DOCK1 insufficiency disrupts trophoblast function and pregnancy outcomes via DUSP4-ERK pathway.

Abnormal trophoblast function is associated with diseases such as recurrent spontaneous abortion, pre-eclampsia, and preterm birth, and endangers maternal and fetal health. However, the underlying regulatory mechanisms remain unclear. In this study, we found DOCK1 expression is decreased in the placental villi of patients with recurrent spontaneous abortion, and that its expression determined the invasive properties of extravillous trophoblasts (EVTs), highlighting a previously unknown role of DOCK1 in regulating EVT function. Furthermore, DOCK1 deficiency disturbed the ubiquitinated degradation of DUSP4, leading to its accumulation. This caused inactivation of the ERK signaling pathway, resulting in inadequate EVT migration and invasion. DOCK1 was implicated in regulating the ubiquitin levels of DUSP4, possibly by modulating the E3 ligase enzyme HUWE1. The results of our in vivo experiments confirmed that the DOCK1 inhibitor TBOPP caused miscarriage in mice by inactivating the DUSP4/ERK pathway. Collectively, our results revealed the crucial role of DOCK1 in the regulation of EVT function via the DUSP4-ERK pathway and a basis for the development of novel treatments for adverse pregnancy outcomes caused by trophoblast dysfunction.

Low serum vitamin D in North Indian multi-drug resistant pulmonary tuberculosis patients: the role of diet and sunlight.

Background: Tuberculosis (TB) and malnutrition are major global health problems, with multidrug-resistant (MDR) TB complicating international efforts. The role of vitamin D in susceptibility to and as an adjunctive treatment for TB is being studied extensively, although no study has included MDR-TB patients in context to dietary profile with vitamin D levels and sunlight exposure.Objective: This study aimed to estimate vitamin D serum levels and examine their association with dietary intake of vitamin D and sun exposure in patients with MDR-TB.Methods: North Indian participants were enrolled in three groups: MDR-TB, drug-susceptible pulmonary TB (DS-PTB), and healthy controls. All consenting participants underwent the estimation of macro- and micronutrient intake and sunlight exposure using structured questionnaires. Serum biochemistry, including 25-hydroxyvitamin D and calcium levels, was measured, and the correlation between variables was determined.Results: 747 participants were enrolled. Significant differences among the three groups were found in mean serum 25-hydroxyvitamin D levels, body mass index, macronutrient intake, dietary vitamin D and calcium content, and sun exposure index (SEI). All except sun exposure (SEI was highest in DS-PTB patients) were found to follow the trend: MDR-TB < DS-PTB < healthy controls. The mean serum vitamin D levels of all groups were deficient and correlated positively with dietary intake and SEI.Conclusion: In this study's we found significant association of serum vitamin D concentrations, dietary intake and sunlight exposure in MDR-TB, DS-PTB patients and healthy controls. Dietary intake may be more important than sun exposure in determining serum levels. However, the significance of this finding is uncertain. Further studies are required to confirm the association, direction, and potential for vitamin D supplementation to treat or prevent MDR-TB infection.

Ensuring the quality of medicines in India: An update on the development, modernization, and harmonization of drug standards in the Indian Pharmacopoeia.

India has a sparkling pharmaceutical sector that holds a distinguished place by producing and supplying high-quality and affordable medicines across the globe. Ensuring the quality and safety of the marketed medicinal products is one of the most important components of the drug regulatory framework and assessment of the quality of medicines is usually achieved by referring to the public standards of the official Pharmacopoeia. In India, the Indian Pharmacopoeia (IP) is published at regular intervals to fulfill the requirements of the Drugs and Cosmetics Act, 1940 to ensure the quality of medicines being manufactured and/or marketed in India. The present article aims to provide an overview of the history of the IP, its standards-setting process, and the current status of monographs in the 9th edition of the IP 2022. Special focus is placed on the newly added and upgraded general chapters and monographs within the IP 2022. There are a total of 223 general chapters and 3152 drug monographs available under various categories in the IP 2022. This study also highlights a total of 92 new drug monograph additions and 412 monograph revisions in the IP 2022. It is anticipated that the standards laid down in the IP 2022 will play an imperative role in delivering quality medicines to patients within and outside India.

