A roundup of research articles published in the previous month (16 March 2023 – 15 April 2023) at the institute:
The paradox of Vitiligo
Vitiligo is a non-life-threatening skin de-pigmentation disease in which melanocytes – the cells that produce the dark pigment melanin – are lost from the deep layers of the skin and in those places, the skin appears white. Apart from melanocytes, skin contains two other cell types – keratinocytes and fibroblasts. In the white patches or lesional skin in vitiligo patients, the communication between these cells is altered due to the absence of the melanocytes and so is their cellular state, down to the gene expression levels. But, least is known about the alterations in the dermal fibroblasts in lesional skin, compared to the non-lesional skin. This study aimed to fill that gap, thus, employing genome-wide screening by means of transcriptomic profiling and subsequent protein-protein interaction mapping of dermal fibroblasts derived from lesional and surrounding non-lesional skin from vitiligo patients. Rohit Gupta, the lead author on this study, shared his journey with team Pulse that can be read here.
Genome-wide profiling reveals pervasive transcriptional alterations in fibroblasts derived from lesional skin in vitiligo including a reduced potential to proliferate. Gupta R, Misri R, Gupta A, Chowdhary M, Singh A. Exp Dermatol. 2023 Apr;32(4):331-340. doi: 10.1111/exd.14702. Epub 2022 Nov 18.
G-4 quadruplexes and COVID-19

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The evolution of SARS-CoV2 strains during the pandemic was witnessed as one of the reasons for reinfections and breakthrough infections in immunized individuals. Drugs that can target the virus at regions that are conserved would not lose effectiveness due to mutations of SARS-CoV2.
G-quadruplexes (G4) are regions in DNA/RNA, wherein stretches of Guanine fold into four stranded secondary structures. G4s are usually present in the regulatory regions and are highly conserved. Potential G4 regions in SARS-CoV2 genome have been reported. When existing FDA approved G4 binding drugs – chlorpromazine and prochlorperazine were tested, they were found to be effective in containing the COVID-19 infection. The need to further study G4 binding drugs for viral infections is highlighted by this study.
G4-binding drugs, chlorpromazine and prochlorperazine, repurposed against COVID-19 infection in hamsters. Roy SS, Sharma S, Rizvi ZA, Sinha D, Gupta D, Rophina M, Sehgal P, Sadhu S, Tripathy MR, Samal S, Maiti S, Scaria V, Sivasubbu S, Awasthi A, Harshan KH, Jain S, Chowdhury S. Front Mol Biosci. 2023 Mar 16;10:1133123.
High throughput diagnostics for Friedreich’s ataxia

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Friedreich’s ataxia (FRDA) is a rare genetic disorder, caused by trinucleotide repeat expansion in the FXN gene that codes for a mitochondrial protein frataxin. The manifestation of trinucleotide repeat expansion disorders is dependent on the trinucleotide repeat length. An earlier age of onset and more severe disease symptoms are seen when the number of repeats is higher. While milder symptoms and late-onset is seen for low number of repeats, which makes it imperative to determine the number of trinucleotide repeats.
A high throughput diagnostics for FDRA using nanopore sequencing, which has the advantage of sequencing long reads, has been demonstrated in this study.
Sequencing through hyperexpanded Friedreich’s ataxia-GAA repeats by nanopore technology: implications in genotype-phenotype correlation. Uppili B, Sharma P, Ahmad I, Sahni S, Asokachandran V, Nagaraja AB, Srivastava AK, Faruq M. Brain Commun. 2023 Mar 29;5(2):fcad020.
Documenting 80 years of dermatophytosis in India

