Brønsted acid-catalyzed regioselective ring opening of 2H-azirines by 2-mercaptopyridines and related heterocycles; one pot access to imidazo[1,2-a]pyridines and imidazo[2,1-b]thiazoles.

A catalytic and versatile synthetic method for the synthesis of imidazo[1,2-a]pyridines has been developed. Brønsted acid-catalysis plays a major role in the regioselective ring opening of 2H-azirines. Nucleophilic attack via the N-centre of mercaptopyridines and their analogues, followed by cyclisation by cleaving the C-S bond, allowed a library of imidazo[1,2-a]pyridines and related heterocycles to be built. The reaction protocol has been applied to various 2H-azirines, 2-mercaptopyridines, and thiazole-2-thiols, illustrating the generality of reaction conditions. The practical applications include the synthesis of pharmaceuticals, such as anti-tumor agents. This study introduces a novel approach to the synthesis of functional molecules with extensive potential.

Regioselective Brønsted acid catalyzed ring opening of aziridines by phenols and thiophenols; a gateway to access functionalized indolines, indoles, benzothiazines, dihydrobenzo-thiazines, benzo-oxazines and benzochromenes.

Brønsted acid catalyzed regioselective ring opening of aziridines by phenols and thiophenols have been reported. Involvement of a series of aziridines with a range of phenols and thiophenols offer the generality of the reported protocol. Completion of the reaction at room temperature within very short time brings the uniqueness of the developed technique. To emphasis on the application of the developed methodology, the products have been used for the further synthesis of a range of useful and novel heterocyclic molecules such as indolines, indoles, benzothiazines, dihydrobenzothiazines, benzo-oxazines and benzochromenes.

Cell Type-Specific Extracellular Vesicles and Their Impact on Health and Disease.

Extracellular vesicles (EVs), a diverse group of cell-derived exocytosed particles, are pivotal in mediating intercellular communication due to their ability to selectively transfer biomolecules to specific cell types. EVs, composed of proteins, nucleic acids, and lipids, are taken up by cells to affect a variety of signaling cascades. Research in the field has primarily focused on stem cell-derived EVs, with a particular focus on mesenchymal stem cells, for their potential therapeutic benefits. Recently, tissue-specific EVs or cell type-specific extracellular vesicles (CTS-EVs), have garnered attention for their unique biogenesis and molecular composition because they enable highly targeted cell-specific communication. Various studies have outlined the roles that CTS-EVs play in the signaling for physiological function and the maintenance of homeostasis, including immune modulation, tissue regeneration, and organ development. These properties are also exploited for disease propagation, such as in cancer, neurological disorders, infectious diseases, autoimmune conditions, and more. The insights gained from analyzing CTS-EVs in different biological roles not only enhance our understanding of intercellular signaling and disease pathogenesis but also open new avenues for innovative diagnostic biomarkers and therapeutic targets for a wide spectrum of medical conditions. This review comprehensively outlines the current understanding of CTS-EV origins, function within normal physiology, and implications in diseased states.

Effects of microRNA-mediated negative feedback on gene expression noise.

MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression post-transcriptionally in eukaryotes by binding with target mRNAs and preventing translation. miRNA-mediated feedback motifs are ubiquitous in various genetic networks that control cellular decision making. A key question is how such a feedback mechanism may affect gene expression noise. To answer this, we have developed a mathematical model to study the effects of a miRNA-dependent negative-feedback loop on mean expression and noise in target mRNAs. Combining analytics and simulations, we show the existence of an expression threshold demarcating repressed and expressed regimes in agreement with earlier studies. The steady-state mRNA distributions are bimodal near the threshold, where copy numbers of mRNAs and miRNAs exhibit enhanced anticorrelated fluctuations. Moreover, variation of negative-feedback strength shifts the threshold locations and modulates the noise profiles. Notably, the miRNA-mRNA binding affinity and feedback strength collectively shape the bimodality. We also compare our model with a direct auto-repression motif, where a gene produces its own repressor. Auto-repression fails to produce bimodal mRNA distributions as found in miRNA-based indirect repression, suggesting the crucial role of miRNAs in creating phenotypic diversity. Together, we demonstrate how miRNA-dependent negative feedback modifies the expression threshold and leads to a broader parameter regime of bimodality compared to the no-feedback case.

An evolutionary divergent thermodynamic brake in ZAP-70 fine-tunes the kinetic proofreading in T cells.

