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Phosphorus is essential in all cells' structural, metabolic and regulatory functions. For fungal cells that import inorganic phosphate (Pi) up a steep concentration gradient, surface Pi transporters are critical capacitators of growth. Fungi must deploy Pi transporters that enable optimal Pi uptake in pH and Pi concentration ranges prevalent in their environments. Single, triple and quadruple mutants were used to characterize the four Pi transporters we identified for the human fungal pathogen Candida albicans, which must adapt to alkaline conditions during invasion of the host bloodstream and deep organs. A high-affinity Pi transporter, Pho84, was most efficient across the widest pH range while another, Pho89, showed high-affinity characteristics only within one pH unit of neutral. Two low-affinity Pi transporters, Pho87 and Fgr2, were active only in acidic conditions. Only Pho84 among the Pi transporters was clearly required in previously identified Pi-related functions including Target of Rapamycin Complex 1 signaling, oxidative stress resistance and hyphal growth. We used in vitro evolution and whole genome sequencing as an unbiased forward genetic approach to probe adaptation to prolonged Pi scarcity of two quadruple mutant lineages lacking all 4 Pi transporters. Lineage-specific genomic changes corresponded to divergent success of the two lineages in fitness recovery during Pi limitation. Initial, large-scale genomic alterations like aneuploidies and loss of heterozygosity eventually resolved, as populations gained small-scale mutations. Severity of some phenotypes linked to Pi starvation, like cell wall stress hypersensitivity, decreased in parallel to evolving populations' fitness recovery in Pi scarcity, while severity of others like membrane stress responses diverged from Pi scarcity fitness. Among preliminary candidate genes for contributors to fitness recovery, those with links to TORC1 were overrepresented. Since Pi homeostasis differs substantially between fungi and humans, adaptive processes to Pi deprivation may harbor small-molecule targets that impact fungal growth, stress resistance and virulence.

Tuberculosis (TB) remains a significant global health challenge, with approximately 1.5 million deaths per year. The Bacillus Calmette-Guérin (BCG) vaccine against TB is used in infants but shows variable protection. Here, we introduce a novel approach using a double gene knockout mutant (DKO) from wild-type Mycobacterium tuberculosis (Mtb) targeting fbpA and sapM genes. DKO exhibited enhanced anti-TB gene expression in mouse antigen-presenting cells, activating autophagy and inflammasomes. This heightened immune response improved ex vivo antigen presentation to T cells. Subcutaneous vaccination with DKO led to increased protection against TB in wild-type C57Bl/6 mice, surpassing the protection observed in caspase 1/11-deficient C57Bl/6 mice and highlighting the critical role of inflammasomes in TB protection. The DKO vaccine also generated stronger and longer-lasting protection than the BCG vaccine in C57Bl/6 mice, expanding both CD62L-CCR7-CD44+/-CD127+ effector T cells and CD62L+CCR7+/-CD44+CD127+ central memory T cells. These immune responses correlated with a substantial ≥ 1.7-log10 reduction in Mtb lung burden. The DKO vaccine represents a promising new approach for TB immunization that mediates protection through autophagy and inflammasome pathways.

The rapid emergence of genetic variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after late 2020, lead to origin of the term “variant of concern” and became the prime issue for the health of the human populations across the globe. Genome surveillance provides the information about the functional consequences of the variants and their divergence. Presently, we report and compare the nucleotide sequences of the isolated SARS-CoV-2 genomes at two different time-frame i.e. first wave (June- September, 2020) and second wave (April-May, 2021) from Lucknow, Uttar Pradesh, India. We employed the Oxford Nanopore MINION system and ARTIC protocol for sequencing, achieving >90x genome coverage in approximately 90% of samples. Increased mutation density in viral spike proteins were the cause of higher transmission and infectivity of second wave. The second wave exhibited a higher mutation density in viral spike proteins, likely contributing to increased transmission and infectivity. Notable spike mutations included receptor-binding domain (RBD) mutations (L452R, T478K, D614G), N-terminal domain (NTD) mutations (T17R, G142D, Δ156–157, A222V), and furin cleavage site (FCS) mutations (P681R, D950N). The functional consequences of common and unique variants among the first and second wave were evaluated by Sorting Intolerant from Tolerant (SIFT) and Protein Variant Effect Analyser (PROVEAN). Furthermore, we extensively investigated phylogenetic clustering of the genome sequences by Nextstrain and identified the contrasting divergence between first and second wave. Different sub division of delta clade (21I, 21 A, 21 J) and 21 B (kappa) with mutations primarily in spike proteins and nucleocapsid proteins, were exclusive to the second wave. Our study identified changes in spike proteins and nucleocapsid potentially contributing to increased transmission and infectivity during the second wave. Loci specific variant map for different countries across the world suggested the appearance of large number of variants associated with ORF1a during the second wave in India. Overall, the data underscores the dynamic nature of viral evolution during different phases of an outbreak, highlighting the importance of continuous genomic surveillance to track and understand viral mutations and their implications for public health interventions.

Introduction: Renal fibrosis is a critical event in the development and progression of chronic kidney disease (CKD), and it is considered the final common pathway for all types of CKD. The prevalence of CKD is higher in females; however, males have a greater prevalence of end-stage renal disease. In addition, low birth weight and low nephron number are associated with increased risk for CKD. This study examined the development and severity of unilateral ureter obstruction (UUO)-induced renal fibrosis in male and female wild-type (ROP +/+) and mutant (ROP Os/+) mice, a mouse model of low nephron number. Methods: Male and female ROP +/+ and ROP Os/+ mice were subjected to UUO, and kidney tissue was collected at the end of the 10-day experimental period. Kidney histological analysis and mRNA expression determined renal fibrosis, tubular injury, collagen deposition, extracellular matrix proteins, and immune cell infiltration. Results: Male and female UUO mice demonstrated marked renal injury, kidney fibrosis, and renal extracellular matrix production. Renal fibrosis and α-smooth muscle actin were increased to a similar degree in ROP +/+ and ROP Os/+ mice with UUO of either sex. There were also no sex differences in renal tubular cast formation or renal infiltration of macrophage in ROP +/+ and ROP Os/+ UUO mice. Interestingly, renal fibrosis and α-smooth muscle actin were 1.5–3-fold greater in UUO-ROP +/+ compared to UUO-ROP Os/+ mice. Renal inflammation phenotypes following UUO were also 30–45% greater in ROP +/+ compared to ROP Os/+ mice. Likewise, expression of extracellular matrix and renal fibrotic genes was greater in UUO-ROP +/+ mice compared to UUO-ROP Os/+ mice. In contrast to these findings, ROP Os/+ mice with UUO demonstrated glomerular hypertrophy with 50% greater glomerular tuft area compared to ROP +/+ with UUO. Glomerular hypertrophy was not sex-dependent in any of the genotypes of ROP mice. These findings provide evidence that low nephron number contributes to UUO-induced glomerular hypertrophy in ROP Os/+ mice but does not enhance renal fibrosis, inflammation, and renal tubular injury. Conclusion: Taken together, we demonstrate that low nephron number contributes to enhanced glomerular hypertrophy but not kidney fibrosis and tubular injury. We also demonstrate that none of the changes caused by UUO was affected by sex in any of the ROP mice genotypes.

