Biology subjects

Patel, P.

Publications and source records attributed to Patel, P..

10 recordsLinked to original sources

bioRxiv2018

Group Based Trajectory Analysis of Cognitive Outcomes in Children with Perinatal HIV

BackgroundCognitive impairment is common in children with perinatally-acquired HIV (pHIV). It is not known whether exposure to HIV-related neuropathogenic mechanisms during vulnerable periods of neurodevelopment may produce distinct long-term cognitive phenotypes as children age. We used group based trajectory modeling to identify clusters of children with pHIV following a unique developmental trajectory across age and predictors of belonging to select cognitive trajectory groups.\n\nMethodsParticipants included children aged 1 to 17 enrolled in the PREDICT resilience study, a cohort study of children with pHIV in Thailand and Cambodia. Cognitive testing was conducted semi-annually over three years. Group based trajectory analyses determined subgroups of children with differing cognitive trajectories using maximum likelihood estimates and Bayesian statistics. Multiple logistic regression identified baseline factors associated with belonging to the lowest scoring trajectory group.\n\nResultsThree distinct cognitive phenotypes were identified for each neurocognitive test categorized as high, medium and low scoring groups. A subgroup of children demonstrated normal developmental patterns for Color Trails Test 1 and 2. Children in the low trajectory group were more likely to present at an older age (>8 years, OR: 2.72; p 0.01) and report lower household income level (OR: 0.33-0.42; p<0.005). Neither CD4 nadir nor treatment arm was associated with cognitive trajectory status.\n\nConclusionOur study reflects the benefit of using group based trajectory modeling to classify the heterogeneity in cognitive outcomes of children with pHIV. Children were described as belonging to three distinct subgroups determined at study onset alluding to the fact that cognitive outcomes are likely to be determined at an early age with little variability over time in children with pHIV. Demographic variables, including older age at presentation and household income, were associated with low scoring cognitive trajectories, whereas HIV related variables were not. These findings mirror other studies and demonstrate the impact of socioeconomic factors on cognitive development in children with pHIV.

neuroscience↗

bioRxiv2018

Using selective lung injury to improve murine models of spatially heterogeneous lung diseases

Many lung diseases, such as acute respiratory distress syndrome (ARDS), display significant regional heterogeneity, with patches of severely injured tissue adjacent to apparently healthy tissue. Current mouse models that aim to mimic ARDS generally produce diffuse injuries that cannot reproducibly generate ARDSs regional heterogeneity. This deficiency prevents the evaluation of how well therapeutic agents reach the most injured regions, and precludes many regenerative medicine studies, since it is not possible to know which apparently healing regions suffered severe injury initially. Finally, these diffuse injury models must be mild to allow for survival, as their diffuse nature does not allow for residual healthy lung to keep an animal alive long enough for many drug and regenerative medicine studies. To solve all of these deficiencies of current animal models, we have created a simple and reproducible technique to selectively induce lung injury in specific areas of the lung. Our technique, catheter-in-catheter selective lung injury (CICSLI), involves guiding an inner catheter to a particular area of the lung and delivering an injurious agent mixed with nanoparticles (fluorescently and/or radioactively labeled) that can be used to track the location and extent of where the initial injury was, days later. Further, we demonstrate that CICSLI can produce a more severe injury than diffuse models, yet has much higher survival since CICSLI intentionally leaves undamaged lung regions. Collectively, these attributes of CICSLI will allow better study of how drugs act within heterogeneous lung pathologies and how regeneration occurs in severely damaged lung tissue, thereby aiding the development of new therapies for ARDS and other lung diseases.

pharmacology and toxicology↗

bioRxiv2018

Selective axonal translation of prenylated Cdc42 mRNA isoform supports axon growth

