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Introduction Carboxyhemoglobinemia is characterised by decreased oxygen delivery to tissues. In severe and critical coronavirus disease 2019 (COVID-19) illness with hypoxia, this can herald a grave and protracted course of illness. Patients with COVID-19 experience respiratory impairment, lowering the pace at which carbon monoxide (CO) is eliminated and raising the likelihood of carboxyhemoglobinemia. We set out to explore early arterial carboxyhemoglobin (COHb) and COVID-19 patient outcomes in non-smokers and its potential as a predictive tool for mortality. Methods Forty-five patients, non-smokers with severe/critical severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection requiring admission in a North Indian 1200-bedded tertiary care hospital, were recruited prospectively from October 2020 to March 2021. Arterial COHb% was evaluated with arterial blood gases using an analyser, which were taken at the time of admission and then every alternate day for the first 10 days. Carboxyhemoglobinemia was defined as COHb% more than 1%. The primary outcome was defined as the patient's hospital outcome (survivor/non-survivor). Results Of the total 45 subjects, 51.1% (n=23) survived. Patients developed carboxyhemoglobinemia with an incidence of 51% during the course of their hospital stay. The mean ± SD of COHb% on admission was 1.0 ± 0.58 and 1.03 ± 0.8 in non-survivors and survivors, respectively (p=0.870). Maximal individual values of 5.3% and 6.1% were seen in survivors and non-survivors, respectively. On serial COHb measurement, non-survivors had significantly higher COHb% on days 6 and 10. No co-relation of COHb% with inflammatory markers was noted. Conclusion Arterial COHb levels in non-survivors were significantly higher than in survivors on days 6 and 10. Our study did not show a prognostic value of serial COHb measurement in patients with severe COVID-19. To establish COHb as a predictive marker in severely ill COVID-19 patients, additional research is required.

Background: Angelman Syndrome (AS) is a congenital non inherited neurodevelopmental disorder. The contemporary AS management is symptomatic and it has been accepted that gene therapy may play a key role in the treatment of AS. Objective: The purpose of this study is to summarize existing and suggested gene therapy approaches to Angelman syndrome. Methods: This is a literature review. Pubmed and Scopus databases were researched with keywords (gene therapy, Angelman’s syndrome, neurological disorders, neonates). Peer-reviewed studies that were closely related to gene therapies in Angelman syndrome and available in English, Greek, Ukrainian or Indonesian were included. Studies that were published before 2000 were excluded and did not align with the aforementioned criteria. Results: UBE3A serves multiple roles in signaling and degradation procedures. Although the restoration of UBE3A expression rather than targeting known activities of the molecule would be the optimal therapeutic goal, it is not possible so far. Reinstatement of paternal UBE3A appears as an adequate alternative. This can be achieved by administering topoisomerase-I inhibitors or reducing UBE3A antisense transcript (UBE3A-ATS), a molecule which silences paternal UBE3A. Conclusion: Understanding UBE3A imprinting unravels the path to an etiologic treatment of AS. Gene therapy models tested on mice appeared less effective than anticipated pointing out that activation of paternal UBE3A cannot counteract the existing CNS defects. On the other hand, targeting abnormal downstream cell signaling pathways has provided promising rescue effects. Perhaps, combined reinstatement of paternal UBE3A expression with abnormal signaling pathways-oriented treatment is expected to provide better therapeutic effects. However, AS gene therapy remains debatable in pharmacoeconomics and ethics context.

Stimulating broadly neutralizing antibodies (bnAbs) directly from germline remains a barrier for HIV vaccines. HIV superinfection elicits bnAbs more frequently than single infection, providing clues of how to elicit such responses. We used longitudinal antibody sequencing and structural studies to characterize bnAb development from a superinfection case. BnAb QA013.2 bound initial and superinfecting viral Env, despite its probable naive progenitor only recognizing the superinfecting strain, suggesting both viruses influenced this lineage. A 4.15 Å cryo-EM structure of QA013.2 bound to native-like trimer showed recognition of V3 signatures (N301/N332 and GDIR). QA013.2 relies less on CDRH3 and more on framework and CDRH1 for affinity and breadth compared to other V3/glycan-specific bnAbs. Antigenic profiling revealed that viral escape was achieved by changes in the structurally-defined epitope and by mutations in V1. These results highlight shared and novel properties of QA013.2 relative to other V3/glycan-specific bnAbs in the setting of sequential, diverse antigens.

