Differential Activation of the Transcription Factor IRF1 Underlies the Distinct Immune Responses Elicited by Type I and Type III Interferons.

Type I and III interferons (IFNs) activate similar downstream signaling cascades, but unlike type I IFNs, type III IFNs (IFNλ) do not elicit strong inflammatory responses in vivo. Here, we examined the molecular mechanisms underlying this disparity. Type I and III IFNs displayed kinetic differences in expression of IFN-stimulated genes and proinflammatory responses, with type I IFNs preferentially stimulating expression of the transcription factor IRF1. Type III IFNs failed to induce IRF1 expression because of low IFNλ receptor abundance and insufficient STAT1 activation on epithelial cells and thus did not activate the IRF1 proinflammatory gene program. Rather, IFNλ stimulation preferentially induced factors implicated in tissue repair. Our findings suggest that IFN receptor compartmentalization and abundance confer a spatiotemporal division of labor where type III IFNs control viral spread at the site of the infection while restricting tissue damage; the transient induction of inflammatory responses by type I IFNs recruits immune effectors to promote protective immunity.

Targeting spike glycans to inhibit SARS-CoV2 viral entry.

SARS-CoV-2 spike harbors glycans which function as ligands for lectins. Therefore, it should be possible to exploit lectins to target SARS-CoV-2 and inhibit cellular entry by binding glycans on the spike protein. Burkholderia oklahomensis agglutinin (BOA) is an antiviral lectin that interacts with viral glycoproteins via N-linked high mannose glycans. Here, we show that BOA binds to the spike protein and is a potent inhibitor of SARS-CoV-2 viral entry at nanomolar concentrations. Using a variety of biophysical approaches, we demonstrate that the interaction is avidity driven and that BOA cross-links the spike protein into soluble aggregates. Furthermore, using virus neutralization assays, we demonstrate that BOA effectively inhibits all tested variants of concern as well as SARS-CoV 2003, establishing that multivalent glycan-targeting molecules have the potential to act as pan-coronavirus inhibitors.

Prairie soil improves wheat establishment and accelerates the developmental transition to flowering compared to agricultural soils.

Less than 1% of native prairie lands remain in the United States. Located in eastern Washington, the rare habitat called Palouse prairie was largely converted to wheat monocropping. With this conversion came numerous physical, chemical, and biological changes to the soil that may ultimately contribute to reduced wheat yields. Here, we explored how wheat (Tritcum aestivum L.) seedling establishment, plant size, and heading, signifying the developmental transition to flowering, were affected by being planted in prairie soil versus agricultural soils. We then sought to understand whether the observed effects were the result of changes to the soil microbiota due to agricultural intensification. We found that prairie soil enhanced both the probability of wheat seedling survival and heading compared to agricultural soil; however, wheat growth was largely unaffected by soil source. We did not detect effects on wheat developmental transitions or phenotype when inoculated with prairie microbes compared with agricultural microbes, but we did observe general antagonistic effects of microbes on plant size, regardless of soil source. This work indicates that agricultural intensification has affected soils in a way that changes early seedling establishment and the timing of heading for wheat, but these effects may not be caused by microbes, and instead may be caused by soil nutrient conditions.

Manganese cobalt-MOF@carbon nanofiber-based non-enzymatic histamine sensor for the determination of food freshness.

Early detection of histamine in foodstuffs/beverages could be useful in preventing various diseases. In this work, we have prepared a free-standing hybrid mat based on manganese cobalt (2-methylimodazole)-metal organic frameworks (Mn-Co(2-MeIm)MOF) and carbon nanofibers (CNFs) and explored as a non-enzymatic electrochemical sensor for determining the freshness of fish and bananas based on histamine estimation. As-developed hybrid mat possesses high porosity with a large specific surface area and excellent hydrophilicity those allow easy access of analyte molecules to the redox-active metal sites of MOF. Furthermore, the multiple functional groups of the MOF matrix can act as active adsorption sites for catalysis. The Mn-Co(2-MeIm)MOF@CNF mat-modified GC electrode demonstrated excellent electrocatalytic activities toward the oxidation of histamine under acidic conditions (pH = 5.0) with a faster electron transfer kinetics and superior fouling resistance. The Co(2-MeIm)MOF@CNF/GCE sensor exhibited a wide linear range from 10 to 1500 µM with a low limit of detection (LOD) of 89.6 nM and a high sensitivity of 107.3 µA mM-1 cm-2. Importantly, as-developed Nb(BTC)MOF@CNF/GCE sensor is enabled to detect histamine in fish and banana samples stored for different periods of time, which thus indicates its practical viability as analytical histamine detector.

