ST-elevation myocardial infarction among cardiac amyloidosis patients; a national readmission database study.

Literature regarding recent trends, mortality outcomes of ST-elevation myocardial infarction (STEMI) in cardiac amyloidosis (CA) patients is limited.To study coronary interventions, and trends in prevalence and mortality outcomes among CA patients with STEMI.Data from the national readmissions database (NRD) sample that constitutes 49.1% of the stratified sample of all hospitals in the USA, representing more than 95% of the national population, were analyzed for hospitalizations associated with CA with STEMI. A linear p-trend was used to assess the trends.Out of the total 4252 adult patients (mean age 73.3 ± 11.7 years, 40.2% females) with diagnosis of CA, 439 (10.3%) had STEMI while 3813 (89.7%) had no STEMI. STEMI-CA patients had higher rates of multi-organ manifestations including VT/VF (12% vs 8.5%; p-value < 0.001), cardiogenic shock (12.7% vs 7.3%; p < 0.001), AKI requiring dialysis (5.3% vs 4%; p < 0.001), and ICU admissions (25.2% vs 15.3%; p < 0.001) compared to CA without STEMI. CA-STEMI had increased mortality rates (23.7% vs 16.1%, p < 0.001) compared to CA without STEMI. On multivariate logistic regression analysis, coronary interventions including PCI (OR 0.6, CI 0.4-1.1; p = 0.3) and CABG (OR 0.7, CI 0.3-1.8; p = 0.2) had no association with mortality among CA patients. The absolute yearly trends for prevalence and mortality associated with STEMI in CA patients remained steady over the study years (linear p-trends 0.2 and 0.6, respectively).CA-STEMI is associated with significant complications and mortality. Coronary interventions may not have significant mortality benefits. Thus, more research will be needed to improve mortality rates among these patients.

Thrombotic superior vena cava syndrome: a national emergency department database study.

Literature regarding etiology and trends of incidence of major thoracic vein thrombosis in the United States is limited. To study the causes, complications, in-hospital mortality rate, and trend in the incidence of major thoracic vein thrombosis which could have led to superior vena cava syndrome (SVCS) between 2010 and 2018. Data from the nationwide emergency department sample (NEDS) that constitutes 20% sample of hospital-owned emergency departments (ED) and in-patient sample in the United States were analyzed using diagnostic codes. A linear p-trend was used to assess the trends. Of the total 1082 million ED visits, 37,807 (3.5/100,000) (mean age 53.81 ± 18.07 years, 55% females) patients were recorded with major thoracic vein thrombosis in the ED encounters. Among these patients, 4070 (10.6%) patients had one or more cancers associated with thrombosis. Pacemaker/defibrillator-related thrombosis was recorded in 2820 (7.5%) patients, while intravascular catheter-induced thrombosis was recorded in 1755 (4.55%) patients. Half of the patients had associated complication of pulmonary embolism. A total of 59 (0.15%) patients died during these hospital encounters. The yearly trend for the thrombosis for every 100,000 ED encounters in the United States increased from 2.17/100,000 in 2010 to 5.98/100,000 in 2018 (liner p-trend < 0.001). Yearly trend for catheter/lead associated thrombosis was also up-trending (p-trend 0.015). SVCS is an uncommon medical emergency related to malignancy and indwelling venous devices. The increasing trend in SVCS incidence, predominantly catheter/lead induced, and the high rate of associated pulmonary embolism should prompt physicians to remain vigilant for appropriate evaluation.

ZnO Nanoparticles of Rubia cordifolia Extract Formulation Developed and Optimized with QbD Application, Considering Ex Vivo Skin Permeation, Antimicrobial and Antioxidant Properties.