Stimulating broadly neutralizing antibodies (bnAbs) directly from germline remains a barrier for HIV vaccines. HIV superinfection elicits bnAbs more frequently than single infection, providing clues of how to elicit such responses. We used longitudinal antibody sequencing and structural studies to characterize bnAb development from a superinfection case. Mature bnAb QA013.2 bound both initial transmitted and superinfecting virus, but its inferred naïve bound only the superinfecting strain and was not neutralizing. QA013.2 requires residues spanning FWRH1-CDRH1 to attain breadth, which is uncommon for V3-specific bnAbs. A 4.15 Å cryo-EM structure of QA013.2 bound to heterologous native-like trimer showed recognition of V3 signatures (N301, N332, and GDIR). Antigenic profiling revealed that viral escape was achieved not only by changes in the structurally-defined epitope, but also by mutations in V1. These results highlight shared and distinct properties of QA013.2 relative to other V3-specific bnAbs in the setting of sequential, diverse antigenic variants.

Stimulating broadly neutralizing antibodies (bnAbs) directly from germline remains a barrier for HIV vaccines. HIV superinfection elicits bnAbs more frequently than single infection, providing clues of how to elicit such responses. We used longitudinal antibody sequencing and structural studies to characterize bnAb development from a superinfection case. Mature bnAb QA013.2 bound both initial transmitted and superinfecting virus, but its inferred naïve bound only the superinfecting strain and was not neutralizing. QA013.2 requires residues spanning FWRH1-CDRH1 to attain breadth, which is uncommon for V3-specific bnAbs. A 4.15 Å cryo-EM structure of QA013.2 bound to heterologous native-like trimer showed recognition of V3 signatures (N301, N332, and GDIR). Antigenic profiling revealed that viral escape was achieved not only by changes in the structurally-defined epitope, but also by mutations in V1. These results highlight shared and distinct properties of QA013.2 relative to other V3-specific bnAbs in the setting of sequential, diverse antigenic variants.

A prerequisite for the design of an HIV vaccine that elicits protective antibodies is understanding the developmental pathways that result in desirable antibody features. The development of antibodies that mediate antibody-dependent cellular cytotoxicity (ADCC) is particularly relevant because such antibodies have been associated with HIV protection in humans. We reconstructed the developmental pathways of six human HIV-specific ADCC antibodies using longitudinal antibody sequencing data. Most of the inferred naive antibodies did not mediate detectable ADCC. Gain of antigen binding and ADCC function typically required mutations in complementarity determining regions of one or both chains. Enhancement of ADCC potency often required additional mutations in framework regions. Antigen binding affinity and ADCC activity were correlated, but affinity alone was not sufficient to predict ADCC potency. Thus, elicitation of broadly active ADCC antibodies may require mutations that enable high-affinity antigen recognition along with mutations that optimize factors contributing to functional ADCC activity., eLife digest Nearly four decades after the human immunodeficiency virus (HIV for short) was first identified, the search for a vaccine still continues. An effective immunisation would require elements that coax the human immune system into making HIV-specific antibodies – the proteins that can recognise, bind to and deactivate the virus. Crucially, antibodies can also help white blood cells to target and destroy cells infected with HIV. This ‘antibody-dependent cellular cytotoxicity’ could be a key element of a successful vaccine, yet it has received less attention than the ability for antibodies to directly neutralize the virus. In particular, it is still unclear how antibodies develop the ability to flag HIV-infected cells for killing. Indeed, over the course of an HIV infection, an immune cell goes through genetic changes that tweak the 3D structure of the antibodies it manufactures. This process can improve the antibodies' ability to fight off the virus, but it was still unclear how it would shape antibody-dependent cellular cytotoxicity. To investigate this question, Doepker et al. retraced how the genes coding for six antibody families changed over time in an HIV-carrying individual. This revealed that antibodies could not initially trigger antibody-dependent cellular cytotoxicity. The property emerged and improved thanks to two types of alterations in the genetic sequences. One set of changes increased how tightly the antibodies could bind to the virus, targeting sections of the antibodies that can often vary. The second set likely altered the 3D structure in others ways, potentially affecting how antibodies bind the virus or how they interact with components of the immune system that help to kill HIV-infected cells. These alterations took place in segments of the antibodies that undergo less change over time. Ultimately, the findings by Doepker et al. suggest that an efficient HIV vaccine may rely on helping antibodies to evolve so they can bind more tightly to the virus and trigger cellular cytotoxicity more strongly.

