Integrated signaling pathway and gene expression regulatory model to dissect dynamics of <em>Escherichia coli </em>challenged mammary epithelial cells

AbstractCells transform external stimuli, through the activation of signaling pathways, which in turn activate gene regulatory networks, in gene expression. As more omics data are generated from experiments, eliciting the integrated relationship between the external stimuli, the signaling process in the cell and the subsequent gene expression is a major challenge in systems biology. The complex system of non-linear dynamic protein interactions in signaling pathways and gene networks regulates gene expression.The complexity and non-linear aspects have resulted in the study of the signaling pathway or the gene network regulation in isolation. However, this limits the analysis of the interaction between the two components and the identification of the source of the mechanism differentiating the gene expression profiles. Here, we present a study of a model of the combined signaling pathway and gene network to highlight the importance of integrated modeling.Based on the experimental findings we developed a compartmental model and conducted several simulation experiments. The model simulates the mRNA expression of three different cytokines (RANTES, IL8 and TNFα) regulated by the transcription factor NFκB in mammary epithelial cells challenged with E. coli. The analysis of the gene network regulation identifies a lack of robustness and therefore sensitivity for the transcription factor regulation. However, analysis of the integrated signaling and gene network regulation model reveals distinctly different underlying mechanisms in the signaling pathway responsible for the variation between the three cytokine's mRNA expression levels. Our key findings reveal the importance of integrating the signaling pathway and gene expression dynamics in modeling. Modeling infers valid research questions which need to be verified experimentally and can assist in the design of future biological experiments

Open-Retrieval Conversational Question Answering

Conversational search is one of the ultimate goals of information retrieval. Recent research approaches conversational search by simplified settings of response ranking and conversational question answering, where an answer is either selected from a given candidate set or extracted from a given passage. These simplifications neglect the fundamental role of retrieval in conversational search. To address this limitation, we introduce an open-retrieval conversational question answering (ORConvQA) setting, where we learn to retrieve evidence from a large collection before extracting answers, as a further step towards building functional conversational search systems. We create a dataset, OR-QuAC, to facilitate research on ORConvQA. We build an end-to-end system for ORConvQA, featuring a retriever, a reranker, and a reader that are all based on Transformers. Our extensive experiments on OR-QuAC demonstrate that a learnable retriever is crucial for ORConvQA. We further show that our system can make a substantial improvement when we enable history modeling in all system components. Moreover, we show that the reranker component contributes to the model performance by providing a regularization effect. Finally, further in-depth analyses are performed to provide new insights into ORConvQA.Comment: Accepted to SIGIR'2

Detection of Staphylococci from nasal samples from healthy and sick dogs in Ho Chi Minh City, Vietnam

Staphylococci are one of the most commonly found opportunistic bacteria in animals and human. The objective of this study was to determine the prevalence of Staphylococcus spp. isolated from healthy and sick dogs visiting veterinary clinics in Ho Chi Minh city, Vietnam from January 2022 to December 2022. A total of 123 nasal swab samples were collected, including 40 samples from healthy dogs and 83 samples from dogs with respiratory symptoms. Staphylococcus spp. were isolated from 47.5% of healthy animals and 60.24% of dogs showing respiratory symptoms. The study showed that isolation rates from confined, semi-confined and free-ranging dogs were 75.86%, 54.84% and 40.63%, respectively. Furthermore, the prevalence was higher in dogs over one year old compared to younger dogs (64.10% and 42.22%, respectively). Several subspecies of Staphylococci, including S. aureus, S. pseudintermedius and S. epidermidis were identified, in which S. pseudintermedius accounted for the highest proportion (48.28%). The prevalence of S. pseudintermedius also varied across different age groups. Coagulase activity of the isolated Staphylococcus strains was also determined and indicated that coagulase-positive Staphylococci constituted 80.46% of the isolates. This study represents the first report on the prevalence of Staphylococci in dogs in Vietnam and reemphasizes the zoonotic significance of Staphylococcus at the interface between dogs and humans

Disruption of Telomere Integrity and DNA Repair Machineries by KML001 Induces T Cell Senescence, Apoptosis, and Cellular Dysfunctions

