The triad of physiological challenges: investigating the intersection of sarcopenia, malnutrition, and malnutrition-sarcopenia syndrome in patients with COPD - a cross-sectional study.

BACKGROUND: One of the most prevalent respiratory disorders in modern society is chronic obstructive pulmonary disease (COPD). Frequent comorbidities in patients with COPD are abnormal nutritional status and body composition variations. Malnutrition-sarcopenia syndrome, which occurs when the 2 conditions - malnutrition and sarcopenia - coexist, raises the risk of death more than either condition alone. The current study sought to determine the prevalence of malnutrition, sarcopenia, and malnutrition-sarcopenia syndrome in patients with COPD as well as the association between these diseases and the severity of COPD. METHODS: The study was an analytical cross-sectional study conducted on hospitalized patients with COPD. The sample size of the study was calculated to be 160. A self-structured questionnaire was used to collect the data, containing sociodemographic characteristics, clinical profiles, anthropometric assessment, and bioimpedance indices. Sarcopenia was diagnosed with low muscle strength and muscle mass by the EWGSOP2 recommendations. Muscle mass is measured by BIA and muscle strength (Handgrip) was measured by a Hand Dynamometer. Assessment of the risk of malnutrition was performed using the Mini Nutritional Assessment-Short Form questionnaire and was confirmed by GLIM criteria. The COPD assessment test (CAT) tool determined the severity of the condition. For the data analysis, comparisons were made using Student's t test and Mann-Whitney test in bivariate analysis. Multivariate logistic regression analyses were performed considering the outcomes of patients with COPD by CAT scores, prolonged length of stay, and hospital readmission 6 months after discharge. RESULTS: The mean age of the participants was 48 ± 5 years. Approximately 61.9% were found to be sarcopenic. Approximately 45.6% of participants had malnutrition. Malnutrition sarcopenia syndrome was diagnosed in 32.5% of patients. The study analysis revealed that patients with COPD with malnutrition-sarcopenia syndrome had more than twice the odds of prolonged hospital stay, re-admission within 6 months, and higher CAT scores. CONCLUSION: The study revealed a high prevalence of sarcopenia, malnutrition, and malnutrition sarcopenia syndrome in patients with COPD. These conditions were found to be statistically significant with prolonged length of stay, re-admission within 6 months, and CAT scores. The findings highlight the importance of addressing these conditions as part of the management of the patients.

Unanchored K48-linked polyubiquitin synthesized by the E3-ubiquitin ligase TRIM6 stimulates the interferon-IKKε kinase-mediated antiviral response.

Type I interferons (IFN-I) are essential antiviral cytokines produced upon microbial infection. IFN-I elicits this activity through the upregulation of hundreds of IFN-I-stimulated genes (ISGs). The full breadth of ISG induction demands activation of a number of cellular factors including the IκB kinase epsilon (IKKε). However, the mechanism of IKKε activation upon IFN receptor signaling has remained elusive. Here we show that TRIM6, a member of the E3-ubiquitin ligase tripartite motif (TRIM) family of proteins, interacted with IKKε and promoted induction of IKKε-dependent ISGs. TRIM6 and the E2-ubiquitin conjugase UbE2K cooperated in the synthesis of unanchored K48-linked polyubiquitin chains, which activated IKKε for subsequent STAT1 phosphorylation. Our work attributes a previously unrecognized activating role of K48-linked unanchored polyubiquitin chains in kinase activation and identifies the UbE2K-TRIM6-ubiquitin axis as critical for IFN signaling and antiviral response.

RIG-I Mediates an Antiviral Response to Crimean-Congo Hemorrhagic Fever Virus.

