Rv2231c, a unique histidinol phosphate aminotransferase from Mycobacterium tuberculosis, supports virulence by inhibiting host-directed defense.

Nitrogen metabolism of M. tuberculosis is critical for its survival in infected host cells. M. tuberculosis has evolved sophisticated strategies to switch between de novo synthesis and uptake of various amino acids from host cells for metabolic demands. Pyridoxal phosphate-dependent histidinol phosphate aminotransferase-HspAT enzyme is critically required for histidine biosynthesis. HspAT is involved in metabolic synthesis of histidine, phenylalanine, tyrosine, tryptophan, and novobiocin. We showed that M. tuberculosis Rv2231c is a conserved enzyme with HspAT activity. Rv2231c is a monomeric globular protein that contains α-helices and ß-sheets. It is a secretory and cell wall-localized protein that regulates critical pathogenic attributes. Rv2231c enhances the survival and virulence of recombinant M. smegmatis in infected RAW264.7 macrophage cells. Rv2231c is recognized by the TLR4 innate immune receptor and modulates the host immune response by suppressing the secretion of the antibacterial pro-inflammatory cytokines TNF, IL-12, and IL-6. It also inhibits the expression of co-stimulatory molecules CD80 and CD86 along with antigen presenting molecule MHC-I on macrophage and suppresses reactive nitrogen species formation, thereby promoting M2 macrophage polarization. Recombinant M. smegmatis expressing Rv2231c inhibited apoptosis in macrophages, promoting efficient bacterial survival and proliferation, thereby increasing virulence. Our results indicate that Rv2231c is a moonlighting protein that regulates multiple functions of M. tuberculosis pathophysiology to increase its virulence. These mechanistic insights can be used to better understand the pathogenesis of M. tuberculosis and to design strategies for tuberculosis mitigation.

Activation of the lysosomal damage response and selective autophagy: the coordinated actions of galectins, TRIM proteins, and CGAS-STING1 in providing immunity against Mycobacterium tuberculosis.

Autophagy is a crucial immune defense mechanism that controls the survival and pathogenesis of M. tb by maintaining cell physiology during stress and pathogen attack. The E3-Ub ligases (PRKN, SMURF1, and NEDD4) and autophagy receptors (SQSTM1, TAX1BP1, CALCOCO2, OPTN, and NBR1) play key roles in this process. Galectins (LGALSs), which bind to sugars and are involved in identifying damaged cell membranes caused by intracellular pathogens such as M. tb, are essential. These include LGALS3, LGALS8, and LGALS9, which respond to endomembrane damage and regulate endomembrane damage caused by toxic chemicals, protein aggregates, and intracellular pathogens, including M. tb. They also activate selective autophagy and de novo endolysosome biogenesis. LGALS3, LGALS9, and LGALS8 interact with various components to activate autophagy and repair damage, while CGAS-STING1 plays a critical role in providing immunity against M. tb by activating selective autophagy and producing type I IFNs with antimycobacterial functions. STING1 activates cGAMP-dependent autophagy which provides immunity against various pathogens. Additionally, cytoplasmic surveillance pathways activated by ds-DNA, such as inflammasomes mediated by NLRP3 and AIM2 complexes, control M. tb. Modulation of E3-Ub ligases with small regulatory molecules of LGALSs and TRIM proteins could be a novel host-based therapeutic approach for controlling TB.

Multipronged regulation of autophagy and apoptosis: emerging role of TRIM proteins.

