Photocatalytic C2-trifluoroethylation and perfluoroalkylation of 3-substituted indoles using fluoroalkyl halides.

A photocatalytic reactivity platform for the C2-trifluoroethylation and perfluoroalkylation of 3-substituted indoles has been developed. A range of fluoroalkyl halides have been employed as radical precursors under mild, transition-metal-free conditions to access new (per)fluorinated chemical space featuring the indole substructure. This general protocol is also applicable to indole-containing peptides.

Spatiotemporal dynamics of prey-predator model incorporating Holling-type II functional response with fear and its carryover effects.

The recent focus in the fields of biology and ecology has centered on the significant attention given to the mathematical modeling and analyzing the spatiotemporal population distribution among species engaged in interactions. This paper explores the dynamics of the temporal and spatiotemporal delayed Bazykin-type prey-predator model, incorporating fear and its carryover effect. In our model, we incorporated a functional response of the Holling-type II. In the temporal model, a detailed dynamic analysis was carried out, investigating the positivity and boundedness of solutions, establishing the uniqueness and existence of positive interior equilibria, and examining both local and global stability. Additionally, we explored the presence of saddle-node, transcritical, and Hopf bifurcations varying attack rate parameter. The delayed system shows highly periodic behavior. Additionally, for the spatiotemporal model, we provide a complete analysis of local and global stability, and we derive the conditions for the existence of Turing instability for both self-diffusion and cross-diffusion, respectively. The two-dimensional diffusive model is further discussed, highlighting various Turing patterns, including holes, stripes, and hot and cold spots, along with their biological significance. Numerical simulations are executed to validate the analytical findings in both temporal and spatiotemporal models.

Urban trees' potential for regulatory services in the urban environment: an exploration of carbon sequestration.

Urbanisation has emerged as a formidable challenge for urban policymakers, reaching unparalleled heights and unsettling the ecological equilibrium of the cities. Urban areas now grapple with many issues encompassing climate change, resource depletion, population surges and increased pollution levels. Many planned cities have planted trees and other vegetation within the urban sectors to enhance air quality, mitigate climate effects and provide valuable ecosystem services. This study assessed tree species diversity and their potential for carbon sequestration in Panjab University Campus, Chandigarh. We established 188 plots, each comprising randomly selected quadrats measuring 10 m × 10 m, encompassing areas with varying levels of vegetation, ranging from low to moderate and high density. We used four different allometric equations to estimate tree biomass and carbon stock. Our findings revealed that 92 tree species belong to 72 genera and 35 families, with a total tree density of 975 ha-1. The total CO2 sequestration in form of carbon stock was 18,769.46 Mg C ha-1, with Manilkara hexandra (1239.20 Mg C ha-1), Ficus benghalensis (1072.24 Mg C ha-1), Kigelia pinnata (989.89 Mg C ha-1) and Lagerstroemia floribunda (716.88 Mg C ha-1) being the top contributors. Specifically, the equation of Chave et al. (2005) without tree height yielded the highest biomass and carbon stock estimates than other equations. The present study underscores the vital role of trees on the campus as potent carbon reservoirs meet to maintain an aesthetic sense for biotic components and alleviate rising levels of CO2 in the atmospheric environment. By emphasising the role of urban trees as potent carbon reservoirs, the study underscores the importance of integrating green infrastructure into urban planning strategies. Furthermore, it offers valuable guidance for urban planners. It suggests that strategic tree planting and maintenance can enhance green spaces, regulate temperatures and ultimately support regional and global climate change mitigation goals. Incorporating these findings into urban planning processes can aid policymakers in developing resilient, ecologically sustainable cities worldwide.

Rules and impacts of nonsense-mediated mRNA decay in the degradation of long noncoding RNAs.

