3R-NbS2 as a highly stable anode for sodium-ion batteries.

Anode materials for advanced sodium-ion batteries (SIBs) require major improvements with regard to their cycling stability, which is a crucial parameter for long-term battery operation. Herein, we report 3R-NbS2, synthesised by a simple solid-state annealing route, as an anode for SIBs with remarkable cycling stability for 2500 cycles at 0.5 A g-1. The stable nature of the NbS2 anode was attributed to its dominant capacitive behaviour.

Metavalent Bonding in 2D Chalcogenides: Structural Origin and Chemical Mechanisms.

An unusual set of anomalous functional properties of rocksalt crystals of Group IV chalcogenides were recently linked to a kind of bonding termed as metavalent bonding (MVB) which involves violation of the 8-N rule. Precise mechanisms of MVB and the relevance of lone pair of Group IV cations are still debated. With restrictions of low dimensionality on the possible atomic coordination, 2D materials provide a rich platform for exploration of MVB. Here, we present first-principles theoretical analysis of the nature of bonding in five distinct 2D lattices of Group IV chalcogenides MX (M: Sn, Pb, Ge and X: S, Se, Te), in which the natural out-of-plane expression of the lone pair versus in-plane bonding can be systematically explored. While their honeycomb lattices respecting the 8-N rule are shown to exhibit covalent bonding, their square and orthorhombic structures exhibit MVB only in-plane, with cationic lone pair activating the out-of-plane structural puckering that controls their relative stability. Anomalies in Born-effective charges, dielectric constants, Grüneisen parameters occur only in their in-plane behaviour, confirming MVB is confined strictly to 2D and originates from p-p orbital interactions. Our work opens up directions for chemical design of MVB based 2D materials and their heterostructures.

Neuromorphic devices realised using self-forming hierarchical Al and Ag nanostructures: towards energy-efficient and wide ranging synaptic plasticity.

Closely mimicking the hierarchical structural topology with emerging behavioral functionalities of biological neural networks in neuromorphic devices is considered of prime importance for the realization of energy-efficient intelligent systems. In this article, we report an artificial synaptic network (ASN) comprising of hierarchical structures of isolated Al and Ag micro-nano structures developed via the utilization of a desiccated crack pattern, anisotropic dewetting, and self-formation. The strategically designed ASN, despite having multiple synaptic junctions between electrodes, exhibits a threshold switching (Vth ∼ 1-2 V) with an ultra-low energy requirement of ∼1.3 fJ per synaptic event. Several configurations of the order of hierarchy in the device architecture are studied comprehensively to identify the importance of the individual metallic components in contributing to the threshold switching and energy-minimization. The emerging potentiation behavior of the conductance (G) profile under electrical stimulation and its permanence beyond are realized over a wide current compliance range of 0.25 to 300 µA, broadly classifying the short- and long-term potentiation grounded on the characteristics of filamentary structures. The scale-free correlation of potentiation in the device hosting metallic filaments of diverse shapes and strengths could provide an ideal platform for understanding and replicating the complex behavior of the brain for neuromorphic computing.

Amide-decorated reusable C18 silica-packed columns for the rapid, efficient and sequential separation of lanthanoids using reversed phase-high performance liquid chromatography.

The current work focuses on the sequential separation of trivalent lanthanides (except Pm3+) using modified C18 silica-packed supports through the reversed-phase high-performance liquid chromatography (RP-HPLC) technique. In the current research, four indigenously synthesized amphiphilic aromatic triamide derivatives, namely N1, N1, N3, N3, N5, N5-hexa(alkyl) benzene-1,3,5-tri carboxamide (alkyl = butyl, hexyl, octyl, and decyl), were employed as column modifiers. The results show that the separation of Ln3+ can be achieved systematically (< 12 min) by tuning the modifiers' functional group and hydrophobic chain and fine-tuning the column modification procedure and separation parameters. The chromatographic studies revealed that the use of 0.168 mmol of N1, N1, N3, N3,N5, N5-hexa(hexyl)benzene-1,3,5-tricarboxamide (HHBTA) coated column and 0.419 mmol of N1, N1, N3, N3, N5, N5-hexa(octyl) benzene-1,3,5-tricarboxamide (HOBTA) modified columns offered excellent separation for the lanthanoids, using 0.1 M α-hydroxyisobutyric acid (HIBA), as mobile phase. The separated lanthanoids were quantified by post-column derivatization reaction (after the separation process) using Arsenazo (III) as the post-column reagent by integrating with a UV-Visible detector fixed at 655 nm (λmax). A systematic study on the influence of various analytical features, such as the effect of the modifier's chain length and its concentration, mobile phase composition and pH, was performed and optimized for achieving the best separation protocols.

