Regulatory roles of microRNAs in modulating mitochondrial dynamics, amyloid beta fibrillation, microglial activation, and cholinergic signaling: Implications for alzheimer's disease pathogenesis.

Alzheimer's Disease (AD) remains a formidable challenge due to its complex pathology, notably involving mitochondrial dysfunction and dysregulated microRNA (miRNA) signaling. This study delves into the underexplored realm of miRNAs' impact on mitochondrial dynamics and their interplay with amyloid-beta (Aß) aggregation and tau pathology in AD. Addressing identified gaps, our research utilizes advanced molecular techniques and AD models, alongside patient miRNA profiles, to uncover miRNAs pivotal in mitochondrial regulation. We illuminate novel miRNAs influencing mitochondrial dynamics, Aß, and tau, offering insights into their mechanistic roles in AD progression. Our findings not only enhance understanding of AD's molecular underpinnings but also spotlight miRNAs as promising therapeutic targets. By elucidating miRNAs' roles in mitochondrial dysfunction and their interactions with hallmark AD pathologies, our work proposes innovative strategies for AD therapy, aiming to mitigate disease progression through targeted miRNA modulation. This contribution marks a significant step toward novel AD treatments, emphasizing the potential of miRNAs in addressing this complex disease.

A protein-miRNA biomic analysis approach to explore neuroprotective potential of nobiletin in human neural progenitor cells (hNPCs).

Chemical-induced neurotoxicity is increasingly recognized to accelerate the development of neurodegenerative disorders (NDs), which pose an increasing health burden to society. Attempts are being made to develop drugs that can cross the blood-brain barrier and have minimal or no side effects. Nobiletin (NOB), a polymethoxylated flavonoid with anti-oxidative and anti-inflammatory effects, has been demonstrated to be a promising compound to treat a variety of NDs. Here, we investigated the potential role of NOB in sodium arsenate (NA)-induced deregulated miRNAs and target proteins in human neural progenitor cells (hNPCs). The proteomics and microRNA (miRNA) profiling was done for different groups, namely, unexposed control, NA-exposed, NA + NOB, and NOB groups. Following the correlation analysis between deregulated miRNAs and target proteins, RT-PCR analysis was used to validate the selected genes. The proteomic analysis showed that significantly deregulated proteins were associated with neurodegeneration pathways, response to oxidative stress, RNA processing, DNA repair, and apoptotic process following exposure to NA. The OpenArray analysis confirmed that NA exposure significantly altered miRNAs that regulate P53 signaling, Wnt signaling, cell death, and cell cycle pathways. The RT-PCR validation studies concur with proteomic data as marker genes associated with autophagy and apoptosis (HO-1, SQSTM1, LC-3, Cas3, Apaf1, HSP70, and SNCA1) were altered following NA exposure. It was observed that the treatment of NOB significantly restored the deregulated miRNAs and proteins to their basal levels. Hence, it may be considered one of its neuroprotective mechanisms. Together, the findings are promising to demonstrate the potential applicability of NOB as a neuroprotectant against chemical-induced neurotoxicity.

X-Linked Lymphoproliferative Syndrome: A Spectrum of Clinical and Immunological Profile and Novel Pathogenic Variants from Chandigarh, India.

INTRODUCTION: X-linked lymphoproliferative syndrome (XLP) is a rare primary immune deficiency. Two types of XLP have been described: XLP-1 and XLP-2. METHODS: We found 7 patients with XLP (3 had XLP-1 and 4 had XLP-2) after reviewing the data from Pediatric Immunodeficiency Clinic from 1997 to 2021. RESULTS: Mean age at diagnosis was 3.8 years, and mean delay in diagnosis was 2.6 years. Five patients had recurrent episodes of infections. Four patients developed at least one episode of hemophagocytic lymphohistiocytosis (HLH) (2 with XLP-1 and 2 with XLP-2). Of these, 2 had recurrent HLH (both with XLP-2). Epstein-Barr virus (EBV) infection was detected in 2 (1 with XLP-1 and 1 with XLP-2). Both these patients had HLH. One child with XLP-2 had inflammatory bowel disease. Hypogammaglobulinemia was seen in 3 (2 with XLP-1 and 1 with XLP-2). Genetic analysis showed previously reported variants in 5, while 2 had novel variants (one in exon 7 of XIAP gene [c.1370dup p.Asn457Lysfs Ter16] and other had splice site variant in intron 1 of SH2D1A gene [c.138-2_138-1insG]). Episodes of HLH were managed with intravenous immunoglobulin (IVIg), methylprednisolone, oral prednisolone, cyclosporine, and rituximab. Inflammatory bowel disease was managed using oral prednisolone and azathioprine. One patient underwent haploidentical hematopoietic stem cell transplantation. One child with XLP-2 and WAS died because of fulminant pneumonia. DISCUSSION/CONCLUSIONS: XLP should be considered as a strong possibility in any patient with features of HLH, repeated infections with hypogammaglobulinemia, persistent EBV infection, and early-onset IBD.

