Biology subjects

Soni, P.

Publications and source records attributed to Soni, P..

4 recordsLinked to original sources

bioRxiv2025

FUNCTIONAL ANALYSIS OF BIPARTITE NRF2 ACTIVATORS THAT OVERCOME FEEDBACK REGULATION FOR AGE-RELATED CHRONIC DISEASES

Activating Nrf2 with small molecules is a promising strategy for countering aging, oxidative stress, inflammation, and various disorders, including neurodegeneration. The primary regulator of Nrf2 protein stability is Keap1, a redox sensor protein and an adapter in the Cullin III ubiquitin ligase complex, which labels Nrf2 for proteasomal degradation. The known Nrf2 activators either chemically modify sensor thiols in Keap1 or competitively displace Nrf2 from the ubiquitin ligase complex. The latter approach is considered the most suitable for continuous administration, as non-specific chemical modifiers of Keap1 thiols also modify active thiols on other proteins, thus causing side effects. However, when transitioning from homogeneous to cell-based assays, genuine displacement activators show a significant loss in potency by several orders of magnitude. As we demonstrate here, this offset is due to the presence of high micromolar concentrations of Keap1 in both the cell lines and brain tissue. A potential solution could involve targeted delivery of an alkylating agent to Keap1 to achieve the desired specificity. Transcriptomic analysis of a cell-permeable Nrf2 peptide bearing an alkylating fumarate moiety indicates selective activation of the Nrf2 genetic program, confirming the high specificity of this approach. The Nrf2-triggered genetic program has a feedback regulation mechanism through the activation of Bach1, an Nrf2 transcriptional repressor, which is elevated in age-related neurodegeneration. Thus, a benign bipartite Nrf2 activator with Bach1 inhibition properties is needed for maximal benefits. The recently developed heterocyclic carboxamide, HPPE, shows overlap with the Nrf2 pathway activated by the fumarate-linked Nrf2 peptide and with zinc and tin protoporphyrins, which are recognized inhibitors of Bach1. Therefore, HPPE presents a promising and unique combination of the two desired activities that could be further optimized to treat age-related neurodegeneration. HighlightsO_LIThe decrease in potency for reversible displacement activators of Nrf2 in biological assays is attributed to high micromolar concentrations of Keap1 and competition with endogenous Keap1 client proteins. C_LIO_LINrf2 activators specific for Keap1 should combine a displacement scaffold with a substitution that undergoes intracellular conversion into active pro-oxidant or alkylating species. C_LIO_LICell-permeable fumarate-linked Nrf2 peptide solely activates the Nrf2 antioxidant genetic program, as demonstrated by transcriptomic analysis. C_LIO_LIHPPE, a small bipartite molecule, exhibits properties of both Nrf2 activation and Bach1 inhibition, to bypass feedback regulation by targeting both Keap1 and Bach1. C_LI

biochemistry↗

bioRxiv2024

EEG data quality in large scale field studies in India and Tanzania

There is a growing imperative to understand the neurophysiological impact of our rapidly changing and diverse technological, social, chemical, and physical environments. To untangle the multidimensional and interacting effects requires data at scale across diverse populations, taking measurement out of a controlled lab environment and into the field. Electroencephalography (EEG), which has correlates with various environmental factors as well as cognitive and mental health outcomes, has the advantage of both portability and cost-effectiveness for this purpose. However, with numerous field researchers spread across diverse locations, data quality issues and researcher idle time due to insufficient participants can quickly become unmanageable and expensive problems. In programs we have established in India and Tanzania, we demonstrate that with appropriate training, structured teams, and daily automated analysis and feedback on data quality, non-specialists can reliably collect EEG data alongside various survey and assessments with consistently high throughput and quality. Over a 30-week period, research teams were able to maintain an average of 25.6 subjects per week, collecting data from a diverse sample of 7,933 participants ranging from Hadzabe hunter-gatherers to office workers. Furthermore, data quality, computed on the first 2,400 records using two common methods, PREP and FASTER, was comparable to benchmark datasets from controlled lab conditions. Altogether this resulted in a cost per subject of under $50, a fraction of the cost typical of such data collection, opening up the possibility for large-scale programs particularly in low- and middle-income countries. Significance StatementWith wide human diversity, a rapidly changing environment and growing rates of neurological and mental health disorders, there is an imperative for large scale neuroimaging studies across diverse populations that can deliver high quality data and be affordably sustained. Here we demonstrate, across two large-scale field data acquisition programs operating in India and Tanzania, that with appropriate systems it is possible to generate high throughput EEG data of quality comparable to controlled lab settings. With effective costs of under $50 per subject, this opens new possibilities for low- and middle-income countries to implement large-scale programs, and to do so at scales that previously could not be considered.