TRIM proteins are characterized by their conserved N-terminal RING, B-box, and coiled-coil domains. These proteins are efficient regulators of autophagy, apoptosis, and innate immune responses and confer immunity against viruses and bacteria. TRIMs function as receptors or scaffold proteins that target substrates for autophagy-mediated degradation. Most TRIMs interact with the BECN1-ULK1 complex to form TRIMosomes, thereby efficiently targeting substrates to autophagosomes. They regulate the functions of ATG proteins through physical interactions or ubiquitination. TRIMs affect the lipidation of MAP1LC3B1 to form MAP1LC3B2, which is a prerequisite for phagophore and autophagosome formation. In addition, they regulate MTOR kinase and TFEB, thereby regulating the expression of ATG genes. TRIM proteins are efficient regulators of apoptosis and are crucial for regulating cell proliferation and tumor formation. Many TRIM proteins regulate intrinsic and extrinsic apoptosis via the cell surface receptors TGFBR2, TNFRSF1A, and FAS. Mitochondria modulate the anti- and proapoptotic functions of BCL2, BAX, BAK1, and CYCS. These proteins use a multipronged approach to regulate the intrinsic and extrinsic apoptotic pathways, culminating in coordinated activation or inhibition of the initiator and executor CASPs. Furthermore, TRIMs can have a dual effect in determining cell fate and are therefore crucial for cellular homeostasis. In this review, we discuss mechanistic insights into the role of TRIM proteins in regulating autophagy and apoptosis, which can be used to better understand cellular physiology. These findings can be used to develop therapeutic interventions to prevent or treat multiple genetic and infectious diseases.

Regulation of autophagy by SARS-CoV-2: The multifunctional contributions of ORF3a.

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) regulates autophagic flux by blocking the fusion of autophagosomes with lysosomes, causing the accumulation of membranous vesicles for replication. Multiple SARS-CoV-2 proteins regulate autophagy with significant roles attributed to ORF3a. Mechanistically, open reading frame 3a (ORF3a) forms a complex with UV radiation resistance associated, regulating the functions of the PIK3C3-1 and PIK3C3-2 lipid kinase complexes, thereby modulating autophagosome biogenesis. ORF3a sequesters VPS39 onto the late endosome/lysosome, inhibiting assembly of the soluble NSF attachement protein REceptor (SNARE) complex and preventing autolysosome formation. ORF3a promotes the interaction between BECN1 and HMGB1, inducing the assembly of PIK3CA kinases into the ER (endoplasmic reticulum) and activating reticulophagy, proinflammatory responses, and ER stress. ORF3a recruits BORCS6 and ARL8B to lysosomes, initiating the anterograde transport of the virus to the plasma membrane. ORF3a also activates the SNARE complex (STX4-SNAP23-VAMP7), inducing fusion of lysosomes with the plasma membrane for viral egress. These mechanistic details can provide multiple targets for inhibiting SARS-CoV-2 by developing host- or host-pathogen interface-based therapeutics.

ArgD of Mycobacterium tuberculosis is a functional N-acetylornithine aminotransferase with moonlighting function as an effective immune modulator.

Mycobacterium tuberculosis (M. tuberculosis) encodes an essential enzyme acetyl ornithine aminotransferase ArgD (Rv1655) of arginine biosynthetic pathway which plays crucial role in M. tuberculosis growth and survival. ArgD catalyzes the reversible conversion of N-acetylornithine and 2 oxoglutarate into glutamate-5-semialdehyde and L-glutamate. It also possesses succinyl diaminopimelate aminotransferase activity and can thus carry out the corresponding step in lysine biosynthesis. These essential roles played by ArgD in amino acid biosynthetic pathways highlight it as an important metabolic chokepoint thus an important drug target. We showed that M. tuberculosis ArgD rescues the growth of ΔargD E. coli grown in minimal media validating its functional importance. Phylogenetic analysis of M. tuberculosis ArgD showed homology with proteins in gram positive bacteria, pathogenic and non-pathogenic mycobacteria suggesting the essentiality of this protein. ArgD is a secretory protein that could be utilized by M. tuberculosis to modulate host innate immunity as its moonlighting function. In-silico analysis predicted it to be a highly antigenic protein. The recombinant ArgD protein when exposed to macrophage cells induced enhanced production of pro-inflammatory cytokines TNF, IL6 and IL12 in a dose dependent manner. ArgD also induced the increased production of innate immune effector molecule NOS2 and NO in macrophages. We also demonstrated ArgD mediated activation of the canonical NFkB pathway. Notably, we also show that ArgD is a specific TLR4 agonist involved in the activation of pro-inflammatory signaling for sustained production of effector cytokines. Intriguingly, ArgD protein treatment activated macrophages to acquire the M1 phenotype through the increased surface expression of MHCII and costimulatory molecules CD80 and CD86. ArgD induced robust B-cell response in immunized mice, validating its antigenicity potential as predicted by the in-silico analysis. These properties of M. tuberculosis ArgD signify its functional plasticity that could be exploited as a possible drug target to combat tuberculosis.