Tick bite-induced Alpha-Gal Syndrome and Immunologic Responses in an Alpha-Gal Deficient Murine Model.

Introduction: Alpha-Gal Syndrome (AGS) is a delayed allergic reaction due to specific IgE antibodies targeting galactose-α-1,3-galactose (α-gal), a carbohydrate found in red meat. This condition has gained significant attention globally due to its increasing prevalence, with more than 450,000 cases estimated in the United States alone. Previous research has established a connection between AGS and tick bites, which sensitize individuals to α-gal antigens and elevate the levels of α-gal specific IgE. However, the precise mechanism by which tick bites influence the hosts immune system and contribute to the development of AGS remains poorly understood. This study investigates various factors related to ticks and the host associated with the development of AGS following a tick bite, using mice with a targeted disruption of alpha-1,3-galactosyltransferase (AGKO) as a model organism. Methods: Lone-star tick (Amblyomma americanum) and gulf-coast tick (Amblyomma maculatum) nymphs were used to sensitize AGKO mice, followed by pork meat challenge. Tick bite site biopsies from sensitized and non-sensitized mice were subjected to mRNA gene expression analysis to assess the host immune response. Antibody responses in sensitized mice were also determined. Results: Our results showed a significant increase in the titer of total IgE, IgG1, and α-gal IgG1 antibodies in the lone-star tick-sensitized AGKO mice compared to the gulf-coast tick-sensitized mice. Pork challenge in Am. americanum -sensitized mice led to a decline in body temperature after the meat challenge. Gene expression analysis revealed that Am. americanum bites direct mouse immunity toward Th2 and facilitate host sensitization to the α-gal antigen, while Am. maculatum did not. Conclusion: This study supports the hypothesis that specific tick species may increase the risk of developing α-gal-specific IgE and hypersensitivity reactions or AGS, thereby providing opportunities for future research on the mechanistic role of tick and host-related factors in AGS development.

Cis P-tau is a central circulating and placental etiologic driver and therapeutic target of preeclampsia.

Preeclampsia (PE) is the leading cause of maternal and fetal mortality globally and may trigger dementia later in life in mothers and their offspring. However, the etiological drivers remain elusive. Cis P-tau is an early etiological driver and blood biomarker in pre-clinical Alzheimer's and after vascular or traumatic brain injury, which can be targeted by stereo-specific antibody, with clinical trials ongoing. Here we find significant cis P-tau in the placenta and serum of PE patients, and in primary human trophoblasts exposed to hypoxia or sera from PE patients due to Pin1 inactivation. Depletion of cis P-tau from PE patient sera by the antibody prevents their ability to disrupt trophoblast invasion and endovascular activity and to cause the PE-like pathological and clinical features in pregnant humanized tau mice. Our studies uncover that cis P-tau is a central circulating etiological driver and its stereo-specific antibody is valuable for early PE diagnosis and treatment.

Gestational Age-Dependent Regulation of Transthyretin in Mice during Pregnancy.

