Biology subjects

Khan, M. Z.

Publications and source records attributed to Khan, M. Z..

8 recordsLinked to original sources

bioRxiv2026

Antibody Correlates of Resilience to Staphylococcus aureus Disease and Recurrence in Children

Staphylococcus aureus remains a major global pathogen with no licensed vaccine and high recurrent infection burden, yet correlates of protection remain undefined. In a prospective pediatric cohort, we profiled 319 children spanning non-carriers, asymptomatic carriers, those with skin and soft tissue infection (SSTI), or invasive disease. We interrogated 182,149 antibody features, generating the most comprehensive S. aureus immune profiling dataset to date. Antibody responses increased with age, marked by expansion of IgG subclasses and Fc-receptor engagement. Asymptomatic carriage was associated with functional antibody profiles targeting conserved surface antigens and select toxins. Multivariate modeling robustly distinguished clinical phenotypes and identified high-value antigens associated with disease resilience. Protection from recurrent disease converged on enhanced Fc{gamma}R binding and antibody effector function. These findings nominate key antigen targets, and highlight anti-Hla neutralizing antibodies and functional antibodies to additional surface antigens that can be recapitulated through Fc engineering, informing next-generation vaccine and monoclonal antibody strategies.

immunology↗

bioRxiv2026

THERAPEUTIC EFFECTS OF AN INSULIN-LIKE GROWTH FACTOR I SENSITIZER IN TRAUMATIC BRAIN INJURY

Traumatic brain injury (TBI) is a condition of high incidence worldwide, but remains mostly undertreated. Previous observations in preclinical studies pointed to a beneficial effect of insulin-like growth factor 1 (IGF-1) in TBI. As brain injury is associated to loss of IGF-1 sensitivity, we tested the therapeutic potential of AIK3a305 (AIK3), a novel IGF-1 sensitizer. Twenty-four hours after mild TBI induced by controlled impact, mice received daily intraperitoneal injections of AIK3 during 4 weeks. We found that TBI-associated sensorimotor disturbances measured with the adhesive-removal test were reverted by AIK3 treatment. In addition, neurological and cognitive disturbances measured by the neurological severity score and Y maze respectively, were also ameliorated by treatment with the IGF-1 sensitizer, whereas increased anxiety after mild TBI was also normalized by AIK3. Circulating levels of IGF-1 were increased after AIK3 treatment in TBI mice, while serum IL-6 levels, a biomarker of inflammation associated to TBI were similar to control mice treated with AIK3. Transcriptomic analysis determined that treatment with AIK3 widely affected gene expression in TBI brains, showing a general reduction in both up- and down-regulated genes. Collectively, these data support the use of IGF-1 sensitizers such as AIK3 for treatment of TBI.

neuroscience↗

bioRxiv2025

The role of amygdala calcitonin gene-related peptide receptors on the development of persistent bladder pain in mice.

Bladder pain significantly impacts millions worldwide, severely affecting their quality of life and posing a major clinical challenge. Understanding the mechanisms underlying persistent bladder pain is critical for developing better therapeutic strategies. In this study, we investigate the effects of cyclophosphamide (CYP)-induced persistent bladder sensitization to explore the lateralized contribution of amygdala calcitonin gene-related peptide receptors (CGRP-Rs) on pain-like changes in mice. We demonstrate that CYP induces hypersensitivity lasting up to 14 days post-injury (DPI) in the urinary bladder distention assay and up to 21 DPI when assessing abdominal mechanical sensitivity. Despite persistent pain-like changes, no significant bladder histological changes were observed. Based on previous findings that CGRP signaling from the parabrachial nucleus contributes to central amygdala (CeA) lateralization, we hypothesized that CGRP-Rs play a key role in driving visceral bladder pain-related hemispherical differences. We show that inhibiting CGRP-R activity with the antagonist CGRP8-37, in the right CeA attenuates bladder pain-like behavior, whereas left CeA inhibition sustains CYP-induced hypersensitivity. Electrophysiological recordings revealed increased firing frequency in CGRP-R positive cells in the right CeA 7 DPI. In vivo single photon calcium imaging demonstrated increased Ca transients in CGRP-R-positive cells in the right CeA, upon the presentation of a stimulus at 0 DPI, and overall at 2DPI, further confirming the pronociceptive role of CGRP-Rs in the right CeA. Taken together, these findings provide a crucial foundation for understanding pain-induced CeA lateralization and for further studies identifying how targeting CGRP signaling could provide bladder pain relief.

