Tuft-Cell-Derived Leukotrienes Drive Rapid Anti-helminth Immunity in the Small Intestine but Are Dispensable for Anti-protist Immunity.

Helminths, allergens, and certain protists induce type 2 immune responses, but the underlying mechanisms of immune activation remain poorly understood. In the small intestine, chemosensing by epithelial tuft cells results in the activation of group 2 innate lymphoid cells (ILC2s), which subsequently drive increased tuft cell frequency. This feedforward circuit is essential for intestinal remodeling and helminth clearance. ILC2 activation requires tuft-cell-derived interleukin-25 (IL-25), but whether additional signals regulate the circuit is unclear. Here, we show that tuft cells secrete cysteinyl leukotrienes (cysLTs) to rapidly activate type 2 immunity following chemosensing of helminth infection. CysLTs cooperate with IL-25 to activate ILC2s, and tuft-cell-specific ablation of leukotriene synthesis attenuates type 2 immunity and delays helminth clearance. Conversely, cysLTs are dispensable for the tuft cell response induced by intestinal protists. Our findings identify an additional tuft cell effector function and suggest context-specific regulation of tuft-ILC2 circuits within the small intestine.

Mechanisms by which small molecules of diverse chemotypes arrest Sec14 lipid transfer activity.

Phosphatidylinositol (PtdIns) transfer proteins (PITPs) enhance the activities of PtdIns 4-OH kinases that generate signaling pools of PtdIns-4-phosphate. In that capacity, PITPs serve as key regulators of lipid signaling in eukaryotic cells. Although the PITP phospholipid exchange cycle is the engine that stimulates PtdIns 4-OH kinase activities, the underlying mechanism is not understood. Herein, we apply an integrative structural biology approach to investigate interactions of the yeast PITP Sec14 with small-molecule inhibitors (SMIs) of its phospholipid exchange cycle. Using a combination of X-ray crystallography, solution NMR spectroscopy, and atomistic MD simulations, we dissect how SMIs compete with native Sec14 phospholipid ligands and arrest phospholipid exchange. Moreover, as Sec14 PITPs represent new targets for the development of next-generation antifungal drugs, the structures of Sec14 bound to SMIs of diverse chemotypes reported in this study will provide critical information required for future structure-based design of next-generation lead compounds directed against Sec14 PITPs of virulent fungi.

Antibodies toward Na+,HCO3--cotransporter NBCn1/SLC4A7 block net acid extrusion and cause pH-dependent growth inhibition and apoptosis in breast cancer.

BACKGROUND: Na+,HCO3--cotransporter NBCn1/Slc4a7 accelerates murine breast carcinogenesis. Lack of specific pharmacological tools previously restricted therapeutic targeting of NBCn1 and identification of NBCn1-dependent functions in human breast cancer. METHODS: We develop extracellularly-targeted anti-NBCn1 antibodies, screen for functional activity on cells, and evaluate (a) mechanisms of intracellular pH regulation in human primary breast carcinomas, (b) proliferation, cell death, and tumor growth consequences of NBCn1 in triple-negative breast cancer, and (c) association of NBCn1-mediated Na+,HCO3--cotransport with human breast cancer metastasis. RESULTS: We identify high-affinity (KD ≈ 0.14 nM) anti-NBCn1 antibodies that block human NBCn1-mediated Na+,HCO3--cotransport in cells, without cross-reactivity towards human NBCe1 or murine NBCn1. These anti-NBCn1 antibodies abolish Na+,HCO3--cotransport activity in freshly isolated primary organoids from human breast carcinomas and lower net acid extrusion effectively in primary breast cancer tissue from patients with macrometastases in axillary lymph nodes. Inhibitory anti-NBCn1 antibodies decelerate tumor growth in vivo by ~50% in a patient-derived xenograft model of triple-negative breast cancer and pH-dependently reduce colony formation, cause G2/M-phase cell cycle accumulation, and increase apoptosis of metastatic triple-negative breast cancer cells in vitro. CONCLUSIONS: Inhibitory anti-NBCn1 antibodies block net acid extrusion in human breast cancer tissue, particularly from patients with disseminated disease, and pH-dependently limit triple-negative breast cancer growth.