Bayesian approaches to include real-world data in clinical studies.

Randomized clinical trials have been the mainstay of clinical research, but are prohibitively expensive and subject to increasingly difficult patient recruitment. Recently, there is a movement to use real-world data (RWD) from electronic health records, patient registries, claims data and other sources in lieu of or supplementing controlled clinical trials. This process of combining information from diverse sources calls for inference under a Bayesian paradigm. We review some of the currently used methods and a novel non-parametric Bayesian (BNP) method. Carrying out the desired adjustment for differences in patient populations is naturally done with BNP priors that facilitate understanding of and adjustment for population heterogeneities across different data sources. We discuss the particular problem of using RWD to create a synthetic control arm to supplement single-arm treatment only studies. At the core of the proposed approach is the model-based adjustment to achieve equivalent patient populations in the current study and the (adjusted) RWD. This is implemented using common atoms mixture models. The structure of such models greatly simplifies inference. The adjustment for differences in the populations can be reduced to ratios of weights in such mixtures. This article is part of the theme issue 'Bayesian inference: challenges, perspectives, and prospects'.

Characteristics of women presenting with hepatitis B at antenatal care services in London, 2008-2018.

BACKGROUND: To support interventions to prevent mother-to-child transmission of hepatitis B and fill gaps in surveillance, the Enhanced Surveillance of Antenatal Hepatitis B (ESAHB) programme was implemented in London from 2008 to 2018 to collect demographic information on women who tested positive for hepatitis B during antenatal screening. We describe the epidemiology of hepatitis B in pregnancy, as reported to ESAHB. METHODS: The characteristics of pregnant women living with hepatitis B were described and rates were calculated by year, local authority and residence deprivation decile (1 being most deprived). Poisson regression tested the association between pregnant women living with hepatitis B and deprivation decile. RESULTS: Between 2008 and 2018, 8879 women living with hepatitis B in London (0.35 per 1000 women) reported 11 193 pregnancies. Annual hepatitis B rates remained stable, but there was strong evidence for an inverse association between rate and deprivation decile (P < 0.001). The majority of women in the cohort presented late to antenatal care, were born outside the UK in a hepatitis B endemic area or required an interpreter for consultations. CONCLUSIONS: ESAHB provided important data to inform service quality improvements for women living with hepatitis B. This analysis highlights the link between deprivation and hepatitis B.

Designing UAV Swarm Experiments: A Simulator Selection and Experiment Design Process.

The rapid advancement and increasing number of applications of Unmanned Aerial Vehicle (UAV) swarm systems have garnered significant attention in recent years. These systems offer a multitude of uses and demonstrate great potential in diverse fields, ranging from surveillance and reconnaissance to search and rescue operations. However, the deployment of UAV swarms in dynamic environments necessitates the development of robust experimental designs to ensure their reliability and effectiveness. This study describes the crucial requirement for comprehensive experimental design of UAV swarm systems before their deployment in real-world scenarios. To achieve this, we begin with a concise review of existing simulation platforms, assessing their suitability for various specific needs. Through this evaluation, we identify the most appropriate tools to facilitate one's research objectives. Subsequently, we present an experimental design process tailored for validating the resilience and performance of UAV swarm systems for accomplishing the desired objectives. Furthermore, we explore strategies to simulate various scenarios and challenges that the swarm may encounter in dynamic environments, ensuring comprehensive testing and analysis. Complex multimodal experiments may require system designs that may not be completely satisfied by a single simulation platform; thus, interoperability between simulation platforms is also examined. Overall, this paper serves as a comprehensive guide for designing swarm experiments, enabling the advancement and optimization of UAV swarm systems through validation in simulated controlled environments.

CG Dinucleotide Removal in Bioluminescent and Fluorescent Reporters Improves HIV-1 Replication and Reporter Gene Expression for Dual Imaging in Humanized Mice.