Our prior studies have shown that protein misfolding and aggregation in the placenta are linked to the development of preeclampsia, a severe pregnancy complication. We identified transthyretin (TTR) as a key component of the aggregated protein complex. However, the regulation of native TTR in normal pregnancy remains unclear. In this study, we found that pregnant mice exhibited a remarkable and progressive decline in serum TTR levels through gestational day (gd) 12-14, followed by an increase in late pregnancy and postpartum. Meanwhile, serum albumin levels showed a modest but statistically significant increase throughout gestation. TTR protein and mRNA levels in the liver, a primary source of circulating TTR, mirrored the changes observed in serum TTR levels during gestation. Intriguingly, a similar pattern of TTR alteration was also observed in the serum of pregnant women and pregnant interleukin-10-knockout (IL-10-/-) mice with high inflammation background. In non-pregnant IL-10-/- mice, serum TTR levels were significantly lower than those in age-matched wild-type mice. Administration of IL-10 to non-pregnant IL-10-/- mice restored their serum TTR levels. Notably, dysregulation of TTR resulted in fewer implantation units, lower fetal weight, and smaller litter sizes in human TTR-overexpressing transgenic mice. Thus, TTR may play a pivotal role as a crucial regulator in normal pregnancy, and inflammation during pregnancy may contribute to the downregulation of serum TTR presence.

Extracellular Vesicles-mediated recombinant IL-10 protects against ascending infection-associated preterm birth by reducing fetal inflammatory response.

Background: Fetal inflammatory response mediated by the influx of immune cells and activation of pro-inflammatory transcription factor NF-κB in feto-maternal uterine tissues is the major determinant of infection-associated preterm birth (PTB, live births < 37 weeks of gestation). Objective: To reduce the incidence of PTB by minimizing inflammation, extracellular vesicles (EVs) were electroporetically engineered to contain anti-inflammatory cytokine interleukin (IL)-10 (eIL-10), and their efficacy was tested in an ascending model of infection (vaginal administration of E. coli) induced PTB in mouse models. Study design: EVs (size: 30-170 nm) derived from HEK293T cells were electroporated with recombinant IL-10 at 500 volts and 125 Ω, and 6 pulses to generate eIL-10. eIL-10 structural characters (electron microscopy, nanoparticle tracking analysis, ExoView [size and cargo content] and functional properties (co-treatment of macrophage cells with LPS and eIL-10) were assessed. To test efficacy, CD1 mice were vaginally inoculated with E. coli (1010CFU) and subsequently treated with either PBS, eIL-10 (500ng) or Gentamicin (10mg/kg) or a combination of eIL-10+gentamicin. Fetal inflammatory response in maternal and fetal tissues after the infection or treatment were conducted by suspension Cytometer Time of Flight (CyTOF) using a transgenic mouse model that express red fluorescent TdTomato (mT+) in fetal cells. Results: Engineered EVs were structurally and functionally stable and showed reduced proinflammatory cytokine production from LPS challenged macrophage cells in vitro. Maternal administration of eIL-10 (10 µg/kg body weight) crossed feto-maternal barriers to delay E. coli-induced PTB to deliver live pups at term. Delay in PTB was associated with reduced feto-maternal uterine inflammation (immune cell infiltration and histologic chorioamnionitis, NF-κB activation, and proinflammatory cytokine production). Conclusions: eIL-10 administration was safe, stable, specific, delayed PTB by over 72 hrs and delivered live pups. The delivery of drugs using EVs overcomes the limitations of in-utero fetal interventions. Protecting IL-10 in EVs eliminates the need for the amniotic administration of recombinant IL-10 for its efficacy.

Plasmonic nanoparticle's anti-aggregation application in sensor development for water and wastewater analysis.

Colorimetric sensors have emerged as a powerful tool in the detection of water pollutants. Plasmonic nanoparticles use localized surface plasmon resonance (LSPR)-based colorimetric sensing. LSPR-based sensing can be accomplished through different strategies such as etching, growth, aggregation, and anti-aggregation. Based on these strategies, various sensors have been developed. This review focuses on the newly developed anti-aggregation-based strategy of plasmonic nanoparticles. Sensors based on this strategy have attracted increasing interest because of their exciting properties of high sensitivity, selectivity, and applicability. This review highlights LSPR-based anti-aggregation sensors, their classification, and role of plasmonic nanoparticles in these sensors for the detection of water pollutants. The anti-aggregation based sensing of major water pollutants such as heavy metal ions, anions, and small organic molecules has been summarized herein. This review also provides some personal insights into current challenges associated with anti-aggregation strategy of LSPR-based colorimetric sensors and proposes future research directions.