RbPbI3 Seed Embedding in PbI2 Substrate Tailors the Facet Orientation and Crystallization Kinetics of Perovskites.

High power conversion efficiencies (PCEs) in perovskite solar cells (PSCs) have always been awe-inspiring, but perovskite films scalability is an exacting precondition for PSCs commercial deployment, generally unachievable through the antisolvent technique. On the contrary, in the two-step sequential method, the perovskite's uncontrolled crystallization and unnecessary PbI2 residue impede the device's performance. These two issues motivated to empower the PbI2 substrate with orthorhombic RbPbI3 crystal seeds, which act as grown nuclei and develop orientated perovskites lattice stacks, improving the perovskite films morphologically and reducing the PbI2 content in eventual perovskite films. Thence, achieving a PCE of 24.17% with suppressed voltage losses and an impressive life span of 1140 h in the open air.

Recent advances in isatin-based chemosensors: A comprehensive review.

A comprehensive review presents an illuminating exploration of the vast potential of isatin, an easily accessible organic compound. This review is a valuable resource, offering a concise yet comprehensive account of the recent breakthroughs in isatin applications in medicinal chemistry, fluorescence sensing, and organic synthesis. Moreover, it dives into the exciting advancements in isatin-based chemosensors, demonstrating their remarkable ability to detect and recognize diverse cations and anions with exceptional precision. Researchers and scientists in the fields of sensing and organic chemistry will find this review indispensable for sparking innovation and developing cutting-edge technologies with significant real-world impact.

Nexuses Between the Chemical Design and Performance of Small Molecule Dopant-Free Hole Transporting Materials in Perovskite Solar Cells.

Perovskite solar cells (PSCs) have grabbed much attention of researchers owing to their quick rise in power conversion efficiency (PCE). However, long-term stability remains a hurdle in commercialization, partly due to the inclusion of necessary hygroscopic dopants in hole transporting materials, enhancing the complexity and total cost. Generally, the efforts in designing dopant-free hole transporting materials (HTMs) are devoted toward small molecule and polymeric HTMs, where small molecule based HTMs (SM-HTMs) are dominant due to their reproducibility, facile synthesis, and low cost. Still, the state-of-art dopant-free SM-HTM has not been achieved yet, mainly because of the knowledge gap between device engineering and molecular designs. From a molecular engineering perspective, this article reviews dopant-free SM-HTMs for PSCs, outlining analyses of chemical structures with promising properties toward achieving effective, low-cost, and scalable materials for devices with higher stability. Finally, an outlook of dopant-free SM-HTMs toward commercial application and insight into the development of long-term stability PSCs devices is provided.

Kernel based quantum machine learning at record rate: Many-body distribution functionals as compact representations.

The feature vector mapping used to represent chemical systems is a key factor governing the superior data efficiency of kernel based quantum machine learning (QML) models applicable throughout chemical compound space. Unfortunately, the most accurate representations require a high dimensional feature mapping, thereby imposing a considerable computational burden on model training and use. We introduce compact yet accurate, linear scaling QML representations based on atomic Gaussian many-body distribution functionals (MBDF) and their derivatives. Weighted density functions of MBDF values are used as global representations that are constant in size, i.e., invariant with respect to the number of atoms. We report predictive performance and training data efficiency that is competitive with state-of-the-art for two diverse datasets of organic molecules, QM9 and QMugs. Generalization capability has been investigated for atomization energies, highest occupied molecular orbital-lowest unoccupied molecular orbital eigenvalues and gap, internal energies at 0 K, zero point vibrational energies, dipole moment norm, static isotropic polarizability, and heat capacity as encoded in QM9. MBDF based QM9 performance lowers the optimal Pareto front spanned between sampling and training cost to compute node minutes, effectively sampling chemical compound space with chemical accuracy at a sampling rate of ∼48 molecules per core second.

A Functional Biological Molecule Restores the PbI2 Residue-Induced Defects in Two-Step Fabricated Perovskites.