Mechanisms of immune evasion by Mycobacterium tuberculosis: the impact of T7SS and cell wall lipids on host defenses.

Emergence of MDR strains exacerbates the TB health crisis.M. tb uses T7SS to disrupt host immune responses.Pathogen counters autophagy, dampening host defense mechanisms.T7SSs critical for protein transport and immune evasion.Understanding T7SSs may lead to new TB therapies.

Teleological cooption of Mycobacterium tuberculosis PE/PPE proteins as porins: Role in molecular immigration and emigration.

Permeation through bacterial cells for exchange or uptake of biomolecules and ions invariably depend upon the existence of pore-forming proteins (porins) in their outer membrane. Mycobacterium tuberculosis (M. tb) harbours one of the most rigid cell envelopes across bacterial genera and is devoid of the classical porins for solute transport across the cell membrane. Though canonical porins are incompatible with the evolution of permeability barrier, porin like activity has been reported from membrane preparations of pathogenic mycobacteria. This suggests a sophisticated transport mechanism that has been elusive until now, along with the protein family responsible for it. Recent evidence suggests that these slow-growing mycobacteria have co-opted some of PE/PPE family proteins as molecular transport channels, in place of porins, to facilitate uptake of nutrients required to thrive in the restrictive host environment. These reports advocate that PE/PPE proteins, due to their structural ability, have a potential role in importing small molecules to the cell's interior. This mechanism unveils how a successful pathogen overcomes its restrictive membrane's transport limitations for selective uptake of nutrients. If extrapolated to have a role in drug transport, these channels could help understand the emergence of drug resistance. Further, as these proteins are associated with the export of virulence factors, they can be exploited as novel drug targets. There remains, however, an interesting question that as the PE/PPE proteins can allow the 'import' of molecules from outside the cell, is the reverse transport also possible across the M. tb membrane. In this review, we have discussed recent evidence supporting PE/PPE's role as a specific transport channel for selective uptake of small molecule nutrients and, as possible molecular export machinery of M. tb. This newly discovered role as transmembrane channels demands further research on this enigmatic family of proteins to comprehend the pathomechanism of this very smart pathogen.

Percutaneous Radiofrequency Ablation of Appendicular Skeleton Chondroblastoma-an Experience from a Tertiary Care Cancer Center.

PURPOSE: To evaluate safety and long-term efficacy of radiofrequency (RF) ablation in treatment of chondroblastoma. MATERIALS AND METHODS: This retrospective analysis comprised 27 consecutive patients with histopathologically proven chondroblastoma treated by RF ablation. The tumors were located in the proximal humerus (n = 6), proximal tibia (n = 8), proximal femur (n = 6), distal femur (n = 5), acromion process (n = 1), and lunate (n = 1). In 19 patients (70.3%), the tumor was in the weight-bearing area of the bone. Clinical response was assessed by comparing pain scores and functional assessment by Musculoskeletal Tumor Society (MSTS) score before and after ablation. Patients were followed for a minimum of 1 year to rule out complications and recurrence. RESULTS: Technical success rate was 100%. Mean pain score before the procedure was 7.34 (range, 7-9); all patients experienced a reduction in pain, with 25 (92.6%) patients reporting complete pain relief at 6 weeks. Mean MSTS score before the procedure was 15.4, whereas mean MSTS score at 6 weeks after the procedure was 28.6, suggesting significant functional improvement (P < .0001). Two patients developed osteonecrosis and collapse of the treated bone. There were no recurrences. CONCLUSIONS: Percutaneous RF ablation is a safe and effective option for treating chondroblastoma of the appendicular skeleton.

CagW, a VirB6 homologue interacts with Cag-type IV secretion system substrate CagA in Helicobacter pylori.