Microvascular changes on nailfold capillaroscopy in acute stage of Kawasaki disease: a new diagnostic paradigm for an enigmatic condition.

OBJECTIVES: Kawasaki disease (KD) is a medium vessel vasculitis with a predilection to involve coronary arteries. However, there is a paucity of literature on microvascular changes in patients with KD. METHODS: Children diagnosed with KD based on American Heart Association guidelines 2017 were enrolled prospectively. Demographic details and echocardiographic changes in coronaries were recorded. Nailfold capillaries were assessed using Optilia Video capillaroscopy and data were analysed using Optilia Optiflix Capillaroscopy software at acute (prior to IVIG administration) and subacute/convalescent phase. RESULTS: We enrolled 32 children with KD (17 boys) with a median age of 3 years. Nailfold capillaroscopy (NFC) was performed in 32 patients in the acute phase (compared with 32 controls) and in 17 during the subacute/convalescent phase at a median follow-up of 15 (15-90) days after IVIG treatment. The following findings were seen in NFC in the acute phase of KD: reduced capillary density (n = 12, 38.6%), dilated capillaries (n = 3, 9.3%), ramifications (n = 3, 9.3%) and capillary haemorrhages (n = 2, 6.2%). Capillary density was reduced significantly in the acute phase of KD (38.6%) as compared with the subacute/convalescent phase (25.4%) (P-value <0.001) and controls (0%) (P-value = 0.03). We observed no correlation between coronary artery involvement and mean capillary density (P = 0.870). CONCLUSION: Results show that patients with KD have significant nailfold capillary changes in the acute phase. These findings may provide a new diagnostic paradigm for KD and a window to predict coronary artery abnormalities.

Uncovering the true burden of hereditary angioedema due to C1-inhibitor deficiency: A focus on the Asia-Pacific region.

Hereditary angioedema (HAE) due to C1-inhibitor deficiency or dysfunction is a rare genetic disorder that causes recurrent episodes of swelling in various parts of the body. Treatment goals of HAE aim to "normalize" life for all patients; however, lack of diagnostic facilities and limited access to effective treatment options in developing nations cause delays in diagnosis and place a significant burden on patients. In this review, we aim to highlight the burden of disease caused by C1-inhibitor HAE across the Asia-Pacific region, considering its epidemiology, morbidity and mortality, and socioeconomic and psychological impact. We also review the availability of guideline-recommended diagnostic facilities and treatments, and how patients are currently managed. Data were collected from published literature and HAE experts in the region, who provided information regarding diagnosis and management in their countries. Current practice was reviewed against international guidelines, as well as local guidelines/consensus used in Australia, Japan, and China. Suggestions are provided for improving the time to diagnosis in the region, increasing access to guideline-recommended treatments, and providing support to reduce the burden on patients and caregivers. There is an urgent need to improve HAE services and provide access to life-saving treatment in developing countries, and efforts should be made to increase awareness of guideline recommendations in high-income economies that do not currently provide long-term prophylactic treatments.

Pesticide mediated silent neurotoxicity and its unmasking: An update on recent progress.

Being human's one of the most protected organs, brain is yet most vulnerable to xenobiotics exposure. Though pesticide-mediated neurotoxicity is well-explored, the fraternity of neurotoxicologists is less focused on the phenomenon of "silent" or "clinically undetectable" neurotoxicity. Silent neurotoxicity defines continual trivial changes in the nervous system that do not manifest any overt signs of toxicity unless unmasked by any natural or experimental event. Although this perception is not novel, insufficient experimental and epidemiological evidence makes it an outlier among toxicological research. A report in 2016 highlighted the need to investigate silent neurotoxicity and its potential challenges. The limited existing experimental data unveiled the unique responsiveness of neurons following silent neurotoxicity unmasking. Concerned studies have shown that low-dose developmental exposure to pesticides sensitizes the nigrostriatal dopaminergic system towards silent neurotoxicity, making it vulnerable to advanced cumulative neurotoxicity following pesticide challenges later in life. Therefore, conducting such studies may explain the precise etiology of pesticide-induced neurological disorders in humans. With no updates on this topic since 2016, this review is an attempt to acquaint the neurotoxicologist with silent neurotoxicity as a serious threat to human health, and proof-of-concept through a narrative using relevant published data so far with future perspectives.