Coating the perovskite layer via a two-step method is an adaptable solution for industries compared to the anti-solvent process. But what about the impact of unreacted PbI2? Usually, it is generated during perovskite conversion in a two-step method and considered beneficial within the grain boundaries, while also being accused of enhancing the interface defects and nonradiative recombination. Several additives are mixed in PbI2 precursors for the purpose of improving the perovskite crystallinity and hindering the Pb2+ defects. Herein, in lieu of adding additives to the PbI2, the effects of the PbI2 residue via the electron transport layer/perovskite interface modification are explored. Consequently, by introducing artemisinin decorated with hydrophobic alkyl units and a ketone group, it reduces the residual PbI2 and improves the perovskites' crystallinity by coordinating with Pb2+. In addition, artemisinin-deposited perovskite enhances both the stability and efficiency of perovskite solar cells by suppressing nonradiative recombination.

Superior possibilities and upcoming horizons for nanoscience in COVID-19: noteworthy approach for effective diagnostics and management of SARS-CoV-2 outbreak.

The outbreak of COVID-19 has caused great havoc and affected many parts of the world. It has imposed a great challenge to the medical and health fraternity with its ability to continue mutating and increasing the transmission rate. Some challenges include the availability of current knowledge of active drugs against the virus, mode of delivery of the medicaments, its diagnosis, which are relatively limited and do not suffice for further prognosis. One recently developed drug delivery system called nanoparticles is currently being utilized in combating COVID-19. This article highlights the existing methods for diagnosis of COVID-19 such as computed tomography scan, reverse transcription-polymerase chain reaction, nucleic acid sequencing, immunoassay, point-of-care test, detection from breath, nanotechnology-based bio-sensors, viral antigen detection, microfluidic device, magnetic nanosensor, magnetic resonance platform and internet-of-things biosensors. The latest detection strategy based on nanotechnology, biosensor, is said to produce satisfactory results in recognizing SARS-CoV-2 virus. It also highlights the successes in the research and development of COVID-19 treatments and vaccines that are already in use. In addition, there are a number of nanovaccines and nanomedicines currently in clinical trials that have the potential to target COVID-19.

Modeling of Efficient Control Strategies for LCC-HVDC Systems: A Case Study of Matiari-Lahore HVDC Power Transmission Line.

With the recent development in power electronic devices, HVDC (High Voltage Direct Current) systems have been recognized as the most prominent solution to transmit electric power economically. Today, several HVDC projects have been implemented physically. The conventional HVDC systems use grid commutation converters, and its commutation relies on an AC system for the provision of voltage. Due to this reason, there are possibilities of commutation failure during fault. Furthermore, once the DC (Direct Current) system power is interrupted momentarily, the reversal of work power is likely to cause transient over-voltage, which will endanger the safety of power grid operation. Hence, it is necessary to study the commutation failure and transient over-voltage issues. To tackle the above issues, in this paper, the dynamic and transient characteristics of Pakistan's first HVDC project, i.e., the Matiari-Lahore ±660 kV transmission line has been analyzed in an electromagnetic transient model of PSCAD/EMTDC. Based on the characteristics of the DC and the off-angle after the failure, a new control strategy has been proposed. The HVDC system along with its proposed control strategy has been tested under various operating conditions. The proposed controller increases the speed of fault detection, reduces the drop of AC voltage and DC and suppresses the commutation failure probability of LCC-HVDC (line commutated converter- high voltage direct current).

An Interacting Quantum Atoms (IQA) and Relative Energy Gradient (REG) Analysis of the Anomeric Effect.

The explanation of the anomeric effect in terms of underlying quantum properties is still controversial almost 70 years after its introduction. Here, we use a method called Relative Energy Gradient (REG), which is able to compute chemical insight with a view to explaining the anomeric effect. REG operates on atomic energy contributions generated by the quantum topological energy decomposition Interacting Quantum Atoms (IQA). Based on the case studies of dimethoxymethane and 2-fluorotetrahydropyran, we show that the anomeric effect is electrostatic in nature rather than governed by hyperconjugation.

Sirtuin 6 deficiency transcriptionally up-regulates TGF-ß signaling and induces fibrosis in mice.