The human body is able to generate a diverse set of high affinity antibodies, the soluble form of B cell receptors (BCRs), that bind to and neutralize invading pathogens. The natural development of BCRs must be understood in order to design vaccines for highly mutable pathogens such as influenza and HIV. BCR diversity is induced by naturally occurring combinatorial "V(D)J" rearrangement, mutation, and selection processes. Most current methods for BCR sequence analysis focus on separately modeling the above processes. Statistical phylogenetic methods are often used to model the mutational dynamics of BCR sequence data, but these techniques do not consider all the complexities associated with B cell diversification such as the V(D)J rearrangement process. In particular, standard phylogenetic approaches assume the DNA bases of the progenitor (or "naive") sequence arise independently and according to the same distribution, ignoring the complexities of V(D)J rearrangement. In this paper, we introduce a novel approach to Bayesian phylogenetic inference for BCR sequences that is based on a phylogenetic hidden Markov model (phylo-HMM). This technique not only integrates a naive rearrangement model with a phylogenetic model for BCR sequence evolution but also naturally accounts for uncertainty in all unobserved variables, including the phylogenetic tree, via posterior distribution sampling., 26 pages

Background: Cooling of starch after cooking is known to cause starch retrogradation which increases resistant starch content. Resistant starch cannot be digested in the gut and acts as dietary fiber. The study aimsed to determine the effect of cooling of carbohydrate rich diet on glycemic response on healthy adults.Methods: The present study was a randomized, single blind, crossover study where 20 healthy subjects were selected. Two rice preparations were used, one freshly prepared hot, second, cooked and cooled at 4°C for 12 hours. All subjects were evaluated after giving both rice preparations separately with a crossover period of 7 days. Glycemic response was checked over a period of 2 hours at various time intervals using ACCU-CHEK® Active glucometer.Results: Glycemic response with cooled white rice was better in comparison to freshly prepared hot white rice at all time points (mean±SD, 121.9±17.4 vs 128.0± 22.1 mg/dl). However, the difference in means at 30 mins was maximum and statistically significant (p

SummaryHIV-infected infants develop broadly neutralizing plasma responses with more rapid kinetics than adults, suggesting the ontogeny of infant responses could better inform a path to achievable vaccine targets. We developed computational methods to reconstruct the developmental lineage of BF520.1, the first example of a HIV-specific broadly neutralizing antibody (bnAb) from an infant. The BF520.1 inferred naïve precursor binds HIV Env and a bnAb evolved within six months of infection and required only 3% mutation. Mutagenesis and structural analyses revealed that for this infant bnAb, substitutions in the kappa chain were critical for activity, particularly in CDRL1. Overall, the developmental pathway of this infant antibody includes features distinct from adult antibodies, including several that may be amenable to better vaccine responses.

Background: Hepatitis C and chronic kidney disease (CKD) both present an unsolved public health problem Hepatitis C virus (HCV) is easily transmitted in haemodialysis units and by kidney transplantation. HCV leads to increased mortality and morbidity due to cirrhosis and hepatocellular carcinoma, while accelerating the progression of CKD. The aim of the study was to describe the demographic, clinical/biochemical profile and prevalence of patients with CKD who have HCV infection.Methods: This was a retrospective analysis of patients with CKD who presented to out/in patient department of medicine in a tertiary care center in Jammu from a period of Feb 2016 to Nov 2018. Detailed clinical history along with previous lab reports were noted and tests for HCV infection were conducted in all patients. Diagnosis of HCV was made via HCV RNA(RT PCR) and positive Anti HCV IgG serology.Results: Total 67 patients were included with median age of 54 years (range 43-72 years) with majority 76.1% being males, and 71.6% within 41-60 years age group. 31.4% were HCV positive out of which 81% were males. 7 patients were found to have co-infection with HIV and HBsAg. Genotype 1 (72%) was found to be more common than Genotype 3. Ultrasonography and Upper GI endoscopy showcased 57% with dilated spleenoportal axis and oesophageal varices respectively.Conclusions: Prevalence of HCV infection in CKD patients is high with genotype 1 being commonest. False negative Anti HCV antibody is common hence screening with HCV RNA is recommended. Strict universal precautions should be employed in hospitals and dialysis units to prevent transmission.

Stochastic mapping is a simulation-based method for probabilistically mapping substitution histories onto phylogenies according to continuous-time Markov models of evolution. This technique can be used to infer properties of the evolutionary process on the phylogeny and, unlike parsimony-based mapping, conditions on the observed data to randomly draw substitution mappings that do not necessarily require the minimum number of events on a tree. Most stochastic mapping applications simulate substitution mappings only to estimate the mean and/or variance of two commonly used mapping summaries: the number of particular types of substitutions (labeled substitution counts) and the time spent in a particular group of states (labeled dwelling times) on the tree. Fast, simulation-free algorithms for calculating the mean of stochastic mapping summaries exist. Importantly, these algorithms scale linearly in the number of tips/leaves of the phylogenetic tree. However, to our knowledge, no such algorithm exists for calculating higher-order moments of stochastic mapping summaries. We present one such simulation-free dynamic programming algorithm that calculates prior and posterior mapping variances and scales linearly in the number of phylogeny tips. Our procedure suggests a general framework that can be used to efficiently compute higher-order moments of stochastic mapping summaries without simulations. We demonstrate the usefulness of our algorithm by extending previously developed statistical tests for rate variation across sites and for detecting evolutionarily conserved regions in genomic sequences., Comment: 24 pages, 6 figures