Protein restriction in adults with chronic kidney disease, with or without diabetes: Integrated Diabetes and Endocrine Academy (IDEA) consensus statement for Indian patients.

BACKGROUND AND AIMS: Most guidelines recommend protein restriction in adults with chronic kidney disease (CKD), with or without diabetes. However, advising protein restriction for every person with CKD is controversial. We aim to arrive at a consensus on this topic, especially among Indian adults with CKD. METHODS: A systematic literature search in the PubMed electronic database was undertaken using specific keywords and MeSH terms until May 1, 2022. All the retrieved literature was circulated and rigorously deliberated upon by the panel members. RESULTS: Seventeen meta-analyses that evaluated the outcomes of protein restriction in adults with CKD, with or without diabetes, met our inclusion criteria and were analyzed. A low-protein diet (LPD) in people with stages 3-5 of CKD (who are not on haemodialysis [HD]) reduces the severity of uremic symptoms and the rate of decline in glomerular filtration rate, leading to a delay in dialysis initiation. However, LPD in patients on maintenance HD may not be desirable because HD-induced protein catabolism may lead to protein-energy malnutrition. Since the average protein intake among Indians is much lower than recommended, this must be taken into consideration before recommending LPD for all Indian adults with CKD, particularly those on maintenance HD. CONCLUSION: It is essential to assess the nutritional status of people with CKD, particularly in countries like India where average daily protein intake is poor, before recommending guideline-directed protein restriction. The prescribed diet, including the quantity and quality of proteins, should be tailored to the person's habits, tastes, and needs.

Laparoscopic evaluation of female genital tuberculosis in infertility: An observational study.

Background & objectives: Female genital tuberculosis (FGTB) is an important variety of extrapulmonary TB causing significant morbidity, especially infertility, in developing countries like India. The aim of this study was to evaluate the laparoscopic findings of the FGTB. Methods: This was a cross-sectional study on 374 cases of diagnostic laparoscopy performed on FGTB cases with infertility. All patients underwent history taking and clinical examination and endometrial sampling/biopsy for acid-fast bacilli, microscopy, culture, PCR, GeneXpert (only last 167 cases) and histopathological evidence of epithelioid granuloma. Diagnostic laparoscopy was performed in all the cases to evaluate the findings of FGTB. Results: Mean age, parity, body mass index and duration of infertility were 27.5 yr, 0.29, 22.6 kg/m2 and 3.78 years, respectively. Primary infertility was found in 81 per cent and secondary infertility in 18.18 per cent of cases. Endometrial biopsy was positive for AFB microscopy in 4.8 per cent, culture in 6.4 per cent and epithelioid granuloma in 15.5 per cent. Positive peritoneal biopsy granuloma was seen in 5.88 per cent, PCR in 314 (83.95%) and GeneXpert in 31 (18.56%, out of last 167 cases) cases. Definite findings of FGTB were seen in 164 (43.86%) cases with beaded tubes (12.29%), tubercles (32.88%) and caseous nodules (14.96%). Probable findings of FGTB were seen in 210 (56.14%) cases with pelvic adhesions (23.52%), perihepatic adhesions (47.86%), shaggy areas (11.7%), pelvic adhesions (11.71%), encysted ascites (10.42%) and frozen pelvis in 3.7 per cent of cases. Interpretation & conclusions: The finding of this study suggests that laparoscopy is a useful modality to diagnose FGTB with a higher pickup rate of cases. Hence it should be included as a part of composite reference standard.

The Role of Autophagy in the Female Reproduction System: For Beginners to Experts in This Field.