Protein translocating Cag type IV secretion system of Helicobacter pylori is a diverse multi-protein complex. Here, we have characterized one of its key subunit CagW to identify its interacting partners. Our results demonstrate for the first time that this VirB6 homologue interacts with the substrate of the secretion system CagA. CagW forms multimer and its absence affects cellular levels of pilus forming components, CagL, CagI and CagH. Our results support the notion that the protein is essential for the transport of CagA across the bacterial membrane barrier and would aid in improving our understanding of structural and functional aspects of the inner membrane part of Cag-T4SS channel complex for the passage of substrate CagA.

Enhanced methane potential of rice straw with microwave assisted pretreatment and its kinetic analysis.

Biogas has become an alternative clean source of energy. Agricultural residues being renewable and abundant resources could be efficiently used as a feed for methane production. The recalcitrant behaviour of rice straw marks pretreatment an important step to facilitate the transformation into renewable (methane) energy source. Microwave pretreatment has been considered as one of the most effective method, as it can directly (thermal and nonthermal effects) react with the feedstock and destroy its complex matrix. The present study considered the different temperature and exposure time (i.e., 130-230 °C, 2-5 min). Biochemical methane potential was assessed corresponding to the maximum solubilization rate; specific methane yield was obtained as 325.76 mL/g/VS. The total net energy gain of 3288.576 J/g/VS was obtained. The performance parameters were calculated by using different kinetic models. It followed the trend as modified Gompertz > transference function > logistic function models. Field Emission Scanning Electron Microscopy (FESEM) and Fourier Transform Infrared (FTIR) analysis confirmed the breakdown of lignocellulose structure resulting from the rupture of cuticular surface.

Non-heat shock responsive roles of HSF1 in Candida albicans are essential under iron deprivation and drug defense.

Recently, we have reported that the conditional mutant of the heat shock factor-1 (HSF1) in Candida albicans displays enhanced susceptibility not only towards a plant alkaloid, berberine, but also to diverse antifungal drugs. The present study attempts to identify additional phenotypes highlighting the non-heat shock responsive roles of HSF1 that could be correlated with the enhanced drug susceptibility. We uncover an intricate relationship between cellular iron and HSF1 mediated drug susceptibility of C. albicans. Interestingly, at 30°C, the conditional deletion of HSF1 while presented no growth defect, exhibited low intracellular iron. Notably, exogenous supplementation of iron reversed growth defects of HSF1 mutant when grown at 37°C. We provide evidence that the HSF1 mutant presents interesting phenotypes at basal conditions and are implicated in enhanced drug susceptibilities, dysfunctional mitochondria, decreased resistance towards oxidative stress and compromised cell wall integrity, all of which could be fully reversed upon iron supplementation. The HSF1 mutant also displayed defective filamentation at basal conditions under various solid hypha inducing media. Further, chelation of iron of HSF1 mutant cells led to severe growth defects and apparently triggers an iron starvation signal in the cell thus, demonstrating that HSF1 is essential for C. albicans cells to tolerate the iron deprivation stress. Together, apart from the well-established roles of HSF1 in reciprocation of thermal stress, this study extends its role under basal conditions and provides molecular insights into the role of HSF1 in iron deprivation and drug defense of C. albicans.

PRKAA2, MTOR, and TFEB in the regulation of lysosomal damage response and autophagy.

Lysosomes function as critical signaling hubs that govern essential enzyme complexes. LGALS proteins (LGALS3, LGALS8, and LGALS9) are integral to the endomembrane damage response. If ESCRT fails to rectify damage, LGALS-mediated ubiquitination occurs, recruiting autophagy receptors (CALCOCO2, TRIM16, and SQSTM1) and VCP/p97 complex containing UBXN6, PLAA, and YOD1, initiating selective autophagy. Lysosome replenishment through biogenesis is regulated by TFEB. LGALS3 interacts with TFRC and TRIM16, aiding ESCRT-mediated repair and autophagy-mediated removal of damaged lysosomes. LGALS8 inhibits MTOR and activates TFEB for ATG and lysosomal gene transcription. LGALS9 inhibits USP9X, activates PRKAA2, MAP3K7, ubiquitination, and autophagy. Conjugation of ATG8 to single membranes (CASM) initiates damage repair mediated by ATP6V1A, ATG16L1, ATG12, ATG5, ATG3, and TECPR1. ATG8ylation or CASM activates the MERIT system (ESCRT-mediated repair, autophagy-mediated clearance, MCOLN1 activation, Ca2+ release, RRAG-GTPase regulation, MTOR modulation, TFEB activation, and activation of GTPase IRGM). Annexins ANAX1 and ANAX2 aid damage repair. Stress granules stabilize damaged membranes, recruiting FLCN-FNIP1/2, G3BP1, and NUFIP1 to inhibit MTOR and activate TFEB. Lysosomes coordinate the synergistic response to endomembrane damage and are vital for innate and adaptive immunity. Future research should unveil the collaborative actions of ATG proteins, LGALSs, TRIMs, autophagy receptors, and lysosomal proteins in lysosomal damage response.