Caloric restriction has been associated with increased life span and reduced aging-related disorders and reduces fibrosis in several diseases. Fibrosis is characterized by deposition of excess fibrous material in tissues and organs and is caused by aging, chronic stress, injury, or disease. Myofibroblasts are fibroblast-like cells that secrete high levels of extracellular matrix proteins, resulting in fibrosis. Histological studies have identified many-fold increases of myofibroblasts in aged organs where myofibroblasts are constantly generated from resident tissue fibroblasts and other cell types. However, it remains unclear how aging increases the generation of myofibroblasts. Here, using mouse models and biochemical assays, we show that sirtuin 6 (SIRT6) deficiency plays a major role in aging-associated transformation of fibroblasts to myofibroblasts, resulting in tissue fibrosis. Our findings suggest that SIRT6-deficient fibroblasts transform spontaneously to myofibroblasts through hyperactivation of transforming growth factor ß (TGF-ß) signaling in a cell-autonomous manner. Importantly, we noted that SIRT6 haploinsufficiency is sufficient for enhancing myofibroblast generation, leading to multiorgan fibrosis and cardiac dysfunction in mice during aging. Mechanistically, SIRT6 bound to and repressed the expression of key TGF-ß signaling genes by deacetylating SMAD family member 3 (SMAD3) and Lys-9 and Lys-56 in histone 3. SIRT6 binding to the promoters of genes in the TGF-ß signaling pathway decreased significantly with age and was accompanied by increased binding of SMAD3 to these promoters. Our findings reveal that SIRT6 may be a potential candidate for modulating TGF-ß signaling to reduce multiorgan fibrosis during aging and fibrosis-associated diseases.

Feasibility, efficiency & effectiveness of pooled sample testing strategy (pooled NAAT) for molecular testing of COVID-19.

BACKGROUND & OBJECTIVES: During the current COVID-19 pandemic, a large number of clinical samples were tested by real-time PCR. Pooling the clinical samples before testing can be a good cost-saving and rapid alternative for screening large populations. The aim of this study was to compare the performance characteristics, feasibility and effectiveness of pooling nasal swab and throat swab samples for screening and diagnosis of SARS-CoV-2. METHODS: The pool testing was applied on a set of samples coming from low COVID-19 positivity areas. A total of 2410 samples were tested in pools of five samples each. A total of five pools of five samples each were generated and tested for E gene. RESULTS: Of the total of 482 pools (2410 samples) 24 pools flagged positive. Later on pool de-convolution, a total of 26 samples were detected as positive for COVID-19, leading to positivity of about one per cent in the test population. For the diagnosis of individual samples, the pooling strategies resulted in cost savings of 75 per cent (5 samples per pool). INTERPRETATION & CONCLUSIONS: It was observed that testing samples for COVID-19 by reverse transcription (RT)- PCR after pooling could be a cost-effective method which would save both in manpower and cost especially for resource-poor countries and at a time when test kits were short in supply.

SIRT6 transcriptionally regulates global protein synthesis through transcription factor Sp1 independent of its deacetylase activity.

Global protein synthesis is emerging as an important player in the context of aging and age-related diseases. However, the intricate molecular networks that regulate protein synthesis are poorly understood. Here, we report that SIRT6, a nuclear-localized histone deacetylase represses global protein synthesis by transcriptionally regulating mTOR signalling via the transcription factor Sp1, independent of its deacetylase activity. Our results suggest that SIRT6 deficiency increases protein synthesis in mice. Further, multiple lines of in vitro evidence suggest that SIRT6 negatively regulates protein synthesis in a cell-autonomous fashion and independent of its catalytic activity. Mechanistically, SIRT6 binds to the zinc finger DNA binding domain of Sp1 and represses its activity. SIRT6 deficiency increased the occupancy of Sp1 at key mTOR signalling gene promoters resulting in enhanced expression of these genes and activation of the mTOR signalling pathway. Interestingly, inhibition of either mTOR or Sp1 abrogated the increased protein synthesis observed under SIRT6 deficient conditions. Moreover, pharmacological inhibition of mTOR restored cardiac function in muscle-specific SIRT6 knockout mice, which spontaneously develop cardiac hypertrophy. Overall, these findings have unravelled a new layer of regulation of global protein synthesis by SIRT6, which can be potentially targeted to combat aging-associated diseases like cardiac hypertrophy.