The small Rho-family GTPase Cdc42 has long been known to have a role in cell motility and axon growth. The eukaryotic CDC42 gene is alternatively spliced to generate mRNAs with two different 3UTRs that encode proteins with distinct C-termini. The C-termini of these Cdc42 proteins include CAAX and CCAX motifs for post-translational prenylation and palmitoylation, respectively. Palmitoyl-Cdc42 protein was previously shown to contribute to dendrite maturation, while the prenyl-Cdc42 protein contributes to axon specification and its mRNA was detected in neurites. Here, we show that the mRNA encoding prenyl-Cdc42 isoform preferentially localizes into PNS axons and this localization selectively increases in vivo during PNS axon regeneration. Isoform specific siRNA knockdowns, rescue experiments with siRNA-resistant Cdc42 isoforms, and pharmacologically targeting Cdc42 activity indicate that prenyl-Cdc42 promotes axon growth while the palmitoyl-Cdc42 has little growth promoting activity. The growth promotion by prenyl-Cdc42 requires axonal mRNA localization with localized translation and an intact C-terminal CaaX motif for localized prenylation of the encoded protein. Together, these data show that alternative splicing of the CDC42 gene product generates an axon growth promoting locally synthesized prenyl-Cdc42 protein. SUMMARY STATEMENTAxon regeneration drives selective localization of alternatively spliced CDC42 isoform to PNS axons.

neuroscience↗

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

Reproductive phasiRNAs in grasses are compositionally distinct from other classes of small RNAs

Summary and keywordsO_LILittle is known about the characteristics and function of reproductive phased, secondary, small interfering RNAs (phasiRNAs) in the Poaceae, despite the availability of significant genomic resources, experimental data, and a growing number of computational tools. We utilized machine-learning methods to identify sequence-based and structural features that distinguish phasiRNAs in rice and maize from other small RNAs (sRNAs).\nC_LIO_LIWe developed Random Forest classifiers that can distinguish reproductive phasiRNAs from other sRNAs in complex sets of sequencing data, utilizing sequence-based (k-mers) and features describing position-specific sequence biases.\nC_LIO_LIThe classification performance attained is >80% in accuracy, sensitivity, specificity, and positive predicted value. Feature selection identified important features in both ends of phasiRNAs. We demonstrated that phasiRNAs have strand specificity and position-specific nucleotide biases potentially influencing AGO sorting; we also predicted targets to infer functions of phasiRNAs, and computationally-assessed their sequence characteristics relative to other sRNAs.\nC_LIO_LIOur results demonstrate that machine-learning methods effectively identify phasiRNAs despite the lack of characteristic features typically present in precursor loci of other small RNAs, such as sequence conservation or structural motifs. The 5-end features we identified provide insights into AGO-phasiRNA interactions; we describe a hypothetical model of competition for AGO loading between phasiRNAs of different nucleotide compositions.\nC_LI

plant biology↗

bioRxiv2017

Resolving the Full Spectrum of Human Genome Variation using Linked-Reads

Large-scale population based analyses coupled with advances in technology have demonstrated that the human genome is more diverse than originally thought. To date, this diversity has largely been uncovered using short read whole genome sequencing. However, standard short-read approaches, used primarily due to accuracy, throughput and costs, fail to give a complete picture of a genome. They struggle to identify large, balanced structural events, cannot access repetitive regions of the genome and fail to resolve the human genome into its two haplotypes. Here we describe an approach that retains long range information while harnessing the advantages of short reads. Starting from only [~]1ng of DNA, we produce barcoded short read libraries. The use of novel informatic approaches allows for the barcoded short reads to be associated with the long molecules of origin producing a novel datatype known as Linked-Reads. This approach allows for simultaneous detection of small and large variants from a single Linked-Read library. We have previously demonstrated the utility of whole genome Linked-Reads (lrWGS) for performing diploid, de novo assembly of individual genomes (Weisenfeld et al. 2017). In this manuscript, we show the advantages of Linked-Reads over standard short read approaches for reference based analysis. We demonstrate the ability of Linked-Reads to reconstruct megabase scale haplotypes and to recover parts of the genome that are typically inaccessible to short reads, including phenotypically important genes such as STRC, SMN1 and SMN2. We demonstrate the ability of both lrWGS and Linked-Read Whole Exome Sequencing (lrWES) to identify complex structural variations, including balanced events, single exon deletions, and single exon duplications. The data presented here show that Linked-Reads provide a scalable approach for comprehensive genome analysis that is not possible using short reads alone.