UNLABELLED: In the cytoplasm, the retinoic acid-inducible gene I (RIG-I) senses the RNA genomes of several RNA viruses. RIG-I binds to viral RNA, eliciting an antiviral response via the cellular adaptor MAVS. Crimean-Congo hemorrhagic fever virus (CCHFV), a negative-sense RNA virus with a 5'-monophosphorylated genome, is a highly pathogenic zoonotic agent with significant public health implications. We found that, during CCHFV infection, RIG-I mediated a type I interferon (IFN) response via MAVS. Interfering with RIG-I signaling reduced IFN production and IFN-stimulated gene expression and increased viral replication. Immunostimulatory RNA was isolated from CCHFV-infected cells and from virion preparations, and RIG-I coimmunoprecipitation of infected cell lysates isolated immunostimulatory CCHFV RNA. This report serves as the first description of a pattern recognition receptor for CCHFV and highlights a critical signaling pathway in the antiviral response to CCHFV. IMPORTANCE: CCHFV is a tick-borne virus with a significant public health impact. In order for cells to respond to virus infection, they must recognize the virus as foreign and initiate antiviral signaling. To date, the receptors involved in immune recognition of CCHFV are not known. Here, we investigate and identify RIG-I as a receptor involved in initiating an antiviral response to CCHFV. This receptor initially was not expected to play a role in CCHFV recognition because of characteristics of the viral genome. These findings are important in understanding the antiviral response to CCHFV and support continued investigation into the spectrum of potential viruses recognized by RIG-I.

Hijacking of RIG-I signaling proteins into virus-induced cytoplasmic structures correlates with the inhibition of type I interferon responses.

UNLABELLED: Recognition of viral pathogens by the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) family results in the activation of type I interferon (IFN) responses. To avoid this response, most viruses have evolved strategies that target different essential steps in the activation of host innate immunity. In this study, we report that the nonstructural protein NSs of the newly described severe fever with thrombocytopenia syndrome virus (SFTSV) is a potent inhibitor of IFN responses. The SFTSV NSs protein was found to inhibit the activation of the beta interferon (IFN-ß) promoter induced by viral infection and by a RIG-I ligand. Astonishingly, we found that SFTSV NSs interacts with and relocalizes RIG-I, the E3 ubiquitin ligase TRIM25, and TANK-binding kinase 1 (TBK1) into SFTSV NSs-induced cytoplasmic structures. Interestingly, formation of these SFTSV NSs-induced structures occurred in the absence of the Atg7 gene, a gene essential for autophagy. Furthermore, confocal microscopy studies revealed that these SFTSV NSs-induced structures colocalize with Rab5 but not with Golgi apparatus or endoplasmic reticulum markers. Altogether, the data suggest that sequestration of RIG-I signaling molecules into endosome-like structures may be the mechanism used by SFTSV to inhibit IFN responses and point toward a novel mechanism for the suppression of IFN responses. IMPORTANCE: The mechanism by which the newly described SFTSV inhibits host antiviral responses has not yet been fully characterized. In this study, we describe the redistribution of RIG-I signaling components into virus-induced cytoplasmic structures in cells infected with SFTSV. This redistribution correlates with the inhibition of host antiviral responses. Further characterization of the interplay between the viral protein and components of the IFN responses could potentially provide targets for the rational development of therapeutic interventions.

ATPase-driven oligomerization of RIG-I on RNA allows optimal activation of type-I interferon.

The cytosolic pathogen sensor RIG-I is activated by RNAs with exposed 5'-triphosphate (5'-ppp) and terminal double-stranded structures, such as those that are generated during viral infection. RIG-I has been shown to translocate on dsRNA in an ATP-dependent manner. However, the precise role of the ATPase activity in RIG-I activation remains unclear. Using in vitro-transcribed Sendai virus defective interfering RNA as a model ligand, we show that RIG-I oligomerizes on 5'-ppp dsRNA in an ATP hydrolysis-dependent and dsRNA length-dependent manner, which correlates with the strength of type-I interferon (IFN-I) activation. These results establish a clear role for the ligand-induced ATPase activity of RIG-I in the stimulation of the IFN response.

DENV inhibits type I IFN production in infected cells by cleaving human STING.