Arginine and tryptophan are pivotal in orchestrating cytokine-driven macrophage polarization and immune activation. Specifically, interferon-gamma (IFN-γ) stimulates inducible nitric oxide synthase (iNOS) expression), leading to the conversion of arginine into citrulline and nitric oxide (NO), while Interleukin-4 (IL4) promotes arginase activation, shifting arginine metabolism toward ornithine. Concomitantly, IFN-γ triggers indoleamine 2,3-dioxygenase 1 (IDO1) and Interleukin-4 induced 1 (IL4i1), resulting in the conversion of tryptophan into kynurenine and indole-3-pyruvic acid. These metabolic pathways are tightly regulated by NAD+-dependent sirtuin proteins, with Sirt2 and Sirt5 playing integral roles. In this review, we present novel insights that augment our understanding of the metabolic pathways of arginine and tryptophan following Mycobacterium tuberculosis infection, particularly their relevance in macrophage responses. Additionally, we discuss arginine methylation and demethylation and the role of Sirt2 and Sirt5 in regulating tryptophan metabolism and arginine metabolism, potentially driving macrophage polarization.

Over the past 20 years, in filament draw texturing, very few developments and innovations have been introduced into production machineries. The growing demand for energy efficiency, faster production rates and greater production flexibility have prompted our investigation into non-traditional approaches to improve yarn control during the texturing. Instead of aprons, small individually driven godets are a solution for high-speed manufacturing, yarn control and energy saving. The drawing godets, where the yarn can be considered an elastic coupling element between two consecutive godets, pose a new challenge for consistency in velocity control. Though some machinery manufacturers have introduced the godet system, the yarn quality produced by the godet system is not systematically evaluated and compared vis-à-vis the apron system. The current study prepared textured yarns in both apron and godet systems while maintaining the same texturing parameters. Differences in the yarn’s bulk, modulus, breaking elongation, tenacity and boiling water shrinkage were assessed and compared. Woven and knitted fabrics were prepared from textured yarns, and a comparative analysis of fabric properties was performed with respect to their tearing strength, air permeability, drape and dyeability. Better quality of yarn and fabrics can be prepared in the godet system, which is energy saving, of higher speed and requires low maintenance technology in comparison to the apron system.

Abstract Background Caroli’s disease is characterized by non-obstructive dilatation of intrahepatic biliary radicals with formation of calculi followed by recurrent episodes of cholangitis. It is a rare congenital malformation and often remains silent, diagnosed accidentally. But if kept unattended, and without any early intervention, it may lead to fatal residual complications. Hence, its early recognition is of utmost importance to prevent recurrent cholangitis, hepatic abscess, liver cirrhosis and cholangiocarcinoma. Hence, we feel that this case must be reported so as to increase awareness among physicians regarding this entity. Case presentation We hereby report a case of 10-year-old boy who reported with complaints of recurrent episodes of fever, breathing difficulty and multiple episodes of epigastric abdominal pain with apparently healthy siblings. His routine investigation, laboratory parameters were within normal limits. Ultrasonography abdomen showed liver with normal echo-texture with varying sized multiple thin walled cysts involving both the lobes, right more than left with saccular dilatation of 2nd and 3rd order intra-hepatic biliary radicals without calcification without any colour flow on Doppler evaluation. The common hepatic and common bile ducts were normal in calibre and lumen. Magnetic resonance imaging abdomen had similar findings and upper GI endoscopy was also normal. He was finally diagnosed to be a case of Caroli’s disease and was managed with broad spectrum antibiotics, ursodeoxycholic acid, multivitamins, and calcium supplements. He made an uneventful recovery thereafter. Parents were counselled about the risk of cholangitis and cholangiocarcinoma and was referred to tertiary care centre for genetic counselling and for future need of liver transplantation. Conclusion Age presentation of Caroli’s disease varies. Majority present during adolescence and early adulthood. This often poses a diagnostic challenge owing its rare entity and silent presentation. A strong index of suspicion and prompt diagnosis is warranted to prevent its fatal residual complications.

The present work comprises the development of Al6061/nano Al2O3 composites with 0 to 4 weight percent in steps of 0.5 wt. % of nano alumina particles by using ultrasonic assisted stir casting. Casted samples were subjected to heat treatment and hot forging. Further forged and heat-treated gear blanks of nano Al2O3 (0 to 3.0 weight %) reinforced nanocomposites were machined to make spur gears for the wear test. The results have shown that nano Al2O3 reinforcement in the Al6061 matrix with heat treatment and forging improves the hardness and compressive strength up to 3.5 wt. %, after that, it starts decreasing because of the agglomeration of nano alumina particles. SEM results reveal grain refinement of the pure alloy after reinforcement. Removal of porosity and voids observed after forging operation. Wear resistance increasing with incorporation of Al2O3 nanoparticles in base alloy, reinforcement wt. %, precipitation hardening and hot forging also improves wear resistance and mechanical properties. These composites have widespread applications in gear, brake discs, crankshaft, clutch plates, pistons, and other components of automobiles and aircraft structures.

Summary: It has been shown that atrial natriuretic peptide (ANP) and its high affinity receptor (NPRA) are involved in the formation of ventricular conduction system (VCS). Inherited genetic variants in fatty acid oxidation (FAO) genes are known to cause conduction abnormalities in newborn children. Although the effect of ANP on energy metabolism in noncardiac cell types is well documented, the role of lipid metabolism in VCS cell differentiation via ANP/NPRA signaling is not known. In this study, histological sections and primary cultures obtained from E11.5 mouse ventricles were analyzed to determine the role of metabolic adaptations in VCS cell fate determination and maturation. Exogenous treatment of E11.5 ventricular cells with ANP revealed a significant increase in lipid droplet accumulation, FAO and higher expression of VCS marker Cx40. Using specific inhibitors, we further identified PPARγ and FAO as critical downstream regulators of ANP-mediated regulation of metabolism and VCS formation.

Alzheimer’s disease (AD) is the most common progressive neurodegenerative disease and is associated with dementia. Presently, various chemical and environmental agents are used to induce in-vitro models of Alzheimer disease to investigate the efficacy of different therapeutic drugs. We screened literature from databases such as PubMed, ScienceDirect, and Google scholar, emphasizing the diverse targeting mechanisms of neuro degeneration explored in in-vitro models. The results revealed studies in which different types of chemicals and environmental agents were used for in-vitro development of Alzheimer-targeting mechanisms of neurodegeneration. Studies using chemically induced in-vitro AD models included in this systematic review will contribute to a deeper understanding of AD. However, none of these models can reproduce all the characteristics of disease progression seen in the majority of Alzheimer’s disease subtypes. Additional modifications would be required to replicate the complex conditions of human AD in an exact manner. In-vitro models of Alzheimer’s disease developed using chemicals and environmental agents are instrumental in providing insights into the disease’s pathophysiology; therefore, chemical-induced in-vitro AD models will continue to play vital role in future AD research. This systematic screening revealed the pivotal role of chemical-induced in-vitro AD models in advancing our understanding of AD pathophysiology and is therefore important to understand the potential of these chemicals in AD pathogenesis.