Inter-individual Variation in Pain Sensitivity among Healthy Young Indian Adults- a pilot study.

Background Pain perception, with inter-individual variability, is a challenge for both patients and clinicians. Distribution of pain sensitivity parameters being less explored in Indian population can vary with reports from outside India. Objective To describe distribution of pain sensitivity parameters using cold pressor test in healthy adults and to explore relationship of pain sensitivity with gender, vascular reactivity and parental history of hypertension. Method Pain was induced with non-dominant hand immersed in cold water (30 C to 50 C) in 150 subjects (75 males and 75 females) selected as per inclusion and exclusion criteria. Pain sensitivity (pain threshold, tolerance and unpleasantness), vascular reactivity (Δ change in blood pressure and pulse rate) were measured. Result Subjects demonstrated pain threshold [17.6 s (10.7, 26.6)], tolerance [40.2 s (30.0, 59.2)] and unpleasantness [7.0 (6.1,8.0)]. Pain unpleasantness showed a weak negative correlation with pain threshold and tolerance (p < 0.001). Pain threshold had moderate positive correlation with tolerance (p < 0.001). Males had significantly higher pain threshold and tolerance than females (p=0.004). Significant rise in posttest systolic and diastolic blood pressure (p < 0.001), decrease in pulse rate (p=0.007) were found compared to resting values. Pain tolerance showed a weak positive correlation with Δ systolic blood pressure (p=0.039). Subjects with positive parental history of hypertension showed higher pain unpleasantness scores (p=0.02). Conclusion The study demonstrated a wide range of pain sensitivity for narrow age and body mass index. Gender difference was observed for pain threshold and tolerance. Vascular reactivity was demonstrated. Subjective pain perception was higher in subjects with parental history of hypertension.

NbO2 a Highly Stable, Ultrafast Anode Material for Li- and Na-Ion Batteries.

Anode materials with fast charging capabilities and stability are critical for realizing next-generation Li-ion batteries (LIBs) and Na-ion batteries (SIBs). The present work employs a simple synthetic strategy to obtain NbO2 and studies its applications as an anode for LIB and SIB. In the case of the LIB, it exhibited a specific capacity of 344 mAh g-1 at 100 mA g-1. It also demonstrated remarkable stability over 1000 cycles, with 92% capacity retention. Additionally, it showed a unique fast charging capability, which takes 30 s to reach a specific capacity of 83 mAh g-1. For the SIB, NbO2 exhibited a specific capacity of 244 mAh g-1 at 50 mA g-1 and showed 70% capacity retention after 500 cycles. Furthermore, detailed density functional theory reveals that various factors like bulk and surface charging processes, lower ion diffusion energy barriers, and superior electronic conductivity of NbO2 are responsible for the observed battery performances.

Novel HDAC inhibitors provide neuroprotection in MPTP-induced Parkinson's disease model of rats.