Dengue virus (DENV) is a pathogen with a high impact on human health. It replicates in a wide range of cells involved in the immune response. To efficiently infect humans, DENV must evade or inhibit fundamental elements of the innate immune system, namely the type I interferon response. DENV circumvents the host immune response by expressing proteins that antagonize the cellular innate immunity. We have recently documented the inhibition of type I IFN production by the proteolytic activity of DENV NS2B3 protease complex in human monocyte derived dendritic cells (MDDCs). In the present report we identify the human adaptor molecule STING as a target of the NS2B3 protease complex. We characterize the mechanism of inhibition of type I IFN production in primary human MDDCs by this viral factor. Using different human and mouse primary cells lacking STING, we show enhanced DENV replication. Conversely, mutated versions of STING that cannot be cleaved by the DENV NS2B3 protease induced higher levels of type I IFN after infection with DENV. Additionally, we show that DENV NS2B3 is not able to degrade the mouse version of STING, a phenomenon that severely restricts the replication of DENV in mouse cells, suggesting that STING plays a key role in the inhibition of DENV infection and spread in mice.

Unravelling the obesity maze in diabetic patients: A comparative analysis of classification methods.

Background: Obesity is a significant health concern among individuals with type 2 diabetes mellitus (T2DM). Emerging evidence suggests that alternative measures, such as abdominal girth (AG) and body fat percentage (BF%), can provide a more accurate reflection of obesity-related metabolic risks in diabetic populations. This study aimed to compare the accuracy of different obesity classification methods, including BMI, AG, and BF%, among individuals with T2DM. Methodology: This was an observational cross-sectional study conducted among T2DM patients who came to the non-communicable diseases clinic of GG Govt Hospital, Jamnagar, Gujarat during the period of March-April 2023. Demographic and anthropometric information was collected. Body fat analysis was done using a validated Omron fat analyzer. Results: The study found the sensitivity of BMI in males and females as 41.6% and 45% against BF%, respectively. It also showed that the sensitivity of BMI in males and females was 38% and 40.7%, respectively, against AG. The present study also found a moderate positive correlation (r = 0.575) between AG and BF% in individuals with T2DM. Conclusion: The findings indicate that BF% and AG provide valuable insights into adiposity, surpassing the limitations of BMI as a measure of body composition. BF% is an indicator of body fat content, whereas AG serves as a proxy for central adiposity. The correlations between BF% and AG suggest that excess abdominal fat accumulation signifies increased body fat. By incorporating measures such as BF% and AG alongside BMI, clinicians can obtain a more comprehensive understanding of body composition and its relationship with metabolic abnormalities.

The Hidden Battle Within: Shedding Light on the Co-existence of Sarcopenia and Sarcopenic Obesity among Participants with Type 2 Diabetes in a Tertiary Care Hospital, Gujarat.

Introduction: Type 2 diabetes (T2DM) is characterised by chronic hyperglycaemia due to abnormal insulin secretion and/or utilisation. Currently, sarcopenia has emerged as a new complication of T2DM, which increases the risk of physical disability, and even death. The study aims to estimate the prevalence of sarcopenia and sarcopenic obesity (SO) as well as their association with various other factors related to T2DM. Methods: The study was an observational hospital-based cross-sectional study conducted among diabetic patients who came to the non-communicable diseases (NCD) clinic of a tertiary care hospital in Gujarat, India, from April 2023 to June 2023. Adult patients with T2DM attending follow-ups were included, with a diagnosis of T2DM for at least 1 year from the date of their electronic medical records, regardless of their mode of therapeutic treatment. They were on regular medical reviews with two or more visits to the study site in the past 1 year. Then a self-structured standard questionnaire was used to collect the data, containing socio-demographic characteristics, clinical profiles, anthropometric assessment (comprising weight, height and body mass index [BMI]), bio-impedance indices like body fat%, skeletal muscle% and handgrip by hand dynamometer. Results: In the study, a total of 404 participants participated. Their mean age was 55 ± 13.5 years and their mean body fat (BF) % was 30 ± 7.4%. BF%-defined obesity was found in 260 (64.4%) participants. A total of 362 (89.6%) had possible sarcopenia, 183 (45.3%) had sarcopenia and 124 (30.7%) had SO. Age (OR: 2.6, CI: 1.7-3.9), duration of diabetes for more than 7 years (OR: 7.5, CI: 3.65-15.4) and BF%-defined obesity (OR: 2.2, CI: 3.6-15) were statistically associated with Sarcopenia, in similar pattern age (OR: 2.4, CI: 1.5-3.7), and duration of diabetes more than 7 years (OR: 18.9, CI: 5.7-62) were associated with SO (P < 0.05). Conclusion: Older age, longer diabetes duration and BF%-defined obesity are associated with an increased likelihood of developing sarcopenia and sarcopenic obesity. Healthcare providers should prioritise regular screening for sarcopenia and SO in elderly individuals with diabetes to facilitate early detection and intervention.