Abstract Heterostructures of Ga $$_2$$ 2 O $$_3$$ 3 with other materials such as Si, SiC or diamond, are a possible way of addressing the low thermal conductivity and lack of p-type doping of Ga $$_2$$ 2 O $$_3$$ 3 for device applications, as well as of improving device reliability. In this work we study the electrical and thermal properties of Ga $$_2$$ 2 O $$_3$$ 3 –SiO $$_2$$ 2 heterostructures. Here, thin-film gallium oxide with thickness ranging between 8 and 30 nm was deposited onto a silicon substrate with a thermal oxide by means of oxidised liquid gallium layer delamination. The resulting heterostructure is then characterised by means of X-ray photoelectron spectroscopy and transient thermoreflectance. The thin-film gallium oxide valence band offset with respect to the SiO $$_2$$ 2 is measured as 0.1 eV and predicted as $$-2.3$$ - 2.3 eV with respect to diamond. The thin-film’s out-of-plane thermal conductivity is determined to be 3 ±0.5 Wm $$^{-1}$$ - 1 K $$^{-1}$$ - 1 , which is higher than what has been previously measured for other polycrystalline Ga $$_2$$ 2 O $$_3$$ 3 films of comparable thickness.

Traumatic peroneal nerve injury is the usual underlying cause for foot drop. Other causes are like neoplastic, metabolic, or infective are rarely seen. We are reporting an extremely rare case of peroneal neuropathy due to a partly cystic schwannoma of common peroneal nerve leading to hallux drop.

This work is focused on prediction of rupture in the tensile tests of SS304 stainless steel sheet. The tensile test experiments were performed up to rupture and the strain was measured using extensometer and digital image correlation (DIC) system. The experimental results obtained from the tensile tests were utilized for the numerical simulation. In the numerical simulation, four macroscopic rupture criteria were used to predict rupture. The numerical results show the good agreement with the experimental results. Damage factor was calculated using the macroscopic rupture criteria in numerical simulation. The critical values of the damage factor based on the macroscopic criteria were obtained at rupture in simulation. These values are unique for all the mechanical tests and can be utilized for prediction of rupture in numerical simulation of mechanical tests. This study shows that Oh, Brozzo and Ayada criteria have good agreement for strain at rupture whereas Rice-Tracey criterion doesn’t show any agreement within the range of triaxiality from 0 to 0.66.

Abstract Circadian (~24 h) rhythms in physiology and behavior are evolutionarily conserved and found in almost all living organisms. The rhythms are endogenously driven by daily oscillatory activities of so-called “clock genes/proteins”, which are widely distributed throughout the mammalian brain. Mammalian (mechanistic) target of rapamycin (mTOR) signaling is a fundamental intracellular signal transduction cascade that controls important neuronal processes including neurodevelopment, synaptic plasticity, metabolism, and aging. Dysregulation of the mTOR pathway is associated with psychiatric disorders including autism spectrum disorders (ASD) and mood disorders (MD), in which patients often exhibit disrupted daily physiological rhythms and abnormal circadian gene expression in the brain. Recent work has found that the activities of mTOR signaling are temporally controlled by the circadian clock and exhibit robust circadian oscillations in multiple systems. In the meantime, mTOR signaling regulates fundamental properties of the central and peripheral circadian clocks, including period length, entrainment, and synchronization. Whereas the underlying mechanisms remain to be fully elucidated, increasing clinical and preclinical evidence support significant crosstalk between mTOR signaling, the circadian clock, and psychiatric disorders. Here, we review recent progress in understanding the trilateral interactions and propose an “interaction triangle” model between mTOR signaling, the circadian clock, and psychiatric disorders (focusing on ASD and MD).

Introduction: It is known that around one third of Coronavirus Disease-2019 (COVID-19) patients develop severe pulmonary complications and acute respiratory distress syndrome, leading to long-term impairments in Pulmonary Function Test (PFT) and physical performance. Due to deteriorating health status of the COVID-19 survivors after their recovery, rehabilitation is must. Aim: To evaluate the effect of soft tissue manual technique and breathing exercises on PFT, chest expansion and functional status in Post COVID-19 Survivors. Materials and Methods: This quasi-experimental study was carried out in the Department of Cardiorespiratory Physiotherapy, MGM hospital, Aurangabad, Maharashtra, India, from November 2021 to July 2022. Total 54 subjects diagnosed with COVID-19 who required oxygen therapy and had persistent respiratory symptoms for three weeks to six months after the infection, were included. All the subjects received one week of soft tissue manual techniques which included proprioceptive neuromuscular function, muscle energy technique for recruitment of diaphragm, muscles of respiration and the ribcage. Breathing exercises were inculcated at the end of the session to ensure relaxation of the subjects. Subjects were assessed for PFT, chest expansion and post COVID-19 Functional Status Scale (PCFS) pre and post-treatment. Data were analysed through Wilcoxon signed-rank Test. Results: Amongst total 54 subjects included, 10 (18.6%) males and 44 (81.4%) females with mean age of 29.92±11.94. After one week of intervention p-value was 0.0001 for Forced Expiratory Volume (FEV1), FEV1/Forced Vital Capacity (FVC), Peak Expiratory Flow (PEF) with mean values for FEV1 at baseline was 1.91±0.51 and post-treatment was 2.45±0.34, FVC was 2.25±0.50 before the treatment whereas it was 2.73±0.36 post-treatment with p-value of 0.002, FEV1/FVC and PEF was 83.99±12.03 and 4.36±1.78 at baseline whereas, post-treatment it was 87.76±7.29 and 5.88±0.95 respectively. The p-value of 0.0001 was also similar for chest expansion. No statistically significant difference was found in post COVID-19 functional status (p-value=0.013). Conclusion: Positive changes in the ribcage’s activation and integration with its muscles were seen in all of the study variables. Therefore, it is concluded that soft tissue manipulation techniques and breathing exercise improves functional status, thoracic expansion, in post COVID-19 survivors.

Abstract In midst of the recent dengue outbreak in Nepal, in 2022, the risk of co‐infection increases and may lead to fatal outcomes if the diagnosis of multiple infections is delayed. Thus, all available diagnostic approaches must be taken to decrease the burden of illness and lessen mortality.

Macrophages are the preeminent phagocytic cells which control multiple infections. Tuberculosis a leading cause of death in mankind and the causative organism Mycobacterium tuberculosis (MTB) infects and persists in macrophages. Macrophages use reactive oxygen and nitrogen species (ROS/RNS) and autophagy to kill and degrade microbes including MTB. Glucose metabolism regulates the macrophage-mediated antimicrobial mechanisms. Whereas glucose is essential for the growth of cells in immune cells, glucose metabolism and its downsteam metabolic pathways generate key mediators which are essential co-substrates for post-translational modifications of histone proteins, which in turn, epigenetically regulate gene expression. Herein, we describe the role of sirtuins which are NAD+-dependent histone histone/protein deacetylases during the epigenetic regulation of autophagy, the production of ROS/RNS, acetyl-CoA, NAD+, and S-adenosine methionine (SAM), and illustrate the cross-talk between immunometabolism and epigenetics on macrophage activation. We highlight sirtuins as emerging therapeutic targets for modifying immunometabolism to alter macrophage phenotype and antimicrobial function.

Khan et al. use human blood and a macaque model of tuberculosis (TB) to assess whether macrophage heterogeneity contributes to TB immunity. They demonstrate that human macrophages show unique patterns of gene expression that enable differential control of TB after infection.