T cell signaling starts with assembling several tyrosine kinases and adapter proteins to the T cell receptor (TCR), following the antigen binding to the TCR. The stability of the TCR-antigen complex and the delay between the recruitment and activation of each kinase determines the T cell response. Integration of such delays constitutes a kinetic proofreading mechanism to regulate T cell response to the antigen binding. However, the mechanism of these delays is not fully understood. Combining biochemical experiments and kinetic modeling, here we report a thermodynamic brake in the regulatory module of the tyrosine kinase ZAP-70, which determines the ligand selectivity, and may delay the ZAP-70 activation upon antigen binding to TCR. The regulatory module of ZAP-70 comprises of a tandem SH2 domain that binds to its ligand, doubly-phosphorylated ITAM peptide (ITAM-Y2P), in two kinetic steps: a fast step and a slow step. We show the initial encounter complex formation between the ITAM-Y2P and tandem SH2 domain follows a fast-kinetic step, whereas the conformational transition to the holo-state follows a slow-kinetic step. We further observed a thermodynamic penalty imposed during the second phosphate-binding event reduces the rate of structural transition to the holo-state. Phylogenetic analysis revealed the evolution of the thermodynamic brake coincides with the divergence of the adaptive immune system to the cell-mediated and humoral responses. In addition, the paralogous kinase Syk expressed in B cells does not possess such a functional thermodynamic brake, which may explain the higher basal activation and lack of ligand selectivity in Syk.

Regioselective Transition Metal-Free Catalytic Ring Opening of 2H-Azirines by Phenols and Naphthols; One-Pot Access to Benzo- and Naphthofurans.

Benzofuran and naphthofuran derivatives are synthesized from readily available phenols and naphthols. Regioselective ring openings of 2H-azirine followed by in situ aromatization using a catalytic amount of Brønsted acid have established the novelty of the methodology. The involvement of a series of 2H-azirines with a variety of phenols, 1-naphthols, and 2-naphthols showed the generality of the protocol. In-depth density functional theory calculations revealed the reaction mechanism with the energies of the intermediates and transition states of a model reaction. An alternate pathway of the mechanism has also been proposed with computer modeling.

Exploring and exploiting the host cell autophagy during Mycobacterium tuberculosis infection.

Tuberculosis, caused by Mycobacterium tuberculosis, is a fatal infectious disease that prevails to be the second leading cause of death from a single infectious agent despite the availability of multiple drugs for treatment. The current treatment regimen involves the combination of several drugs for 6 months that remain ineffective in completely eradicating the infection because of several drawbacks, such as the long duration of treatment and the side effects of drugs causing non-adherence of patients to the treatment regimen. Autophagy is an intracellular degradative process that eliminates pathogens at the early stages of infection. Mycobacterium tuberculosis's unique autophagy-blocking capability makes it challenging to eliminate compared to usual pathogens. The present review discusses recent advances in autophagy-inhibiting factors and mechanisms that could be exploited to identify autophagy-inducing chemotherapeutics that could be used as adjunctive therapy with the existing first-line anti-TB agent to shorten the duration of therapy and enhance cure rates from multidrug-resistant tuberculosis (MDR-TB) and extreme drug-resistant tuberculosis (XDR-TB).

(3 + 2) cycloaddition of 2-alkoxynaphthalenes with azaoxyallyl cations: access to benzo[e]indolones.

A reaction between 2-alkoxynaphthalene and an in situ formed azaoxyallyl cation has been reported under ambient reaction conditions. The (3 + 2) cycloaddition reaction followed by aryl C-OMe/C-OEt bond cleavage produces a variety of benzo[e]indolone derivatives. Based on the isolated intermediate from the control experiment and previous results, a possible mechanism has been drawn. Reduction of the N-O bond of the benzo[e]indolone derivative manifests the possibility of further functionalization of the products towards biologically important heterocyclic molecules.

Similar immunogenicity profiles between the proposed biosimilar MYL-1501D and reference insulin glargine in patients with diabetes mellitus: the phase 3 INSTRIDE 1 and INSTRIDE 2 studies.