Influenza A virus neuraminidase protein enhances cell survival through interaction with carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) protein.

The influenza virus neuraminidase (NA) protein primarily aids in the release of progeny virions from infected cells. Here, we demonstrate a novel role for NA in enhancing host cell survival by activating the Src/Akt signaling axis via an interaction with carcinoembryonic antigen-related cell adhesion molecule 6/cluster of differentiation 66c (C6). NA/C6 interaction leads to increased tyrosyl phosphorylation of Src, FAK, Akt, GSK3ß, and Bcl-2, which affects cell survival, proliferation, migration, differentiation, and apoptosis. siRNA-mediated suppression of C6 resulted in a down-regulation of activated Src, FAK, and Akt, increased apoptosis, and reduced expression of viral proteins and viral titers in influenza virus-infected human lung adenocarcinoma epithelial and normal human bronchial epithelial cells. These findings indicate that influenza NA not only aids in the release of progeny virions, but also cell survival during viral replication.

Considerations for Potential Global Expansion of Serum Institute of India.

In a time of global vaccine shortages, especially for COVID-19 products, Serum Institute of India (SII) is straining to meet demand for vaccines in India. While this organization is not known worldwide, they entered into a recent alliance with AstraZeneca, who is partnered with Oxford University for COVID-19 vaccine, to manufacture their supply of vaccines for distribution in India. Several other such partnerships are also underway. And, SII is considering plans to become a much larger player, not only in India, but globally. This commentary is focused on if, when, where, why, and how global expansion could proceed. Our work was carried out as a class project to identify options and strategies appropriate for expansion and has been expanded subsequently as events continued to develop.

VA TECHNOLOGY TRANSFER PROGRAM RESPONDS TO COVID-19 PANDEMIC.

The COVID-19 pandemic stressed healthcare systems all over the world. Two primary challenges that healthcare systems faced were a shortage of personal protective equipment and the need for new technologies to handle infection prevention for staff and patients. The Department of Veteran's Affairs (VA) Technology Transfer Program responded by prioritizing the development of innovations in the Technology Transfer Assistance Project which addressed the pandemic. This paper describes several innovations that addressed the needs of the VA healthcare system during the pandemic and how they were rapidly developed.

A Dual-Functioning 5'-PPP-NS1shRNA that Activates a RIG-I Antiviral Pathway and Suppresses Influenza NS1.

Retinoic acid-inducible gene-I (RIG-I) is a cytosolic pathogen sensor that is crucial against a number of viral infections. Many viruses have evolved to inhibit pathogen sensors to suppress host innate immune responses. In the case of influenza, nonstructural protein 1 (NS1) suppresses RIG-I function, leading to viral replication, morbidity, and mortality. We show that silencing NS1 with in-vitro-transcribed 5'-triphosphate containing NS1 short hairpin RNA (shRNA) (5'-PPP-NS1shRNA), designed using the conserved region of a number of influenza viruses, not only prevented NS1 expression but also induced RIG-I activation and type I interferon (IFN) expression, resulting in an antiviral state leading to inhibition of influenza virus replication in vitro. In addition, administration of 5'-PPP-NS1shRNA in prophylactic and therapeutic settings resulted in significant inhibition of viral replication following viral challenge in vivo in mice with corresponding increases of RIG-I, IFN-ß, and IFN-λ, as well as a decrease in NS1 expression.