Background. Nepal faced a major dengue outbreak in 2022. The majority of hospitals and laboratories had limited resources for dengue confirmation and had to rely on rapid dengue diagnostic tests. The purpose of the study is to find the predictive hematological and biochemical parameters in each serological phase of dengue infection (NS1 and IgM) that may assist in dengue diagnosis, severity assessment, and patient management via the use of rapid serological tests. Method. A laboratory-based cross-sectional study was conducted among dengue patients. Rapid antigen (NS1) and serological test (IgM/IgG) was performed to diagnose positive dengue cases. Furthermore, hematological and biochemical investigations were carried out and compared between NS1 and/or IgM-positive participants. A logistic regression analysis was used to identify the validity of the hematological and biochemical characteristics for dengue diagnosis as well as patient management. Receiver-operating characteristic (ROC) curve analysis was used to define the best cut-off, sensitivity, and specificity. Result. Multiple logistic regression showed thrombocytopenia (ORA = 1.000; p = 0.006), leukopenia (ORA = 0.999; p

In railway networks, unexpected disruptions happen for numerous reasons, which in-turn induce delays and cancellations that eventually bring about passenger inconvenience. Thus, the Trains Timetable Rescheduling (TTR) is required, but “how to reschedule the railway timetable” is an imperative issue in real train operations. Though the existing research works concentrated on rescheduling the timetable, the delay time along with reliability, still, are not greatly solved. Thus, this paper proposed a multi-objective and dictionary-based checking for effective rescheduling trains. In this proposed system, first, the constraints are extracted, and the MCMIGP metrics are illustrated. Next, the GKACO optimizes the constraints to make optimal rescheduling. In this algorithm, the multi-objective function is viewed as the fitness function, which is the amalgamation of minimization of a train delay, dwell time, timetable deviation, along with the operational cost and augmentation of service reliability. Subsequent to the generation of rescheduling, the rescheduled timetable's feasibility is checked based on the dictionary-based checking technique. If the rescheduled timetable is feasible, then it is denoted as the optimal timetable. Otherwise, the timetable is again rescheduled by using the same GKACO. Lastly, the experimentation's analysis proves the proposed TTR system's performance.

Tuberculosis is a leading cause of death in mankind due to infectious agents, and Mycobacterium tuberculosis (Mtb) infects and survives in macrophages (MФs). Although MФs are a major niche, myeloid-derived suppressor cells (MDSCs) are an alternative site for pathogen persistence. Both MФs and MDSCs express varying levels of leukocyte immunoglobulin-like receptor B (LILRB), which regulate the myeloid cell suppressive function. Herein, we demonstrate that antagonism of LILRB2 by a monoclonal antibody (mab) induced a switch of human MDSCs towards an M1-macrophage phenotype, increasing the killing of intracellular Mtb. Mab-mediated antagonism of LILRB2 alone and its combination with a pharmacological blockade of SHP1/2 phosphatase increased proinflammatory cytokine responses and phosphorylation of ERK1/2, p38 MAPK, and NF-kB in Mtb-infected MDSCs. LILRB2 antagonism also upregulated anti-mycobacterial iNOS gene expression and an increase in both nitric oxide and reactive oxygen species synthesis. Because genes associated with the anti-mycobacterial function of M1-MФs were enhanced in MDSCs following mab treatment, we propose that LILRB2 antagonism reprograms MDSCs from an immunosuppressive state towards a pro-inflammatory phenotype that kills Mtb. LILRB2 is therefore a novel therapeutic target for eradicating Mtb in MDSCs.

In this article, an Improved Frequency Regulation (IFR) for an interconnected hybrid power system under a deregulated scenario is proposed. The analyzed test system comprises of a thermal power system, biogas plant, and Distributed Generation (DG). The impact of the integration of Renewable Energy Sources (RES) has been examined by considering DG system with solar and wind power generation. In order to make the system more realistic, appropriate non-linearities are incorporated into the thermal and biogas system. Electric Vehicle (EV) is also employed to take care of some portion of uncontracted demand. A maiden hybridized fuzzy-Proportional Integral (FPI)-Linear Active Disturbance Rejection Control (LADRC) is proposed and successfully implemented for IFR. Also, a new Quasi-Opposition-based Artificial Electric Field Algorithm (QO-AEFA) is proposed to acquire the optimal controller gain parameters of the tested system. A pertinent performance analysis is also examined for other employed algorithm in this study, to figure out the eminence of the proposed control algorithm. A comprehensive examination and comparison of the proposed controller with other controllers shows its effectiveness for the proposed test system. In order to ensure the reliability of the proposed controller, sensitivity analysis is also carried out for system parameters that reveal its robust nature. Further, case studies for random load variations and comparison with the works in previous literature also manifest the puissance of the current research work. Moreover, the improved results under random weather conditions illustrate the effectiveness of the proposed IFR under deregulation.

Background: Mass gathering (MG) events are associated with public health risks. During the period January 14 to March 4, 2019, Kumbh Mela in Prayagraj, India was attended by an estimated 120 million visitors. An onsite disease surveillance was established to identify and respond to disease outbreaks. Methods: A health coordination committee was established for planning. Disease surveillance was prioritized and risk assessment was done to identify diseases/conditions based on epidemic potential, severity of illness, and reporting requirement under the International Health Regulations (IHR) of 2005. A daily indicator and event-based disease surveillance was planned. The indicator-based surveillance (IBS) manually and electronically recorded data from patient hospital visits and collected MG area water testing data to assess trends. The event-based surveillance (EBS) helped identify outbreak signals based on pre-identified event triggers from the media, private health facilities, and the food safety department. Epidemic intelligence was used to analyse the data and events to detect signals, verify alerts, and initiate the response. Results: At Kumbh Mela, disease surveillance was established for 22 acute diseases/syndromes. Sixty-five health facilities reported 156 154 illnesses (21% of a total 738 526 hospital encounters). Among the reported illnesses, 95% (n = 148 834) were communicable diseases such as acute respiratory illness (n = 52 504, 5%), acute fever (n = 41 957, 28%), and skin infections (n = 27 094, 18%). The remaining 5% (n = 7300) were non-communicable diseases (injuries n = 6601, 90%; hypothermia n = 224, 3%; burns n = 210, 3%). Water samples tested inadequate for residual chlorine in 20% of samples (102/521). The incident command centre generated 12 early warning signals from IBS and EBS: acute diarrheal disease (n = 8, 66%), vector-borne disease (n = 2, 16%), vaccine-preventable disease (n = 1, 8%), and thermal event (n = 1, 8%). There were two outbreaks (acute gastroenteritis and chickenpox) that were investigated and controlled. Conclusions: This onsite disease surveillance imparted a public health legacy by successfully implementing an epidemic intelligence enabled system for early disease detection and response to monitor public health risks. Acute respiratory illnesses emerged as a leading cause of morbidity among visitors. Future MG events should include disease surveillance as part of planning and augment capacity for acute respiratory illness diagnosis and management.

Abstract In this paper, we establish a new estimate for the degree of approximation of functions f ( x , y ) $f(x,y)$ belonging to the generalized Lipschitz class L i p ( ( ξ 1 , ξ 2 ) ; r ) $Lip ((\xi _{1}, \xi _{2} );r )$ , r ≥ 1 $r \geq 1$ , by double Hausdorff matrix summability means of double Fourier series. We also deduce the degree of approximation of functions from L i p ( ( α , β ) ; r ) $Lip ((\alpha ,\beta );r )$ and L i p ( α , β ) $Lip(\alpha ,\beta )$ in the form of corollary. We establish some auxiliary results on trigonometric approximation for almost Euler means and ( C , γ , δ ) $(C, \gamma , \delta )$ means.