T cells in chronic viral infections are featured by premature aging with accelerated telomere erosion, but the mechanisms underlying telomere attrition remain unclear. Here, we employed human CD4 T cells treated with KML001 (a telomere-targeting drug) as a model to investigate the role of telomere integrity in remodeling T cell senescence. We demonstrated that KML001 could inhibit cell proliferation, cytokine production, and promote apoptosis via disrupting telomere integrity and DNA repair machineries. Specifically, KML001-treated T cells increased dysfunctional telomere-induced foci (TIF), DNA damage marker γH2AX, and topoisomerase cleavage complex (TOPcc) accumulation, leading to telomere attrition. Mechanistically, KML001 compromised telomere integrity by inhibiting telomeric repeat binding factor 2 (TRF2), telomerase, topoisomerase I and II alpha (Top1/2a), and ataxia telangiectasia mutated (ATM) kinase activities. Importantly, these KML001-induced telomeric DNA damage and T cell senescent phenotype and machineries recapitulated our findings in patients with clinical HCV or HIV infection in that their T cells were also senescent with short telomeres and thus more vulnerable to KML001-induced apoptosis. These results shed new insights on the T cell aging network that is critical and essential in protecting chromosomal telomeres from unwanted DNA damage and securing T cell survival during cell crisis upon genomic insult

Values of sexual behaviour in Central and Eastern Europe

Despite the profusion of social cognitive models for the prediction of sexual behaviour, we have only limited knowledge as to the role of individual values in predicting risky sexual activity. This study assessed the relationship between a recently developed value structure and sexual behaviour in the context of rising HIV infection in central and eastern Europe. Five hundred and three respondents (business people, doctors and nurses) from Estonia, Georgia, Hungary, Poland and Russia completed Schwartz’s Portrait Values Questionnaire and reported their condom use, partnership history and record of sexual disease. Results indicated that values had a moderate but consistent relationship with sexual behaviour, with riskier sexual activity reported by those high on Openness to Change, Hedonism and Self-Enhancement. These findings are discussed in the context of the need for culturally sensitive interventions in order to tackle the growing HIV epidemic in this region.This project was supported by a research grant from the Research Support Scheme operated by the Soros Foundation, Prague

Evaluation of macrophage migration inhibitory factor as an imaging marker for hepatocellular carcinoma in murine models

Objective. Macrophage migration inhibitory factor (MIF) is considered as an important mediator in the pathogenesis of neoplasia. The aim of the present study was to evaluate whether MIF could be used as a marker for hepatocellular carcinoma (HCC) detection. Material and methods. Biodistribution and whole-body autoradiography studies of 131I-labeled anti-MIF monoclonal antibody (McAb) and 131I-labeled control IgG were performed. The HCC-bearing mice were injected with 3.7 MBq of each agent and killed at 24, 48, and 72 h postinjection (p.i.). The organs, blood, and HCC tissues were removed from model mice, weighed, and counted using a gamma-counter. The expression of MIF mRNA and protein within HCC tissues was confirmed by RT-PCR and immunohistochemistry. Results. HCCs in model mice could be adequately visualized at 24 h p.i. The target-to-non-target (T/NT) ratios were 6.72 ± 1.09 (24 h), 9.85 ± 0.81 (48 h), and 12.31 ± 0.57 (72 h) for 131I-labeled anti-MIF McAb group, whereas in the control group of 131I-IgG, T/NT ratios were 4.65 ± 0.63 (24 h), 6.12 ± 0.60 (48 h), and 8.23 ± 0.35 (72 h) (p < 0.05). MIF mRNA expression was twofold higher in the HCC tissues than in the healthy liver tissues. MIF protein expression was much higher in the HCC tissues than in controls. Conclusions. Our findings suggested that 131I-anti-MIF McAb could be rapidly and specifically localized in tumors. Thus, MIF could be used as a marker for HCC tumor detection

Evaluation of microscopic observation drug susceptibility assay for diagnosis of multidrug-resistant Tuberculosis in Viet Nam