Angiomatosis: a case with metaplastic ossification.

Angiomatosis is defined as a hemangioma that affects a large segment of the body in a contiguous fashion, either by vertical extension to involve multiple tissue planes (eg, skin, subcutis, muscle, bone) or by crossing muscle compartments to involve similar tissue types (eg, multiple muscles). Such lesions usually present in the first 2 decades of life and have a highly characteristic but not totally specific histological pattern. Histology usually shows a haphazard mixture of small and medium-sized vessels, fat, connective tissue, and lymphatics. Large amounts of mature fat frequently accompany the vascular elements, suggesting that the lesion may possibly be a more generalized mesenchymal proliferation rather than an exclusively vascular lesion. Here we present what we believe to be the first case of angiomatosis showing osseous metaplasia.

Interference with the lower gut-liver axis induces remission of primary sclerosing cholangitis in a patient with ulcerative colitis.

The gut-liver axis describes the complex interactions between gut microbiota, the small and large bowel, the immune system and the liver. Current evidence associates abnormalities within the gut-liver axis with liver disease such as primary sclerosing cholangitis (PSC). PSC is believed to be an immune-mediated disease though the exact mechanism of its pathogenesis remains unknown. Here, we report a case of a 66 -year-old woman with treatment-resistant ulcerative colitis and PSC which continued to be active following subtotal colectomy. Interestingly, her PSC achieved full remission after proctectomy for treatment-resistant proctitis in the rectal stump. This case report supports existing hypotheses that PSC is an immune-mediated disease triggered by antigens within the gut. More notably, it suggests the yet unidentified pathogens may be localised to the lower gastrointestinal tract including the rectum.

Gold nanoparticle-polymer nanocomposites synthesized by room temperature atmospheric pressure plasma and their potential for fuel cell electrocatalytic application.

Conductive polymers have been increasingly used as fuel cell catalyst support due to their electrical conductivity, large surface areas and stability. The incorporation of metal nanoparticles into a polymer matrix can effectively increase the specific surface area of these materials and hence improve the catalytic efficiency. In this work, a nanoparticle loaded conductive polymer nanocomposite was obtained by a one-step synthesis approach based on room temperature direct current plasma-liquid interaction. Gold nanoparticles were directly synthesized from HAuCl4 precursor in poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS). The resulting AuNPs/PEDOT:PSS nanocomposites were subsequently characterized under a practical alkaline direct ethanol fuel cell operation condition for its potential application as an electrocatalyst. Results show that AuNPs sizes within the PEDOT:PSS matrix are dependent on the plasma treatment time and precursor concentration, which in turn affect the nanocomposites electrical conductivity and their catalytic performance. Under certain synthesis conditions, unique nanoscale AuNPs/PEDOT:PSS core-shell structures could also be produced, indicating the interaction at the AuNPs/polymer interface. The enhanced catalytic activity shown by AuNPs/PEDOT:PSS has been attributed to the effective electron transfer and reactive species diffusion through the porous polymer network, as well as the synergistic interfacial interaction at the metal/polymer and metal/metal interfaces.

Dengue virus NS2B protein targets cGAS for degradation and prevents mitochondrial DNA sensing during infection.

During the last few decades, the global incidence of dengue virus (DENV) has increased dramatically, and it is now endemic in more than 100 countries. To establish a productive infection in humans, DENV uses different strategies to inhibit or avoid the host innate immune system. Several DENV proteins have been shown to strategically target crucial components of the type I interferon system. Here, we report that the DENV NS2B protease cofactor targets the DNA sensor cyclic GMP-AMP synthase (cGAS) for lysosomal degradation to avoid the detection of mitochondrial DNA during infection. Such degradation subsequently results in the inhibition of type I interferon production in the infected cell. Our data demonstrate a mechanism by which cGAS senses cellular damage upon DENV infection.