Visualizing the transmission and dissemination of human immunodeficiency virus type 1 (HIV-1) in real time in humanized mouse models is a robust tool to investigate viral replication during treatments and in tissue reservoirs. However, the stability and expression of HIV-1 reporter genes are obstacles for long-term serial imaging in vivo. Two replication-competent CCR5-tropic HIV-1 reporter constructs were created that encode either nanoluciferase (nLuc) or a near-infrared fluorescent protein (iRFP) upstream of nef. HIV-1 reporter virus replication and reporter gene expression was measured in cell culture and in humanized mice. While reporter gene expression in vivo correlated initially with plasma viremia, expression decreased after 4 to 5 weeks despite high plasma viremia. The reporter genes were codon optimized to remove cytosine/guanine (CG) dinucleotides, and new CO-nLuc and CO-iRFP viruses were reconstructed. Removal of CG dinucleotides in HIV-1 reporter viruses improved replication in vitro and reporter expression in vivo and ex vivo. Both codon-optimized reporter viruses could be visualized during coinfection and in vivo reporter gene expression during treatment failure preceded detection of plasma viremia. While the dynamic range of CO-iRFP HIV-1 was lower than that of CO-nLuc HIV-1, both viruses could have utility in studying and visualizing HIV-1 infection in humanized mice. IMPORTANCE Animal models are important for studying HIV-1 pathogenesis and treatments. We developed two viruses each encoding a reporter gene that can be expressed in cells after infection. This study shows that HIV-1 infection can be visualized by noninvasive, whole-body imaging in mice with human immune cells over time by reporter expression. We improved reporter expression to reflect HIV-1 replication and showed that two viral variants can be tracked over time in the same animal and can predict failure of antiretroviral therapy to suppress virus.

Whose trait is it anyways? Coevolution of joint phenotypes and genetic architecture in mutualisms.

Evolutionary biologists typically envision a trait's genetic basis and fitness effects occurring within a single species. However, traits can be determined by and have fitness consequences for interacting species, thus evolving in multiple genomes. This is especially likely in mutualisms, where species exchange fitness benefits and can associate over long periods of time. Partners may experience evolutionary conflict over the value of a multi-genomic trait, but such conflicts may be ameliorated by mutualism's positive fitness feedbacks. Here, we develop a simulation model of a host-microbe mutualism to explore the evolution of a multi-genomic trait. Coevolutionary outcomes depend on whether hosts and microbes have similar or different optimal trait values, strengths of selection and fitness feedbacks. We show that genome-wide association studies can map joint traits to loci in multiple genomes and describe how fitness conflict and fitness feedback generate different multi-genomic architectures with distinct signals around segregating loci. Partner fitnesses can be positively correlated even when partners are in conflict over the value of a multi-genomic trait, and conflict can generate strong mutualistic dependency. While fitness alignment facilitates rapid adaptation to a new optimum, conflict maintains genetic variation and evolvability, with implications for applied microbiome science.

Long-Acting Rilpivirine (RPV) Preexposure Prophylaxis Does Not Inhibit Vaginal Transmission of RPV-Resistant HIV-1 or Select for High-Frequency Drug Resistance in Humanized Mice.