Nonsense-mediated mRNA decay (NMD) is a quality-control process that selectively degrades mRNAs having premature termination codon, upstream open reading frame, or unusually long 3'UTR. NMD detects such mRNAs and rapidly degrades them during initial rounds of translation in the eukaryotic cells. Since NMD is a translation-dependent cytoplasmic mRNA surveillance process, the noncoding RNAs were initially believed to be NMD-resistant. The sequence feature-based analysis has revealed that many putative long noncoding RNAs (lncRNAs) have short open reading frames, most of which have translation potential. Subsequent transcriptome-based molecular studies showed an association of a large set of such putative lncRNAs with translating ribosomes, and some of them produce stable and functionally active micropeptides. The translationally active lncRNAs typically have relatively longer and unprotected 3'UTR, which can induce their NMD-dependent degradation. This review defines the mechanism and regulation of NMD-dependent degradation of lncRNAs and its impact on biological processes related to the functions of lncRNAs or their encoded micropeptides. This article is categorized under: RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Turnover and Surveillance > Regulation of RNA Stability RNA in Disease and Development > RNA in Disease.

Photocatalytic, α-Aminoalkyl Radical-Mediated, Methylene-Extrusive Ring-Closing Transformation of o-Alkynyl and o-Cyano Acrylamides.

Herein we report a visible-light-induced, α-aminoalkyl radical-mediated cascade reaction of 1,7-enynes that establishes a unique ring-closing enyne transformation pathway which occurs with concomitant loss of a methylene moiety. The α-aminoalkyl radical derived from N,N-dimethylaniline was demonstrated to be a traceless promoter of enyne reorganization leading to 4-alkylquinolinones. The reaction can also be extended to nitrile-substituted acrylamide systems, leading to carbostyrils. Experiments with deuterated N,N-dimethylaniline-d6 (PhN(CD3)2) established the involvement of 1,5-H atom transfer in the mechanism.

Olfactory Sensitivity in Covid 19 Infection Recovered Subjects.

Sense of smell is a vital perception in mammals. Temporary loss of smell is the main neurological symptom and one of the earliest and most commonly reported indicators of COVID-19. A observational hospital based analytical study carried out at a tertiary care centre for a period of 22 months from January 2021 to October 2022. All the patients were subjected to sniffin stick test and all the data were noted, tabulated and compared to know the correlation of olfactory sensitivity to different parameters. Males were affected with hyposmia slightly more than females. There was not much difference in the olfactory sensitivity in various phases of uterine cycle. Olfactory sensitivity had a negative correlation with serum oestrogen and serum progesterone levels, which was significant. Mean olfactory sensitivity of males for different odours were slightly higher than females. BMI has a negative correlation with olfactory sensitivity in males as well as females, which was significant.

Intrinsic and Extrinsic Contributors to the Cardiac Benefits of Exercise.

Among its many cardiovascular benefits, exercise training improves heart function and protects the heart against age-related decline, pathological stress, and injury. Here, we focus on cardiac benefits with an emphasis on more recent updates to our understanding. While the cardiomyocyte continues to play a central role as both a target and effector of exercise's benefits, there is a growing recognition of the important roles of other, noncardiomyocyte lineages and pathways, including some that lie outside the heart itself. We review what is known about mediators of exercise's benefits-both those intrinsic to the heart (at the level of cardiomyocytes, fibroblasts, or vascular cells) and those that are systemic (including metabolism, inflammation, the microbiome, and aging)-highlighting what is known about the molecular mechanisms responsible.

Kinetically Controlled Polyelectrolyte Complex Assembly of microRNA-Peptide Nanoparticles toward Treating Mesothelioma.