Autophagy is a fundamental process involved in regulating cellular homeostasis. Autophagy has been classically discovered as a cellular process that degrades cytoplasmic components non-selectively to produce energy. Over the past few decades, this process has been shown to work in energy production, as well as in the reduction of excessive proteins, damaged organelles, and membrane trafficking. It contributes to many human diseases, such as neurodegenerative diseases, carcinogenesis, diabetes mellitus, development, longevity, and reproduction. In this review, we provide important information for interpreting results related to autophagic experiments and present the role of autophagy in this field.

Predictive performance of interferon-gamma release assays and the tuberculin skin test for incident tuberculosis: an individual participant data meta-analysis.

Background: Evidence on the comparative performance of purified protein derivative tuberculin skin tests (TST) and interferon-gamma release assays (IGRA) for predicting incident active tuberculosis (TB) remains conflicting. We conducted an individual participant data meta-analysis to directly compare the predictive performance for incident TB disease between TST and IGRA to inform policy. Methods: We searched Medline and Embase from 1 January 2002 to 4 September 2020, and studies that were included in previous systematic reviews. We included prospective longitudinal studies in which participants received both TST and IGRA and estimated performance as hazard ratios (HR) for the development of all diagnoses of TB in participants with dichotomised positive test results compared to negative results, using different thresholds of positivity for TST. Secondary analyses included an evaluation of the impact of background TB incidence. We also estimated the sensitivity and specificity for predicting TB. We explored heterogeneity through pre-defined sub-group analyses (e.g. country-level TB incidence). Publication bias was assessed using funnel plots and Egger's test. This review is registered with PROSPERO, CRD42020205667. Findings: We obtained data from 13 studies out of 40 that were considered eligible (N = 32,034 participants: 36% from countries with TB incidence rate ≥100 per 100,000 population). All reported data on TST and QuantiFERON Gold in-Tube (QFT-GIT). The point estimate for the TST was highest with higher cut-offs for positivity and particularly when stratified by bacillus Calmette-Guérin vaccine (BCG) status (15 mm if BCG vaccinated and 5 mm if not [TST5/15 mm]) at 2.88 (95% CI 1.69-4.90). The pooled HR for QFT-GIT was higher than for TST at 4.15 (95% CI 1.97-8.75). The difference was large in countries with TB incidence rate <100 per 100,000 population (HR 10.38, 95% CI 4.17-25.87 for QFT-GIT VS. HR 5.36, 95% CI 3.82-7.51 for TST5/15 mm) but much of this difference was driven by a single study (HR 5.13, 95% CI 3.58-7.35 for TST5/15 mm VS. 7.18, 95% CI 4.48-11.51 for QFT-GIT, when excluding the study, in which all 19 TB cases had positive QFT-GIT results). The comparative performance was similar in the higher burden countries (HR 1.61, 95% CI 1.23-2.10 for QFT-GIT VS. HR 1.72, 95% CI 0.98-3.01 for TST5/15 mm). The predictive performance of both tests was higher in countries with TB incidence rate <100 per 100,000 population. In the lower TB incidence countries, the specificity of TST (76% for TST5/15 mm) and QFT-GIT (74%) for predicting active TB approached the minimum World Health Organization target (≥75%), but the sensitivity was below the target of ≥75% (63% for TST5/15 mm and 65% for QFT-GIT). The absolute differences in positive and negative predictive values between TST15 mm and QFT-GIT were small (positive predictive values 2.74% VS. 2.46%; negative predictive values 99.42% VS. 99.52% in low-incidence countries). Egger's test did not show evidence of publication bias (0.74 for TST15 mm and p = 0.68 for QFT-GIT). Interpretation: IGRA appears to have higher predictive performance than the TST in low TB incidence countries, but the difference was driven by a single study. Any advantage in clinical performance may be small, given the numerically similar positive and negative predictive values. Both IGRA and TST had lower performance in countries with high TB incidence. Test choice should be contextual and made considering operational and likely clinical impact of test results. Funding: YH, IA, and MXR were supported by the National Institute for Health and Care Research (NIHR), United Kingdom (RP-PG-0217-20009). MQ was supported by the Medical Research Council [MC_UU_00004/07].