Effective Connectivity for Decoding Electroencephalographic Motor Imagery Using a Probabilistic Neural Network.

Motor imagery (MI)-based brain-computer interfaces have gained much attention in the last few years. They provide the ability to control external devices, such as prosthetic arms and wheelchairs, by using brain activities. Several researchers have reported the inter-communication of multiple brain regions during motor tasks, thus making it difficult to isolate one or two brain regions in which motor activities take place. Therefore, a deeper understanding of the brain's neural patterns is important for BCI in order to provide more useful and insightful features. Thus, brain connectivity provides a promising approach to solving the stated shortcomings by considering inter-channel/region relationships during motor imagination. This study used effective connectivity in the brain in terms of the partial directed coherence (PDC) and directed transfer function (DTF) as intensively unconventional feature sets for motor imagery (MI) classification. MANOVA-based analysis was performed to identify statistically significant connectivity pairs. Furthermore, the study sought to predict MI patterns by using four classification algorithms-an SVM, KNN, decision tree, and probabilistic neural network. The study provides a comparative analysis of all of the classification methods using two-class MI data extracted from the PhysioNet EEG database. The proposed techniques based on a probabilistic neural network (PNN) as a classifier and PDC as a feature set outperformed the other classification and feature extraction techniques with a superior classification accuracy and a lower error rate. The research findings indicate that when the PDC was used as a feature set, the PNN attained the greatest overall average accuracy of 98.65%, whereas the same classifier was used to attain the greatest accuracy of 82.81% with the DTF. This study validates the activation of multiple brain regions during a motor task by achieving better classification outcomes through brain connectivity as compared to conventional features. Since the PDC outperformed the DTF as a feature set with its superior classification accuracy and low error rate, it has great potential for application in MI-based brain-computer interfaces.

Emerging Prospects for Combating Fungal Infections by Targeting Phosphatidylinositol Transfer Proteins.

The emergence of fungal "superbugs" resistant to the limited cohort of anti-fungal agents available to clinicians is eroding our ability to effectively treat infections by these virulent pathogens. As the threat of fungal infection is escalating worldwide, this dwindling response capacity is fueling concerns of impending global health emergencies. These developments underscore the urgent need for new classes of anti-fungal drugs and, therefore, the identification of new targets. Phosphoinositide signaling does not immediately appear to offer attractive targets due to its evolutionary conservation across the Eukaryota. However, recent evidence argues otherwise. Herein, we discuss the evidence identifying Sec14-like phosphatidylinositol transfer proteins (PITPs) as unexplored portals through which phosphoinositide signaling in virulent fungi can be chemically disrupted with exquisite selectivity. Recent identification of lead compounds that target fungal Sec14 proteins, derived from several distinct chemical scaffolds, reveals exciting inroads into the rational design of next generation Sec14 inhibitors. Development of appropriately refined next generation Sec14-directed inhibitors promises to expand the chemical weaponry available for deployment in the shifting field of engagement between fungal pathogens and their human hosts.

Severity of dengue illness and presence of anti DV IgG in serum of laboratory confirmed dengue cases.

BACKGROUND & OBJECTIVES: Presence of dengue is reported from India since 1960s. Secondary dengue infection may be more severe than primary, hence, distinction between primary and secondary dengue is essential. A way to detect secondary dengue is demonstration of anti DV IgG in patients' serum. In this study we explored the association of dengue severity with anti DV IgG positivity. METHODS: Laboratory confirmed cases of dengue (positive for anti DV IgM/ NS-1 Antigen/ DV -RNA), presenting to the hospital within 7 days of illness, were consecutively enrolled for a period of one month (September 1-30, 2018) and were tested for anti DV IgG in their serum. All PCR positive samples were serotyped. Cases positive for anti-dengue IgG were labeled as secondary cases. Clinical details were collected to assess the severity of illness. Association of dengue severity with anti DV IgG positivity was calculated. RESULTS: Of the 128 dengue positive cases, 89 (69.5%) were anti DV IgM positive, 72 (56.3%) were Dengue NS-1 positives and 37 (28.9%) were DV-RNA positive. Only 39 (30.5%) cases were having detectable anti-dengue IgG in their serum (secondary dengue). Anti-dengue IgM positivity was significantly higher in secondary dengue cases. No association of anti DV IgG positivity was seen with severity of dengue illness. INTERPRETATION & CONCLUSION: No association of IgG positivity with severity of illness was seen. D4 serotype is first time reported from Uttar Pradesh, India.