The objective of the current research is to develop ZnO-Manjistha extract (ZnO-MJE) nanoparticles (NPs) and to investigate their transdermal delivery as well as antimicrobial and antioxidant activity. The optimized formulation was further evaluated based on different parameters. The ZnO-MJE-NPs were prepared by mixing 10 mM ZnSO4·7H2O and 0.8% w/v NaOH in distilled water. To the above, a solution of 10 mL MJE (10 mg) in 50 mL of zinc sulfate was added. Box-Behnken design (Design-Expert software 12.0.1.0) was used for the optimization of ZnO-MJE-NP formulations. The ZnO-MJE-NPs were evaluated for their physicochemical characterization, in vitro release activity, ex vivo permeation across rat skin, antimicrobial activity using sterilized agar media, and antioxidant activity by the DPPH free radical method. The optimized ZnO-MJE-NP formulation (F13) showed a particle size of 257.1 ± 0.76 nm, PDI value of 0.289 ± 0.003, and entrapment efficiency of 79 ± 0.33%. Drug release kinetic models showed that the formulation followed the Korsmeyer-Peppas model with a drug release of 34.50 ± 2.56 at pH 7.4 in 24 h. In ex vivo studies ZnO-MJE-NPs-opt permeation was 63.26%. The antibacterial activity was found to be enhanced in ZnO-MJE-NPs-opt and antioxidant activity was found to be highest (93.14 ± 4.05%) at 100 µg/mL concentrations. The ZnO-MJE-NPs-opt formulation showed prolonged release of the MJE and intensified permeation. Moreover, the formulation was found to show significantly (p < 0.05) better antimicrobial and antioxidant activity as compared to conventional suspension formulations.

Emerging antibody therapies for pancreatic adenocarcinoma: a review of recent phase 2 trials.

Introduction: Pancreatic adenocarcinoma is now the third-leading cause of cancer-related deaths in the US which can be attributed to rising incidence, diagnosis at advanced stages and early development of metastasis. Systemic therapy remains palliative with early development of resistance possibly related to the constitutive activation of 'undruggable' KRAS, immunosuppressive microenvironment, and intense desmoplasia. The advancements in molecular biology has led to the development and investigation of targeted and immune therapeutics.Areas covered: This study provides a comprehensive review of the literature to further the understanding of molecular targets with their respective antibody-based therapies in clinical development in pancreatic cancer. PubMed was systematically searched for English-language articles discussing antibody-based therapies under phase 2 clinical trial investigation in pancreatic adenocarcinoma.Expert opinion: PDAC remains highly resistant to chemotherapy with no significant improvement in survival for patients with advanced or metastatic cancer. Unfortunately, the majority of the antibody-based targeted and immune therapeutics have failed to meet their primary efficacy endpoints in early phase trials. However, there are a few promising antibody-based drugs with intriguing preliminary data that merit further investigation, while many more continue to be developed and investigated preclinically, and in early phase trials.

Anticoagulation Management and Outcomes in Patients With Covid-19 With Propensity Score Matching: A Multicenter Retrospective Cohort Study.

BACKGROUND: Therapeutic doses of anticoagulation have been administered to patients with coronavirus-19 disease (Covid-19) without thromboembolism, although there is a lack of robust evidence supporting this practice. STUDY QUESTION: To compare outcomes between patients admitted to the hospital for Covid-19 who received full-dose anticoagulation purely for the indication of Covid-19 and patients who received prophylactic doses of anticoagulation. STUDY DESIGN: This is a multicenter retrospective cohort study, including 7 community hospitals in Michigan. Patients were >18 years of age, confirmed positive for Covid-19 by polymerase chain reaction, and admitted to the hospital between March 10 and May 3, 2020. Exposed group: Patients receiving therapeutic dose anticoagulation for Covid-19 for any duration excluding clinically evident venous thromboembolism, atrial fibrillation, and myocardial infarction; control group: Patients receiving prophylactic anticoagulation. Propensity score matching was used to adjust for the nonrandomized nature of the study. MEASURES AND OUTCOMES: The primary endpoint: 30-day in-hospital mortality. Secondary endpoints: intubation, length of hospital stay, and readmissions in survivors. RESULTS: A total of 115 exposed and 115 control patients were analyzed. Rates of 30-day in-hospital mortality were similar (exposed: 33.0% vs. control: 28.7%). Controlling for institution, there was no significant association between treatment and 30-day in-hospital mortality (hazard ratio: 0.63; 95% confidence interval: 0.37-1.06). Survivors had statistically similar length of hospital stay and readmission rates. CONCLUSIONS: We found no difference in mortality in patients with Covid-19 without clinically evident venous thromboembolism, atrial fibrillation, and myocardial infarction who received therapeutic versus prophylactic doses of anticoagulation.

Genome wide association mapping and candidate gene analysis for pod shatter resistance in Brassica juncea and its progenitor species.

