Culex quinquefasciatus

The Southern house mosquito, Culex quinquefasciatus (Cx. quinquefasciatus) is an important vector that transmit multiple diseases including West Nile encephalitis, Japanese encephalitis, St. Louis encephalitis and lymphatic filariasis. Long noncoding RNAs (lncRNAs) involve in many biological processes such development, infection, and virus-host interaction. However, there is no systematic identification and characterization of lncRNAs in Cx. quinquefasciatus. Here, we report the first ever lncRNA identification in Cx. quinquefasciatus. By using 31 public RNA-seq datasets, a total of 4,763 novel lncRNA transcripts were identified, of which 3,591, 569, and 603 were intergenic, intronic, and antisense respectively. Examination of genomic features revealed that Cx. quinquefasciatus shared similar characteristics with other species such as short in length, low GC content, low sequence conservation, and low coding potential. Furthermore, compared to protein-coding genes, Cx. quinquefasciatus lncRNAs had lower expression values, and tended to be expressed in temporally-specific fashion. In addition, weighted correlation network and functional annotation analyses showed that lncRNAs may have roles in blood meal acquisition of adult female Cx. quinquefasciatus mosquitoes. This study presents the first systematic identification and analysis of Cx. quinquefasciatus lncRNAs and their association with blood feeding. Results generated from this study will facilitate future investigation on the function of Cx. quinquefasciatus lncRNAs.

genomics↗

bioRxiv2020

The strength and form of natural selection on transcript abundance in the wild

Gene transcription variation is known to contribute to disease susceptibility and adaptation, but we currently know very little about how contemporary natural selection shapes transcript abundance. We estimated selection on transcript abundance in cohort of a wild salmonid fish (Salmo trutta) affected by a myxozoan parasite through mark-recapture field sampling and the integration of RNA-seq with classical regression-based selection analysis. We show, based on fin transcriptomes of the host, that infection by an extracellular myxozoan parasite (Tetracapsuloides bryosalmonae) and subsequent host survival is linked to the upregulation of mitotic cell cycle genes. We also detect a widespread signal of disruptive selection; intermediate transcription levels were frequently associated with reduced host survival. Our results provide insights how selection can be measured at the transcriptome level to dissect the molecular mechanisms of contemporary natural selection driven by climate change and emerging anthropogenic threats.

evolutionary biology↗

bioRxiv2020

Recallable but not Recognizable: The Influence of Semantic Priming in Recall Paradigms

When people can successfully recall a studied word, they should be able to recognize it as having been studied. In cued recall paradigms, however, participants sometimes correctly recall words in the presence of strong semantic cues but then fail to recognize those words as actually having been studied. Although the conditions necessary to produce this unusual effect are known, the underlying neural correlates have not been investigated. Across two experiments, involving both behavioral and electrophysiological methods (EEG), we investigated the cognitive and neural processes that underlie recognition failures. Experiments 1A and 1B showed that, in cued recall paradigms, presuming that recalled items can be recognized is a flawed assumption: Recognition failures occur in the presence of cues, regardless of whether those failures are measured. Experiment 2 showed that successfully recalled words that are recognized are driven by recollection at recall and by a combination of recollection and familiarity at recognition; in contrast, recognition failures are driven by semantic priming at recall and followed by negative-going ERP effects consistent with implicit processes such as repetition fluency and context familiarity at recognition. These results demonstrate that recall--long-characterized as predominantly reflecting recollection-based processing in episodic memory--can at times also be served by a confluence of implicit cognitive processes.

neuroscience↗

bioRxiv2019

Feature-Specific Neural Reactivation during Episodic Memory

When recalling an experience of the past, many of the component features of the original episode may be, to a greater or lesser extent, reconstructed in the minds eye. There is strong evidence that the pattern of neural activity that occurred during an initial perceptual experience is recreated during episodic recall (neural reactivation), and that the degree of reactivation is correlated with the subjective vividness of the memory. However, while we know that reactivation occurs during episodic recall, we have lacked a way of precisely characterizing the contents--in terms of its featural constituents--of a reactivated memory. Here we present a novel approach, feature-specific informational connectivity (FSIC), that leverages hierarchical representations of image stimuli derived from a deep convolutional neural network to decode neural reactivation in fMRI data collected while participants performed an episodic recall task. We show that neural reactivation associated with low-level visual features (e.g. edges), high-level visual features (e.g. facial features), and semantic features (e.g. \"terrier\") occur throughout the dorsal and ventral visual streams and extend into the frontal cortex. Moreover, we show that reactivation of both low- and high-level visual features correlate with the vividness of the memory, whereas only reactivation of low-level features correlates with recognition accuracy when the lure and target images are semantically similar. In addition to demonstrating the utility of FSIC for mapping feature-specific reactivation, these findings resolve the relative contributions of low- and high-level features to the vividness of visual memories, clarify the role of the frontal cortex during episodic recall, and challenge a strict interpretation the posterior-to-anterior visual hierarchy.