GM-CSF is an important cytokine that regulates the proliferation of monocytes/macrophages and its various functions during health and disease. Although growing evidences support the notion that GM-CSF could play a major role in immunity against tuberculosis (TB) infection, the mechanism of GM-CSF mediated protective effect against TB remains largely unknown. Here in this study we examined the secreted levels of GM-CSF by human macrophages from different donors along with the GM-CSF dependent cellular processes that are critical for control of M. tuberculosis infection. While macrophage of different donors varied in their ability to produce GM-CSF, a significant correlation was observed between secreted levels of GM-CSF, survial of macrophages and intra-macrophage control of Mycobacterium tuberculosis bacilli. GM-CSF levels secreted by macrophages negatively correlated with the intra-macrophage M. tuberculosis burden, survival of infected host macrophages positively correlated with their GM-CSF levels. GM-CSF-dependent prolonged survival of human macrophages also correlated with significantly decreased bacterial burden and increased expression of self-renewal/cell-survival associated genes such as BCL-2 and HSP27. Antibody-mediated depletion of GM-CSF in macrophages resulted in induction of significantly elevated levels of apoptotic/necrotic cell death and a simultaneous decrease in autophagic flux. Additionally, protective macrophages against M. tuberculosis that produced more GM-CSF, induced a stronger granulomatous response and produced significantly increased levels of IL-1β, IL-12 and IL-10 and decreased levels of TNF-α and IL-6. In parallel, macrophages isolated from the peripheral blood of active TB patients exhibited reduced capacity to control the intracellular growth of M. tuberculosis and produced significantly lower levels of GM-CSF. Remarkably, as compared to healthy controls, macrophages of active TB patients exhibited significantly altered metabolic state correlating with their GM-CSF secretion levels. Altogether, these results suggest that relative levels of GM-CSF produced by human macrophages plays a critical role in preventing cell death and maintaining a protective differentiation and metabolic state of the host cell against M. tuberculosis infection.

BackgroundAlthough advanced analytical techniques falling under the umbrella heading of artificial intelligence (AI) may improve health care, the use of AI in health raises safety and ethical concerns. There are currently no internationally recognized governance mechanisms (policies, ethical standards, evaluation, and regulation) for developing and using AI technologies in health care. A lack of international consensus creates technical and social barriers to the use of health AI while potentially hampering market competition. ObjectiveThe aim of this study is to review current health data and AI governance mechanisms being developed or used by Global Digital Health Partnership (GDHP) member countries that commissioned this research, identify commonalities and gaps in approaches, identify examples of best practices, and understand the rationale for policies. MethodsData were collected through a scoping review of academic literature and a thematic analysis of policy documents published by selected GDHP member countries. The findings from this data collection and the literature were used to inform semistructured interviews with key senior policy makers from GDHP member countries exploring their countries’ experience of AI-driven technologies in health care and associated governance and inform a focus group with professionals working in international health and technology to discuss the themes and proposed policy recommendations. Policy recommendations were developed based on the aggregated research findings. ResultsAs this is an empirical research paper, we primarily focused on reporting the results of the interviews and the focus group. Semistructured interviews (n=10) and a focus group (n=6) revealed 4 core areas for international collaborations: leadership and oversight, a whole systems approach covering the entire AI pipeline from data collection to model deployment and use, standards and regulatory processes, and engagement with stakeholders and the public. There was a broad range of maturity in health AI activity among the participants, with varying data infrastructure, application of standards across the AI life cycle, and strategic approaches to both development and deployment. A demand for further consistency at the international level and policies was identified to support a robust innovation pipeline. In total, 13 policy recommendations were developed to support GDHP member countries in overcoming core AI governance barriers and establishing common ground for international collaboration. ConclusionsAI-driven technology research and development for health care outpaces the creation of supporting AI governance globally. International collaboration and coordination on AI governance for health care is needed to ensure coherent solutions and allow countries to support and benefit from each other’s work. International bodies and initiatives have a leading role to play in the international conversation, including the production of tools and sharing of practical approaches to the use of AI-driven technologies for health care.

Purpose: The technology of 3D printing (3DP) exists for quite some time, but it is still not utilized to its full potential in the field of orthopaedics and traumatology, such as underestimating its worth in virtual preoperative planning (VPP) and designing various models, templates, and jigs. It can be a significant tool in the reduction of surgical morbidity and better surgical outcome avoiding various associated complications. Methods: An observational study was done including 91 cases of complex trauma presented in our institution requiring operative fixation. Virtual preoperative planning and 3DP were used in the management of these fractures. Surgeons managing these cases were given a set of questionnaire and responses were recorded and assessed as a quantitative data. Results: In all the 91 cases, where VPP and 3DP were used, the surgeons were satisfied with the outcome which they got intraoperatively and postoperatively. Surgical time was reduced, with a better outcome. Three dimensional models of complex fracture were helpful in understanding the anatomy and sketching out the plans for optimum reduction and fixation. The average score of the questionnaire was 4.5, out of a maximum of 6, suggesting a positive role of 3DP in orthopaedics. Conclusion: 3DP is useful in complex trauma management by accurate reduction and placement of implants, reduction of surgical time and with a better outcome. Although there is an initial learning curve to understand and execute the VPP and 3DP, these become easier with practice and experience. Keywords: Three-dimensional printing, Bone fractures, Fracture dislocation, X-ray computed tomography

While most fungi have the ability to reproduce sexually, multiple independent lineages have lost meiosis and developed parasexual cycles in its place. Emergence of parasexual cycles is particularly prominent in medically relevant fungi from the CUG paraphyletic group of Candida species. Since the discovery of parasex in C. albicans roughly two decades ago, it has served as the model for Candida species. Importantly, parasex in C. albicans retains hallmarks of meiosis including genetic recombination and chromosome segregation, making it a potential driver of genetic diversity. Furthermore, key meiotic genes play similar roles in C. albicans parasex and highlights parallels between these processes. Yet, the evolutionary role of parasex in Candida adaptation and the extent of resulting genotypic and phenotypic diversity remain as key knowledge gaps in this facultative reproductive program. Here, we present our current understanding of parasex, the mechanisms governing its regulation, and its relevance to Candida biology.

The digital image correlation (DIC) method is widely used in deformation measurements as it has the advantages of being a non-contact, high precision method that provides full field measurements, and requires simple experimental equipment. Traditionally, the grayscale speckle patterns captured by a monochromatic camera are used in the DIC method. With the growing development of consumer color cameras, there is great potential for developing color information in the DIC method. This paper proposes a displacement- and stress–strain-invariant DIC deformation measurement method based on the integer-pixel matching approach for speckle patterns during a tension test. For the integer-pixel matching stage, the load and displacement and stress–strain-invariant histories feature is used to estimate the initial value of the deformation parameters. In addition, this paper proposes a reverse retrieve strategy, instead of a forward search, to reduce the search time. Experiments show that the proposed DIC deformation measurement approach is not only capable of displacement invariance measurement, with robustness and high efficiency, but also that the average accuracy of the stress–strain result can reach 0.1%.