Parkinson's Disease (PD) is the most rapidly growing neurological disorder globally in terms of disability and mortality. While symptomatic treatment is available for PD, there is a critical unmet need for effective disease-modifying therapies. Recently, histone deacetylase inhibitors (HDACi), an important class of epigenetic modulators grabbed significant attention as drug targets for neurodegenerative diseases including PD. In this regard, novel pan-HDACi, cinnamyl sulphonamide hydroxamate derivatives (NMJ-2 and NMJ-3), synthesized and characterized in our laboratory, were screened for neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rat model of PD. Twenty-four hours after the bilateral intranigral injection of MPTP, rats were administered orally with NMJ-2 or NMJ-3 (150 mg/kg) daily for 30 days. MPTP administration resulted in a marked rise in lipid peroxidation, and interleukin-1ß concentration accompanied by reduced tyrosine hydroxylase and dopamine levels in the striatum compared to the sham group. These biochemical changes were associated with functional motor and non-motor deficits as revealed by loss of motor coordination (rota rod test), impaired grip strength (beam walk test), enhanced rigidity (catalepsy scores), loss of memory (novel object recognition test) and depressive-like behaviour (forced swim test). However, oral treatment with NMJ-2 or NMJ-3, or valproic acid for 30 days significantly attenuated the PD-induced adverse changes in motor and non-motor functions by ameliorating the oxidative stress as well as inflammation, and restoring the dopamine levels in the striatum comparable to the valproic acid group. These results suggest that targeting HDACi could be a rational therapeutic strategy for the development of disease-modifying therapies for PD.

Unusual Case of a Foreign Body in Tracheo-Esophageal Party wall.

Foreign body ingestion is a common problem among children and less so with adults. Most patients are asymptomatic and require no treatment while some need acute management depending on type, size, shape, duration, symptoms and physical findings. Here we present an unusual case of foreign body ingestion which perorated through the pyriform fossa and lodged in tracheoesophageal party wall requiring surgical exploration. Supplementary Information: The online version contains supplementary material available at 10.1007/s12070-023-03698-1.

An in-depth appraisal of clinico-biochemical and radiological findings of COVID-19 patients during the COVID-19 pandemic in a dedicated COVID Care Hospital in Eastern India and its outcome in relation to the COVAXIN vaccination status: A 2-year study.

Introduction: COVID-19 pandemic hit Odisha province from April 2020 to December 2020, then from April 2021 to August 2021 and from February 2022 to April 2022 as the first, second, and third waves, respectively, with the most severe form witnessed during the second wave. Kalinga Institute of Medical Sciences hospital in Odisha was declared a Dedicated COVID Hospital (DCH) during those three waves and witnessed 9485 cases of admissions among which there were 1214 deaths. COVAXIN vaccination of the vulnerable population was launched in February 2021 onwards. This study has been done to know the clinic-biochemical profiles, radiologic findings of COVID-19 admitted patients, the predictors of mortality in the second wave, and clinical outcomes in the three waves in relation to COVAXIN vaccination status. Material and Methods: This was a serial three-round retrospective study from the electronic medical records using multistage random sampling where we collected and critically analyzed the demographic, and all the relevant possible health data of the cases that consist of 514 cases admitted in three waves. The data from death certificates among the 555 cases in the second wave have been analyzed to conclude predictors of mortality. Results: Mortality increased with age, male gender, comorbidities, and raised C-reactive protein level. High NL ratio, extent of pulmonary involvement. There was a wide variation in incidence and spectrum of illness starting from 79% incidence of mild symptomatic in the initial and third wave, but remained in the range of 35-65% in the second wave, respectively, and the most noticeable symptomatic illness was that of the upper respiratory tract. In fulminant cases, the mode of presentations was severe pneumonia and acute respiratory distress syndrome. Males were more sufferers than females. Children had better outcomes compared to adults. COVID-associated coagulopathy had a normal platelet count. Subsequently, in 2021 year onwards vaccination of the vulnerable population was launched in a phased manner that changed the dynamics of the disease outcome by better survival chances despite intercurrent COVID infection by induction of herd immunity. On the contrary, there was a higher prevalence of serious illness among non-vaccinated individuals. While the cases continued during the second wave of the pandemic, long COVID became a clinical entity of symptomatic that persisted or recurred among the COVID illness recovered cases after reverse transcriptase polymerase chain reaction results for COVID-19 became negative. The symptoms consisted of fatigue, cough, dyspnea as pulmonary manifestations and extra-pulmonary involvement of the cardiac, renal, and central nervous systems and the pulmonary imaging features consisted of interstitial pneumonia, consolidation, cavity pattern, and prone to microbial infection. These events lead to morbidity and admission. Coinciding with the vaccination of all population of Odisha province with the first dose of the vaccine by around the period of the first quarter of 2022, there was a new variant named Omicron responsible in the third wave, in which the majority of the admitted cases had.mild upper respiratory illness. This was not as lethal as its predecessors due to its lower propensity to invade the lungs and blood vessels. Conclusion: Immune dysregulation plays a central role in the pathogenesis of the manifestations. Vaccine-induced protection and the induction of herd immunity played a proactive role in the waning of the severity of clinical presentations.