neuroscience↗

bioRxiv2019

LXRβ controls glioblastoma cell growth, lipid balance, and immune modulation independently of ABCA1

Cholesterol is a critical component of membranes and a precursor for hormones and other signaling molecules. Previously, we showed that unlike astrocytes, glioblastoma cells do not downregulate cholesterol synthesis when plated at high density. In this report, we show that high cell density induces ABCA1 expression in glioblastoma cells, enabling them to get rid of excess cholesterol generated by an activated cholesterol biosynthesis pathway. Because oxysterols are agonists for Liver X Receptors (LXRs), we investigated whether increased cholesterol activates LXRs to maintain cholesterol homeostasis in highly-dense glioblastoma cells. We observed that dense cells had increased oxysterols, which activated LXR{beta} to upregulate ABCA1. Cells with CRISPR-mediated knockdown of LXR{beta}, but not ABCA1, had decreased cell cycle progression and cell survival, and decreased feedback repression of the mevalonate pathway in densely-plated glioma cells. LXR{beta} gene expression poorly correlates with ABCA1 in glioblastoma patients, and expression of each gene correlates with poor patient prognosis in different prognostic subtypes. Finally, gene expression and lipidomics analyses of crLXR{beta} cells revealed that LXR{beta} regulates the expression of immune response gene sets and lipids known to be involved in immune modulation. Thus, therapeutic targeting of LXR{beta} in glioblastoma might be effective through diverse mechanisms.

cancer biology↗

bioRxiv2019

Knockdown of PTOV1 and PIN1 Exhibit Common Phenotypic Anti-Cancer Effects in MDA-MB-231 Cells

BackgroundEarlier, we have identified PTOV1 as a novel interactome of PIN1 in PC-3 cells. This study aims to explore the functional similarity and the common role of both genes in breast cancer cell proliferation.\n\nMethodsCTG, crystal violet assay, clonogenic assay, wound healing assay, cell cycle analysis, Hoechst staining and ROS measurement were performed to assess cell viability were performed after knocking down of PTOV1 and PIN1 by siRNAs in MDA-MB-231 and MCF-7 cells. CO-IP, qPCR and western blot were performed for interaction, transcriptional and translational regulation of both genes.\n\nResultsKnockdown of PTOV1 and PIN1 inhibited the cell proliferation, colony formation, migration cell cycle, and induces nuclear condensation as well as ROS production. Interaction of PTOV1 and PIN1 was validated by Co-IP in MDA-MB-231 cells. Genes involved in cell proliferation, migration, cell cycle, and apoptosis were regulated by PIN1 and PTOV1. PTOV1 knockdown inhibited Bcl-2, Bcl-xL and induces BAX, LC3 and Beclin-1. Overexpression of PIN1 increased the expression of PTOV1. Knockdown of both genes inhibited the expression of cyclin D1, c-Myc, and {beta}-catenin.\n\nConclusionsPTOV1 and PIN1 interacts and exert oncogenic role in MDA-MB-231 cells by sharing the similar expression profile at transcriptional and translational level which can be a promising hub for therapeutic target.

cell biology↗

bioRxiv2018

Structural and functional impact of non- synonymous SNPs in the CST complex subunit TEN1: Structural genomics approach