Background: The combination of time-lapse imaging and artificial intelligence (AI) offers novel potential for embryo assessment by allowing a vast quantity of image data to be analysed via machine learning. Most algorithms developed to date have used neural networks which are uninterpretable (“black-box”) and cannot be understood by doctors, embryologists and patients, which raises ethical and epistemic concerns for embryo selection in a clinical setting. Aim: This study aims to discuss ethical and epistemic considerations surrounding clinical implementation of “black-box” based embryo selection algorithms. Method: A scoping review was performed by evaluating publications reporting “black-box” embryo selection algorithms. Potential ethical and epistemic issues were identified and discussed. Results: No randomised controlled trial was identified in the literature evaluating clinical effectiveness of “black-box” embryo selection algorithms. Several ethical and epistemic concerns were identified. Potential ethical issues included (1) lack of randomised controlled trials, (2) impact on the shared decision-making process in embryo selection between clinicians and patients, (3) misrepresentation of patient values due to hidden reasoning process in “black-box” algorithms, (4) social impacts if algorithm subsequently proven to be biased, and (5) unclear responsibility when algorithm makes obviously poor choices of embryos. Potential epistemic issues included (1) information asymmetries between algorithm developers and doctors, embryologists and patients; (2) risk of biased prediction due to data selection during training process; (3) inability to troubleshoot for data training purposes due to limited interpretability; and (4) the economics of buying into commercial proprietary add-ons. Conclusion: There are significant epistemic and ethical concerns with “black-box” embryo selection. No published randomised controlled trial is available to support its clinical implementation. AI embryo selection in general, however, is potentially useful but must be done carefully and transparently. Interpretable AI would be preferred alternative in causing fewer issues.

In this paper, theoretical analysis of receiver tube misalignment, the design of secondary reflector and experimental analysis of a small-sized solar parabolic trough collector (PTC) with and without secondary reflectors are represented. Experimental analysis of PTC has been done using a parabolic secondary reflector (PSR) and triangular secondary reflector (TSR) and compared with PTC without secondary reflector (WSR). The maximum outlet temperature of heat transfer fluid is observed as 49.2°C, 47.3°C and 44.2°C in the case of PSR, TSR and WSR conditions, respectively. The maximum thermal efficiency of 24.3%, 22.5% and 17.8% is observed in the case of PSR, TSR and WSR conditions, respectively. The circumferential temperature difference on the outer surface of the receiver tube is obtained more uniform in the case of PSR and TSR than WSR condition. This indicates that the use of a secondary reflector can improve the performance of a solar PTC system.

Abstract Background Osteoarthritis (OA) is a common cause of musculoskeletal disability among elders and is characterized by late-onset degeneration of articular cartilage. OA affects various joints, commonly hand, knee, and hip, with clinical features that are unique to each joint. This study was initiated to identify and evaluate the role of the ASPN and COMP genes in the development of knee OA. Methods A case–control study was carried out involving 500 cases with knee OA (diagnosed by the American College of Rheumatology) and an equal number of healthy controls. Blood was drawn for genomic DNA isolation. PCR-RFLP and TaqMan assay methods were used to identify the SNPs. mRNA and protein expression of genes were carried out in peripheral blood lymphocytes (PBLs) by RT-PCR and Western immunoblotting. The data obtained were analyzed for the statistical significance between control and case groups. Results The variant genotype of ASPN and COMP genes was found to be present at a relatively higher frequency in cases than controls. RT-PCR and immunochemical studies revealed increased mRNA and protein expression of such gene in PBLs isolated from cases of knee OA as compared to healthy control. Conclusion The allelic alteration in ASPN and COMP genes in knee OA cases points to the role of these genes in the development of knee OA. Further, increased mRNA and protein expression of ASPN and COMP in peripheral blood samples of patients with the disease suggest that expression profile of candidate gene could be used as a biomarker for predicting the development and progression of knee OA.

Background: The host genetic factors play important role in determining the outcome of visceral leishmaniasis (VL). Macrophage migration inhibitory factor (MIF) is an important host cytokine, which is a key regulator of innate immune system. Genetic variants in MIF gene have been found to be associated with several inflammatory and infectious diseases. Role of MIF is well documented in leishmaniasis diseases, including Indian visceral leishmaniasis, where elevated level of serum MIF has been associated with VL phenotypes. However, there was no genetic study to correlate MIF variants in VL, therefore, we aimed to study the possible association of three reported MIF gene variants −794 CATT, −173G > C and non-coding RNA gene LOC284889 in Indian VL phenotype. Methods: Study subjects comprised of 214 VL patients along with ethnically and demographically matched 220 controls from VL endemic regions of Bihar state in India. Results: We found no significant difference between cases and controls in allelic, genotypic and haplotype frequency of the markers analysed [-794 CATT repeats (χ2 = 0.86; p = 0.35; OR = 0.85; 95% CI = 0.61–1.19); −173 G > C polymorphism (χ2 = 1.11; p = 0.29; OR = 0.83; 95% CI = 0.59–1.16); and LOC284889 (χ2 = 0.78; p = 0.37; OR = 0.86; 95% CI = 0.61–1.20)]. Conclusion: Since we did not find any significant differences between case and control groups, we conclude that sequencing of complete MIF gene and extensive study on innate and adaptive immunity genes may help in identifying genetic variations that are associated with VL susceptibility/resistance among Indians. Keywords: Visceral leishmaniasis (VL), Macrophage Migration Inhibitory Factor (MIF), Leishmania major, Leishmania donovani, Genetic polymorphism, Indian population

Engineering the grain boundary size of chemical vapor deposited monolayer graphene can reversibly tune its electronic properties. Here, the authors report a thermodynamic correlation for 100 μm long channels in graphene by reversibly changing its electronic mobilities from 1,000 to 20,000 cm2 V−1 s−1.

Abstract Introduction Nowadays, the most significant challenges in the stock market is to predict the stock prices. The stock price data represents a financial time series data which becomes more difficult to predict due to its characteristics and dynamic nature. Case description Support Vector Machines (SVM) and Artificial Neural Networks (ANN) are widely used for prediction of stock prices and its movements. Every algorithm has its way of learning patterns and then predicting. Artificial Neural Network (ANN) is a popular method which also incorporate technical analysis for making predictions in financial markets. Discussion and evaluation Most common techniques used in the forecasting of financial time series are Support Vector Machine (SVM), Support Vector Regression (SVR) and Back Propagation Neural Network (BPNN). In this article, we use neural networks based on three different learning algorithms, i.e., Levenberg-Marquardt, Scaled Conjugate Gradient and Bayesian Regularization for stock market prediction based on tick data as well as 15-min data of an Indian company and their results compared. Conclusion All three algorithms provide an accuracy of 99.9% using tick data. The accuracy over 15-min dataset drops to 96.2%, 97.0% and 98.9% for LM, SCG and Bayesian Regularization respectively which is significantly poor in comparison with that of results obtained using tick data.

