Biology subjects

Suri, P.

Publications and source records attributed to Suri, P..

7 recordsLinked to original sources

bioRxiv2022

Species-specific CD4+ T cells Enable Prediction of Mucosal Immune Phenotypes from Microbiota Composition

How bacterial strains within a complex human microbiota collectively shape intestinal T cell homeostasis is not well-understood. Methods that quickly identify effector strains or species that drive specific mucosal T cell phenotypes are needed to define general principles for how the microbiota modulates host immunity. We colonize germ-free mice with defined communities of cultured strains and profile antigen-specific responses directed towards individual strains ex vivo. We find that lamina propria T cells are specific to bacterial strains at the species level and can discriminate between strains of the same species. Ex vivo restimulations consistently identify the strains within complex communities that induce Th17 responses in vivo providing the potential to shape baseline immune tone via community composition. Using an adoptive transfer model of colitis, we find that lamina propria T cells respond to different bacterial strains in conditions of inflammation versus homeostasis. Collectively, our approach represents a novel method for efficiently predicting the relative impact of individual bacterial strains within a complex community and for parsing microbiota-dependent phenotypes into component fractions. SIGNIFICANCEDetermining the mechanisms by which the gut microbiome modulates the host immune system has translational potential for treating or preventing immune mediated disease. A key challenge is identifying the immunogenic bacterial strains in the setting of a complex microbiota. We use a combination of anaerobic culturing, in vitro T cell assays, gnotobiotic mouse models, and ex vivo T cell restimulations to explore the influence of species and strain diversity on the specificity of mucosal T cells. Our approach efficiently predicts the relative impact of individual bacterial strains within a complex community and can be used to parse microbiota-dependent phenotypes into component fractions.

immunology↗

bioRxiv2021

Glycosylated Antibiotics: New Promising Bacterial 1 Efflux Pumps Inhibitors

BackgroundAntimicrobial resistance is considered a major concern problem; bacteria have evolved mechanisms to overcome antibiotics action through evolutionary process. One main resistance mechanism that bacteria developed is the pumping of the antibiotics out of bacterial cells by transmembrane transporter proteins known as efflux pumps. Materials and methodsTo overcome bacterial resistance guided by efflux pumps, efflux pumps inhibitors (EPIs) are small molecules that obstruct efflux pumps binding sites and its structural assembly leading to disability in the efflux pumps normal function, new EPIs which under the current study are created by modifying the chemical structure of most common antibiotics including Ampicillin, Penicillin, Chloramphenicol, Ciprofloxacin and Tetracycline, such antibiotics are modified by adding N-acetyl glucose amine moiety to acceptor OH group of the respective antibiotic, the newly modified antibiotics are glycosylated EPIs. To test the effectiveness of the new EPIs in inhibiting AcrB-TolC and MexA-OprM efflux pumps functions, ADME properties for all of glycosylated antibiotics have been measured through applying Lipinskis role of 5, docking and simulation studies have been included as well. ResultsDocked glycosylated tetracycline has given the highest binding energy in the active sites of both pumps, with -9.4 against AcrB and -8.8 against MexA. The simulation study has confirmed the binding of the glycosylated tetracycline in the active sites of both pumps, as well as its stability during the biological dynamicity of both pumps (opening and closing channels). ConclusionThe results validation requires a long simulation time about 50 ns or more which was un applicable due to cost limitation, however, the newly glycosylated antibiotics have promising results that might make it eligible as drug candidates to overcome bacterial resistance.

bioinformatics↗

bioRxiv2020

Chromosomal instability accelerates the evolution of resistance to anti-cancer therapies

Aneuploidy is a ubiquitous feature of human tumors, but the acquisition of aneuploidy is typically detrimental to cellular fitness. To investigate how aneuploidy could contribute to tumor growth, we triggered periods of chromosomal instability (CIN) in human cells and then exposed them to a variety of different culture environments. While chromosomal instability was universally detrimental under normal growth conditions, we discovered that transient CIN reproducibly accelerated the ability of cells to adapt and thrive in the presence of anti-cancer therapeutic agents. Single-cell sequencing revealed that these drug-resistant populations recurrently developed specific whole-chromosome gains and losses. We independently derived one aneuploidy that was frequently recovered in cells exposed to paclitaxel, and we found that this chromosome loss event was sufficient to decrease paclitaxel sensitivity. Finally, we demonstrated that intrinsic levels of CIN correlate with poor responses to a variety of systemic therapies in a collection of patient-derived xenografts. In total, our results show that while chromosomal instability generally antagonizes cell fitness, it also provides phenotypic plasticity to cancer cells that can allow them to adapt to diverse stressful environments. Moreover, our findings suggest that aneuploidy may function as an under-explored cause of therapy failure in human tumors.

cancer biology↗

bioRxiv2020

Complement factor C1q mediates chronic neuron loss and inflammation post-brain injury