<p>Abstract</p> <p>Background</p> <p>Early diagnosis of tuberculosis (TB) and multidrug resistant tuberculosis (MDR TB) is important for the elimination of TB. We evaluated the microscopic observation drug susceptibility (MODS) assay as a direct rapid drug susceptibility testing (DST) method for MDR-TB screening in sputum samples</p> <p>Methods</p> <p>All adult TB suspects, who were newly presenting to Pham Ngoc Thach Hospital from August to November 2008 were enrolled into the study. Processed sputum samples were used for DST by MODS (DST-MODS) (Rifampicin (RIF) 1 μg/ml and Isoniazid (INH) 0.4 μg/ml), MGIT culture (Mycobacterial Growth Indicator Tube) and Lowenstein Jensen (LJ) culture. Cultures positive by either MGIT or LJ were used for proportional DST (DST-LJ) (RIF 40 μg/ml and INH 0.2 μg/ml). DST profiles on MODS and LJ were compared. Discrepant results were resolved by multiplex allele specific PCR (MAS-PCR).</p> <p>Results</p> <p>Seven hundred and nine TB suspects/samples were enrolled into the study, of which 300 samples with DST profiles available from both MODS and DST-LJ were analyzed. Cording in MODS was unable to correctly identify 3 Mycobacteria Other Than Tuberculosis (MOTT) isolates, resulting in 3 false positive TB diagnoses. None of these isolates were identified as MDR-TB by MODS. The sensitivity and specificity of MODS were 72.6% (95%CI: 59.8, 83.1) and 97.9% (95%CI: 95.2, 99.3), respectively for detection of INH resistant isolates, 72.7% (95%CI: 30.9, 93.7) and 99.7% (95%CI: 98.1, 99.9), respectively for detecting RIF resistant isolates and 77.8% (95%CI: 39.9, 97.1) and 99.7% (95%CI: 98.1, 99.9), respectively for detecting MDR isolates. The positive and negative predictive values (PPV and NPV) of DST-MODS were 87.5% (95%CI: 47.3, 99.6) and 99.3% (95%CI: 97.5, 99.9) for detection of MDR isolates; and the agreement between MODS and DST-LJ was 99.0% (kappa: 0.8, <it>P </it>< 0.001) for MDR diagnosis. The low sensitivity of MODS for drug resistance detection was probably due to low bacterial load samples and the high INH concentration (0.4 μg/ml). The low PPV of DST-MODS may be due to the low MDR-TB rate in the study population (3.8%). The turnaround time of DST-MODS was 9 days and 53 days for DST-LJ.</p> <p>Conclusion</p> <p>The DST-MODS technique is rapid with low contamination rates. However, the sensitivity of DST-MODS for detection of INH and RIF resistance in this study was lower than reported from other settings.</p

A Multicentre Molecular Analysis of Hepatitis B and Blood-Borne Virus Coinfections in Viet Nam

Hepatitis B (HBV) infection is endemic in Viet Nam, with up to 8.4 million individuals estimated to be chronically infected. We describe results of a large, multicentre seroepidemiological and molecular study of the prevalence of HBV infection and blood-borne viral coinfections in Viet Nam. Individuals with varying risk factors for infection (n = 8654) were recruited from five centres; Ha Noi, Hai Phong, Da Nang, Khanh Hoa and Can Tho. A mean prevalence rate of 10.7% was observed and levels of HBsAg were significantly higher in injecting drug users (IDUs) (17.4%, n = 174/1000) and dialysis patients (14.3%, n = 82/575) than in lower-risk groups (9.4%; p<0.001). Coinfection with HIV was seen in 28% of HBV-infected IDUs (n = 49/174) and 15.2% of commercial sex workers (CSWs; n = 15/99). HCV infection was present in 89.8% of the HBV-HIV coinfected IDUs (n = 44/49) and 40% of HBV-HIV coinfected CSWs (n = 16/40). Anti-HDV was detected in 10.7% (n = 34/318) of HBsAg positive individuals. Phylogenetic analysis of HBV S gene (n = 187) showed a predominance of genotype B4 (82.6%); genotypes C1 (14.6%), B2 (2.7%) and C5 (0.5%) were also identified. The precore mutation G1896A was identified in 35% of all specimens, and was more frequently observed in genotype B (41%) than genotype C (3%; p<0.0001). In the immunodominant ‘a’ region of the surface gene, point mutations were identified in 31% (n = 58/187) of sequences, and 2.2% (n = 4/187) and 5.3% (n = 10/187) specimens contained the major vaccine escape mutations G145A/R and P120L/Q/S/T, respectively. 368 HBsAg positive individuals were genotyped for the IL28B SNP rs12979860 and no significant association between the IL28B SNP and clearance of HBsAg, HBV viral load or HBeAg was observed. This study confirms the high prevalence of HBV infection in Viet Nam and also highlights the significant levels of blood-borne virus coinfections, which have important implications for hepatitis-related morbidity and development of effective management strategies