Broad size distributions and poor long-term colloidal stability of microRNA-carrying nanoparticles, especially those formed by polyelectrolyte complexation, represent major hurdles in realizing their clinical translation. Herein, peptide design is used alongside optimized flash nanocomplexation (FNC) to produce uniform peptide-based miRNA particles of exceptional stability that display anticancer activity against mesothelioma in vitro and in vivo. Modulating the content and display of lysine-based charge from small intrinsically disordered peptides used to complex miRNA proves essential in achieving stable colloids. FNC facilitates kinetic isolation of the mechanistic steps involved in particle formation to allow the preparation of particles of discrete size in a highly reproducible, scalable, and continuous manner, facilitating pre-clinical studies. To the best of the authors knowledge, this work represents the first example of employing FNC to prepare polyelectrolyte complexes of miRNA and peptide. Encapsulation of these particles into an injectable hydrogel matrix allows for their localized in vivo delivery by syringe. A one-time injection of a gel containing particles composed of miRNA-215-5p and the peptide PKM1 limits tumor progression in a xenograft model of mesothelioma.

Tsyn-Seq: a T-cell Synapse-Based Antigen Identification Platform.

Tools for genome-wide rapid identification of peptide-major histocompatibility complex targets of T-cell receptors (TCR) are not yet universally available. We present a new antigen screening method, the T-synapse (Tsyn) reporter system, which includes antigen-presenting cells (APC) with a Fas-inducible NF-κB reporter and T cells with a nuclear factor of activated T cells (NFAT) reporter. To functionally screen for target antigens from a cDNA library, productively interacting T cell-APC aggregates were detected by dual-reporter activity and enriched by flow sorting followed by antigen identification quantified by deep sequencing (Tsyn-seq). When applied to a previously characterized TCR specific for the E7 antigen derived from human papillomavirus type 16 (HPV16), Tsyn-seq successfully enriched the correct cognate antigen from a cDNA library derived from an HPV16-positive cervical cancer cell line. Tsyn-seq provides a method for rapidly identifying antigens recognized by TCRs of interest from a tumor cDNA library. See related Spotlight by Makani and Joglekar, p. 515.

A Dual Therapeutic Approach to Diabetes Mellitus via Bioactive Phytochemicals Found in a Poly Herbal Extract by Restoration of Favorable Gut Flora and Related Short-Chain Fatty Acids.

Diabetes mellitus (DM), a metabolic and endocrine condition, poses a serious threat to human health and longevity. The emerging role of gut microbiome associated with bioactive compounds has recently created a new hope for DM treatment. UHPLC-HRMS methods were used to identify these compounds in a poly herbal ethanolic extract (PHE). The effects of PHE on body weight (BW), fasting blood glucose (FBG) level, gut microbiota, fecal short-chain fatty acids (SCFAs) production, and the correlation between DM-related indices and gut microbes, in rats were investigated. Chebulic acid (0.368%), gallic acid (0.469%), andrographolide (1.304%), berberine (6.442%), and numerous polysaccharides were the most representative constituents in PHE. A more significant BW gain and a reduction in FBG level towards normal of PHE 600 mg/kg treated rats group were resulted at the end of 28th days of the study. Moreover, the composition of the gut microbiota corroborated the study's hypothesis, as evidenced by an increased ratio of Bacteroidetes to Firmicutes and some beneficial microbial species, including Prevotella copri and Lactobacillus hamster. The relative abundance of Bifidobacterium pseudolongum, Ruminococcus bromii, and Blautia producta was found to decline in PHE treatment groups as compared to diabetic group. The abundance of beneficial bacteria in PHE 600 mg/kg treatment group was concurrently associated with increased SCFAs concentrations of acetate and propionate (7.26 nmol/g and 4.13 nmol/g). The findings of this study suggest a promising approach to prevent DM by demonstrating that these naturally occurring compounds decreased FBG levels by increasing SCFAs content and SCFAs producing gut microbiota.

Synthetic and biopolymers-based antimicrobial hybrid hydrogels: a focused review.

