Upsurge in hospitalization of pediatric patients with severe acute respiratory infections in Kolkata and surrounding districts caused by recombinant human respiratory adenovirus type B 7/3.

Globally, different genotypes of human adenoviruses are associated with outbreaks of acute respiratory infection (ARI) though such evidence is lacking from India. In the present study, we report a sudden increase in the positivity of respiratory adenovirus among hospitalized children with ARI from Kolkata and the surrounding districts of West Bengal, India, from December 2022 to date. A sharp rise in the positivity rate of respiratory adenovirus was found which ranged from 22.1% in early December 2022 to 52.6% in mid-March 2023. The overall positivity was 40.4% during the period and children in the 2 to <5 years (51.0%) age group were mostly affected. Single infection with adenovirus was found in 72.4% of cases while co-infection with rhinovirus was the maximum (9.4%). Around 97.5% of positive cases required hospitalization. Cough, breathlessness, and wheeze were the most common clinical features among positive patients. Phylogenetic analysis of the hexon and fiber gene of all the sequenced strains revealed HAdV-B 7/3 recombination with more than 99% homology within themselves. This report of a respiratory adenovirus outbreak in West Bengal, India causing severe illness in the pediatric population underscores the need for regular monitoring of the circulating strains.

Molecular epidemiology of circulating human adenoviruses among acute respiratory infection patients seeking healthcare facilities in West Bengal, India.

Human adenovirus (HAdV) causes acute respiratory infections leading to mortality in children. This study analyzes the circulating respiratory HAdV genotypes in West Bengal, India during 2018-2022 among symptomatic patients. The overall positivity rate was 6.8%, out of which 26.4% were co-infected with other respiratory viruses. Children aged 2 to 5 years were mostly infected. Phylogenetic analysis revealed that the recombinant HAdV-B type 7/3, which has remarkable outbreak potential, predominantly circulated in this region followed by the non-recombinant HAdV-B type 3/3. Moreover, the amino acid sequences encoded by both the hexon and fiber genes of these two circulating strains possessed a few mutations that mostly diverged from the prototype strain, although the divergence was less pronounced in case of the amino acids encoded by the fiber gene of HAdV-B type 3/3. Overall, the results underscore the need for continuous surveillance of respiratory HAdV types to combat future possible epidemics.

Cardiomyocyte targeted overexpression of IGF1 during detraining restores compromised cardiac condition via mTORC2 mediated switching of PKCδ to PKCα.

Altered cardiac adaptation of physiologically hypertrophied heart during detraining remained obscure for long time. We had previously reported the switching of protein kinase C (PKC) isoforms (-α to -δ) associated with functional deterioration of heart at detraining in mice undergone swim exercise. Here we report that, myocardium targeted overexpression of insulin-like growth factor 1 (IGF1) and knockdown of insulin-like growth factor 1 receptor (IGF1R) during detraining and exercise respectively altered the activation of PKCs and eventual cardiac condition. Moreover, downregulation of mammalian target of rapamycin complex 2 (mTORC2) was recorded in both IGF1R knockdown or detraining groups. Additionally, knocking down of mTORC2 during exercise exhibited impaired cardiac condition. Interestingly, significantly increased interactions of mTORC2 with both PKCα and δ was recorded exclusively in exercise group. This interaction resulted into hydrophobic motif phosphorylation of both PKCs (Serine657-PKCα; Serine662-PKCδ). Serine phosphorylation on one hand activated PKCα mediated cell survival and on the other hand alleviated the apoptotic activity of PKCδ during exercise. Mutation of Serine662 of PKCδ in exercised mice showed higher Tyrosine311 phosphorylation with increased apoptotic load similar to that in detrained animals. These observations confirmed that differential and conditional activation of PKCs depend upon IGF1 induced mTORC2 activation. Furthermore, blocking of PKCα resulted in activated p53 which in turn repressed IGF1 expression during swim, mimicking the condition of detrained heart. In conclusion, this is the first report to unravel the intricate molecular mechanism of switching a physiologically hypertrophied heart to a pathologically hypertrophied heart during exercise withdrawal.

Nanotized PPARα Overexpression Targeted to Hypertrophied Myocardium Improves Cardiac Function by Attenuating the p53-GSK3ß-Mediated Mitochondrial Death Pathway.

AIMS: Metabolic remodeling of cardiac muscles during pathological hypertrophy is characterized by downregulation of fatty acid oxidation (FAO) regulator, peroxisome proliferator-activated receptor alpha (PPARα). Thereby, we hypothesized that a cardiac-specific induction of PPARα might restore the FAO-related protein expression and resultant energy deficit. In the present study, consequences of PPARα augmentation were evaluated for amelioration of chronic oxidative stress, myocyte apoptosis, and cardiac function during pathological cardiac hypertrophy. RESULTS: Nanotized PPARα overexpression targeted to myocardium was done by a stearic acid-modified carboxymethyl-chitosan (CMC) conjugated to a 20-mer myocyte-targeted peptide (CMCP). Overexpression of PPARα ameliorated pathological hypertrophy and improved cardiac function. Augmented PPARα in hypertrophied myocytes revealed downregulated p53 acetylation (lys 382), leading to reduced apoptosis. Such cells showed increased binding of PPARα with p53 that in turn reduced interaction of p53 with glycogen synthase kinase-3ß (GSK3ß), which upregulated inactive phospho-GSK3ß (serine [Ser]9) expression within mitochondrial protein fraction. Altogether, the altered molecular milieu in PPARα-overexpressed hypertrophy groups restored mitochondrial structure and function both in vitro and in vivo. INNOVATION: Cardiomyocyte-targeted overexpression of a protein of interest (PPARα) by nanotized plasmid has been described for the first time in this study. Our data provide a novel insight towards regression of pathological hypertrophy by ameliorating mitochondrial oxidative stress in targeted PPARα-overexpressed myocardium. CONCLUSION: PPARα-overexpression during pathological hypertrophy showed substantial betterment of mitochondrial structure and function, along with downregulated apoptosis. Myocardium-targeted overexpression of PPARα during pathological cardiac hypertrophy led to an overall improvement of cardiac energy deficit and subsequent cardiac function, thereby, opening up a potential avenue for cardiac tissue engineering during hypertrophic cardiac pathophysiology.