Biology subjects

Patel, H.

Publications and source records attributed to Patel, H..

9 recordsLinked to original sources

bioRxiv2018

Sonic stimulation, and low power microwave radiation can modulate bacterial virulence towards Caenorhabditis elegans

Caenorhabditis elegans worms infected with different pathogenic bacteria were subjected to sonic treatment to investigate whether such sound treatment can exert any therapeutic effect on the infected worms. Sonic therapy corresponding to 400 Hz, and the divine sound om were found to confer protective effect on this nematode worm in face of bacterial infection, particularly that caused by Serratia marcescens or Staphylococcus aureus. The observed effect seemed to occur due to influence of sound on bacteria, and not on the worm. In addition to this, effect of microwave exposure on bacterial virulence was also investigated, wherein microwave exposure was found to reduce virulence of S. aureus towards C. elegans.

microbiology↗

bioRxiv2018

Repression of divergent noncoding transcription by a sequence-specific transcription factor

Many active eukaryotic gene promoters exhibit divergent noncoding transcription, but the mechanisms restricting expression of these transcripts are not well understood. Here we demonstrate how a sequence-specific transcription factor represses divergent noncoding transcription at highly expressed genes in yeast. We find that depletion of the transcription factor Rap1 induces noncoding transcription in a large fraction of Rap1 regulated gene promoters. Specifically, Rap1 prevents transcription initiation at cryptic promoters near its binding sites, which is uncoupled from transcription regulation in the protein-coding direction. We further provide evidence that Rap1 acts independently of chromatin-based mechanisms to repress cryptic or divergent transcription. Finally, we show that divergent transcription in the absence of Rap1 is elicited by the RSC chromatin remodeller. We propose that a sequence-specific transcription factor limits access of basal transcription machinery to regulatory elements and adjacent sequences that act as divergent cryptic promoters, thereby providing directionality towards productive transcription.

molecular biology↗

bioRxiv2018

Knowledge, attitudes and awareness of the human papillomavirus among health professionals in New Zealand

BackgroundHuman papillomavirus (HPV) is a common sexually transmitted infection that is implicated in 99.7% of cervical cancers and several other cancers that affect both men and women. Despite the role that HPV plays in an estimated 5% of all cancers and the evolving role of HPV vaccination and testing in protecting the public against these cancers, preliminary research in New Zealand health care professionals suggest knowledge about HPV may not be sufficient.\n\nMethodsA total of 230 practice nurses, smear takers and other clinical and laboratory staff who attended a range of training events completed a cross-sectional survey between April 2016 and July 2017. The survey explored four broad areas: demographics and level of experience, HPV knowledge (general HPV knowledge, HPV triage and test of cure (TOC) knowledge and HPV vaccine knowledge), attitudes towards the HPV vaccine and self-perceived adequacy of HPV knowledge.\n\nResultsThe mean score on the general HPV knowledge questions was 13.2 out of 15, with only 25.2% of respondents scoring 100%. In response to an additional question, 14.0% thought (or were unsure) that HPV causes HIV/AIDS. The mean score on the HPV Triage and TOC knowledge questions was 7.4 out of 10, with only 9.1% scoring 100%. The mean score on the HPV vaccine knowledge questions was 6.0 out of 7 and 44.3% scored 100%. Only 62.6% of respondents agreed or strongly agreed that they were adequately informed about HPV, although 71.8% agreed or strongly agreed that they could confidently answer HPV-related questions asked by patients. Multivariate analyses revealed that knowledge in each domain predicted confidence in responding to patient questions. Furthermore, the number of years since training predicted both HPV knowledge and Triage and TOC knowledge.\n\nDiscussionAlthough overall level of knowledge was adequate, there were significant gaps in knowledge, particularly about the role of HPV testing in the New Zealand National Cervical Screening Programme. More education is required to ensure that misinformation and stigma do not inadvertently result from interactions between health practitioners and the public.

pathology↗

bioRxiv2018

Dynamic interplay of innate and adaptive immunity during sterile retinal inflammation: Insights from the transcriptome