High-Flux lamellar MoSe2 membranes for efficient dye/salt separation.

Membrane-based technology is emerging as an efficient technique for wastewater treatment in recent years. Membranes made up of two-dimensional materials provide high selectivity and water flux compared to conventional polymeric membranes. Herein, we report the synthesis and use of MoSe2 membrane for dye and drug separation in wastewater, mainly from textile and pharmaceutical industries. The as-prepared MoSe2 membrane shows âˆ¼ 100% rejection for organic dyes and ciprofloxacin drug with a water flux reaching up to âˆ¼ 900 Lm-2h-1bar-1. Further, the MoSe2 membrane shows lower NaCl rejection of âˆ¼ 1.9% for the dye/salt mixture. The interlayer spacing in the MoSe2 membrane allows the water molecules and ions from the salt to pass through freely but restricts the movement of large contaminants. The membrane is stable against the bovine albumin serum fouling with a flux recovery rate of 96%. It also shows good performance even in harsh environments (pH 3-10). To the best of our knowledge, the MoSe2 membranes were fabricated for the first time for wastewater treatment application. The dye/salt separation performance of the MoSe2 membrane is significantly better than several other membranes. This work highlights the promising potential for using two-dimensional materials for textile and pharmaceutical wastewater treatment.

Serum Electrolytes in Patients Presenting With Acute Exacerbation of Chronic Obstructive Pulmonary Disease (COPD) and Their Comparison With Stable COPD Patients.

Introduction Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality, which may be further aggravated by episodes of acute exacerbation of COPD (AECOPD). Electrolyte imbalances during these episodes may add to the duration of hospitalization and disease outcome. Aims and objectives This study aims to compare the serum electrolyte levels of patients with AECOPD and stable COPD and correlate them with the severity of exacerbation and disease outcome. Materials and methods The study was conducted as a case-control study between January 2021 and December 2022. Patients with AECOPD and stable COPD were included as "cases" and "controls," respectively. The various serum electrolyte levels were defined as per recent guidelines. Statistical analysis was performed using SPSS 20.0 (IBM Corp., Armonk, NY). Results A total of 75 patients were included with 41 in the study group and 34 in the control group. The majority of people were between the ages of 61 and 70. The most frequent electrolyte abnormality found was hyponatremia. The mean serum sodium and calcium levels were lower in patients with AECOPD while the mean serum potassium levels were higher. A total of five deaths were recorded in patients with two or more electrolyte imbalances. The latter also had a requirement for home oxygen or non-invasive ventilation at the time of discharge. Conclusion Patients of AECOPD with multiple electrolyte imbalances need scrutinized treatment as they are more prone to develop complications, have poorer outcomes, and prolonged hospital stays.

Pest scenario of Helicoverpa armigera (Hub.) on pigeonpea during future climate change periods under RCP based projections in India.

