Nuclear entry of poliovirus protease-polymerase precursor 3CD: implications for host cell transcription shut-off

AbstractHost cell transcription mediated by all three RNA polymerases is rapidly inhibited after infection of mammalian cells with poliovirus (PV). Both genetic and biochemical studies have shown that the virus-encoded protease 3C cleaves the TATA-binding protein and other transcription factors at glutamine–glycine sites and is directly responsible for host cell transcription shut-off. PV replicates in the cytoplasm of infected cells. To shut-off host cell transcription, 3C or a precursor of 3C must enter the nucleus of infected cells. Although the 3C protease itself lacks a nuclear localization signal (NLS), amino acid sequence examination of 3D identified a potential single basic type NLS, KKKRD, spanning amino acids 125–129 within this polypeptide. Thus, a plausible scenario is that 3C enters the nucleus in the form of its precursor, 3CD, which then generates 3C by auto-proteolysis ultimately leading to cleavage of transcription factors in the nucleus. Using transient transfection of enhanced green fluorescent protein (EGFP) fusion polypeptides, we demonstrate here that both 3CD and 3D are capable of entering the nucleus in PV-infected cells. However, both polypeptides remain in the cytoplasm in uninfected HeLa cells. Mutagenesis of the NLS sequence in 3D prevents nuclear entry of 3D and 3CD in PV-infected cells. We also demonstrate that 3CD can be detected in the nuclear fraction from PV-infected HeLa cells as early as 2 h postinfection. Significant amount of 3CD is found associated with the nuclear fraction by 3–4 h of infection. Taken together, these results suggest that both the 3D NLS and PV infection are required for the entry of 3CD into the nucleus and that this may constitute a means by which viral protease 3C is delivered into the nucleus leading to host cell transcription shut-off

Synthesis and Characterisation of Some New Aluminium Derivatives of Schiff Bases Containing N, O and S Donor Atoms and the Anti Fertility Activity of the Derivative Al[SC6H4N:C(CH3)CH2COCH3]3

Some new compounds of aluminium having the general formula AI[SC6H4N:C(R) CH2 C(O)R’]3 where R = CH3, R' = CH3 (1); R' = CH3, R' = C6H5 (2); R = CF3, R’ = -C = CH - CH = CHS (3); R = CF3, R’ = C6H5 (4) have been synthesised by the reactions of Al(OPri)3 and the corresponding ligands in 1:3 molar ratios in benzene. Elemental and spectroscopic (IR, 1H, 13C, and 27AI NMR) characterisation of these monomeric compounds reveals monofunctional bidentate behaviour of ligand moiety and the octahedral geometry around aluminium atom. Compound (1), AI[SC6H4N:C(CH3)CH2COCH3], has been tested for its antifertility activity in male albino rats. The oral administration of this compound at the dose level 6.5 rag/rat/day reduced the weights of testes and epididymides. Significant decrease in sperm motility as well as sperm density resulted in the reduction of male fertility by 100%. Production of primary spermatocytes (preleptotene and pachytene), secondary spermatocytes and step-19 spermatids declined by 56.10%, 44.42 %, 63.35 % and 64.57 % respectively. These results indicate that the administration of compound (1) in male rats brought about an interference with spermatogenesis which ultimately caused infertility

LINGO : Visually Debiasing Natural Language Instructions to Support Task Diversity

Cross-task generalization is a significant outcome that defines mastery in natural language understanding. Humans show a remarkable aptitude for this, and can solve many different types of tasks, given definitions in the form of textual instructions and a small set of examples. Recent work with pre-trained language models mimics this learning style: users can define and exemplify a task for the model to attempt as a series of natural language prompts or instructions. While prompting approaches have led to higher cross-task generalization compared to traditional supervised learning, analyzing 'bias' in the task instructions given to the model is a difficult problem, and has thus been relatively unexplored. For instance, are we truly modeling a task, or are we modeling a user's instructions? To help investigate this, we develop LINGO, a novel visual analytics interface that supports an effective, task-driven workflow to (1) help identify bias in natural language task instructions, (2) alter (or create) task instructions to reduce bias, and (3) evaluate pre-trained model performance on debiased task instructions. To robustly evaluate LINGO, we conduct a user study with both novice and expert instruction creators, over a dataset of 1,616 linguistic tasks and their natural language instructions, spanning 55 different languages. For both user groups, LINGO promotes the creation of more difficult tasks for pre-trained models, that contain higher linguistic diversity and lower instruction bias. We additionally discuss how the insights learned in developing and evaluating LINGO can aid in the design of future dashboards that aim to minimize the effort involved in prompt creation across multiple domains.Comment: 13 pages, 6 figures, Eurovis 202

A study to correlate admission non stress test and immediate post-partum umbilical cord arterial pH with neonatal outcome

Background: Continuous electronic fetal monitoring in labour has become a standard practice in developed countries; this may not be possible in low middle-income countries. So, this study was conducted to correlate admission non stress test (NST) and immediate post-partum umbilical cord arterial (UCA) pH with neonatal outcome.Methods: This prospective observational study was conducted at tertiary care centre in North India. After informed and written consent, 100 pregnant women with singleton live pregnancy of gestational age ≥32 weeks admitted in labour, were subjected to admission NST and immediately after delivery sample for UCA pH was taken. Clinically relevant neonatal outcome was correlated with admission NST and UCA pH. Appropriate statistical tests were used and p-value <0.05 taken as significant.Results: Admission NST was normal, suspicious, pathological in 67%, 27%, 6% subjects, respectively. Study found statistically significant correlation between admission NST and UCA pH with neonatal outcomes (i.e. fetal distress, need of advanced resuscitation, delayed oral feeding). Fetal distress was seen in 9 newborns, in these 8 delivered by CS and 1 required ventous application. Admission NST had high sensitivity (88.89%) and NPV (98.5%) for detection of fetal distress. The optimal cut off for pH and lactate was 7.25 and 2.55 mmol/L, respectively to predict fetal distress.Conclusions: Admission NST can be considered as a screening modality to detect fetus in distress and it showed good correlation with umbilical cord arterial pH for predicting short term neonatal outcome.

