Study On the Human Gut Bacteria Under Different Ecological Conditions: Antibiotic Perturbation And Dietary Quercetin

The human intestine encompasses a vast community of microorganisms known as the gut microbiota that play a crucial role in maintaining health. Common perturbations such as changes in the normal diet, antibiotic treatment, and changes in environmental conditions can alter the gut microbiome. This can create dysbiosis in the gut leading to disease conditions. Therefore, it becomes important to determine the forces that influence the gut microbial ecology. In the first study, we focus on antibiotic perturbations on microbial succession and resilience in a synthetic consortium consisting of the most prevalent gut bacteria in humans. In addition, we investigated the ability of the consortium to provide colonization resistance against the gut enteric pathogen Clostridium difficile. The results show that the 14-species synthetic community formed after antibiotic perturbation is able to resist C. difficile, providing us insights for understanding the community effect against the pathogen and the possibility of using the synthetic community as a therapeutic. The bacteria Bacteroides caccae, Bacteroides thetataimicron, and Parabacteroides distanosis appear to increase significantly after antibiotic perturbation, accenting their role in inhibiting C. difficile growth. In the second study, we focus on the effects of supplementing quercetin on the gut microbiome. By using bioinformatic analysis, we predicted a subset of gut bacteria capable of degrading the flavonoid quercetin. From this information, we propose a set of quercetin degraders in the healthy individual that may be capable of producing antiproliferative metabolites through quercetin biotransformation. The bioinformatic analysis showed 64 gut bacteria were predicted to have enzymes capable of degrading quercetin. The abundance of the 64 bacteria was determined by analyzing shotgun metagenomes public datasets of healthy and colorectal cancer (CRC) patients and resulted in 11 bacteria being significantly higher in the healthy population. The two studies lay the groundwork to study the gut communities under different ecological conditions in further depth. Understanding the niche an organism occupies in the gut, its survival strategies, the interactions with other microbes and advantage of certain phenotypes of gut communities under stress can provide the answer to the basic functioning of the human microbiota

Voice Based Email System

As the technology advances the applications available for users can be made more user-friendly. This Voice Based Email System is developed for the people who require comfort and who are physically challenged. With the advent of technology, many technological solutions have been implemented so that people get benefited by utilizing them. Considering it as a key idea we propose to develop an application, Voice Based Email System which will be useful for every person to access the email functionalities in a hassle free manner. We have used 'Text to Speech' and �Speech to Text� voice converter named �Speech Recognition Anywhere� to facilitate sending and reading of emails. The speech synthesis can read aloud any written text avoiding eye strain and save time reading on computer. The existing email system, its drawbacks and our proposed methodology to overcome them have been discussed in this paper. Related work that has been done already is referred and taken as a guideline to finish our system

Excessive reactive oxygen species induce transcription-dependent replication stress.

Elevated levels of reactive oxygen species (ROS) reduce replication fork velocity by causing dissociation of the TIMELESS-TIPIN complex from the replisome. Here, we show that ROS generated by exposure of human cells to the ribonucleotide reductase inhibitor hydroxyurea (HU) promote replication fork reversal in a manner dependent on active transcription and formation of co-transcriptional RNA:DNA hybrids (R-loops). The frequency of R-loop-dependent fork stalling events is also increased after TIMELESS depletion or a partial inhibition of replicative DNA polymerases by aphidicolin, suggesting that this phenomenon is due to a global replication slowdown. In contrast, replication arrest caused by HU-induced depletion of deoxynucleotides does not induce fork reversal but, if allowed to persist, leads to extensive R-loop-independent DNA breakage during S-phase. Our work reveals a link between oxidative stress and transcription-replication interference that causes genomic alterations recurrently found in human cancer. [Abstract copyright: © 2023. The Author(s).

Excessive reactive oxygen species induce transcription-dependent replication stress

Elevated levels of reactive oxygen species (ROS) reduce replication fork velocity by causing dissociation of the TIMELESS-TIPIN complex from the replisome. Here, we show that ROS generated by exposure of human cells to the ribonucleotide reductase inhibitor hydroxyurea (HU) promote replication fork reversal in a manner dependent on active transcription and formation of co-transcriptional RNA:DNA hybrids (R-loops). The frequency of R-loop-dependent fork stalling events is also increased after TIMELESS depletion or a partial inhibition of replicative DNA polymerases by aphidicolin, suggesting that this phenomenon is due to a global replication slowdown. In contrast, replication arrest caused by HU-induced depletion of deoxynucleotides does not induce fork reversal but, if allowed to persist, leads to extensive R-loop-independent DNA breakage during S-phase. Our work reveals a link between oxidative stress and transcription-replication interference that causes genomic alterations recurrently found in human cancer

Efficient pre-mRNA cleavage prevents replication-stress-associated genome instability

Cellular mechanisms that safeguard genome integrity are often subverted in cancer. To identify cancer-related genome caretakers, we employed a convergent multi-screening strategy coupled to quantitative image-based cytometry and ranked candidate genes according to multivariate readouts reflecting viability, proliferative capacity, replisome integrity, and DNA damage signaling. This unveiled regulators of replication stress resilience, including components of the pre-mRNA cleavage and polyadenylation complex. We show that deregulation of pre-mRNA cleavage impairs replication fork speed and leads to excessive origin activity, rendering cells highly dependent on ATR function. While excessive formation of RNA:DNA hybrids under these conditions was tightly associated with replication-stress-induced DNA damage, inhibition of transcription rescued fork speed, origin activation, and alleviated replication catastrophe. Uncoupling of pre-mRNA cleavage from co-transcriptional processing and export also protected cells from replication-stress-associated DNA damage, suggesting that pre-mRNA cleavage provides a mechanism to efficiently release nascent transcripts and thereby prevent gene gating-associated genomic instability

A Multi-Modal AI-Driven Cohort Selection Tool to Predict Suboptimal Non-Responders to Aflibercept Loading-Phase for Neovascular Age-Related Macular Degeneration: PRECISE Study Report 1

Patients diagnosed with exudative neovascular age-related macular degeneration are commonly treated with anti-vascular endothelial growth factor (anti-VEGF) agents. However, response to treatment is heterogeneous, without a clinical explanation. Predicting suboptimal response at baseline will enable more efficient clinical trial designs for novel, future interventions and facilitate individualised therapies. In this multicentre study, we trained a multi-modal artificial intelligence (AI) system to identify suboptimal responders to the loading-phase of the anti-VEGF agent aflibercept from baseline characteristics. We collected clinical features and optical coherence tomography scans from 1720 eyes of 1612 patients between 2019 and 2021. We evaluated our AI system as a patient selection method by emulating hypothetical clinical trials of different sizes based on our test set. Our method detected up to 57.6% more suboptimal responders than random selection, and up to 24.2% more than any alternative selection criteria tested. Applying this method to the entry process of candidates into randomised controlled trials may contribute to the success of such trials and further inform personalised care

Chlamydial infertility in women: Diagnosis, epidemiology and immune response

This project primarily focused on the development of a novel, non-invasive peptide-based ELISA to diagnose C. trachomatis-related infertility in women. In this study, an in silico approach was applied to identify and design novel peptide antigens that are specific to women with C. trachomatis-related infertility. The serological assay was developed such that it could potentially replace invasive techniques for early infertility investigation. The thesis further investigated the sero-prevalence of chlamydial infertility in women from a low-resource, high prevalence setting. In addition, the thesis also identified immune markers that were associated with the C. trachomatis-related infertility in women