Bedside Ultrasound-Guided Percutaneous Cholecystostomy in Critically Ill Patients-Outcomes in 51 Patients.

Purpose The aim of this study was to report technical and clinical success of bedside ultrasound-guided percutaneous cholecystostomy (PC) tube placement in intensive care unit (ICU). Materials and Methods This is a retrospective study of 51 patients (36 males:15 females, mean age: 67 years) who underwent ultrasound-guided PC from May 2015 to January 2020. The indication for cholecystostomy tube placement, comorbidities, imaging finding, technical success, clinical success, timing of surgery post-cholecystostomy tube placement, indwelling catheter time, complications, and follow-up were recorded. Results Indications for cholecystostomy tube placement were acute calculous cholecystitis ( n = 43; 84.3%), perforated cholecystitis ( n = 5; 9.8%), and emphysematous cholecystitis ( n = 3; 5.9%). Most of the patients had multiple comorbidities; these were diabetes mellitus, hypertension, cardiovascular disease, chronic renal disease, underlying malignancy, and multisystem disease with sepsis. All patients had undergone PC through transhepatic approach under ultrasound guidance in ICU. Technical success rate of the procedure was 100%. Clinical success rate was 92.1% (47/51) and among these 44/51 (86.2%) patients underwent definitive elective cholecystectomy, 3/51 (5.9%) patients had elective tube removal. Three of fifty-one (5.9%) patients did not improve; among these two underwent emergency surgery, while there was 1/51 (1.9%) mortality due to ongoing sepsis and multiorgan dysfunction. There were no procedure-related mortalities or procedure-related major complications. One patient had bile leak due to multiple attempts for cholecystostomy placement. Mean tube indwelling time was 13 days (range: 3-45 days). Conclusion Ultrasound-guided PC can be safely performed in ICU in critically ill patients unfit for surgery with high technical and clinical success rates. Early laparoscopic cholecystectomy should be preferred after stabilization of clinical condition following cholecystostomy.

The Gut Health Revolution: Herbs and Dietary Phytochemicals in Balancing Gut Microbiota for Optimal Human Health.

The gut microbiota is a varied population of microorganisms that live in the human gastrointestinal system. Emerging research emphasizes the importance of this microbial ecology in general health and its influence on a variety of disorders. The review explores the synergy between herbal treatment and traditional medicine, emphasizing their cultural significance and therapeutic benefits. It delves into the intricate relationship between herbal remedies, traditional healing practices, and their sustained usage over centuries. The review highlights the pivotal role of the gut microbiota in herbal medicine, elucidating how treatments influence the gastrointestinal microorganisms, impacting overall health. Dietary phytochemicals are underscored for their significance in herbal medicine and nutritional well-being, along with the interdependence of plant extracts and botanicals. The investigation explores the molecular connections between phytoconstituents and gut microbiota, aiming to deepen the understanding of herbal medicine's tailored approach to specific health challenges. The summary concludes by emphasizing herbal treatments' unique ability to regulate gut flora, contributing to overall gastrointestinal wellbeing. In closing, the review provides a concise overview, serving as a valuable resource for integrative medicine research, with recommendations for future exploration of herbal medicine's potential in healthcare.