BACKGROUND: MYL-1501D is a proposed biosimilar to insulin glargine. The noninferiority of MYL-1501D was demonstrated in patients with type 1 diabetes and type 2 diabetes in 2 phase 3 trials. Immunogenicity of MYL-1501D and reference insulin glargine was examined in both studies. METHODS: INSTRIDE 1 and INSTRIDE 2 were multicenter, open-label, randomized, parallel-group studies. In INSTRIDE 1, patients with type 1 diabetes received MYL-1501D or insulin glargine over a 52-week period. In INSTRIDE 2, patients with type 2 diabetes treated with oral antidiabetic drugs, insulin naive or not, received MYL-1501D or reference insulin glargine over a 24-week period. Incidence rates and change from baseline in relative levels of antidrug antibodies (ADA) and anti-host cell protein (anti-HCP) antibodies in both treatment groups were determined by a radioimmunoprecipitation assay and a bridging immunoassay, respectively. Results were analyzed using a mixed-effects model (INSTRIDE 1) or a nonparametric Wilcoxon rank sum test (INSTRIDE 2). RESULTS: Total enrollment was 558 patients in INSTRIDE 1 and 560 patients in INSTRIDE 2. The incidence of total and cross-reactive ADA was comparable between treatment groups in INSTRIDE 1 and INSTRIDE 2 (P > 0.05 for both). A similar proportion of patients had anti-HCP antibodies in both treatment groups in INSTRIDE 1 at week 52 (MYL-1501D, 93.9 %; reference insulin glargine, 89.6 %; P = 0.213) and in INSTRIDE 2 at week 24 (MYL-1501D, 87.3 %; reference insulin glargine, 86.9 %; P > 0.999). CONCLUSIONS: In INSTRIDE 1 and INSTRIDE 2, similar immunogenicity profiles were observed for MYL-1501D and reference insulin glargine in patients with type 1 diabetes and type 2 diabetes, respectively. TRIAL REGISTRATION: ClinicalTrials.gov, INSTRIDE 1 ( NCT02227862 ; date of registration, August 28, 2014); INSTRIDE 2 ( NCT02227875 ; date of registration, August 28, 2014).

Cortical dynamics within and between parietal and motor cortex in essential tremor.

BACKGROUND: Evidence from functional imaging in essential tremor suggests that activity within parietal and motor cortices may be associated with worsening of tremor at increased visual feedback. OBJECTIVES: Examine how cortical oscillations within these regions and the connectivity between these regions is associated with worsening of tremor in essential tremor in response to high visual feedback. METHOD: The study included 24 essential tremor participants and 17 controls. We measured cortical activity and tremor magnitude at low and high feedback conditions. Cortical activity was measured using high-density electroencephalogram and isolated using source localization. RESULTS: Changes in power across feedback in the 4-12 Hz and 12-30 Hz bands were reduced within the contralateral motor cortex of essential tremor patients compared to controls. The 12-30 Hz bidirectional connectivity between the parietal and contralateral motor cortex was decreased in essential tremor patients. Worsening of tremor from low to high visual feedback was associated with 4-12 Hz activity in contralateral motor cortex. The greatest separation between groups was found when using the difference of the contralateral motor cortex activity at high and low feedback, rather than either feedback condition alone. CONCLUSION: Our findings provide new evidence that tremor in essential tremor is associated with reduced power across feedback in the motor cortex and reduced connectivity between the parietal and motor cortices. Combined with previous work on the cerebellar-thalamo-cortical motor circuit, our findings suggest that the network level disturbances associated with essential tremor extend to the cortico-cortical pathway between the parietal cortex and motor cortex. © 2018 International Parkinson and Movement Disorder Society.

Automated classification of pain perception using high-density electroencephalography data.

The translation of brief, millisecond-long pain-eliciting stimuli to the subjective perception of pain is associated with changes in theta, alpha, beta, and gamma oscillations over sensorimotor cortex. However, when a pain-eliciting stimulus continues for minutes, regions beyond the sensorimotor cortex, such as the prefrontal cortex, are also engaged. Abnormalities in prefrontal cortex have been associated with chronic pain states, but conventional, millisecond-long EEG paradigms do not engage prefrontal regions. In the current study, we collected high-density EEG data during an experimental paradigm in which subjects experienced a 4-s, low- or high-intensity pain-eliciting stimulus. EEG data were analyzed using independent component analyses, EEG source localization analyses, and measure projection analyses. We report three novel findings. First, an increase in pain perception was associated with an increase in gamma and theta power in a cortical region that included medial prefrontal cortex. Second, a decrease in lower beta power was associated with an increase in pain perception in a cortical region that included the contralateral sensorimotor cortex. Third, we used machine learning for automated classification of EEG data into low- and high-pain classes. Theta and gamma power in the medial prefrontal region and lower beta power in the contralateral sensorimotor region served as features for classification. We found a leave-one-out cross-validation accuracy of 89.58%. The development of biological markers for pain states continues to gain traction in the literature, and our findings provide new information that advances this body of work.NEW & NOTEWORTHY The development of a biological marker for pain continues to gain traction in literature. Our findings show that high- and low-pain perception in human subjects can be classified with 89% accuracy using high-density EEG data from prefrontal cortex and contralateral sensorimotor cortex. Our approach represents a novel neurophysiological paradigm that advances the literature on biological markers for pain.