Gram pod borer, Helicoverpa armigera (Hub.) is the major insect pest of pigeonpea and prediction of number of generations (no. of gen.) and generation time (gen. time) using growing degree days (GDD) approach during three future climate change periods viz., Near (NP), Distant (DP) and Far Distant (FDP) periods at eleven major pigeonpea growing locations of India was attempted. Multi-model ensemble of Maximum (Tmax) and Minimum (Tmin) temperature data of four Representative Concentration Pathways viz., RCP 2.6, 4.5, 6.0 and 8.5 of Coupled Model Inter comparison Project 5 (CMIP5) models was adopted here. The increase in projected Tmax and Tmin are significant during 3 climate change periods (CCPs) viz., the NP, DP and FDP over base line (BL) period under four RCP scenarios at all locations and would be higher (4.7-5.1 °C) in RCP 8.5 and in FDP. More number of annual (10-17) and seasonal (5-8) gens. are expected to occur with greater percent increase in FDP (8 to 38%) over base line followed by DP (7 to 22%) and NP (5to 10%) periods with shortened annual gen. time (4 to 27%) across 4 RCPs. The reduction of crop duration was substantial in short, medium and long duration pigeonpeas at all locations across 4 RCPs and 3 CCPs. The seasonal no.of gen. is expected to increase (5 to 35%) with shortened gen. time (4 to 26%) even with reduced crop duration across DP and FDP climate periods of 6.0 and 8.5 RCPs in LD pigeonpea. More no. of gen. of H. armigera with reduced gen. time are expected to occur at Ludhiana, Coimbatore, Mohanpur, Warangal and Akola locations over BL period in 4 RCPs when normal duration of pigeonpeas is considered. Geographical location (66 to 72%), climate period (11 to 19%), RCPs (5-7%) and their interaction (0.04-1%) is vital and together explained more than 90% of the total variation in future pest scenario. The findings indicate that the incidence of H. armigera would be higher on pigeonpea during ensuing CCPs in India under global warming context.

Emphasizing the Crosstalk Between Inflammatory and Neural Signaling in Post-traumatic Stress Disorder (PTSD).

Post-traumatic stress disorder (PTSD) is a chronic incapacitating condition with recurrent experience of trauma-related memories, negative mood, altered cognition, and hypervigilance. Agglomeration of preclinical and clinical evidence in recent years specified that alterations in neural networks favor certain characteristics of PTSD. Besides the disruption of hypothalamus-pituitary-axis (HPA) axis, intensified immune status with elevated pro-inflammatory cytokines and arachidonic metabolites of COX-2 such as PGE2 creates a putative scenario in worsening the neurobehavioral facet of PTSD. This review aims to link the Diagnostic and Statistical Manual of mental disorders (DSM-V) symptomology to major neural mechanisms that are supposed to underpin the transition from acute stress reactions to the development of PTSD. Also, to demonstrate how these intertwined processes can be applied to probable early intervention strategies followed by a description of the evidence supporting the proposed mechanisms. Hence in this review, several neural network mechanisms were postulated concerning the HPA axis, COX-2, PGE2, NLRP3, and sirtuins to unravel possible complex neuroinflammatory mechanisms that are obscured in PTSD condition.

Fast and selective reversed-phase high performance liquid chromatographic separation of UO2 2+ and Th4+ ions using surface modified C18 silica monolithic supports with target specific ionophoric ligands.

Reprocessing nuclear-spent fuels is highly demanded for enhanced resource efficacy and removal of the associated radiotoxicity. The present work elucidates the rapid separation of UO2 2+ and Th4+ ions using a reversed-phase high-performance liquid chromatographic (RP-HPLC) technique by dynamically modifying the surface of a C18 silica monolith column with target-specific ionophoric ligands. For the dynamic modification, four analogous aromatic amide ligands, N 1,N 1,N 3,N 3,N 5,N 5-hexa(alkyl)benzene-1,3,5-tricarboxamide (alkyl = butyl, hexyl, octyl, and decyl) as column modifiers were synthesized. The complexation properties and retention profiles of the amide-based column modifiers for the selective and sequential separation of UO2 2+ and Th4+ ions were investigated. In addition, the selective separation of UO2 2+ and Th4+ ions among the competitive ions of similar chemical properties were also studied. The ionophore immobilized C18 silica monolith columns demonstrated a varying degree of retention behavior for UO2 2+ and Th4+ ions (UO2 2+ is retained longer than Th4+ under all analytical conditions), eventually leading to rapid separations within a period of ≤5 min. A 0.1 M solution of 2-hydroxyisobutyric acid (HIBA, 1 mL min-1) served as the mobile phase, and the qualitative and quantitative assessment of the sequentially separated 5f metal ions was achieved through post-column derivatization reaction, using arsenazo(iii) as a post-column reagent (PCR; 1.5 mL min-1) prior to analysis using a UV-vis detector, at 665 nm (λ max). The developed technique was further evaluated by standardizing various analytical parameters, including modifier concentration, mobile phase pH, mobile phase flow rate, etc., to yield the best chromatographic separation. Also, the conceptual role of alkyl chain length (in the modifier) on the retention behavior of the studied metal ions was evaluated for cutting-edge future applications.