As a long-acting formulation of the nonnucleoside reverse transcriptase inhibitor rilpivirine (RPV LA) has been proposed for use as preexposure prophylaxis (PrEP) and the prevalence of transmitted RPV-resistant viruses can be relatively high, we evaluated the efficacy of RPV LA to inhibit vaginal transmission of RPV-resistant HIV-1 in humanized mice. Vaginal challenges of wild-type (WT), Y181C, and Y181V HIV-1 were performed in mice left untreated or after RPV PrEP. Plasma viremia was measured for 7 to 10 weeks, and single-genome sequencing was performed on plasma HIV-1 RNA in mice infected during PrEP. RPV LA significantly prevented vaginal transmission of WT HIV-1 and Y181C HIV-1, which is 3-fold resistant to RPV. However, it did not prevent transmission of Y181V HIV-1, which has 30-fold RPV resistance in the viruses used for this study. RPV LA did delay WT HIV-1 dissemination in infected animals until genital and plasma RPV concentrations waned. Animals that became infected despite RPV LA PrEP did not acquire new RPV-resistant mutations above frequencies in untreated mice or untreated people living with HIV-1, and the mutations detected conferred low-level resistance. These data suggest that high, sustained concentrations of RPV were required to inhibit vaginal transmission of HIV-1 with little or no resistance to RPV but could not inhibit virus with high resistance. HIV-1 did not develop high-level or high-frequency RPV resistance in the majority of mice infected after RPV LA treatment. However, the impact of low-frequency RPV resistance on virologic outcome during subsequent antiretroviral therapy still is unclear.IMPORTANCE The antiretroviral drug rilpivirine was developed into a long-acting formulation (RPV LA) to improve adherence for preexposure prophylaxis (PrEP) to prevent HIV-1 transmission. A concern is that RPV LA will not inhibit transmission of drug-resistant HIV-1 and may select for drug-resistant virus. In female humanized mice, we found that RPV LA inhibited vaginal transmission of WT or 3-fold RPV-resistant HIV-1 but not virus with 30-fold RPV resistance. In animals that became infected despite RPV LA PrEP, WT HIV-1 dissemination was delayed until genital and plasma RPV concentrations waned. RPV resistance was detected at similar low frequencies in untreated and PrEP-treated mice that became infected. These results indicate the importance of maintaining RPV at a sustained threshold after virus exposure to prevent dissemination of HIV-1 after vaginal infection and low-frequency resistance mutations conferred low-level resistance, suggesting that RPV resistance is difficult to develop after HIV-1 infection during RPV LA PrEP.

Modeling Stripe Formation on Growing Zebrafish Tailfins.

As zebrafish develop, black and gold stripes form across their skin due to the interactions of brightly colored pigment cells. These characteristic patterns emerge on the growing fish body, as well as on the anal and caudal fins. While wild-type stripes form parallel to a horizontal marker on the body, patterns on the tailfin gradually extend distally outward. Interestingly, several mutations lead to altered body patterns without affecting fin stripes. Through an exploratory modeling approach, our goal is to help better understand these differences between body and fin patterns. By adapting a prior agent-based model of cell interactions on the fish body, we present an in silico study of stripe development on tailfins. Our main result is a demonstration that two cell types can produce stripes on the caudal fin. We highlight several ways that bone rays, growth, and the body-fin interface may be involved in patterning, and we raise questions for future work related to pattern robustness.

Cholesterol homeostasis and cell proliferation by mitogenic homologs: insulin, benzo-α-pyrene and UV radiation.

Low-Density Lipoprotein (LDL) is known to promote the unregulated proliferation of cells that is progression of cancer. We aimed to investigate the effect of mitogens on the expression of cell cycle proteins, nuclear cholesterol and cell proliferation. We observed that insulin and benzo-α-pyrene (BaP) induced the expression of Low-Density Lipoprotein receptor (LDLR) on HepG2 cells, thereby enhancing the uptake of LDL. The internalized LDL increased the concentration of cholesterol in the cytoplasm and nucleus of the cell. At the same time, insulin and BaP also stimulated the expression of cell cycle proteins viz., Cyclin E and Cdk2, and thus induced more incorporation of Bromodeoxyuridine (BrdU) in cultured cells indicating increased DNA synthesis. Increased expression of cell cycle proteins and DNA synthesis are the indications of DNA replication and new cell synthesis. This suggests a link between the enhanced nuclear cholesterol concentration and new cell formation. On the other hand, UV irradiation with selectively given dose of cell death eventually decreases nuclear cholesterol concentration and LDLR expression. Reduced LDLR shows low functional activity. This, again, repeated the plausibility of the same link between intracellular cholesterol concentration and cell population. The biasness of adverse effect observed by UV irradiation has been compromised by inactivating LDLR with anti-LDLR antibody, resulting in similar effects on Cyclin E expression in the cultured cells. Hence, we concluded that in all the conditions, LDLR expression was found to be a translational event of its transcription factor, SREBP-2, by the induction of insulin, BaP and UV irradiation.

Interrelationship between iodine nutritional status of lactating mothers and their absolutely breast-fed infants in coastal districts of Gangetic West Bengal in India.