The pathogenesis of many retinal degenerations, such as age-related macular degeneration (AMD), is punctuated by an ill-defined network of sterile inflammatory responses. The delineation of innate and adaptive immune milieu amongst the broad leukocyte infiltrate, and the gene networks which construct these responses, are poorly described in the eye. Using photo-oxidative damage in a rodent model of subretinal inflammation, we employed a novel RNA-sequencing framework to map the global gene network signature of retinal leukocytes. This revealed a previously uncharted interplay of adaptive immunity during subretinal inflammation, including prolonged enrichment of myeloid and lymphocyte migration, antigen presentation, and the alternative arm of the complement cascade involving Factor B. We demonstrate Factor B-deficient mice are protected against macrophage infiltration and subretinal inflammation. Suppressing the drivers of retinal leukocyte proliferation, or their capacity to elicit complement responses, may help preserve retinal structure and function during sterile inflammation in diseases such as AMD.

neuroscience↗

bioRxiv2018

TCR-MHC Interaction Strength Defines Trafficking and Resident Memory Status of CD8 T cells in the Brain

T cell receptor-Major histocompatibility complex (TCR-MHC) affinities span a wide range in a polyclonal T cell response, yet it is undefined how affinity shapes long-term properties of CD8 T cells during chronic infection with persistent antigen. Here, we investigate how the affinity of the TCR-MHC interaction shapes the phenotype of memory CD8 T cells in the chronically Toxoplasma gondii-infected brain. We employed CD8 T cells from three lines of transnuclear (TN) mice that harbour in their endogenous loci different T cell receptors specific for the same Toxoplasma antigenic epitope ROP7. The three TN CD8 T cell clones span a wide range of affinities to MHCI-ROP7. These three CD8 T cell clones have a distinct and fixed hierarchy in terms of effector function in response to the antigen measured as proliferation capacity, trafficking, T cell maintenance and memory formation. In particular, the T cell clone of lowest affinity does not home to the brain. The two higher affinity T cell clones show differences in establishing resident memory populations (CD103+) in the brain with the higher affinity clone persisting longer in the host during chronic infection. Transcriptional profiling of naive and activated ROP7-specific CD8 T cells revealed that Klf2 encoding a transcription factor that is known to be a negative marker for T cell trafficking is upregulated in the activated lowest affinity ROP7 clone. Our data thus suggest that TCR-MHC affinity dictates memory CD8 T cell fate at the site of infection.

immunology↗

bioRxiv2018

Effect of cytochrome CYP2C19 metabolizing activity on antidepressant response and side effects: meta-analysis of data from genome-wide association studies

Cytochrome (CYP) P450 enzymes have a primary role in antidepressant metabolism and variants in these polymorphic genes are targets for pharmacogenetic investigation. This is the first meta-analysis to investigate how CYP2C19 polymorphisms predict citalopram/escitalopram efficacy and side effects.\n\nCYP2C19 phenotypes comprise poor metabolizers (PM), intermediate and intermediate+ metabolizers (IM; IM+), extensive and extensive+ metabolizers (EM [wild type]; EM+) and ultra-rapid metabolizers (UM) defined by the two most common CYP2C19 functional polymorphisms (rs4244285 and rs12248560) in Caucasians. These polymorphisms were genotyped or imputed from genome-wide data in four samples treated with citalopram or escitalopram (GENDEP, STAR*D, GenPod, PGRN-AMPS). Treatment efficacy was percentage symptom improvement and remission. Side effect data were available at weeks 2-4, 6 and 9 in three of the investigated samples. A fixed-effects meta-analysis was performed using EM as the reference group.\n\nAnalysis of 2558 patients for efficacy and 2037 patients for side effects showed that PMs had higher symptom improvement (SMD=0.43, CI=0.19-0.66) and higher remission rates (OR=1.55, CI=1.23-1.96) compared to EMs. At weeks 2-4, PMs showed higher risk of gastro-intestinal (OR=1.26, CI=1.08-1.47), neurological (OR=1.28, CI=1.07-1.53) and sexual side effects (OR=1.52, CI=1.23-1.87; week 6 values similar). No difference was seen at week 9 or in total side effect burden. PMs did not have higher risk of dropout at week 4 compared to EMs. Antidepressant dose was not different among CYP2C19 groups.\n\nCYP2C19 polymorphisms may provide helpful information for guiding citalopram/escitalopram treatment, despite PMs are relatively rare among Caucasians (~2%).

genetics↗

bioRxiv2017

Does genetic risk help to predict amyloid burden in a non-demented population? A Bayesian approach.