neuroscience↗

bioRxiv2025

INFLUENCE OF LIFESTYLE ON BRAIN SENSITIVITY TO CIRCULATING INSULIN-LIKE GROWTH FACTOR 1

Life style conditions such as social relationships and diet impinge on mood homeostasis, a mechanism that becomes dysregulated in high-incidence mental illnesses such as depression or Alzheimers dementia (AD). Since insulin-like growth factor 1 (IGF-1) modulates mood and its blood levels are altered both in AD and in affective disorders, we investigated whether its activity was altered in the brain of mice submitted to isolation or fed with a high-fat diet (HFD). As in humans, both life style conditions increased anxiety and depression-like behavior. Significantly, both life style conditions abrogated neuronal responses to systemic IGF-1. Thus, enhanced neuronal activity in response to intraperitoneal IGF-1, as determined by Ca++ fiber-photometry in the prefrontal cortex, was lost in isolated or HFD-fed mice. However, only the latter had elevated serum IGF-1 levels. These findings suggest that loss of brain IGF-1 input may contribute to mood disturbances observed in lonely and obese subjects. Furthermore, they provide additional insight into the heightened risk of depression and Alzheimers disease associated with these conditions. Importantly, since the reduction of IGF-1 activity in the brain is not consistently mirrored by its serum levels, serum measurements do not reliably reflect brain IGF-1 activity.

neuroscience↗

bioRxiv2023

A mitochondrial quality control mechanism reverses the phagosome maturation arrest caused by Mycobacterium tuberculosis

Phagosome maturation arrest (PMA) imposed by Mycobacterium tuberculosis (Mtb) is a classic tool that helps Mtb evade macrophage anti-bacterial responses. The exclusion of RAB7, a small GTPase, from Mtb-phagosomes causes PMA. Here, we report an unexpected mechanism that triggers crosstalk between the mitochondrial quality control (MQC) and the phagosome maturation pathways that reverses the PMA. CRISPR-mediated p62/SQSTM1 depletion (p62KD) does not appear to impact mitochondrial quality. The p62KD cells are restrictive to Mtb growth, triggered by an increasingly oxidative environment and increased lysosomal targeting. The lysosomal targeting of Mtb is facilitated by enhanced TOM20+ mitochondria-derived vesicles (MDVs) biogenesis, a key MQC mechanism. In p62KD cells, TOM20+-MDVs biogenesis is MIRO1/MIRO2-dependent and gets delivered to lysosomes for degradation in a RAB7-dependent manner. Upon infection in p62KD cells, TOM20+-MDVs get extensively targeted to Mtb-phagosomes, inadvertently facilitating RAB7 recruitment, PMA reversal and lysosomal targeting of Mtb; the phenotype also replicated in p62/SQSTM1 knockout cells. Triggering MQC collapse in p62KDcells further diminishes Mtb survival, signifying cooperation between redox- and lysosome-mediated mechanisms. The MQC-anti-bacterial pathway crosstalk could be exploited for host-directed anti-tuberculosis therapies.

microbiology↗

bioRxiv2022

Fully Transient CRISPR/Cas12f system in plants capable of broad-spectrum resistance against Begomovirus