NADPH Oxidase 1 Is Associated with Altered Host Survival and T Cell Phenotypes after Influenza A Virus Infection in Mice.

The role of the reactive oxygen species-producing NADPH oxidase family of enzymes in the pathology of influenza A virus infection remains enigmatic. Previous reports implicated NADPH oxidase 2 in influenza A virus-induced inflammation. In contrast, NADPH oxidase 1 (Nox1) was reported to decrease inflammation in mice within 7 days post-influenza A virus infection. However, the effect of NADPH oxidase 1 on lethality and adaptive immunity after influenza A virus challenge has not been explored. Here we report improved survival and decreased morbidity in mice with catalytically inactive NADPH oxidase 1 (Nox1*/Y) compared with controls after challenge with A/PR/8/34 influenza A virus. While changes in lung inflammation were not obvious between Nox1*/Y and control mice, we observed alterations in the T cell response to influenza A virus by day 15 post-infection, including increased interleukin-7 receptor-expressing virus-specific CD8+ T cells in lungs and draining lymph nodes of Nox1*/Y, and increased cytokine-producing T cells in lungs and spleen. Furthermore, a greater percentage of conventional and interstitial dendritic cells from Nox1*/Y draining lymph nodes expressed the co-stimulatory ligand CD40 within 6 days post-infection. Results indicate that NADPH oxidase 1 modulates the innate and adaptive cellular immune response to influenza virus infection, while also playing a role in host survival. Results suggest that NADPH oxidase 1 inhibitors may be beneficial as adjunct therapeutics during acute influenza infection.

Enhanced Dispersion of TiO2 Nanoparticles in a TiO2/PEDOT:PSS Hybrid Nanocomposite via Plasma-Liquid Interactions.

A facile method to synthesize a TiO2/PEDOT:PSS hybrid nanocomposite material in aqueous solution through direct current (DC) plasma processing at atmospheric pressure and room temperature has been demonstrated. The dispersion of the TiO2 nanoparticles is enhanced and TiO2/polymer hybrid nanoparticles with a distinct core shell structure have been obtained. Increased electrical conductivity was observed for the plasma treated TiO2/PEDOT:PSS nanocomposite. The improvement in nanocomposite properties is due to the enhanced dispersion and stability in liquid polymer of microplasma treated TiO2 nanoparticles. Both plasma induced surface charge and nanoparticle surface termination with specific plasma chemical species are proposed to provide an enhanced barrier to nanoparticle agglomeration and promote nanoparticle-polymer binding.

ATP hydrolysis by the viral RNA sensor RIG-I prevents unintentional recognition of self-RNA.

The cytosolic antiviral innate immune sensor RIG-I distinguishes 5' tri- or diphosphate containing viral double-stranded (ds) RNA from self-RNA by an incompletely understood mechanism that involves ATP hydrolysis by RIG-I's RNA translocase domain. Recently discovered mutations in ATPase motifs can lead to the multi-system disorder Singleton-Merten Syndrome (SMS) and increased interferon levels, suggesting misregulated signaling by RIG-I. Here we report that SMS mutations phenocopy a mutation that allows ATP binding but prevents hydrolysis. ATPase deficient RIG-I constitutively signals through endogenous RNA and co-purifies with self-RNA even from virus infected cells. Biochemical studies and cryo-electron microscopy identify a 60S ribosomal expansion segment as a dominant self-RNA that is stably bound by ATPase deficient RIG-I. ATP hydrolysis displaces wild-type RIG-I from this self-RNA but not from 5' triphosphate dsRNA. Our results indicate that ATP-hydrolysis prevents recognition of self-RNA and suggest that SMS mutations lead to unintentional signaling through prolonged RNA binding.