The constantly accelerating occurrence of microbial infections and their antibiotic resistance has spurred advancement in the field of material sciences and has guided the development of novel materials with anti-bacterial properties. To address the clinical exigencies, the material of choice should be biodegradable, biocompatible, and able to offer prolonged antibacterial effects. As an attractive option, hydrogels have been explored globally as a potent biomaterial platform that can furnish essential antibacterial attributes owing to its three-dimensional (3D) hydrophilic polymeric network, adequate biocompatibility, and cellular adhesion. The current review focuses on the utilization of different antimicrobial hydrogels based on their sources (natural and synthetic). Further, the review also highlights the strategies for the generation of hydrogels with their advantages and disadvantages and their applications in different biomedical fields. Finally, the prospects in the development of hydrogels-based antimicrobial biomaterials are discussed along with some key challenges encountered during their development and clinical translation.

Sirtuin 2 inhibition modulates chromatin landscapes genome-wide to induce senescence in ATRX-deficient malignant glioma.

BACKGROUND: Functional inactivation of ATRX characterizes large subgroups of malignant gliomas in adults and children. ATRX deficiency in glioma induces widespread chromatin remodeling, driving transcriptional shifts and oncogenic phenotypes. Effective strategies to therapeutically target these broad epigenomic sequelae remain undeveloped. METHODS: We utilized integrated multiomics and the Broad Institute Connectivity Map (CMAP) to identify drug candidates that could potentially revert ATRX-deficient transcriptional changes. We then employed disease-relevant experimental models to evaluate functional phenotypes, coupling these studies with epigenomic profiling to elucidate molecular mechanism(s). RESULTS: CMAP analysis and transcriptional/epigenomic profiling implicated the Class III HDAC Sirtuin2 (SIRT2) as a central mediator of ATRX-deficient cellular phenotypes and a driver of unfavorable prognosis in ATRX-deficient glioma. SIRT2 inhibitors reverted Atrx-deficient transcriptional signatures in murine neuroepithelial progenitor cells (mNPCs), impaired cell migration in Atrx/ATRX-deficient mNPCs and human glioma stem cells (GSCs), and increased expression of senescence markers in glioma models. Moreover, SIRT2 inhibition impaired growth and increased senescence in ATRX-deficient GSCs in vivo. These effects were accompanied by genome-wide shifts in enhancer-associated H3K27ac and H4K16ac marks, with the latter in particular demonstrating compelling transcriptional links to SIRT2-dependent phenotypic reversals. Motif analysis of these data identified the transcription factor KLF16 as a mediator of phenotype reversal in Atrx-deficient cells upon SIRT2 inhibition. CONCLUSIONS: Our findings indicate that SIRT2 inhibition selectively targets ATRX-deficient gliomas for senescence through global chromatin remodeling, while demonstrating more broadly a viable approach to combat complex epigenetic rewiring in cancer.

Unlocking the potential of RNA-based therapeutics in the lung: current status and future directions.

Awareness of RNA-based therapies has increased after the widespread adoption of mRNA vaccines against SARS-CoV-2 during the COVID-19 pandemic. These mRNA vaccines had a significant impact on reducing lung disease and mortality. They highlighted the potential for rapid development of RNA-based therapies and advances in nanoparticle delivery systems. Along with the rapid advancement in RNA biology, including the description of noncoding RNAs as major products of the genome, this success presents an opportunity to highlight the potential of RNA as a therapeutic modality. Here, we review the expanding compendium of RNA-based therapies, their mechanisms of action and examples of application in the lung. The airways provide a convenient conduit for drug delivery to the lungs with decreased systemic exposure. This review will also describe other delivery methods, including local delivery to the pleura and delivery vehicles that can target the lung after systemic administration, each providing access options that are advantageous for a specific application. We present clinical trials of RNA-based therapy in lung disease and potential areas for future directions. This review aims to provide an overview that will bring together researchers and clinicians to advance this burgeoning field.

Targeting FAcilitates Chromatin Transcription complex inhibits pleural mesothelioma and enhances immunotherapy.