CRISPR/Cas system has emerged as the most efficient genome editing technology for both eukaryotic and prokaryotic cells. Recently, biologist have started using CRISPR/Cas9 as a defence machinery in plants against DNA viruses by targeting conserve regions of their genome. Considerable resistance requires formation of stable transgenic lines with multiple gRNAs, targeting specific viruses. Development of such transgenic plants is not only time consuming but also there will always be some uncertainty of their efficiency and off targets in plant genome. Newly discovered miniature CRISPR/Cas12f (Cas14a) system has unique ability to chop down every ssDNA fragment once activated through targeted cleavage. Here we report first fully functional transient CRISPR/Cas12f system in plants. We also show that Cas12f with just one gRNA is enough for substantial broad-spectrum resistance against Gemini viruses. Plant phenotype showed nearly complete recovery and qPCR results showed multifold decrease infection of CLCuV in CRISPR/Cas12f treated plants compare to the infected plants (infected with CLCuMuV and CLCuKV). Smaller size, broad range and more efficiency make Cas12f a superior alternative of Cas9 against diverse group of ssDNA viruses.

plant biology↗

bioRxiv2021

Metabolic engineering of Bacillus subtilis with an Endopolygalacturonase gene Isolated from Pectobacterium carotovorum; a Plant Pathogenic bacterial strain.

Pectinolytic enzymes (pectinases) produced by microbes are highly important for their biotechnological use in processing of vegetables and fruits beverages and use in pulp and paper industry. A pectinase, namely endo-polygalacturonase (endo-PGase), encoding gene isolated from Pectobacterium carotovorum, a plant pathogenic strain of bacteria was successfully cloned into a secretion vector pHT43 having {sigma}A-dependent promoter P grac. For enhanced expression analysis, competent cells of Bacillus subtilis (WB800N) were prepared at stationary phase using high salt medium. The recombinant B. subtilis competent cells, harbouring the engineered pHT43 with the endo-PGase gene were cultured in 2X-yeast extract tryptone medium. The recombinant endo-PGase enzyme was secreted directly into the medium after 72 hours of the first IPTG induction. The recombinant endo-PGase was screened for its activity at various temperatures and pH ranges. Optimal activity was found at pH 5.0 and a temperature of 40{degrees}C with a stability ranging from pH 5.0-9.0. For detection of metal ion effect, recombinant enzyme was incubated with 1mM concentration of; Ca++, Mg++, Zn++, EDTA, K++ for 45 minutes. Resultantly, Ca++, EDTA and Zn++ strongly inhibited the enzyme activity. The chromatographic analysis of enzymatic hydrolysate of polygalacturonic acid (PGA) and pectin substrates using HPLC and TLC revealed that tri and tetra-galacturonates were the end products of hydrolysis. The study led to the conclusion that endo-PGase gene from the plant pathogenic strain was successfully expressed in Bacillus subtilis and could be assessed for enzyme production using a very simple medium with IPTG induction. These findings proposed that the Bacillus expression system might be safe for commercial enzyme production as compared to yeast and fungi to escape endotoxins.

bioengineering↗

bioRxiv2017

RNA virus interference via CRISPR/Cas13a system in plants

CRISPR/Cas systems confer immunity against invading nucleic acids and phages in bacteria and archaea. CRISPR/Cas13a (known previously as C2c2) is a class 2 type VI-A ribonuclease capable of targeting and cleaving single stranded RNA (ssRNA) molecules of the phage genome. Here, we employ CRISPR/Cas13a to engineer interference with an RNA virus, Turnip Mosaic Virus (TuMV), in plants. CRISPR/Cas13a produced interference against green fluorescent protein (GFP) expressing TuMV in transient assays and stable overexpression lines of Nicotiana benthamiana. crRNAs targeting the HC-Pro and GFP sequences exhibited better interference than those targeting other regions such as coat protein (CP) sequence. Cas13a can also process pre-crRNAs into functional crRNAs. Our data indicate that CRISPR/Cas13a can be used for engineering interference against RNA viruses, providing a potential novel mechanism for RNA-guided immunity against RNA viruses, and for other RNA manipulations in plants.

molecular biology↗