genomics↗

bioRxiv2017

Pervasive epistasis in cell proliferation pathways modulates neurodevelopmental defects of autism-associated 16p11.2 deletion

As opposed to syndromic CNVs caused by single genes, extensive phenotypic heterogeneity in variably-expressive CNVs complicates disease gene discovery and functional evaluation. Here, we propose a complex interaction model for pathogenicity of the autism-associated 16p11.2 deletion, where CNV genes interact with each other in conserved pathways to modulate expression of the phenotype. Using multiple quantitative methods in Drosophila RNAi lines, we identified a range of neurodevelopmental phenotypes for knockdown of individual 16p11.2 homologs in different tissues. We tested 565 pairwise knockdowns in the developing eye, and identified 24 interactions between pairs of 16p11.2 homologs and 46 interactions between 16p11.2 homologs and neurodevelopmental genes that suppressed or enhanced cell proliferation phenotypes compared to one-hit knockdowns. These interactions within cell proliferation pathways were also enriched in a human brain-specific network, providing translational relevance in humans. Our study indicates a role for genetic interactions within CNVs and identifies potential therapeutic targets for neurodevelopmental disorders.

genomics↗

bioRxiv2017

Anti-infective potential of a quorum modulatory polyherbal extract (Panchvalkal) against certain pathogenic bacteria

Anti-infective potential of a polyherbal ayurvedic formulation namely panchvalkal was assayed against three pathogenic bacteria. This formulation was found to exert quorum-modulatory effect on Chromobacterium violaceum, Serratia marcescens, and Staphylococcus aureus at 250-750 g/mL. Besides altering production of the quorum sensing-regulated pigments in these bacteria, the test formulation also had in vitro effect on antibiotic susceptibility, catalase activity and hemolytic potential of the pathogens. In vivo assay confirmed the protective effect of this panchvalkal formulation on Caenorhabditis elegans, when challenged with the pathogenic bacteria. Repeated exposure of S. aureus to panchvalkal did not induce resistance in this bacterium. To the best of our awareness, this the first report on quorum-modulatory potential of panchvalkal formulation, validating the anti-infective potential and moderate prebiotic property of this polyherbal preparation.

microbiology↗

bioRxiv2017

PHASIS: A computational suite for de novo discovery and characterization of phased, siRNA-generating loci and their miRNA triggers

Phased, secondary siRNAs (phasiRNAs) are found widely in plants, from protein-coding transcripts and long, non-coding RNAs; animal piRNAs are also phased. Integrated methods characterizing \"PHAS\" loci are unavailable, and existing methods are quite limited and inefficient in handling large volumes of sequencing data. The PHASIS suite described here provides complete tools for the computational characterization of PHAS loci, with an emphasis on plants, in which these loci are numerous. Benchmarked comparisons demonstrate that PHASIS is sensitive, highly scalable and fast. Importantly, PHASIS eliminates the requirement of a sequenced genome and PARE/degradome data for discovery of phasiRNAs and their miRNA triggers.

bioinformatics↗

bioRxiv2017

Frequency-dependent response of Chromobacterium violaceum to sonic stimulation, and altered gene expression associated with enhanced violacein production at 300 Hz

Chromobacterium violaceum was subjected to sonic (100-2000 Hz) stimulation, and the effect on its cell yield and quorum sensing regulated pigment (violacein) production was investigated. Sound corresponding to the 300 Hz was found to promote (by 1.52 fold) violacein production the most, with only marginal impact on cell yield. Whole transcriptome analysis revealed that a total of 342 genes (i.e. 4.63% of whole genome) were significantly up-regulated in the sonic stimulated culture. Enhanced violacein production in the sound stimulated culture seems to have stemmed from enhanced expression of the genes involved in glucose metabolism through pentose phosphate pathway, resulting in increased availability of erythrose-4-phosphate, to be used for synthesis of tryptophan, the precursor for violacein synthesis. Multiple ribosomal subunit genes, enzyme coding genes, and those associated with secretion/transport were up-regulated owing to sonic stimulation. This study is a good demonstration of the ability of sound waves to alter bacterial metabolism.

microbiology↗