BACKGROUND: Diffuse pleural mesothelioma (DPM) is an aggressive therapy-resistant cancer with unique molecular features. Numerous agents have been tested, but clinically effective ones remain elusive. Herein, we propose to use a small molecule CBL0137 (curaxin) that simultaneously suppresses nuclear factor-κB (NF-κB) and activates tumor suppressor p53 via targeting FAcilitates Chromatin Transcription (FACT) complex, a histone chaperone critical for DNA repair. METHODS: We used DPM cell lines, murine models (xeno- and allo-grafts), plus DPM patient samples to characterize anti-tumor effects of CBL0137 and to delineate specific molecular mechanisms. RESULTS: We verified that CBL0137 induced cell cycle arrest and apoptosis. We also discovered that DPM is a FACT-dependent cancer with overexpression of both subunits structure-specific recognition protein 1 (SSRP1), a poor prognosis indicator, and suppressor of Ty 16 (SUPT16H). We defined several novel uses of CBL0137 in DPM therapy. In combination with cisplatin, CBL0137 exhibited additive anti-tumor activity compared to monotherapy. Similarly, CBL0137 (systemic) could be combined with other novel agents like microRNA-215 (intrapleural) as a more effective regimen. Importantly, we established that CBL0137 induces immunogenic cell death that contributes to activating immune response pathways in DPM. Therefore, when CBL0137 is combined with dual immune checkpoint inhibitors DPM tumor growth is significantly suppressed. CONCLUSIONS: We identified an unrecognized molecular vulnerability of DPM based on FACT dependency. CBL0137 alone and in several combinations with different therapeutics showed promising efficacy, including that of improved anti-tumor immunity. Overall, these preclinical findings suggest that CBL0137 could be ideally suited for use in DPM clinical trials.

Molecular surveillance of insecticide resistance in Phlebotomus argentipes targeted by indoor residual spraying for visceral leishmaniasis elimination in India.

Molecular surveillance of resistance is an increasingly important part of vector borne disease control programmes that utilise insecticides. The visceral leishmaniasis (VL) elimination programme in India uses indoor residual spraying (IRS) with the pyrethroid, alpha-cypermethrin to control Phlebotomus argentipes the vector of Leishmania donovani, the causative agent of VL. Prior long-term use of DDT may have selected for knockdown resistance (kdr) mutants (1014F and S) at the shared DDT and pyrethroid target site, which are common in India and can also cause pyrethroid cross-resistance. We monitored the frequency of these marker mutations over five years from 2017-2021 in sentinel sites in eight districts of north-eastern India covered by IRS. Frequencies varied markedly among the districts, though finer scale variation, among villages within districts, was limited. A pronounced and highly significant increase in resistance-associated genotypes occurred between 2017 and 2018, but with relative stability thereafter, and some reversion toward more susceptible genotypes in 2021. Analyses linked IRS with mutant frequencies suggesting an advantage to more resistant genotypes, especially when pyrethroid was under-sprayed in IRS. However, this advantage did not translate into sustained allele frequency changes over the study period, potentially because of a relatively greater net advantage under field conditions for a wild-type/mutant genotype than projected from laboratory studies and/or high costs of the most resistant genotype. Further work is required to improve calibration of each 1014 genotype with resistance, preferably using operationally relevant measures. The lack of change in resistance mechanism over the span of the study period, coupled with available bioassay data suggesting susceptibility, suggests that resistance has yet to emerge despite intensive IRS. Nevertheless, the advantage of resistance-associated genotypes with IRS and under spraying, suggest that measures to continue monitoring and improvement of spray quality are vital, and consideration of future alternatives to pyrethroids for IRS would be advisable.

Isolation and characterization of a novel mycobacteriophage Kashi-VT1 infecting Mycobacterium species.