Recent insight into autophagy and immunity at the maternal-fetal interface.

Autophagy is a lysosomal degradation pathway that supports metabolic adaptation and energy cycling. It is essential for cell homeostasis, differentiation, development, and survival. Recent studies have shown that autophagy could influence immune responses by regulating immune cell functions. Reciprocally, immune cells strongly influence autophagy. Immune cells at the maternal-fetal interface are thought to play essential roles in pregnancy. Here, we review the induction of autophagy at the maternal-fetal interface and its role in decidualization and placental development. Additionally, we emphasize the role of autophagy in the immune microenvironment at the maternal-fetal interface, including innate immunity, adaptive immunity, and immune tolerance molecules. It also suggests new research directions and prospects.

Chloroquine is a safe autophagy inhibitor for sustaining the expression of antioxidant enzymes in trophoblasts.

Inhibition of autophagy contributes to the pathophysiology of preeclampsia. Although chloroquine (CHQ) is an autophagy inhibitor, it can reduce the occurrence of preeclampsia in women with systemic lupus erythematosus. To clarify this important clinical question, this study aimed to address the safety of CHQ in trophoblast cells from the viewpoint of homeostasis, in which the anti-oxidative stress (OS) response and autophagy are involved. We used Western blotting to evaluate the protein levels in the trophoblast cells. The expression levels of heme oxygenase-1 (HO-1), an anti-OS enzyme, mediate resistance to OS induced by hydrogen peroxide (H2O2) in trophoblast cell lines. Among the autophagy modulators, bafilomycin A1 (BAF), an autophagy inhibitor, but not autophagy activators, suppressed HO-1 expression in BeWo cells; CHQ did not suppress HO-1 expression in BeWo cells. To clarify the role of autophagy in HO-1 induction, we observed no difference in HO-1 induction by H2O2 between autophagy-normal and autophagy-deficient cells. As for the mechanism of HO-1 induction by OS, BAF suppressed HO-1 induction by downregulating the expression of neighbor of BRCA1 gene 1 (NBR1) in the selective p62-NBR1-nuclear factor erythroid 2-related factor 2 (Nrf2) autophagy pathway. CHQ did not inhibit HO-1 expression by sustaining NBR1 expression in human villous tissues compared to BAF treatment. In conclusion, CHQ is a safer medicine than BAF for sustaining NBR1, which resist against OS in trophoblasts by connecting selective autophagy and the anti-OS response.

Association Between Hypertensive Disorders of Pregnancy and Dementia: a Systematic Review and Meta-Analysis.

BACKGROUND: Prior meta-analyses report a 2- to 4-fold increased risk of later cardiovascular disease among women with a history of hypertensive disorders of pregnancy (HDP). Given HDP's vascular underpinnings, it is hypothesized to also be a risk factor for later dementia. We aim to summarize the evidence for the impact of HDP on dementia and consider unique associations between HDP and dementia subtypes. METHODS: Observational studies on the relationship between HDP and dementia were identified from online electronic databases to July 1, 2021 (PROSPERO identifier: CRD42020185630). We included observational studies published in English. Exposure among women was any HDP and HDP subtypes: gestational hypertension, preeclampsia/eclampsia, or other/unspecified HDP. Outcome was any dementia and dementia subtypes: Alzheimer's disease, vascular dementia, or other/unspecified dementias. RESULTS: For our primary analyses, we included 5 cohort studies with a total of 183 874 women with and 2 309 705 women without HDP. Pooled analysis found a 38% higher risk of all-cause dementia among women with, versus without, any type of HDP (adjusted hazard ratio, 1.38 [95% CI, 1.18-1.61]; P<0.01). When examining association by HDP and dementia subtypes, we found that women with, versus without, any type of HDP had over a 3-fold higher risk of vascular dementia (adjusted hazard ratio, 3.14 [95% CI, 2.32-4.24]; P<0.01). CONCLUSIONS: Our findings indicate that maternal history of HDP is an important risk factor for later development of vascular and all-cause dementia. Further research among more racially/ethnically diverse populations quantifying HDP's effect on all-cause dementia, and specifically vascular dementia, is warranted.