We investigated phenotypic variations for pod shattering, pod length and number of seeds per pod in large germplasm collections of Brassica juncea (2n = 36; AABB) and its progenitor species, B. rapa (2n = 20; AA) and B. nigra (2n = 16; BB). Pod shatter resistance was measured as energy required for rupturing a mature dry pod, with a specially fabricated pendulum machine. Rupture energy (RE) ranged from 3.3 to 11.0 mJ in B. juncea. MCP 633, NR 3350 and Albeli required maximum energy to shatter a pod. It ranged from 2.5 to 7.8 mJ for B. rapa with an average of 5.5 mJ. B. nigra possessed easy to rupture pods. Correlation analysis showed strong associations among these traits in B. juncea and B. rapa. Genome wide association studies were conducted with select sets of B. juncea and B. rapa germplasm lines. Significant and annotated associations predict the role of FRUITFULL, MANNASE7, and NAC secondary wall thickening promoting factor (NST2) in the genetic regulation of shatter resistance in B. juncea. NST2 and SHP1 appeared important for pod length and seeds per pod in B. rapa. Candidate gene based association mapping also confirmed the role of SHP1 and NST2 in regulating pod shattering and related pod traits in B. rapa and B. juncea. Footprints of selection were detected in SHP1, SHP2 (B. rapa, B. nigra and B. juncea), RPL (B. rapa) and NAC (B. juncea). Our results provide insights into the genetic architecture of three pod traits. The identified genes are relevant to improving and securing crop productivity of mustard crop.

Molecular interactions of milk protein with phenolic components in oat-based liquid formulations following UHT treatment and prolonged storage.

BACKGROUND: Nowadays there is a growing demand for nutritionally balanced breakfast beverages enriched with functional ingredients including wholegrain oat, which is rich in phenolic acids. Such beverages typically contain added food ingredients (e.g. milk protein, sugar and lipids) and undergo thermal processing that initiates many molecular processes. Therefore, this work aims to investigate the molecular interactions between milk protein and phenolic acids that govern bioactivity in model oat-based beverages. RESULTS: Findings showed the susceptibility of ferulic and p-coumaric acids, in model oat beverages, to ultra-high temperature (UHT) processing at 145 °C for 8 s. Among model beverages, those with added milk protein demonstrated a considerable loss of phenolic acids following UHT processing due to the interaction between these micronutrients and the protein. The nature of molecular interactions was mainly categorized as covalent with hydrogen bonds playing a supportive role. CONCLUSION: UHT processing of oat-based beverage formulations facilitates the formation of protein-phenolic acid complexes, which are largely covalent and static in nature. This finding underlines the ability of UHT treatment to induce chemical modifications of food ingredients. © 2017 Society of Chemical Industry.

PET radiotracer development for imaging high-affinity state of dopamine D2 and D3 receptors: Binding studies of fluorine-18 labeled aminotetralins in rodents.

Imaging the high-affinity, functional state (HA) of dopamine D2 and D3 receptors has been pursued in PET imaging studies of various brain functions. We report further evaluation of 18 F-5-OH-FPPAT, and the newer 18 F-5-OH-FHXPAT and 18 F-7-OH-FHXPAT. Syntheses of 18 F-5-OH-FHXPAT and 18 F-7-OH-FHXPAT were improved by modifications of our previously reported procedures. Brain slices and brain homogenates from male Sprague-Dawley rats were used with the 3 radiotracers (74-111 kBq/cc). Competition with dopamine (1-100 nM) and Gpp(NH)p (10-50 µM) were carried out to demonstrate binding to dopamine D2 and D3 HA-states and binding kinetics of 18 F-5-OH-FPPAT measured. Ex vivo brain slice autoradiography was carried out on rats administered with 18 F-5-OH-FHXPAT to ascertain HA-state binding. PET/CT imaging in rats and wild type (WT) and D2 knock-out mice were carried out using 18 F-7-OH-FHXPAT (2-37 MBq). Striatum was clearly visualized by the three radiotracers in brain slices and dopamine displaced more than 80% of binding, with dissociation rate in homogenates of 2.2 × 10-2 min-1 for 18 F-5-OH-FPPAT. Treatment with Gpp(NH)p significantly reduced 50-80% striatal binding with faster dissociation rates (5.0 × 10-2 min-1 ), suggesting HA-state binding of 18 F-5-OH-FPPAT and 18 F-5-OH-FHXPAT. Striatal binding of 18 F-5-OH-FHXPAT in ex vivo brain slices were sensitive to Gpp(NH)p, suggesting HA-state binding in vivo. PET binding ratios of 18 F-7-OH-FHXPAT in rat brain were ventral striatum/cerebellum = 2.09 and dorsal striatum/cerebellum = 1.65; similar binding ratios were found in the D2 WT mice. These results suggest that in vivo PET measures of agonists in the brain at least in part reflect binding to the membrane-bound HA-state of the dopamine receptor.