Iodine nutritional status of 128 lactating mothers and their breast-fed infants (1-3 months) from iodine-replete villages during post-salt iodization period was evaluated. Mothers' urine, blood, and breast milk (BM) and infants' urine and blood were collected and analyzed for iodine and serum FT4 and TSH estimation. Mothers' and infants' age, parity, occupation, education, and household income were recorded. Median urinary iodine concentration (UIC) of infants was 250 µg/L, indicating their iodine intake was more than adequate. Mothers' median UIC was 185 µg/L, indicating adequate iodine nutrition; however, 13.28% had mild to severe deficiency. Median breast milk iodine concentration (BMIC) was 230 µg/L, which was more than their median UIC 185 µg/L. In iodine-deficient mothers, positive correlation was found between mothers' and infants' serum FT4 and TSH levels, and negative correlation was found between mothers' and infants' serum FT4 and TSH levels in excessive iodine nutrition group. CONCLUSION: Iodine intake of breast-fed infants was at the limit of above requirement, and they are possibly at the risk of excess iodine intake. In iodine deficient and excessive iodine intake mothers, their infants' serum FT4 and TSH are independent on their iodine nutritional status but dependent on thyroid hormone profile of their mothers but differently. What is Known: • A median urinary iodine of 100 µg/L is used to define adequate iodine intake of lactating mothers and children < 2 years. However, adequate iodine intake in terms of urinary iodine of infants of age 1-3 months is not known. What is New: • Iodine intake of absolutely breast-fed infants (1-3 months) was more than adequate, though their mother's intake was adequate as breast milk contains more iodine than urine. The infants of iodine deficient and excessive iodine intake mothers, infants' hormonal profile is independent of their iodine nutritional status but dependent on their mothers thyroid hormone profile.

Assessment of the Effectiveness of Combat Eyewear Protection Against Blast Overpressure.

It is unclear whether combat eyewear used by U. S. Service members is protective against blast overpressures (BOPs) caused by explosive devices. Here, we investigated the mechanisms by which BOP bypasses eyewear and increases eye surface pressure. We performed experiments and developed three-dimensional (3D) finite element (FE) models of a head form (HF) equipped with an advanced combat helmet (ACH) and with no eyewear, spectacles, or goggles in a shock tube at three BOPs and five head orientations relative to the blast wave. Overall, we observed good agreement between experimental and computational results, with average discrepancies in impulse and peak-pressure values of less than 15% over 90 comparisons. In the absence of eyewear and depending on the head orientation, we identified three mechanisms that contributed to pressure loading on the eyes. Eyewear was most effective at 0 deg orientation, with pressure attenuation ranging from 50 (spectacles) to 80% (goggles) of the peak pressures observed in the no-eyewear configuration. Spectacles and goggles were considerably less effective when we rotated the HF in the counter-clockwise direction around the superior-inferior axis of the head. Surprisingly, at certain orientations, spectacles yielded higher maximum pressures (80%) and goggles yielded larger impulses (150%) than those observed without eyewear. The findings from this study will aid in the design of eyewear that provides better protection against BOP.

Co-relation Between Total Cholesterol, High Density Lipoprotein, Low Density Lipoprotein and Glycosylated Haemoglobin (HbA1c) in Diabetic Patients with Acute Coronary Syndrome (ACS).

BACKGROUND: Patients with diabetes & dyslipidaemia are at increased risk of developing coronary artery disease that many time manifests as life threatening ACS. AIM: To study co-relation between HbA1c &total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL) in diabetic patients with acute coronary syndrome and also their co-relationship with severity of ACS independently. MATERIALS AND METHOD: Blood samples of 51 known diabetic patients presented to emergency with ACS were sent for HbA1c & lipid profile estimation. All patients underwent coronary angiography. Obtained results were statistically analysed & co-related. RESULTS: Patients were divided as having: 1. HDL <40, >40; 2. LDL <100, >100; 3. Total cholesterol <200, >200; 4. HbA1c 6.5-8.4, >8.4; 5. Single vessel disease (SVD) / multi vessel disease (MVD). Statistically significant direct co-relationship was found between HbA1c, LDL, Total cholesterol, ACS severity (SVD/MVD) & inverse co-relationship with HDL. CONCLUSION: Severity & incidence of ACS in diabetic patients can be minimised by maintaining adequate glycaemic control & also by keeping circulating lipids under control.

Lichenoid Dermatitis in an Adult with Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX) Syndrome.