INTRODUCTIONIn this study we investigate the association between A{beta} levels in cerebrospinal fluid (CSF) and genetic risk in a non-demented population. This paper presents the first analysis to use a Bayesian methodology in this area.\n\nMETHODSData from the Alzheimers Disease Neuroimaging Initiative (ADNI) and the EDAR* and DESCRIPA** studies was used in a Bayesian logistic regression analysis. We modeled CSF A{beta} burden using age, diagnosis (healthy control or mild cognitive impairment), APOE and a polygenic risk score (PGRS) associated with Alzheimers Disease (AD). We compared models built using informative priors on age, diagnosis and APOE with non-informative priors on all variables.\n\nRESULTSThe use of informative priors did not improve model performance in the majority of cases. Models using only age, diagnosis and APOE genotype showed the best predictive ability.\n\nDISCUSSIONA previous study indicated that a PGRS of AD case/control status was associated with CSF A{beta} burden in healthy controls. The current study suggests that this association does not lead to models that are more predictive of amyloid positivity than already known factors such as age and APOE.\n\n* Beta amyloid oligomers in the early diagnosis of AD and as marker for treatment response\n\n** Development of screening guidelines and criteria for pre-dementia Alzheimers disease

bioinformatics↗

bioRxiv2017

New insights on the pharmacogenomics of antidepressant response from the GENDEP and STAR*D studies: rare variant analysis and high-density imputation

Genome-wide association studies have generally failed to identify polymorphisms associated with antidepressant response. Possible reasons include limited coverage of genetic variants that this study tried to address by exome genotyping and dense imputation.\n\nA meta-analysis of Genome-Based Therapeutic Drugs for Depression (GENDEP) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies was performed at SNP, gene and pathway level. Coverage of genetic variants was increased compared to previous studies by adding exome genotypes to previously available genome-wide data and using the Haplotype Reference Consortium panel for imputation. Standard quality control was applied. Phenotypes were symptom improvement and remission after 12 weeks of antidepressant treatment. NEWMEDS consortium samples and Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) served for replication.\n\n7,062,950 SNPs were analysed in GENDEP (n=738) and STAR*D (n=1409). rs116692768 (p=1.80e-08, ITGA9 (integrin alpha 9)) and rs76191705 (p=2.59e-08, NRXN3 (neurexin 3)) were significantly associated with symptom improvement during citalopram/escitalopram treatment. At gene level, no consistent effect was found. At pathway level, the Gene Ontology terms GO:0005694 (chromosome) and GO:0044427 (chromosomal part) were associated with improvement (corrected p=0.007 and 0.045, respectively). The association between rs116692768 and symptom improvement was replicated in PGRN-AMPS (p=0.047), while rs76191705 was not. The two SNPs did not replicate in NEWMEDS.\n\nITGA9 codes for a membrane receptor for neurotrophins and NRXN3 is a transmembrane neuronal adhesion receptor involved in synaptic differentiation. Despite their meaningful biological rationale for being involved in antidepressant effect, no convincing replication was achieved. Further studies may help in clarifying their role.

genomics↗

bioRxiv2017

Applying polygenic risk scoring for psychiatric disorders within a family context

We aim to investigate the application of polygenic risk scoring within a family context. Polygenic risk profiles could aid in unraveling the role that common variation confers on disease risk within a pedigree that would have traditionally been viewed through the prism of monogenic inheritance only. We illustrate our discussion by analyzing polygenic risk scores for schizophrenia, major depressive disorder and bipolar disorder in a large pedigree (n~260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. We apply polygenic risk scores to study patterns of assortative mating and anticipation, whereby it appears increased polygenic risk for psychiatric disorders is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations in the family. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity of a disease increases over the generations of a family. Joint analyses of both rare and common variation may be the most powerful way to understand the familial genetics of mood and psychiatric disorders.

genetics↗