Biology subjects

Khalid, M. F.

Publications and source records attributed to Khalid, M. F..

4 recordsLinked to original sources

bioRxiv2024

Causality Mapping Using Resting-state fMRI Reveals Hyperactivity and Hypoconnectivity in Schizophrenia Patients

Schizophrenia (SZ) is a debilitating disorder in which patients exhibit psychotic behavior due to aberrant connectivity between different regions of the brain. Advances in neuroimaging have now enabled the diagnosis and analysis of SZ in order to elucidate the whole brain functional connectivity networks. In the present study, we have used resting-state functional magnetic resonance imaging (rs-fMRI) to elucidate the causal relationships amongst the differentially activated brain regions between SZ patients (n=10) and healthy controls (n=10). Vector auto-regression (VAR) model and Granger causality (GC) were then applied to construct a functional connectivity network and analyze the causal effects in SZ patients. Our results revealed that the average voxel activation in the frontal lobe (FL), basal ganglia (BG), and ventricular system (VS) was significantly higher in patients indicating hyper-activity as compared to controls. Conversely, cerebellum white matter (CBWM) showed higher activation in the controls as compared to patients. A higher Pearson correlation was observed between the controls as compared to patients while VAR and GC showed higher functional connectivity among all the regions of interest (ROIs) along with more causal relations in the controls. Finally, mediation analysis showed that right middle superior frontal gyrus acts as a strong partial mediator between left accumbens area and left middle superior frontal gyrus. Taken together, this study decodes the dysregulated brain activity in schizophrenia showing hyperactivation in patients when compared with the healthy controls which leads to alterations in neural connections resulting in hypoconnectivity.

neuroscience↗

bioRxiv2022

The Solvation of the E. coli CheY Phosphorylation SiteMapped by XFMS

The Escherichia coli CheY protein belongs to a large bacterial response regulator superfamily. X-ray hydroxy radical foot-printing with mass spectroscopy (XFMS) has shown that allosteric activation of CheY by its motor target triggers a concerted internalization of aromatic sidechains. We reanalyzed the XFMS data to compare polar versus non-polar CheY residue positions. The polar residues around and including the 57D phosphorylated site had an elevated hydroxy radical reactivity. Bioinformatic measures revealed that a water-mediated hydrogen bond network connected this ring of residues with the central 57D. These residues solvated 57D to energetically stabilize the apo-CheY fold. The abundance of these reactive residues was reduced upon activation. This result was supported by the bioinformatics and consistent with the previously reported activation-induced increase in core hydrophobicity. It further illustrated XFMS detection of structural waters. Direct contacts between the ring residues and the phosphorylation site would stabilize the aspartyl phosphate. In addition, we report that the ring residue, 18R, is a constant central node in the 57D solvation network and that 18R non-polar substitutions determine CheY diversity as assessed by its evolutionary trace in bacteria with well-studied chemotaxis. These results showcase the importance of structured water dynamics for phosphorylation-mediated signal transduction.

biochemistry↗

bioRxiv2022

CanSeer: A Method for Development and Clinical Translation of Personalized Cancer Therapeutics

Computational modeling and analysis of biomolecular network models annotated with cancer patient-specific multi-omics data can enable the development of personalized therapies. Current endeavors aimed at employing in silico models towards personalized cancer therapeutics remain to be fully translated. In this work, we present "CanSeer" a novel multi-stage methodology for developing in silico models towards clinical translation of personalized cancer therapeutics. The proposed methodology integrates state-of-the-art dynamical analysis of biomolecular network models with patient-specific genomic and transcriptomic data to assess the individualized therapeutic responses to targeted drugs and their combinations. CanSeers translational approach employs transcriptomic data (RNA-seq based gene expressions) with genomic profile (CNVs, SMs, and SVs). Specifically, patient-specific cancer driver genes are identified, followed by the selection of druggable and/or clinically actionable targets for therapeutic interventions. To exemplify CanSeer, we have designed three case studies including (i) lung squamous cell carcinoma, (ii) breast invasive carcinoma, and (iii) ovarian serous cystadenocarcinoma. The case study on lung squamous cell carcinoma concluded that restoration of Tp53 activity together with an inhibition of EGFR as an efficacious combinatorial treatment for patients with Tp53 and EGFR cancer driver genes. The findings from the cancer case study helped identify personalized treatments including APR-246, APR-246+palbociclib, APR-246+osimertinib, APR-246+afatinib, APR-246+osimertinib+dinaciclib, and APR-246+afatinib+dinaciclib. The second case study on breast invasive carcinoma revealed CanSeers potential to elucidate drug resistance against targeted drugs and their combinations including KU-55933, afuresertib, ipatasertib, and KU-55933+afuresertib. Lastly, the ovarian cancer case study revealed the combinatorial efficacy of APR-246+carmustine, and APR-246+dinaciclib for treating ovarian serous cystadenocarcinoma. Taken together, CanSeer outlines a novel method for systematic identification of optimal tailored treatments with mechanistic insights into patient-to-patient variability of therapeutic response, drug resistance mechanism, and cytotoxicity profiling towards personalized medicine.

systems biology↗

bioRxiv2020

Loss of Activating Transcription Factor 3 prevents KRAS-mediated pancreatic cancer

The unfolded protein response (UPR) is activated in pancreatic pathologies and suggested as a target for therapeutic intervention. In this study, wxe examined Activating Transcription Factor 3 (ATF3), a mediator of the UPR which promotes acinar-to-ductal metaplasia (ADM) in response to pancreatic injury. Since ADM is an initial step in the progression to pancreatic ductal adenocarcinoma (PDAC), we hypothesized ATF3 is required for initiation and progression of PDAC. We generated mice carrying a germ line mutation of Atf3 (Atf3-/-) combined with acinar-specific induction of oncogenic KRAS (Ptf1acreERT/+KrasLSL-G12D). Atf3-/- mice with (termed APK) and without KRASG12D were exposed to cerulein-induced pancreatitis. In response to recurrent pancreatitis, Atf3-/- mice showed decreased ADM and enhanced regeneration based on morphological and biochemical analysis. Similarly, an absence of ATF3 reduced spontaneous pancreatic intraepithelial neoplasia formation and PDAC in Ptf1acreERT/+KrasLSL-G12D mice. In response to injury, KRASG12D bipassed the requirement for ATF3 with a dramatic loss in acinar tissue and PanIN formation observed regardless of ATF3 status. However, unlike Ptf1acreERT/+KrasLSL-G12D mice, APK mice exhibited a cachexia-like phenotype, did not progress through to PDAC, and showed altered pancreatic fibrosis and immune cell infiltration. These findings suggest a complex, multifaceted role for ATF3 in pancreatic cancer pathology.

cancer biology↗