neuroscience↗

bioRxiv2024

Potassium ferric oxalate nanoparticles prevent human blood clotting and thrombosis in a mouse model

Blood clot creates occlusion in the veins and arteries, which leads to pernicious effects. Here, the anticoagulation properties of potassium ferric oxalate nanoparticles (KFeOx-NPs) in human blood were demonstrated for blood clot management. The mechanism involves the chelation of calcium ions from the blood by the oxalate present in the KFeOx-NPs. Various commercial assays were used to determine the clotting time for the KFeOx-NPs and identified the hindrance in activating factor XII in the intrinsic pathway. We used animal models to show toxicity and biodistribution profiles and determined the safety and efficacy. Intravenously injected KFeOx-NPs increased clotting time and thrombosis prevention in a mouse model confirmed by ultrasound and the power Doppler images. Coating catheters with KFeOx-NPs prevents clot formation with reduced protein attachment when incubated with blood, enhancing blood flow properties. In biological applications, KFeOx-NPs may improve the long-term prevention of blood clot formation and enhance the efficiency of medical devices. TOC O_FIG O_LINKSMALLFIG WIDTH=188 HEIGHT=200 SRC="FIGDIR/small/621820v1_ufig1.gif" ALT="Figure 1"> View larger version (68K): org.highwire.dtl.DTLVardef@1292afeorg.highwire.dtl.DTLVardef@1c5ba81org.highwire.dtl.DTLVardef@576f23org.highwire.dtl.DTLVardef@4186e9_HPS_FORMAT_FIGEXP M_FIG C_FIG PVP-stabilized novel potassium ferric oxalate nanoparticles were synthesized for the application of blood clot management and thrombosis prevention.

pathology↗

bioRxiv2024

Discordance in Genotypic and Phenotypic anti-tuberculosis drug susceptibility results: time to reconsider critical concentration.

ObjectiveTo correlate rpoB mutations found on the sanger sequencing in Mycobacterium tuberculosis (MTB) isolates with Minimum Inhibitory Concentrations (MICs) to the rifampicin. MethodsWe assessed the minimum inhibitory concentrations (MICs) for 151 archived clinical MTB isolates that were determined phenotypically susceptible to RIF (101;66.89%) and remaining fifty (50;33.11%) were resistant to RIF by BACTEC MGIT SIRE DST. MIC values were determined using colorimetric redox indicator (Resazurin/REMA) method and results were correlated with rpoB gene mutations associate with rifampicin resistance found. ResultsComparing the MIC and critical concentration, we found that 15 of these 101 (14.85%) isolates were misclassified by MGIT-960 as sensitive at standard critical concentration (1.0{micro}g/mL) though these were found to have low-level RIF resistance by CRI assay (MIC 0.50{micro}g/mL to 1.0{micro}g/mL) and sanger sequencing. We found that all of 15 isolates contained non-synonymous mutations, the commonest being the Ile572Phe (7, 46.66%), followed by Leu533Pro (3, 20.0%), His526Leu (2, 13.33%), His526Asn+Ile572Phe (1), Asp516Tyr (1), and Leu533Pro+Pro564Arg (1). These mutations are reported to confer low-level RIF resistance. But we did not find any mutation at MIC <0.25g/mL. ConclusionWe found that a significant number of MTB isolates have phenotypic and genotypic discordance. Taking 1.0{micro}g/mL of rifampicin as critical concentration, isolates from approximately 15% patients are misidentified as susceptible to rifampicin, even when these strains carry low level drug resistance conferring mutations and have potential to develop clinical MDR-TB.

microbiology↗