While traumatic brain injury (TBI) acutely disrupts the cortex, most TBI-related disabilities reflect secondary injuries that accrue over time. The thalamus is a likely site of secondary damage because of its reciprocal connections with the cortex. Using a mouse model of cortical injury that does not directly damage subcortical structures, we found a chronic increase in C1q expression specifically in the corticothalamic circuit. Increased C1q expression co-localized with neuron loss and chronic inflammation, and correlated with altered cortical rhythms. Blocking C1q counteracted most of these outcomes, suggesting that C1q is a disease modifier in TBI. Since the corticothalamic circuit is important for sensory processing, attention, cognition, and sleep, all of which can be impaired by TBI, this circuit could be a new target for treating TBI-related disabilities.

neuroscience↗

bioRxiv2019

Analysis of genetically independent phenotypes identifies shared genetic factors associated with chronic musculoskeletal pain at different anatomic sites

Chronic musculoskeletal pain has a negative impact on all aspects of human life. Genetic studies of pain are complicated by the high complexity and heterogeneity of pain phenotypes. In this research, we aimed to reduce phenotype heterogeneity and reveal genes and pathways shared by chronic musculoskeletal pain at four locations: back, neck/shoulder, hip, and knee. Our study was based on the results of genome-wide association studies performed using UK Biobank data with a total sample size of 456,000 individuals. We applied principal component analysis based on the matrix of genetic covariances between the studied pain traits and constructed four genetically independent phenotypes (GIPs). The leading GIP (GIP1) explains the largest proportion of the genetic variance of and covariance between the analyzed phenotypes (78.4%), and the later GIPs (GIP2-4) explain progressively less. We identified and replicated five loci associated with GIP1 and one locus associated with GIP2. The genes decisively prioritized for the GIP1-associated loci were SLC39A8, ECM1, and FOXP2. For the remaining two GIP1-associated loci, we proposed several candidates (AMIGO3, BSN, RBM6, FAM212A, RNF123, UBA7 and MIR7114, NSMF, NOXA1, GRIN1), but were unable to prioritize any of them convincingly. The most likely causal gene in the locus associated with GIP2 was GDF5. For GIP1, gene set/tissue/cell type enrichment analyses identified multiple terms related to the nervous system. Genetic correlations analysis revealed a genetic overlap between GIP1 and osteoarthritis as well as a set of anthropometric (such as overweight and waist circumference), sociodemographic (such as age of first birth and college completion) and psychiatric/personality (such as depressive symptoms and neuroticism) traits. We suggest that GIP1 represents a biopsychological component of chronic musculoskeletal pain, related to physiological and psychological aspects and likely reflecting pain perception and processing.

genomics↗

bioRxiv2018

Insight into the genetic architecture of back pain and its risk factors from a study of 509,000 individuals

Back pain (BP) is a common condition of major social importance and poorly understood pathogenesis. Combining data from the UK Biobank and CHARGE consortium cohorts allowed us to perform a very large GWAS (total N = 509,070) and examine the genetic correlation and pleiotropy between BP and its clinical and psychosocial risk factors. We identified and replicated three BP associated loci, including one novel region implicating SPOCK2/CHST3 genes. We provide evidence for pleiotropic effects of genetic factors underlying BP, height, and intervertebral disc problems. We also identified independent genetic correlations between BP and depression symptoms, neuroticism, sleep disturbance, overweight, and smoking. A significant enrichment for genes involved in central nervous system and skeletal tissue development was observed. The study of pleiotropy and genetic correlations, supported by the pathway analysis, suggests at least two strong molecular axes of BP genesis, one related to structural/anatomic factors such as intervertebral disk problems and anthropometrics; and another related to the psychological component of pain perception and pain processing. These findings corroborate with the current biopsychosocial model as a paradigm for BP. Overall, the results demonstrate BP to have an extremely complex genetic architecture that overlaps with the genetic predisposition to its biopsychosocial risk factors. The work sheds light on pathways of relevance in the prevention and management of LBP.

genetics↗

bioRxiv2018

Genome-wide Meta-analysis of 158,000 Individuals of European Ancestry Identifies Three Loci Associated with Chronic Back Pain

OBJECTIVESTo conduct a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP).\n\nMETHODSAdults of European ancestry were included from 16 cohorts in Europe and North America. CBP cases were defined as those reporting back pain present for >3-6 months; non-cases were included as comparisons (\"controls\"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5x10-8. Suggestive (p<5x10-7) and genome-wide significant (p<5x10-8) variants were carried forward for replication or further investigation in an independent sample.\n\nRESULTSThe discovery sample was comprised of 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p=7.2x10-10). This was subsequently replicated in an independent sample of 283,752 subjects, including 50,915 cases (OR 1.06, p=5.3x10-11), and exceeded genome-wide significance in joint meta-analysis (0R=1.07, p=4.5x10-19). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p=4.4x10-13), and an intronic variant, rs4384683, in DCC (OR 0.97, p=2.4x10-10).\n\nDISCUSSIONIn this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).

genomics↗