A biological is a substance which either comprises, contains, or is derived from human cells or human tissues. The use of biological products is associated with the risk of infection transmission, allergic reactions, and other adverse events (AEs). The science and activities relating to the detection, assessment, understanding, and prevention of AEs or any other problems related to biological products (blood, cells, tissues, organs, and vaccine in international perspective) are termed as biovigilance. With more and more biologicals being marketed and the rapid revolutionary changes in transplant-related services, the importance of biovigilance is increasing day by day. Although specific types of vigilance systems (pharmacovigilance and materiovigilance) exist, activities related to “biovigilance” are still in an infancy stage. Many developed countries such as the USA, Europe, and Australia have implemented nationwide biovigilance programs. In India, the National Institute of Biologicals, in collaboration with the Indian Pharmacopoeia Commission, has launched the Biovigilance Programme of India. In this article, the biovigilance systems of different countries across the globe have been reviewed along with highlights of the current biovigilance needs.

Background: India recently launched Ayushman Bharat – National Health Protection Mission – an upgraded version of Rashtriya Swasthya Bima Yojna (RSBY), which is projected as world's largest public insurance scheme by numbers. The new scheme can certainly draw learning from the former (RSBY) to ensure better reach and success. RSBY has been extensively analyzed for supply-side barriers but sparsely for demand and supply-side barriers simultaneously. Objectives: Through this study, authors intend to determine causality as well as configurations (pathways) of demand and supply barriers that make beneficiary vulnerable even under the scheme. The study explores the interaction of barriers that lead to patient dis/satisfaction, overcharging for a medical procedure and high disease severity among beneficiaries. Methods: The study uses RSBY insurance claim records from 2013 to 2015 backed up by posthospitalization survey of the state of Chhattisgarh, India. It employs a fuzzy set qualitative comparative analysis to determine causality and configuration (path-way) of parameters leading to the outcome. Results: Provision of medicine emerges as a necessary condition for patient satisfaction. Waiting time did not appear as a necessary parameter of satisfaction. Overcharging the cashless card in case of minor surgical procedures is observed irrespective of beneficiaries' education and occupation status. Urban male and rural female appear to bear high disease severity. Conclusions: Results have implication for policymakers and implementors to recognize the segment that remains vulnerable under the scheme and gain insights on the parameters of patient satisfaction.

Congenital heart defects (CHD) are the most common type of birth defects. Several human case studies and genetically altered animal models have identified abnormalities in the development of ventricular conduction system (VCS) in the heart. While cell-based therapies hold promise for treating CHDs, translational efforts are limited by the lack of suitable in vitro models for feasibility and safety studies. A better understanding of cell differentiation pathways can lead to development of cell-based therapies for individuals living with CHD/VCS disorders. Here, we describe a new and reproducible 3-D cell culture method for studying cardiac cell lineage differentiation in vitro. We used primary ventricular cells isolated from embryonic day 11.5 (E11.5) mouse embryos, which can differentiate into multiple cardiac cell types including VCS cells. We compared 3-D cultures with three types of basement membrane extracts (BME) for their abilities to support E11.5 ventricular cell differentiation. In addition, the effects of atrial natriuretic peptide (ANP) and an inhibitor for its high affinity receptor were tested on cell differentiation in 3-D cultures. Following the cell culture, protocols for immunofluorescence imaging, cell extraction and protein isolation from the 3-D culture matrix and in-cell western methods are described. Further, these approaches can be used to study the effects of various ligands and genetic interventions on VCS cell development. We propose that these methodologies may also be extended for differentiation studies using other sources of stem cells such as induced pluripotent stem cells.

Approximately 50–80% of children with autism spectrum disorders (ASDs) exhibit sleep problems, but the contribution of circadian clock dysfunction to the development of ASDs remains largely unknown. The essential clock gene Bmal1 (Arntl or Mop3) has been associated with human sociability, and its missense mutation is found in ASD. Our recent study found that Bmal1-null mice exhibit a variety of autism-like phenotypes. Here, we further investigated whether an incomplete loss of Bmal1 function could cause significant autism-like behavioral changes in mice. Our results demonstrated that heterozygous Bmal1 deletion (Bmal1+/−) reduced the Bmal1 protein levels by ~50–75%. Reduced Bmal1 expression led to decreased levels of clock proteins, including Per1, Per2, Cry 1, and Clock but increased mTOR activities in the brain. Accordingly, Bmal1+/− mice exhibited aberrant ultrasonic vocalizations during maternal separation, deficits in sociability and social novelty, excessive repetitive behaviors, impairments in motor coordination, as well as increased anxiety-like behavior. The novel object recognition memory remained intact. Together, these results demonstrate that haploinsufficiency of Bmal1 can cause autism-like behavioral changes in mice, akin to those identified in Bmal1-null mice. This study provides further experimental evidence supporting a potential role for disrupted clock gene expression in the development of ASD.

Background Tumor endothelial marker 1 (TEM1) is a protein expressed in the tumor-associated endothelium and/or stroma of various types of cancer. We previously demonstrated that immunization with a plasmid-DNA vaccine targeting TEM1 reduced tumor progression in three murine cancer models. Radiation therapy (RT) is an established cancer modality used in more than 50% of patients with solid tumors. RT can induce tumor-associated vasculature injury, triggering immunogenic cell death and inhibition of the irradiated tumor and distant non-irradiated tumor growth (abscopal effect). Combination treatment of RT with TEM1 immunotherapy may complement and augment established immune checkpoint blockade.Methods Mice bearing bilateral subcutaneous CT26 colorectal or TC1 lung tumors were treated with a novel heterologous TEM1-based vaccine, in combination with RT, and anti-programmed death-ligand 1 (PD-L1) antibody or combinations of these therapies, tumor growth of irradiated and abscopal tumors was subsequently assessed. Analysis of tumor blood perfusion was evaluated by CD31 staining and Doppler ultrasound imaging. Immunophenotyping of peripheral and tumor-infiltrating immune cells as well as functional analysis was analyzed by flow cytometry, ELISpot assay and adoptive cell transfer (ACT) experiments.Results We demonstrate that addition of RT to heterologous TEM1 vaccination reduces progression of CT26 and TC1 irradiated and abscopal distant tumors as compared with either single treatment. Mechanistically, RT increased major histocompatibility complex class I molecule (MHCI) expression on endothelial cells and improved immune recognition of the endothelium by anti-TEM1 T cells with subsequent severe vascular damage as measured by reduced microvascular density and tumor blood perfusion. Heterologous TEM1 vaccine and RT combination therapy boosted tumor-associated antigen (TAA) cross-priming (ie, anti-gp70) and augmented programmed cell death protein 1 (PD-1)/PD-L1 signaling within CT26 tumor. Blocking the PD-1/PD-L1 axis in combination with dual therapy further increased the antitumor effect and gp70-specific immune responses. ACT experiments show that anti-gp70 T cells are required for the antitumor effects of the combination therapy.Conclusion Our findings describe novel cooperative mechanisms between heterologous TEM1 vaccination and RT, highlighting the pivotal role that TAA cross-priming plays for an effective antitumor strategy. Furthermore, we provide rationale for using heterologous TEM1 vaccination and RT as an add-on to immune checkpoint blockade as triple combination therapy into early-phase clinical trials.

Tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB) kills about 1.5 million people each year and the widely used Bacille Calmette-Guérin (BCG) vaccine provides a partial protection against TB in children and adults. Because BCG vaccine evades lysosomal fusion in antigen presenting cells (APCs), leading to an inefficient production of peptides and antigen presentation required to activate CD4 T cells, we sought to boost its efficacy using novel agonists of RIG-I and NOD2 as adjuvants. We recently reported that the dinucleotide SB 9200 (Inarigivir) derived from our small molecule nucleic acid hybrid (SMNH)® platform, activated RIG-I and NOD2 receptors and exhibited a broad-spectrum antiviral activity against hepatitis B and C, Norovirus, RSV, influenza and parainfluenza. Inarigivir increased the ability of BCG-infected mouse APCs to secrete elevated levels of IL-12, TNF-α, and IFN-β, and Caspase-1 dependent IL-1β cytokine. Inarigivir also increased the ability of macrophages to kill MTB in a Caspase-1-, and autophagy-dependent manner. Furthermore, Inarigivir led to a Capsase-1 and NOD2- dependent increase in the ability of BCG-infected APCs to present an Ag85B-p25 epitope to CD4 T cells in vitro. Consistent with an increase in immunogenicity of adjuvant treated APCs, the Inarigivir-BCG vaccine combination induced robust protection against tuberculosis in a mouse model of MTB infection, decreasing the lung burden of MTB by 1-log10 more than that afforded by BCG vaccine alone. The Inarigivir-BCG combination was also more efficacious than a muramyl-dipeptide-BCG vaccine combination against tuberculosis in mice, generating better memory T cell responses supporting its novel adjuvant potential for the BCG vaccine.

Although classically associated with myelopoiesis, granulocyte-macrophage colony-stimulating factor (GM-CSF) is being increasingly recognized for its potential role in innate resistance against tuberculosis (TB). While the GM-CSF is produced by a variety of host cells, including conventional and non-conventional T cells, macrophages, alveolar epithelial cells, the cell population that promotes GM-CSF mediated innate protection against Mycobacterium tuberculosis infection remains unclear. This is because studies related to the role of GM-CSF so far have been carried out in murine models of experimental TB, which is inherently susceptible to TB as compared to humans, who exhibit a resolution of infection in majority of cases. We found a significantly higher amount of GM-CSF production by human macrophages, compared to mouse macrophages, after infection with M. tuberculosis in vitro. The higher levels of GM-CSF produced by human macrophages were also directly correlated with their increased life span and ability to control M. tuberculosis infection. Other evidence from recent studies also support that M. tuberculosis infected human macrophages display heterogeneity in their antibacterial capacity, and cells with increased expression of genes involved in GM-CSF signaling pathway can control intracellular M. tuberculosis growth more efficiently. Collectively, these emerging evidence indicate that GM-CSF produced by lung resident macrophages could be vital for the host resistance against M. tuberculosis infection in humans. Identification of GM-CSF dependent key cellular pathways/processes that mediate intracellular host defense can lay the groundwork for the development of novel host directed therapies against TB as well as other intracellular infections.

Background: The genus Mycobacterium has an ability to persist in hostile environments for years before its reactivation in favorable conditions. The major bottleneck in decades of mycobacterial research is a poor understanding of molecular mechanism which assists bacteria to attain dormancy and reactivation later. Methods: In this study, hydroxyl radical was quantified in aerobically growing mycobacterial cells using 2-deoxy-D-ribose assay. Furthermore, extraneous addition of hydroxyl radical in Wayne's dormancy model induced reactivation of dormant cells. The whole proteome of all three samples, namely, aerobic, Wayne dormancy, and hydroxyl radical reactivated cells was isolated, trypsin digested, and peptides are quantitatively characterized by liquid chromatography-elevated energy mass spectrometry. Results: This study reports the generation of highly reactive hydroxyl radical by Mycobacterium smegmatis during aerobic respiration. The hydroxyl radical levels can be managed by modulation of iron ions in the cellular pool. Proteomic characterization of resuscitation process highlights the increase in the level of ATPases, iron acquisition, redox response, changes in cell membrane dynamics, and cell wall hydrophobicity which is coupled with restoration of protein synthesis, carbohydrate, and lipid metabolism. In addition, two uncharacterized universal stress proteins MSMEG5245 and MSMEG3950 were uniquely identified in reactivated cells. Conclusion: Overall, the 1-hydroxypyridine-2-thione-induced reactivation process is a controlled and stepwise exit from dormancy.

The growing demand for composite materials with improved properties is attracting a lot of attention from industries such as automotive, aerospace, military, aviation, and other manufacturing. Aluminium metal matrix composites (AMMCs), with various reinforcements such as continuous/discontinuous fibers, whiskers, and particulates, have captured the attention due to their superior tribological, mechanical, and microstructural characteristics as compared to bare Al alloy. AMMCs have undergone extensive research and development with different reinforcements in order to obtain the materials with the desired characteristics. In this paper, we present a review on AMMCs produced through stir casting routes. This review focuses on the following aspects: (i) different reinforcing materials in AMMCs; (ii) microstructural study of reinforced metal matrix composites (MMCs) through stir casting. Both reinforcing micro- and nanoparticles are focused. Micro- and nanoreinforced AMMCs have the attractive properties of combination such asthe low-weight-to-high-strength rati and, low density; (iii) various tribological and mechanical properties with the consideration of different input parameters; (iv) outlook and perspective.

ABSTRACT BACKGROUND: Succinylcholine is commonly used to achieve profound neuromuscular blockade of rapid onset and short duration. OBJECTIVE: The present study compared the efficacy of pregabalin for prevention of succinylcholine-induced fasciculation and myalgia. DESIGN: Prospective, randomized, placebo controlled, double blinded study. MATERIALS AND METHODS: Patients of both genders undergoing elective spine surgery were randomly assigned to two groups. Patients in Group P (pregabalin group) received 150 mg of pregabalin orally 1 h prior to induction of anesthesia with sips of water and patients in Group C (control group) received placebo. Anesthesia was induced with fentanyl 1.5 mcg/kg, propofol 1.5-2.0 mg/kg followed by succinylcholine 1.5 mg/kg. The intensity of fasciculations was assessed by an observer blinded to the group allotment of the patient on a 4-point scale. A blinded observer recorded postoperative myalgia grade after 24 h of surgery. Patients were provided patient-controlled analgesia with fentanyl for postoperative pain relief. RESULTS: Demographic data of both groups were comparable (p > 0.05). The incidence of muscle fasciculation's was not significant between two groups (p = 0.707), while more patients in group C had moderate to severe fasciculation's compared to group P (p = 0.028). The incidence and severity of myalgia were significantly lower in group P (p < 0.05). CONCLUSION: Pregabalin 150 mg prevents succinylcholine-induced fasciculations and myalgia and also decreases the fentanyl consumption in elective sine surgery.

Purpose: Dexmedetomidine and magnesium sulfate have been used in anesthesia as adjuvant to provide hemodynamic stability and anesthetic agents sparing effect. We compared these effects of dexmedetomidine and magnesium sulfate in spine surgeries. Methods: Ninety patients were randomly assigned to three groups. Group D received dexmedetomidine loading dose 1 µg/kg over a period of 15 minutes and maintenance 0.5 µg/kg/h throughout the surgery. Group M received magnesium sulfate loading dose 50 mg/kg over a period of 15 minutes and maintenance 15 mg/kg/h throughout the surgery. Group C received same volume of normal saline. Heart rate (HR) and blood pressure values were recorded at various intervals. The induction and maintenance doses of anesthetics and recovery parameters were also recorded. Results: Heart rate in group D and group M were significantly decreased (p