Characterization of RNase J.

RNase J is involved in RNA maturation as well as degradation of RNA to the level of mononucleotides. This enzyme plays a vital role in maintaining intracellular RNA levels and governs different steps of the cellular metabolism in bacteria. RNase J is the first ribonuclease that was shown to have both endonuclease and 5'-3' exonuclease activity. RNase J enzymes can be identified by their characteristic sequence features and domain architecture. The quaternary structure of RNase J plays a role in regulating enzyme activity. The structure of RNase J has been characterized from several homologs. These reveal extensive overall structural similarity alongside a distinct active site topology that coordinates a metal cofactor. The metal cofactor is essential for catalytic activity. The catalytic activity of RNase J is influenced by oligomerization, the choice and stoichiometry of metal cofactors, and the 5' phosphorylation state of the RNA substrate. Here we describe the sequence and structural features of RNase J alongside phylogenetic analysis and reported functional roles in diverse organisms. We also provide a detailed purification strategy to obtain an RNase J enzyme sample with or without a metal cofactor. Different methods to identify the nature of the bound metal cofactor, the binding affinity and stoichiometry are presented. Finally, we describe enzyme assays to characterize RNase J using radioactive and fluorescence-based strategies with diverse RNA substrates.

CD40 gene polymorphism and its expression in children with Kawasaki disease from North India: a preliminary case-control study and meta-analysis.

Introduction: CD40 gene single-nucleotide polymorphisms (SNPs) have been associated with susceptibility and development of coronary artery abnormalities (CAAs) in children with Kawasaki disease (KD) in Japanese, Chinese, and Taiwanese populations. However, data on SNPs of the CD40 gene in patients with KD from the Indian subcontinent are not available. We studied the CD40 gene polymorphisms and its expression in children with KD from North India. Methods: SNPs of the CD40 gene (rs4810485, rs1535045) were studied using Sanger sequencing. CD40 expression was studied by flow cytometry. Meta-analysis was carried out to assess the role of both SNPs of the CD40 gene in KD. GRADEpro GDT software (v.3.2) was used to assess the "certainty of evidence." Results: Forty-one patients with KD and 41 age-, sex-matched febrile controls were enrolled. However, none of the alleles and genotypes of the CD40 gene were found to be associated with KD. CD40 expression was higher in KD and in KD with CAAs compared to controls, but it failed to reach statistical significance. In a meta-analysis, the T allele of rs153045 was found to be significantly associated with KD (OR = 1.28; 95% confidence interval (: 1.09-1.50; p = 0.002). The GRADE of evidence for this outcome, however, is of " very low certainty." Conclusion: The present study found no association between SNPs (rs4810485 and rs153045) and susceptibility to KD. This could be a reflection of a modest sample size. CD40 expression was higher in KD and in KD with CAAs. In the meta-analysis, the T allele of rs153045 was significantly associated with KD. Our study confirms a significant genetic heterogeneity in KD among different ethnicities.

Tuberculosis and Bacillus Calmette-Guérin Disease in Patients with Chronic Granulomatous Disease: an Experience from a Tertiary Care Center in North India.

Chronic granulomatous disease (CGD) is a phagocytic defect characterized by recurrent bacterial and fungal infections. We report clinical profile of patients with CGD and mycobacterial infections in a cohort from North India. A review of clinical and laboratory records was carried out for patients with CGD registered at our center between 1990 and 2021. Of the 99 patients with CGD, 22 had mycobacterial infections-Mycobacterium tuberculosis and M. bovis-BCG in 11 each. Among the children with M. bovis-BCG infection, 6 had localized and 5 had disseminated BCG disease. Median age at onset of symptoms and diagnosis of BCG disease was 5 months and 15 months, respectively. While disseminated forms of BCG were noted only in CYBB defect, none of the patients with NCF1 defect developed complications due to BCG vaccine. A recurring radiological feature was left axillary lymph node calcification, which was present in around 50% of CGD patients with BCG infections. Of 11 patients with tuberculosis, pulmonary, pleuro-pulmonary, abdominal, and disseminated forms were present in 6, 1, 2, and 2, respectively. Median age at onset of symptoms and diagnosis of tuberculosis was 129 months and 130 months, respectively. Molecular defects were identified in CYBB (5), NCF1 (4), and CYBA (1). Incidence of tuberculosis and BCG-related complications in patients with CGD is higher than the normal population. Screening for CGD is warranted in any patient with adverse reactions to BCG vaccination, calcification of left axillary lymph node, and persistent, recurrent or disseminated forms of tuberculosis.