Barriers encountered during online classes among undergraduate nursing students during COVID-19 pandemic in India

Background: The advents of new technologies are providing a variety of effective learning environment. However, many adult students still prefer traditional, academic settings and do not want to take online or hybrid classes.Methods: Present study included cross sectional descriptive survey design which was carried out on 394 undergraduate nursing students. Convenient sampling technique was chosen for selection of samples. A five-point Likert self-structured scale was used for data collection. Descriptive and inferential statistics were used to analyze the data in SPSS.Results: Study findings showed that there were 209 (53%) female participants. Significant difference (p=0.05) was found among participants’ gender and year of study, area of residence, father education, family income and whether they had ever attended online classes. Lack of control over the group was top perceived barrier with highest score (261 marks). Majority of participants (61%) perceived barriers encountered during online classes. Mann Whitney U test showed the significant differences of participants’ perceived barriers among male and female participants by their age, year of study, fathers’ education and family income (p<0.05).Conclusions: As more students are growing up familiar with internet-based learning, many students were still opposing to go with online classes. Barriers explored in the study can limit the acceptance of online classes among undergraduate nursing students. Higher authorities must find the ways for making online education user friendly

A REVIEW ON CURRENT SCENARIO OF ORAL CANCER IN INDIA WITH SPECIAL EMPHASIS ON MODERN DETECTION SYSTEMS AND BIOMARKERS

Oral squamous cell carcinoma is a major public health concern worldwide and a growing threat for rapidly developing economies such as India, where it ranks among the top three cancers. This review aims to discuss the national status of oral cancer in terms of incidences and mortality. We have added the emphasis on clinical characteristics of oral potentially malignant disorders and emerging optical diagnostic techniques to detect oral lesions which would otherwise go undetected by a conventional oral examination. Modern detection systems such as autofluorescence, chemiluminiscence, Narrowband imaging and Raman spectroscopy will definitely aid Conventional oral examination for diagnosis. Definitive diagnosis of oral cancer by using saliva and serum-based noninvasive biomarkers can minimize the need of tissue biopsies and patient discomfort. Urgent research efforts are required to find new ways to identify and examine high-risk population for the early diagnosis and prevention of Oral squamous cell carcinoma

Acute-on-chronic liver failure: Consensus recommendations of the Asian pacific association for the study of the liver (APASL): An update

The first consensus report of the working party of the Asian Pacific Association for the Study of the Liver (APASL) set up in 2004 on acute-on-chronic liver failure (ACLF) was published in 2009. With international groups volunteering to join, the APASL ACLF Research Consortium (AARC) was formed in 2012, which continued to collect prospective ACLF patient data. Based on the prospective data analysis of nearly 1400 patients, the AARC consensus was published in 2014. In the past nearly four-and-a-half years, the AARC database has been enriched to about 5200 cases by major hepatology centers across Asia. The data published during the interim period were carefully analyzed and areas of contention and new developments in the field of ACLF were prioritized in a systematic manner. The AARC database was also approached for answering some of the issues where published data were limited, such as liver failure grading, its impact on the \u27Golden Therapeutic Window\u27, extrahepatic organ dysfunction and failure, development of sepsis, distinctive features of acute decompensation from ACLF and pediatric ACLF and the issues were analyzed. These initiatives concluded in a two-day meeting in October 2018 at New Delhi with finalization of the new AARC consensus. Only those statements, which were based on evidence using the Grade System and were unanimously recommended, were accepted. Finalized statements were again circulated to all the experts and subsequently presented at the AARC investigators meeting at the AASLD in November 2018. The suggestions from the experts were used to revise and finalize the consensus. After detailed deliberations and data analysis, the original definition of ACLF was found to withstand the test of time and be able to identify a homogenous group of patients presenting with liver failure. New management options including the algorithms for the management of coagulation disorders, renal replacement therapy, sepsis, variceal bleed, antivirals and criteria for liver transplantation for ACLF patients were proposed. The final consensus statements along with the relevant background information and areas requiring future studies are presented here

Pathogenic T cell responses against aquaporin 4

Inflammatory lesions in the central nervous system of patients with neuromyelitis optica are characterized by infiltration of T cells and deposition of aquaporin-4-specific antibodies and complement on astrocytes at the glia limitans. Although the contribution of aquaporin-4-specific autoantibodies to the disease process has been recently elucidated, a potential role of aquaporin-4-specific T cells in lesion formation is unresolved. To address this issue, we raised aquaporin-4-specific T cell lines in Lewis rats and characterized their pathogenic potential in the presence and absence of aquaporin-4-specific autoantibodies of neuromyelitis optica patients. We show that aquaporin-4-specific T cells induce brain inflammation with particular targeting of the astrocytic glia limitans and permit the entry of pathogenic anti-aquaporin-4-specific antibodies to induce NMO-like lesions in spinal cord and brain. In addition, transfer of aquaporin-4-specific T cells provoked mild (subclinical) myositis and interstitial nephritis. We further show that the expression of the conformational epitope, recognized by NMO patient-derived aquaporin-4-specific antibodies is induced in kidney cells by the pro-inflammatory cytokine gamma-interferon. Our data provide further support for the view that NMO lesions may be induced by a complex interplay of T cell mediated and humoral immune responses against aquaporin-4