Tick bite-induced alpha-gal syndrome and immunologic responses in an alpha-gal deficient murine model.

Introduction: Alpha-Gal Syndrome (AGS) is a delayed allergic reaction due to specific IgE antibodies targeting galactose-α-1,3-galactose (α-gal), a carbohydrate found in red meat. This condition has gained significant attention globally due to its increasing prevalence, with more than 450,000 cases estimated just in the United States alone. Previous research has established a connection between AGS and tick bites, which sensitize individuals to α-gal antigens and elevate the levels of specific IgE. However, the precise mechanism by which tick bites influence the host's immune system and contribute to the development of AGS remains poorly understood. This study investigates various factors related to ticks and the host associated with the development of AGS following a tick bite, using mice with a targeted disruption of alpha-1,3-galactosyltransferase (AGKO) as a model organism. Methods: Lone-star tick (Amblyomma americanum) and gulf-coast tick (Amblyomma maculatum) nymphs were used to sensitize AGKO mice, followed by pork meat challenge. Tick bite site biopsies from sensitized and non-sensitized mice were subjected to mRNA gene expression analysis to assess the host immune response. Antibody responses in sensitized mice were also determined. Results: Our results showed a significant increase in the total IgE, IgG1, and α-gal IgG1 antibodies titers in the lone-star tick-sensitized AGKO mice compared to the gulf-coast tick-sensitized mice. Pork challenge in Am. americanum -sensitized mice led to a decline in body temperature after the meat challenge. Gene expression analysis revealed that Am. americanum bites direct mouse immunity toward Th2 and facilitate host sensitization to the α-gal antigen. Conclusion: This study supports the hypothesis that specific tick species may increase the risk of developing α-gal-specific IgE and hypersensitivity reactions or AGS, thereby providing opportunities for future research on the mechanistic role of tick and host-related factors in AGS development.

Replication Compartments of Eukaryotic and Bacterial DNA Viruses: Common Themes Between Different Domains of Host Cells.

Subcellular organization is essential for life. Cells organize their functions into organelles to concentrate their machinery and supplies for optimal efficiency. Likewise, viruses organize their replication machinery into compartments or factories within their host cells for optimal replicative efficiency. In this review, we discuss how DNA viruses that infect both eukaryotic cells and bacteria assemble replication compartments for synthesis of progeny viral DNA and transcription of the viral genome. Eukaryotic DNA viruses assemble replication compartments in the nucleus of the host cell while DNA bacteriophages assemble compartments called phage nuclei in the bacterial cytoplasm. Thus, DNA viruses infecting host cells from different domains of life share common replication strategies.

A study on the effect of mobile phone use on sleep.

Background & objectives: Several studies have been conducted globally to assess the impact of usage of mobile phones on quality and duration of sleep as also on day time sleepiness. The objective of the present study was to assess the effect of mobile phone usage on the quality and composition of sleep in a sample from Indian population. Methods: The study was conducted at two tertiary care hospitals in north India from July 2014 to September 2019. A total of 566 participants were recruited in this study from both the centres. Sleep quality was assessed with the help of the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Subsequently, actigraphy was done in 96 participants and polysomnography in 95 participants. Results: Of the 566 participants, 128 (22.61%) had PSQI ≥5, reflecting poor sleep quality. A higher use of mobile phone was significantly associated with a poor sleep quality as a component of PSQI questionnaire (P=0.01) and higher overall PSQI score (P=0.01). The latency from sleep onset to N2 and N3 sleep stages was significantly shorter in participants having a higher mobile phone usage as compared to those with a lower usage [Median (range): 13.5 min (1.5-109) vs. 6.5 min (0-89); P=0.02] and [Median (range): 49 min (8.5-220.5) vs. 28.75 min (0-141); P=0.03], respectively. Interpretation & conclusions: This study focused on the maladaptive changes brought on by mobile phone usage on sleep. More studies with larger sample sizes need to be done that may serve to confirm the hypothesis generating findings of our study.