Occurrence of Kawasaki disease and neoplasms in temporal proximity-single-center experience and systematic review of literature.

Various factors (e.g., infections) have been postulated to trigger Kawasaki disease (KD) in genetically predisposed individuals. Whether neoplasms can trigger KD is largely unknown due to paucity of data. Herein, we provide a detailed account of KD occurring in temporal proximity (within 6 months) to neoplasms ('neoplasm-KD'). Patients with 'neoplasm-KD' diagnosed/treated at our center from January 1994 to May 2021 were included. Additionally, we performed a systematic literature review (as per PRISMA 2020 guidelines) utilizing PubMed, Web of Science and Scopus databases to retrieve details of all patients with 'neoplasm-KD' reported till June 2021. Patients with multisystem inflammatory syndrome in children were excluded. As all reports pertained to case description(s), risk of bias assessment was not performed. The details of patients with 'neoplasm-KD' were analyzed using SPSS software. Primary and secondary outcomes were occurrence of coronary artery abnormalities (CAAs) and clinical characteristics of 'neoplasm-KD', respectively. A total of 25 patients (data from 18 reports) were included in the 'neoplasm-KD' dataset. The most frequently diagnosed neoplasm was acute lymphoblastic leukemia followed by neuroblastoma and acute myeloblastic leukemia. Overall, CAAs were noted in 48% of patients. Interval between diagnoses of KD and neoplasm was shorter in patients with CAAs as compared to patients with normal coronary arteries (p-value = 0.03). Besides providing a comprehensive description of 'neoplasm-KD', this study raises a possibility that neoplasms might trigger KD. Also, 'neoplasm-KD' may be associated with a higher risk of development of CAAs. However, the small size of 'neoplasm-KD' dataset precludes definitive conclusions regarding this association. Funding: nil. Registration: PROSPERO (CRD42021270458).

This study is the first exhaustive description of cancers and Kawasaki disease (KD) occurring in close temporal proximity. Nearly half of these patients develop coronary artery abnormalities. In KD, persistent lymphadenopathy, enlargement of liver/spleen and development of low blood cell counts should trigger evaluation for cancer. Our study also raises a possibility that cancers might occasionally trigger KD.

Effect of Asanas in Yoga on Intraocular Pressure of Practicing Healthy Individuals: a Prospective Observational Study.

Introduction: Yoga is focused attention by breath and mantra. This forms the basis for a scientific investigation of its effect on various physiological functions such as intraocular pressure (IOP). Objective: To evaluate the effect of asanas in Yoga on the IOP of practicing individuals. Methods:A prospective, observational study was performed on 107 volunteers practising the asanas such as Sun salutation exercise (Surya Namaskar), Skull shining breath (Kapalabhati Pranayama), Downward facing dog (Adho Mukha Svanasana), Standing forward bend (Uttanasana), Legs up the wall pose (Viparita Karani), Alternate breathing technique (Anulom Vilom), Deep meditation (Dhyana), Bellows breath (Bhastrika Pranayama), Yoga head stand (Shirshasana) and control of breathing exercise (Pranayama) each for five minutes/day (40-60 minutes) for at least five days in a week for 12 weeks. The IOP measurement was performed for each asana (before and after) at baseline and every four weeks. The primary outcome was the change in IOP. Statistical analyses were performed using Statistical Package for Social Sciences version 23.0. A p-value of less than 0.05 was considered statistically significant. Results:The mean age of the participants was 42.64±7 years, and the male to female ratio was 1.2:1. Skull shinning breath, Sun salutation, Downward facing dog, Standing forward bend, Legs up the wall pose, Deep meditation and alternate breathing techniques showed a significant mean reduction in IOP at baseline, followed by every four weeks, till week 12, while Yoga head stand, Bellows breath and control of breath led to a significant increase in IOP. Conclusion:Yoga head stand, Bellows breath and control of breathing technique worsen IOP transiently.