TEN1 protein is a key component of CST complex, implicated in maintaining the telomere homeostasis, and provide stability to the eukaryotic genome. Mutations in TEN1 gene have higher chances of deleterious impact; thus, interpreting the number of mutations and their consequential impact on the structure, stability and function is essentially important. Here, we have investigated the structural and functional consequences of nsSNPs in the TEN1 gene. A wide array of sequence- and structure-based computational prediction tools were employed to identify the effects of 78 nsSNPs on the structure and function of TEN1 protein and deleterious nsSNPs were identified. These deleterious or destabilizing nsSNPs are scattered throughout the structure of TEN1. However, major mutations were observed in the 1-helix (12-16) and {beta}5-strand (88-96). We further observed that mutations at C-terminal region were have higher tendency to form aggregate. In-depth structural analysis of these mutations reveals that the pathogenecity of these mutations are driven mainly through larger structural changes because of alterations in non-covalent interactions. This work provides a blue print to pinpoint the possible consequences of pathogenic mutations in the CST complex subunit TEN1.

evolutionary biology↗

bioRxiv2018

Genetic determinants of risk and survival in pulmonary arterial hypertension

BackgroundPulmonary arterial hypertension (PAH) is a rare disorder leading to premature death. Rare genetic variants contribute to disease etiology but the contribution of common genetic variation to disease risk and outcome remains poorly characterized.\n\nMethodsWe performed two separate genome-wide association studies of PAH using data across 11,744 European-ancestry individuals (including 2,085 patients), one with genotypes from 5,895 whole genome sequences and another with genotyping array data from 5,849 further samples. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. We functionally annotated associated variants and tested associations with duration of survival.\n\nFindingsA locus at HLA-DPA1/DPB1 within the class II major histocompatibility (MHC) region and a second near SOX17 were significantly associated with PAH. The SOX17 locus contained two independent signals associated with PAH. Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. PAH risk variants determined haplotype-specific enhancer activity and CRISPR-inhibition of the enhancer reduced SOX17 expression. Analysis of median survival showed that PAH patients with two copies of the HLA-DPA1/DPB1 risk variant had a two-fold difference (>16 years versus 8 years), compared to patients homozygous for the alternative allele.\n\nInterpretationWe have found that common genetic variation at loci in HLA-DPA1/DPB1 and an enhancer near SOX17 are associated with PAH. Impairment of Sox17 function may be more common in PAH than suggested by rare mutations in SOX17. Allelic variation at HLA-DPB1 stratifies PAH patients for survival following diagnosis, with implications for future therapeutic trial design.\n\nFundingUK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, Inserm, Universite Paris-Sud, and French ANR.

genetics↗

bioRxiv2018

Silencing of the CSNK2β gene by siRNA inhibits invasiveness and growth of MDA-MB-231 cells

BackgroundBreast cancer is most common cancer and accounts for one-fourth of all cancer diagnoses worldwide. Treatment of triple-negative breast cancer is major challenge and identification of specific drivers is required for targeted therapies. The aim of our present study is to elucidate the therapeutic potential of CSNK2{beta} silencing in triple negative breast cancer MDA-MB-231 cell.\n\nMethodsCSNK2{beta} gene has been knockdown using siRNA and silencing was estimated by both real time and western blot. Cell Titer-Glo (CTG) and colony formation assay and wound healing assay, cell cycle analysis by flow cytometry was performed to assess the role of CSNK2{beta} in cell proliferation, migration, cell cycle, and oncogenesis. Morphological assessment of nuclear condensation, apoptosis by Hoechst staining and measurement of intracellular ROS production was examined using fluorescence microscopy. Real time PCR and western blot was done to study the expression of genes related to cell proliferation, survival, metastasis, apoptosis, and autophagy.\n\nResultsSilencing of CSNK2{beta} in MDA-MB-231 cells resulted in decreased cell viability, colony formation, and migratory potential. Cell cycle analysis showed that growth inhibitory effect was mediated by arresting the cells in G2/M phase. Furthermore, we demonstrated that silencing of CSNK2{beta} increased the nuclear condensation and intracellular ROS production. CSNK2{beta} regulates the expression of BAX, Bcl-xL, caspase 3, Beclin-1, LC3-I, p-ERK, p38-, c-Myc, MAPK, c-Jun, NF-B, {beta}-catenin, E2F1, PCNA. We have also shown the functional relationship between CSNK2{beta}, PIN1, and PTOV1 by western blotting. We have first time reported that silencing CSNK2{beta} using siRNA can inhibit invasiveness and proliferation of MDA-MB-213 cells.\n\nConclusionOur results suggested that CSNK2{beta} silencing may offer future therapeutic target in triple negative breast cancer.

cancer biology↗