Development of a novel cup cake with unique properties of essential oil of betel leaf (Piper betle L.) for sustainable entrepreneurship.

Betel vine (Piper betle L.) is a root climber with deep green heart shaped leaves. It belongs to the Piperaceae family. There is a huge wastage of the leaves during glut season and it can be reduced by various means including extraction of medicinal essential oil which can be considered as GRAS (generally recognized as safe) materials. Therefore, attempts were made to develop a novel cup cake by incorporating essential oil of betel leaf. The textural properties of the cakes were measured by texture analyzer instrument; whereas the organoleptic properties were adjudged by human preferences using sensory tables containing 9-point hedonic scale. Price estimation was done considering all costs and charges. Finally, all parameters of the developed cake were compared with different cup cakes available in the market for ascertaining consumer acceptability of the newly developed product in terms of quality and market price. Results revealed that the Novel cup cake developed with 0.005 % (v/w) essential oil of betel leaf occupied the 1st place among the four developed novel cup cakes. However, it occupied 4th place among the nine cup cakes in the overall preference list prepared based on the textural and organoleptic qualities, though its market price was calculated to be comparable to all the leading cupcakes available in the market. This indicates that manufacturing of novel cup cake with essential oil of betel leaf would be a profitable and self-sustaining entrepreneurship.

Applications of Inorganic Nanomaterials against Tuberculosis: A Comprehensive Review.

Tuberculosis (TB) continues to pose a significant global health threat, with millions of new infections recorded annually. Current treatment strategies, such as Directly Observed Treatment (DOT), face challenges, including patient non-compliance and the emergence of drug-resistant TB strains. In response to these obstacles, innovative approaches utilizing inorganic/metallic nanomaterials have been developed to enhance drug delivery to target alveolar macrophages, where Mycobacterium tuberculosis resides. These nanomaterials have shown effectiveness against various strains of TB, offering benefits such as improved drug efficacy, minimized side effects, and sustained drug release at the infection site. This comprehensive review explores the applications of different metal nanoparticles, metal oxide nanoparticles, and metal-metal oxide hybrid nanoparticles in the management of TB, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. The synergistic effects of combining inorganic nanoparticles with conventional anti-TB drugs have demonstrated promising results in combating TB infections. Further research and development in this field hold great promise for overcoming the challenges faced in current TB therapy and improving patient outcomes.

Cytochrome bd oxidase: an emerging anti-tubercular drug target.

Cytochrome bd (cyt-bd) oxidase, one of the two terminal oxidases in the Mycobacterium tuberculosis (Mtb) oxidative phosphorylation pathway, plays an indispensable role in maintaining the functionality of the metabolic pathway under stressful conditions. However, the absence of this oxidase in eukaryotic cells allows researchers to select it as a potential drug target for the synthesis of anti-tubercular (anti-TB) molecules. Cyt-bd inhibitors have often been combined with cytochrome bcc/aa3 super-complex inhibitors in anti-TB drug regimens to achieve a desired bactericidal response. The functional redundancy between both the terminal oxidases is responsible for this. The cryo-EM structure of cyt-bd oxidase from Mtb (PDB ID: 7NKZ) further accelerated the research to identify its inhibitor. Herein, we have summarized the reported anti-TB cyt-bd inhibitors, insight into the rationale behind targeting cyt-bd oxidase, and an outline of the architecture of Mtb cyt-bd oxidase.

Role of transcription termination factor Rho in anti-tuberculosis drug discovery.

Mycobacterial infections, including multidrug and extreme drug-resistant (MDR and XDR) infections, are a severe challenge and create a virtual antibiotic-deficient era. Bacterial transcription is an established antimicrobial drug target. In mycobacteria, efficient transcription termination relies on the ATP-dependent RNA helicase factor Rho. Rho factor is essential for Mycobacterium tuberculosis (Mtb) survival, and is a valid antibacterial drug target with no homolog in eukaryotes. Rho maintains genomic stability and virulence and prevents pervasive transcription in Mtb. In this review, we provide an overview of the essentiality of Rho in Mtb, which makes it an attractive drug target for inhibitor discovery.

Tweaking host immune responses for novel therapeutic approaches against Mycobacterium tuberculosis.