Regulation of Type I Interferon and Autophagy in Immunity against Mycobacterium Tuberculosis: Role of CGAS and STING1.

Mycobacterium tuberculosis (M. tb) is a significant intracellular pathogen responsible for numerous infectious disease-related deaths worldwide. It uses ESX-1 T7SS to damage phagosomes and to enter the cytosol of host cells after phagocytosis. During infection, M. tb and host mitochondria release dsDNA, which activates the CGAS-STING1 pathway. This pathway leads to the production of type I interferons and proinflammatory cytokines and activates autophagy, which targets and degrades bacteria within autophagosomes. However, the role of type I IFNs in immunity against M. tb is controversial. While previous research has suggested a protective role, recent findings from cgas-sting1 knockout mouse studies have contradicted this. Additionally, a study using knockout mice and non-human primate models uncovered a new mechanism by which neutrophils recruited to lung infections form neutrophil extracellular traps. Activating plasmacytoid dendritic cells causes them to produce type I IFNs, which interfere with the function of interstitial macrophages and increase the likelihood of tuberculosis. Notably, M. tb uses its virulence proteins to disrupt the CGAS-STING1 signaling pathway leading to enhanced pathogenesis. Investigating the CGAS-STING1 pathway can help develop new ways to fight tuberculosis.

Complications with the use of Angio-Seal vascular closure device and their management.

Vascular closure devices (VCDs) are being increasingly used for achieving hemostasis after diagnostic and therapeutic endovascular procedures. Although uncommon, complications may be encountered which are associated with the use of these VCDs. We report four cases where the use of Angio-Seal (Terumo, Somerset, New Jersey, USA) was followed by complications. Three cases presented with acute limb ischemia, among them, two patients had arterial occlusion at the vascular access site and one patient had embolization of the footplate anchor of the closure device. One case presented with pseudoaneurysm at the common femoral artery access site along with occlusion at origin of the superficial femoral artery. We have described the mechanism in which these complications occur and the successful management of these cases preventing potential amputation and limb loss. The risk factors which increase the risk of complications with the use of Angio-Seal VCD were reviewed and the strategy to avoid these complications with particular emphasis on the utility of ultrasound when using Angio-Seal VCD is discussed. A strategy to manage these complications has been discussed while deciding on endovascular management or surgical management, especially in patients with challenging presentation and those with multiple comorbidities making them at very high risk for surgery.

Point-of-care optical devices in clinical imaging and screening: A review on the state of the art.

Integration of optical technologies in biomedical sciences permitted light manipulation at smaller time-length scales for specific detection and imaging of biological entities. Similarly, advances in consumer electronics and wireless telecommunications strengthened the development of affordable and portable point-of-care (POC) optical devices, circumventing the necessity of conventional clinical analyses by trained personnel. However, many of the POC optical technologies translated from bench to bedside require industrial support for their commercialization and dissemination to the population. This review aims to demonstrate the intriguing progress and challenges of emerging POC devices utilizing optics for clinical imaging (depth-resolved and perfusion imaging) and screening (infections, cancer, cardiac health, and haematologic disorders) with a focus on research studies over the previous 3 years. Special attention is given to POC optical devices that can be utilized in resource-constrained environments.

CRISPR­based diagnostic approaches: Implications for rapid management of future pandemics (Review).