Functional diversification of the chemical landscapes of yeast Sec14-like phosphatidylinositol transfer protein lipid-binding cavities.

Phosphatidylinositol-transfer proteins (PITPs) are key regulators of lipid signaling in eukaryotic cells. These proteins both potentiate the activities of phosphatidylinositol (PtdIns) 4-OH kinases and help channel production of specific pools of phosphatidylinositol 4-phosphate (PtdIns(4)P) dedicated to specific biological outcomes. In this manner, PITPs represent a major contributor to the mechanisms by which the biological outcomes of phosphoinositide are diversified. The two-ligand priming model proposes that the engine by which Sec14-like PITPs potentiate PtdIns kinase activities is a heterotypic lipid-exchange cycle where PtdIns is a common exchange substrate among the Sec14-like PITP family, but the second exchange ligand varies with the PITP. A major prediction of this model is that second-exchangeable ligand identity will vary from PITP to PITP. To address the heterogeneity in the second exchange ligand for Sec14-like PITPs, we used structural, computational, and biochemical approaches to probe the diversities of the lipid-binding cavity microenvironments of the yeast Sec14-like PITPs. The collective data report that yeast Sec14-like PITP lipid-binding pockets indeed define diverse chemical microenvironments that translate into differential ligand-binding specificities across this protein family.

Upsurge of chikungunya cases in Uttar Pradesh, India.

BACKGROUND & OBJECTIVES: Chikungunya (CHIK) re-emerged in India in 2006 after a gap of three decades. In Uttar Pradesh (UP), <100 confirmed cases per million were reported during this outbreak. Based on an upsurge of CHIK cases at UP, this retrospective study was conducted to investigate clinical and serological profile of CHIK cases in UP. METHODS: A retrospective study was done on all clinically suspected CHIK cases that had been tested by ELISA for anti-CHIK virus IgM antibodies from September 2012 to December 2017. Based on clinical features, a subset of patients had earlier been tested serologically for dengue and Japanese encephalitis (JE). RESULTS: Of the 3240 cases enrolled, 771 (23.8%) were seropositive. Patients had a range of clinical manifestations with seropositivity highest in those exhibiting arthralgia with fever (40%), followed by fever of unknown origin (FUO) (22%), encephalitis (13%) and fever with rash (12%). Cases (total, seropositive) increased over 20-fold in 2016 (1389, 412) and 2017 (1619, 341), compared to 2012-2015. Nearly a third of dengue serology-positive cases and a fifth of JE serology-positive cases were co-positive for CHIKV. INTERPRETATION & CONCLUSIONS: Archival data from 2006-2011 and data from this study (2012-2017) indicated that UP experienced first CHIK outbreak in the decade in 2016, as part of a large-scale upsurge across northern India. CHIK should be considered as a differential diagnosis in patients presenting with fever of unknown origin or fever with rash or acute encephalitis, in addition to classical arthralgia.

Potential risk factors related to academic failure in a medical college: A comparative approach.

OBJECTIVE: To compare risk factors related to medical students' failure based on gender, year of study and living away from home. METHODS: The cross-sectional, non-interventional, comparative study was conducted at a private medical college of Islamabad, Pakistan from 2015 to 2017, and comprised students who had even once scored <50% marks in their professional examinations. Data was collected using a questionnaire that was scored on a five-point Likert scale. Data was analyzed using SPSS 23. RESULTS: Of the 115 students, 62(52%) were day scholars compared to 55(48%) hostellers; 64(56%) were females compared to 51(44%) males; and 50(43%) belonged to the second year. Overall, differences in terms of gender, year of study and living away from home were not significant (p>0.05). CONCLUSIONS: Risk factors for poor academic performance were found to be common among all students.