In TB, combat between the human host and Mycobacterium tuberculosis involves intricate interactions with immune cells. M. tuberculosis has evolved a complex evasion system to circumvent immune cells, leading to persistence and limiting its clearance by the host. Host-directed therapies are emerging approaches to modulate host responses, including inflammatory responses, cytokine responses, and autophagy, by using small molecules to curb mycobacterial infections. Targeting host immune pathways reduces the chances of antibiotic resistance to M. tuberculosis because, unlike antibiotics, this approach acts directly on the cells of the host. In this review, we discuss the role of immune cells during M. tuberculosis proliferation, provide a updated understanding of immunopathogenesis, and explore the range of host-modulating options for the clearance of this pathogen.

GC-MS-Guided Antimicrobial Defense Responsive Secondary Metabolites from the Endophytic Fusarium solani Isolated from Tinospora cordifolia and Their Multifaceted Biological Properties.

Medicinal plants are hosts to an infinite number of microorganisms, commonly referred to as endophytes which are rich in bioactive metabolites yielding favorable biological activities. The endophytes are known to have a profound impact on their host plant by promoting the accumulation of secondary metabolites which are beneficial to humankind. In the present study, the fungal endophyte, Fusarium solani (ABR4) from the medicinal plant Tinospora cordifolia, was assessed for its bioactive secondary metabolites employing fermentation on a solid rice medium. The crude ABR4 fungal extract was sequentially purified using the solvent extraction method and characterized using different spectroscopic and analytical techniques namely TLC, UV spectroscopic analysis, HRESI-MS, FTIR, and GC-MS analysis. The GC-MS analysis revealed the presence of pyridine, benzoic acid, 4-[(trimethylsilyl)oxy]-trimethylsilyl ester, hexadecanoic acid trimethylsilyl ester, and oleic acid trimethylsilyl ester. The cytotoxic ability of ABR4 was evaluated by MTT assay against lung cancer (A549) and breast cancer (MCF-7) cell lines. The compounds did not exhibit significant cytotoxicity against the tested cell lines. The endophytic ABR4 extract was evaluated for its antimicrobial potential against human pathogens (S. aureus, B. cereus, E. coli, S. typhimurium, P. aeruginosa, and C. albicans) by recording 47 to 54% inhibition. Taken together, the endophytic fungal strain ABR4 demonstrated a remarkable antimicrobial activity against the tested pathogens. Furthermore, the functional metabolites isolated from the endophytic strain ABR4 reveal its broader usage as antimicrobial agents for newer drug development in the pharmaceutical industry.

Methyltrifluoromethanesulfonate Catalyst in Direct Nucleophilic Substitution of Alcohols; One-Pot Synthesis of 4H-Chromene Derivatives.

The catalytic activity of methyltrifluoromethanesulfonate (MeOTf) has been explored toward direct nucleophilic substitution of the hydroxyl group of nonmanipulated alcohols such as benzylic, allylic, propargylic, and tertiary alcohols with a wide range of uncharged nucleophiles such as 1,3-dicarbonyl compounds, amides, alkynes, and indoles to generate functionalized 1,3-dicarbonyl compounds, amides, alkynes, and indoles, respectively. Thus, the present protocol defines an alternate pathway to construct new C-C, C-N, and C-O bonds with the formation of water as the byproduct under mild conditions without any acids or metals. A completely different mechanism was established through several control experiments to explain the reaction methodology. As an application of the reported protocol, 1H-indene derivatives have been synthesized in one pot when benzylic alcohols were subjected to react with internal alkynes. The scope of the reaction has been further extended toward a tandem benzylation-cyclization-dehydration of 1,3-dicarbonyl compounds with 2-hydroxybenzyl alcohols, which furnish biologically important 4H-chromene derivatives.

Unravelling the flexibility of Mycobacterium tuberculosis: an escape way for the bacilli.

The persistence of Mycobacterium tuberculosis makes it difficult to eradicate the associated infection from the host. The flexible nature of mycobacteria and their ability to adapt to adverse host conditions give rise to different drug-tolerant phenotypes. Granuloma formation restricts nutrient supply, limits oxygen availability and exposes bacteria to a low pH environment, resulting in non-replicating bacteria. These non-replicating mycobacteria, which need high doses and long exposure to anti-tubercular drugs, are the root cause of lengthy chemotherapy. Novel strategies, which are effective against non-replicating mycobacteria, need to be adopted to shorten tuberculosis treatment. This not only will reduce the treatment time but also will help prevent the emergence of multi-drug-resistant strains of mycobacteria.