A 23-year-old man presented to our practice with erythroderma and an unusual retiform eruption, along with alopecia universalis and nail dystrophy. He had had no skin findings at birth, but since early infancy had had localized eczematous eruptions of his skin. At 10 years of age, he had developed a generalized eczematous flare requiring hospitalization, and another generalized episode occurred in October 2010. He was prescribed prednisone 60 mg daily, which initially provided an improvement, but tapering of the corticosteroid resulted in another generalized flare.

Mortality audit of medical patients at armed forces hospitals.

The mortality statistics of the medical patients at our tertiary care hospitals are sparse and lacking. We studied the mortality characteristics of the patients admitted to medical wards and intensive care unit at two hospitals based on the available fatal documents. Our objectives include analysis of the cause of death, duration of stay and presence of sepsis. The deceased (103 males, 47 females) had a mean age of 64.6 ± 15.5 yrs and mean duration of stay 7.1 ± 12.3 days. Infections and sepsis syndrome (33%), respiratory (17%), neurological (15%) and cardiovascular disorders (10%) were the top four causes of the mortality. Comorbid ailments were present in 71% of the deceased and the ventilator was used in 39% of them prior to the death. Age of the patients did not show any correlation with the duration of hospital stay (P = 0.8322). Infections and sepsis syndrome are the major reasons of death in medical patients. Mortality audit helps in identifying the prevalent causes of death in the hospital.

Dermal Mucinosis in Chronic Sclerodermoid Graft-Versus-Host Disease.

Dermal mucinosis is characterized by the deposition of glycosaminoglycans (mucin), either focally or diffusely within the dermis. This may occur as a primary idiopathic disorder or secondary to several dermatoses, most notably lupus erythematous, scleroderma, and dermatomyositis. The authors present an unusual finding of dermal mucinosis in association with chronic sclerodermoid graft-versus-host disease.

Differential Expressions of p53, p53R2, hRRM2 and PBR in Chronic Lymphocytic Leukemia: A Correlation with Intracellular Cholesterol.

Regulation of intracellular cholesterol homeostasis exists under balance between intracellular biosynthesis and uptake from extracellular origin by cell surface transport proteins. Expected role of cholesterol on either tumor suppressor gene and/or DNA synthesis has been aimed in the present study to explore intracellular cholesterol homeostasis in CLL subjects. Higher expressions of p53R2 (p53 dependent subunit of ribonucleotide reductase) and p53 were found in lymphocytes of chronic human lymphocytic leukemia as comparison to their normal counterparts. Inverse relation was found with p53 independent R2 subunit (in human hRRM2) of ribonucleotide reductase, which was found to be decreased from its control group. More expression of peripheral type benzodiazepine receptor, a cholesterol transporter, was noticed in isolated nuclear fraction with simultaneous increase of cholesterol concentration in cytoplasmic and nuclear compartments. A parallel increase of cholesterol in cell nucleus with increased p53R2 expression shows priority of the involvement of cholesterol in the process of cell replication.

Concomitant leptospirosis-hantavirus co-infection in acute patients hospitalized in Sri Lanka: implications for a potentially worldwide underestimated problem.

Two global (re-)emerging zoonoses, leptospirosis and hantavirus infections, are clinically indistinguishable. Thirty-one patients, hospitalized in Sri Lanka for acute severe leptospirosis, were after exclusion of other potentially involved pathogens, prospectively screened with IgM ELISA for both pathogens. Of these, nine (29·0%) were positive for leptospirosis only, one (3·2%) for hantavirus only, seven (22·5%) for both pathogens concomitantly, whereas 13 (41·9%) remained negative for both. Moreover, in a retrospective study of 23 former patients, serologically confirmed for past leptospirosis, six (26·0%) were also positive in two different IgG ELISA hantavirus formats. Surprisingly, European Puumala hantavirus (PUUV) results were constantly higher, although statistically not significantly different, than Asian Hantaan virus (HTNV), suggesting an unexplained cross-reaction, since PUUV is considered absent throughout Asia. Moreover, RT-PCR on all hantavirus IgM ELISA positives was negative. Concomitant leptospirosis-hantavirus infections are probably heavily underestimated worldwide, compromising epidemiological data, therapeutical decisions, and clinical outcome.