A new precursor route for the growth of NbO2thin films by chemical vapor deposition.

Niobium dioxide (NbO2) exhibits metal-insulator transition (Mott transition) and shows the potential for application in memristors and neuromorphic devices. Presently growth of NbO2thin films requires high-temperature reduction of Nb2O5films using H2or sophisticated techniques such as molecular beam epitaxy and pulsed laser deposition. The present study demonstrates a simple chemical route of the direct growth of crystalline NbO2films by chemical vapor deposition using a freshly prepared Nb-hexadecylamine (Nb-HDA) complex. X-ray diffraction studies confirm the NbO2phase with a distorted rutile body-centered-tetragonal structure and the film grown with a highly preferred orientation onc-sapphire. X-ray photoelectron spectroscopy confirms the +4 oxidation state. The present method offers facile growth of NbO2films without post-reduction steps which will be assumed to be a cost-effective process for NbO2based devices.

Online patient literature related to oesophageal surgery: the need for greater readability, accreditation and higher quality.

INTRODUCTION: Oesophageal cancer is the sixth most common cause of death worldwide but is treatable through surgery. As part of the consenting process, surgeons may guide patients towards online information leaflets to understand more about their condition and treatment. This review aimed to systematically analyse some of the current resources that can be accessed via the internet. METHODS: A stringent search criteria was used to select online patient information leaflets for oesophageal cancer surgery. Leaflets were scored based on the Flesch-Kincaid Reading Ease score, DISCERN score, Health on the Net Code of Conduct (HONcode) certification/Information Standard Certification and International Patient Decision Aid Standards (IPDAS) score. FINDINGS: Only five sites had achieved HONcode certification. Only three sources were deemed readable using the Flesch-Kincaid scoring system and no sources reached the recommended readability using IPDAS. No source reached a maximum score with DISCERN, with the mean overall quality being 2.98. There was no significant difference between accredited and unaccredited sources. From our sample, patient information sources on oesophageal cancer surgery have a low readability. CONCLUSIONS: More research is required to ascertain patient behaviour with regards to accessing the literature. Patients and healthcare professionals should liaise with each other to produce more readable, high-quality patient information on oesophageal cancer surgery.

The Cost-effectiveness of Watch and Wait for Rectal Cancer.

The existing literature suggests with a high degree of certainty that watch and wait is more cost-effective than initial total mesorectal excision. However, it is heavily reliant on poor-quality health-related quality of life data. Furthermore, the cost-effectiveness of organ preservation from a broader societal perspective has not been studied. Finally, the cost-effectiveness of emerging adjuncts to watch and wait for organ preservation, such as contact X-ray brachytherapy, local excision and total neoadjuvant therapy, need to be characterised.

Metavalent Bonding Origins of Unusual Properties of Group IV Chalcogenides.

A distinct type of metavalent bonding (MVB) is recently proposed to explain an unusual combination of anomalous functional properties of group IV chalcogenide crystals, whose electronic mechanisms and origin remain controversial. Through theoretical analysis of evolution of bonding along continuous paths in structural and chemical composition space, emergence of MVB in rocksalt chalcogenides is demonstrated as a consequence of weakly broken symmetry of parent simple-cubic crystals of Group V metalloids. High electronic degeneracy at the nested Fermi surface of parent metal drives spontaneous breaking of its translational symmetry with structural and chemical fields, which open up a small energy gap and mediate strong coupling between conduction and valence bands making metavalent crystals highly polarizable, conductive, and sensitive to bond-lengths. Stronger symmetry-breaking structural and chemical fields, however, transform them discontinuously to covalent and ionic semiconducting states. MVB involves bonding-antibonding pairwise interactions alternating along linear chains of at least five atoms, which facilitate long-range electron transfer in response to polar fields causing unusual properties. The precise picture of MVB predicts anomalous second-order Raman scattering as an addition to set off their unusual properties, and will guide in design of new metavalent materials with improved thermoelectric, ferroelectric and nontrivial electronic topological properties.