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One of the most common skin infections is dermatophytosis (fungal infections) which is caused by fungal species of Trichophyton genus. The rising cases of antimicrobial resistance haven’t spared antifungals, which presses upon the need to trace and identify the Trichophyton species within the country more than ever.
In this study, 80 years of retrospective data (mined from existing literature) have been analyzed to identify how the various Trichophyton species have changed over time in India. T. rubrum has been seen as the most common species during 1939 – 2015 and a shift towards T. mentagrophytes/ T. interdigitale during 2015 – 2021. What is interesting is that there have been no reported cases of drug resistant Trichophyton spp before 2015 in India. The reasons for these findings are still being investigated.
Insights into Changing Dermatophyte Spectrum in India Through Analysis of Cumulative 161,245 Cases Between 1939 and 2021. Kumar P, Ramachandran S, Das S, Bhattacharya SN, Taneja B. Mycopathologia. 2023 Mar 28
Multi-modal binding of Nucleolin to DNA/RNA G-quadruplexes
Nucleic acids are diverse in their nature and functions. During their synthesis, turnover and processing, they interact with several proteins. Binding of proteins to nucleic acids can be either sequence-dependent or structure-mediated and this mode determinea the fate and functions of nucleic acids. Several DNA/RNA adapt canonical and non-canonical structures, e.g., telomeric regions at chromosomal ends are widely known to form G-quadruplex structures which help in maintenance of telomeres. Nucleolin is a highly conserved multifunctional nucleic acid binding protein which predominantly resides in the nucleolus. Structurally, nucleolin consists of four nucleic acid binding domain (RRMs) which helps in binding to various nucleic acid structures. Nucleolin preferentially binds to guanine rich G-quadruplex structure present at telomeric ends. This study highlights the domain specific interaction of nucleolin towards RNA and DNA G-quadruplex and its implication upon binding. It is able to bind to both DNA (telo) G-quadruplex as well as RNA (TERRA) G-quadruplex, and it destabilizes the telo G-quadruplex by changing its conformation from hybrid to parallel. The RRMs domain shows preferred binding towards RNA G-quadruplex over DNA.
Biophysical Characterization of Nucleolin Domains Crucial for Interaction with Telomeric and TERRA G-Quadruplexes. Khan Y, Azam T, Sundar JS, Maiti S, Ekka MK. Biochemistry. 2023 Apr 4;62(7):1249-1261. doi: 10.1021/acs.biochem.2c00641. Epub 2023 Mar 23. PMID: 36951307.
Innate immune memory and SARS-CoV2 vaccination breakthroughs
It is interesting to observe the response of double dose vaccinated individuals to breakthrough infections. The faster recovery and milder symptoms – desired effect of vaccination – provide an opportunity to dig deeper into the immune regulatory mechanisms at work post vaccination.
By comparing infected and vaccinated individuals with breakthrough infections, ribosomal proteins along with immune response genes have been found to be downregulated, accompanied by differential expression of an array of transcription factors and epigenetic factors. Immune tolerance or innate immune memory thus suppressing the severity of symptoms due to an overactive innate immune response.
Additionally, a decrease in T-cell populations along with an increase in memory B cells has been observed on comparing the gene expression data which would further help in infection clearance.
Intertwined Dysregulation of Ribosomal Proteins and Immune Response Delineates SARS-CoV-2 Vaccination Breakthroughs. Maurya R, Shamim U, Mishra P, Swaminathan A, Raina A, Tarai B, Budhiraja S, Pandey R. Microbiol Spectr. 2023 Apr 6:e0429222.
Role of monocytes in COVID-19 associated fungal infections
Mucormycosis, a fungal infection, complicated the management of COVID-19 in individuals with co-morbidities like diabetes and those who were given corticosteroids to suppress the hyperactive immune response.
Since the clearance of fungus is mediated by phagocytes, the activity of monocytes has been assessed using transcriptomic analysis of FACS sorted monocytes. Decreased activation markers were noted. A reduction in plasma cytokine that activates monocytes has also been observed. Both experiments point towards a decreased phagocytosis in individuals that developed the fungal infection.
Since the study used a small cohort for their analysis, which necessitated further investigations in a larger cohort.
Deficient Phagocytosis in Circulating Monocytes from Patients with COVID-19-Associated Mucormycosis. Sinha BP, Mehta P, Hoque MA, Bandopadhyay P, Nandi A, Saha I, Nandi Mitra A, Mondal A, Bhattacharjee B, Chamilos G, Pandey R, Basu K, Ganguly D. mBio. 2023 Apr 13:e0059023. doi: 10.1128/mbio.00590-23. Epub ahead of print.