Mycobacteriophages are viruses that infect members of genus Mycobacterium. Because of the rise in antibiotic resistance in mycobacterial diseases such as tuberculosis, mycobacteriophages have received renewed attention as alternative therapeutic agents. Mycobacteriophages are highly diverse, and, on the basis of their genome sequences, they are grouped into 30 clusters and 10 singletons. In this article, we have described the isolation and characterization of a novel mycobacteriophage Kashi-VT1 (KVT1) infecting Mycobacterium >smegmatis mc2 155 (M. smegmatis) and Mycobacterium fortuitum isolated from Varanasi, India. KVT1 is a cluster K1 temperate phage that belongs to Siphoviridae family as visualized in transmission electron microscopy. The phage genome is 61,010 base pairs with 66.5% Guanine/Cytosine (GC) content, encoding 101 putative open reading frames. The KVT1 genome encodes an immunity repressor, a tyrosine integrase, and an excise protein, which are the characteristics of temperate phages. It also contains genes encoding holin, lysin A, and lysin B involved in host cell lysis. The one-step growth curve demonstrated that KVT1 has a latency time of 90 min and an average burst size of 101 phage particles per infected cell. It can withstand a temperature of up to 45°C and has a maximum viability between pH 8 and 9. Some mycobacteriophages from cluster K are known to infect the pathogenic Mycobacterium tuberculosis (M. tuberculosis); hence, KVT1 holds potential for the phage therapy against tuberculosis, and it can also be engineered to convert into an exclusively lytic phage.

Cascade Cyclizations Triggered by Photochemically Generated Carbamoyl Radicals Derived from Alkyl Amines.

We report on a visible light-mediated cascade carbamoylation/cyclization of acrylamides using dihydropyridyl carbamoyl donors derived from alkyl amines. Diversely selected acrylamides including 2-cyano-N-arylacrylamides, indolyl- and benzimidazolyl acrylamides, and 2-alkynyl-N-aryl acrylamides participate in this reaction, providing products in good yields. The highlights of this photochemical method include the application of alkyl amine-derived carbamoyl donors, peroxide-free reaction conditions, and a broad scope.

Visible-light mediated, oxygen-promoted regioselective cross-dehydrogenative coupling of coumarins and dimethylanilines.

Herein, we report a regioselective, photocatalytic C3 α-aminoalkylation of coumarins via a cross-dehydrogenative coupling of dimethylanilines and coumarins. Molecular oxygen was utilized as the oxidizing agent in this transformation, which exhibits a wide substrate scope and affords the products in good yields. It was established that 4-amino-substituted coumarin reacts via a different mechanism compared to coumarin derivatives that are unsubstituted at the 4-position.

The machine learning and geostatistical approach for assessment of arsenic contamination levels using physicochemical properties of water.

Arsenic contamination in groundwater due to natural or anthropogenic sources is responsible for carcinogenic and non-carcinogenic risks to humans and the ecosystem. The physicochemical properties of groundwater in the study area were determined in the laboratory using the samples collected across the Varanasi region of Uttar Pradesh, India. This paper analyses the physicochemical properties of water using machine learning, descriptive statistics, geostatistical and spatial analysis. Pearson correlation was used for feature selection and highly correlated features were selected for model creation. Hydrochemical facies of the study area were analyzed and the hyperparameters of machine learning models, i.e., multilayer perceptron, random forest (RF), naïve Bayes, and decision tree were optimized before training and testing the groundwater samples as high (1) or low (0) arsenic contamination levels based on the WHO 10 µg/L guideline value. The overall performance of the models was compared based on accuracy, sensitivity, and specificity value. Among all models, the RF algorithm outclasses other classifiers, as it has a high accuracy of 92.30%, a sensitivity of 100%, and a specificity of 75%. The accuracy result was compared to prior research, and the machine learning model may be used to continually monitor the amount of arsenic pollution in groundwater.

Visible light-mediated ring-ablative functionalization of oxazoles: oxidative azidation and demethylative amination.

Photochemical functionalization of alkoxyoxazoles with trimethylsilyl azide and N,N-dimethylanilines is described. These C-N bond forming reactions proceed with concomitant oxidative ring-opening assisted by organic dyes as photocatalyst and molecular oxygen, providing access to novel chemical space. Unusual demethylative C-N bond formation in the case of N,N-dimethylanilines establishes a new reactivity pattern for these precursors.