An efficient human stem cells derived cardiotoxicity testing platform for testing oncotherapeutic analogues of quercetin and cinnamic acid.

Oncotherapeutics research is progressing at a rapid pace, however, not many drugs complete the successful clinical trial because of severe off-target toxicity to cardiomyocytes which ultimately leads to cardiac dysfunction. It is thus important to emphasize the need for early testing for possible cardiotoxicity of emerging oncotherapeutics. In this study, we assessed a novel stem cell-derived cardiac model for testing for cardiotoxicity of novel oncotherapeutics. We evaluated the cardiotoxic effect of synthesized derivatives of oncotherapeutics, quercetin (QMJ-2, -5, and -6) and cinnamic acid (NMJ-1, -2, and -3) using human Wharton's jelly mesenchymal stem cells-derived cardiomyocytes (WJCM) against known cardiotoxic oncologic drugs, doxorubicin, 5-fluorouracil, cisplatin. QMJ-6, NMJ-2, and NMJ-3 were not cardiotoxic and had minimum cardiac side effects. They did not show any effect on cardiomyocyte viability, caused low LDH release, and intracellular ROS production kept the calcium flux minimal and protected the active mitochondrial status in cardiomyocytes. They persevered cardiac-specific gene expression as well. However, compounds QMJ-2, QMJ-5, and NMJ-1 were cardiotoxic and the concentration needs to be reduced to prevent toxic effects on cardiomyocytes. Significantly, we were able to demonstrate that WJCM is an efficient cardiac testing model to analyze the cardiotoxicity of drugs in a human context.

Lhb-/-Lhr-/- Double Mutant Mice Phenocopy Lhb-/- or Lhr-/- Single Mutants and Display Defects in Leydig Cells and Steroidogenesis.

In the mouse, two distinct populations of Leydig cells arise during testis development. Fetal Leydig cells arise from a stem cell population and produce T required for masculinization. It is debated whether they persist in the adult testis. A second adult Leydig stem cell population gives rise to progenitor-immature-mature adult type Leydig cells that produce T in response to LH to maintain spermatogenesis. In testis of adult null male mice lacking either only LH (Lhb-/-) or LHR (Lhr-/-), mature Leydig cells are absent but fetal Leydig cells persist. Thus, it is not clear whether other ligands signal via LHRs in Lhb null mice or LH signals via other receptors in the absence of LHR in Lhr null mice. Moreover, it is not clear whether truncated LHR isoforms generated from the same Lhr gene promoter encode functionally relevant LH receptors. To determine the in vivo roles of LH-LHR signaling pathway in the Leydig cell lineage, we generated double null mutant mice lacking both LH Ligand and all forms of LHR. Phenotypic analysis indicated testis morpho-histological characteristics are identical among double null and single mutants which all showed poorly developed interstitium with a reduction in Leydig cell number and absence of late stage spermatids. Gene expression analyses confirmed that the majority of the T biosynthesis pathway enzyme-encoding mRNAs expressed in Leydig cells were all suppressed. Expression of thrombospondin-2, a fetal Leydig cell marker gene was upregulated in single and double null mutants indicating that fetal Leydig cells originate and develop independent of LH-LHR signaling pathway in vivo. Serum and intratesticular T levels were similarly suppressed in single and double mutants. Consequently, expression of AR-regulated genes in Sertoli and germ cells were similarly affected in single and double mutants without any evidence of any additive effect in the combined absence of both LH and LHR. Our studies unequivocally provide genetic evidence that in the mouse testis, fetal Leydig cells do not require LH-LHR signaling pathway and a one-to-one LH ligand-LHR signaling pathway exists in vivo to regulate adult Leydig cell lineage and spermatogenesis.