Infant BCG vaccination and risk of pulmonary and extrapulmonary tuberculosis throughout the life course: a systematic review and individual participant data meta-analysis.

BACKGROUND: BCG vaccines are given to more than 100 million children every year, but there is considerable debate regarding the effectiveness of BCG vaccination in preventing tuberculosis and death, particularly among older children and adults. We therefore aimed to investigate the age-specific impact of infant BCG vaccination on tuberculosis (pulmonary and extrapulmonary) development and mortality. METHODS: In this systematic review and individual participant data meta-analysis, we searched MEDLINE, Web of Science, BIOSIS, and Embase without language restrictions for case-contact cohort studies of tuberculosis contacts published between Jan 1, 1998, and April 7, 2018. Search terms included "mycobacterium tuberculosis", "TB", "tuberculosis", and "contact". We excluded cohort studies that did not provide information on BCG vaccination or were done in countries that did not recommend BCG vaccination at birth. Individual-level participant data for a prespecified list of variables, including the characteristics of the exposed participant (contact), the index case, and the environment, were requested from authors of all eligible studies. Our primary outcome was a composite of prevalent (diagnosed at or within 90 days of baseline) and incident (diagnosed more than 90 days after baseline) tuberculosis in contacts exposed to tuberculosis. Secondary outcomes were pulmonary tuberculosis, extrapulmonary tuberculosis, and mortality. We derived adjusted odds ratios (aORs) using mixed-effects, binary, multivariable logistic regression analyses with study-level random effects, adjusting for the variable of interest, baseline age, sex, previous tuberculosis, and whether data were collected prospectively or retrospectively. We stratified our results by contact age and Mycobacterium tuberculosis infection status. This study is registered with PROSPERO, CRD42020180512. FINDINGS: We identified 14 927 original records from our database searches. We included participant-level data from 26 cohort studies done in 17 countries in our meta-analysis. Among 68 552 participants, 1782 (2·6%) developed tuberculosis (1309 [2·6%] of 49 686 BCG-vaccinated participants vs 473 [2·5%] of 18 866 unvaccinated participants). The overall effectiveness of BCG vaccination against all tuberculosis was 18% (aOR 0·82, 95% CI 0·74-0·91). When stratified by age, BCG vaccination only significantly protected against all tuberculosis in children younger than 5 years (aOR 0·63, 95% CI 0·49-0·81). Among contacts with a positive tuberculin skin test or IFNγ release assay, BCG vaccination significantly protected against tuberculosis among all participants (aOR 0·81, 95% CI 0·69-0·96), participants younger than 5 years (0·68, 0·47-0·97), and participants aged 5-9 years (0·62, 0·38-0·99). There was no protective effect among those with negative tests, unless they were younger than 5 years (0·54, 0·32-0·90). 14 cohorts reported on whether tuberculosis was pulmonary or extrapulmonary (n=57 421). BCG vaccination significantly protected against pulmonary tuberculosis among all participants (916 [2·2%] in 41 119 vaccinated participants vs 334 [2·1%] in 16 161 unvaccinated participants; aOR 0·81, 0·70-0·94) but not against extrapulmonary tuberculosis (106 [0·3%] in 40 318 vaccinated participants vs 38 [0·2%] in 15 865 unvaccinated participants; 0·96, 0·65-1·41). In the four studies with mortality data, BCG vaccination was significantly protective against death (0·25, 0·13-0·49). INTERPRETATION: Our results suggest that BCG vaccination at birth is effective at preventing tuberculosis in young children but is ineffective in adolescents and adults. Immunoprotection therefore needs to be boosted in older populations. FUNDING: National Institutes of Health.