Sudden viral outbreaks have increased in the early part of the 21st century, such as those of severe acute respiratory syndrome coronavirus (SARS­CoV), Middle East respiratory syndrome corona virus, and SARS­CoV­2, owing to increased human access to wildlife habitats. Therefore, the likelihood of zoonotic transmission of human­associated viruses has increased. The emergence of severe acute respiratory syndrome coronavirus 2 in China and its spread worldwide within months have highlighted the need to be ready with advanced diagnostic and antiviral approaches to treat newly emerging diseases with minimal harm to human health. The gold­standard molecular diagnostic approaches currently used are time­consuming, require trained personnel and sophisticated equipment, and therefore cannot be used as point­of­care devices for widespread monitoring and surveillance. Clustered regularly interspaced short palindromic repeats (CRISPR)­associated (Cas) systems are widespread and have been reported in bacteria, archaea and bacteriophages. CRISPR­Cas systems are organized into CRISPR arrays and adjacent Cas proteins. The detection and in­depth biochemical characterization of class 2 type V and VI CRISPR­Cas systems and orthologous proteins such as Cas12 and Cas13 have led to the development of CRISPR­based diagnostic approaches, which have been used to detect viral diseases and distinguish between serotypes and subtypes. CRISPR­based diagnostic approaches detect human single nucleotide polymorphisms in samples from patients with cancer and are used as antiviral agents to detect and destroy viruses that contain RNA as a genome. CRISPR­based diagnostic approaches are likely to improve disease detection methods in the 21st century owing to their ease of development, low cost, reduced turnaround time, multiplexing and ease of deployment. The present review discusses the biochemical properties of Cas12 and Cas13 orthologs in viral disease detection and other applications. The present review expands the scope of CRISPR­based diagnostic approaches to detect diseases and fight viruses as antivirals.

Mycobacterium tuberculosis protein MoxR1 enhances virulence by inhibiting host cell death pathways and disrupting cellular bioenergetics.

Mycobacterium tuberculosis (M. tb) utilizes the multifunctionality of its protein factors to deceive the host. The unabated global incidence and prevalence of tuberculosis (TB) and the emergence of multidrug-resistant strains warrant the discovery of novel drug targets that can be exploited to manage TB. This study reports the role of M. tb AAA+ family protein MoxR1 in regulating host-pathogen interaction and immune system functions. We report that MoxR1 binds to TLR4 in macrophage cells and further reveal how this signal the release of proinflammatory cytokines. We show that MoxR1 activates the PI3K-AKT-MTOR signalling cascade by inhibiting the autophagy-regulating kinase ULK1 by potentiating its phosphorylation at serine 757, leading to its suppression. Using autophagy-activating and repressing agents such as rapamycin and bafilomycin A1 suggested that MoxR1 inhibits autophagy flux by inhibiting autophagy initiation. MoxR1 also inhibits apoptosis by suppressing the expression of MAPK JNK1/2 and cFOS, which play critical roles in apoptosis induction. Intriguingly, MoxR1 also induced robust disruption of cellular bioenergetics by metabolic reprogramming to rewire the citric acid cycle intermediates, as evidenced by the lower levels of citric acid and electron transport chain enzymes (ETC) to dampen host defence. These results point to a multifunctional role of M. tb MoxR1 in dampening host defences by inhibiting autophagy, apoptosis, and inducing metabolic reprogramming. These mechanistic insights can be utilized to devise strategies to combat TB and better understand survival tactics by intracellular pathogens.

Conductive polythiophene/graphitic-carbon nitride nanocomposite for the detection of ethanol mixing in petrol.

The automobile vehicles must be operated on fuel containing no more than 10% ethanol. Use of fuel having more than 10% ethanol may cause engine malfunction, starting and running issues, and material degradation. These negative impacts could cause irreversible damage to the vehicles. Therefore, ethanol mixing in petrol should be controlled below 10% level. The current work is the first to report sensing of ethanol mixing in petrol with reference to the variation in the DC electrical conductivity of polythiophene/graphitic-carbon nitride (PTh/gC3N4) nanocomposite. The in situ chemical oxidative method of polymerization was used for synthesizing PTh and PTh/gC3N4 nanocomposite. Fourier transform infrared spectroscopy (FT-IR), X-rays diffraction (XRD), thermo-gravimetric analysis (TGA), transmittance electron microscopy (TEM) as well as scanning electron microscopy (SEM) analysis were used for confirmation of the structure along with morphology of the PTh and PTh/gC3N4 nanocomposite. The thermal stability of DC electrical conductivity of PTh and PTh/gC3N4 nanocomposite were tested under isothermal and cyclic ageing condition. The sensing response of PTh and PTh/gC3N4 nanocomposite as a function of DC electrical conductivity were recorded in petrol and ethanol atmosphere. The sensing response of PTh/g-C3N4 nanocomposite in petrol atmosphere was 6.1 times higher than that of PTh with lower detection limit to 0.005 v/v% of ethanol prepared in n-hexane.