Comparative analysis of Luminex-based donor-specific antibody mean fluorescence intensity values with complement-dependent cytotoxicity & flow crossmatch results in live donor renal transplantation.

BACKGROUND & OBJECTIVES: Antibodies specific to donor human leucocyte antigen (HLA) play a critical role in graft rejection and graft loss. In recent years, techniques for their detection have evolved significantly providing an ever-increasing degree of sensitivity and specificity, from the conventional cell-based assays to the advanced solid-phase system based on the Luminex platform. Consensus is still evolving on the routine employment of all these methods, either stand alone or in combination. The objective of this study was to explore the near-accurate mean fluorescence intensity (MFI) cut-off values detected on Luminex platform predicting the strength of cell-based crossmatch results. METHODS: Serum samples from 116 primary renal transplant recipients awaiting transplantation were tested for the presence of antidonor antibodies by the complement-dependent cytotoxicity (CDC) and flow crossmatch (FCXM) methods with their corresponding donors as well as for HLA-donor-specific antibodies (DSA) detection using a sensitive single antigen bead (SAB) assay. RESULTS: None of the patients having HLA Class I DSA with MFI values <1000 showed positivity for T-cell FCXM or CDC crossmatch, while in the group having MFI values between 1000 and 3000, 54 per cent showed positivity for the FCXM but none by the CDC method. However, in the group having MFI values >3000, 95 per cent of cases were positive for FCXM. Further, those groups with MFI values between 3000 and 5000, only 36 per cent were positive for CDC crossmatch, while 90 per cent showed positivity in the group with MFI >7000. INTERPRETATION & CONCLUSIONS: A cut-off MFI value of 3000 for Luminex SAB-based assay was found to significantly correlate with the FCXM positivity while a MFI value of 7000 and above predicted a positive CDC crossmatch. MFI cut-off value obtained as a surrogate marker for CDC and FCXM tests will help in resolving the limitations of different cell-based techniques.

Juvenile systemic sclerosis: experience from a tertiary care center from India.

Juvenile systemic sclerosis (JSSc) is a rare disorder with paucity of information on its treatment and longterm  outcome. Herein, we are sharing our experience with this rare entity. Case records of children, diagnosed to have systemic sclerosis attending Pediatric Rheumatology Clinic at All India Institute of Medical Sciences, New Delhi from January 1998 to June 2016 were reviewed. The demographic, clinical, laboratory, treatment and outcome details were recorded. Disease outcome was classified arbitrarily as controlled, partly controlled or non-responsive/progressive based on: (A) ability to perform activities of daily life (ADL) and (B) presence or absence of musculoskeletal symptoms, skin changes (ulceration/progressive digital pitting/gangrene), and visceral organ involvement (dyspahgia, cardiopulmonary symptoms). Controlled: ability to perform ADL and absence of B features for at least 6 months. Partly controlled: inability to perform ADL or any of the B features. Non-responsive/progressive disease: presence of both A and any of B features. Thirty-two children (21, girls) diagnosed as systemic sclerosis for whom follow-up of more than 6 months was available were included for this retrospective analysis. Mean (SD) age at presentation was 112.79 (30.05) months, while the median (IQR) delay in diagnosis was 28.5 (9-47.25) months. Of the 32 children 17 (53.12%) had diffuse systemic sclerosis (dSSc), 5 (15.62%) had limited systemic sclerosis (lSSc) and 10 (31.25%) had sclerosis with overlap syndrome. The common clinical features apart from sclerosis/induration proximal to metacarpophalangeal joint were Raynauds phenomenon (n = 22, 68.7%), skin rash (n = 20, 62%), arthritis or arthralgia (n = 16, 50%), and muscular weakness (n = 10, 31.2%). Among those for whom data regarding investigations were available; ANA was positive in 50% (12/24), whereas Anti Scl70 was positive in one out three cases. Treatment regimen included naproxen, methotrexate, calcium channel blockers with or without steroids. HCQ was added in children with skin rash or in children with partial control. Median (IQR) follow-up period was 19.75 (12-31.75) months. With the above treatment protocol, 19 (59.3%) children achieved disease control on treatment, 8 (26.6%) had partial control while 5 (16.6%) showed no response or progressive disease. Esophageal dysmotility and intertitial lung disease (ILD) were documented in three children each. Complication (cataract and herpes zoster) related to immunosuppressive therapy were observed in two children. There was no mortality during the study period. Juvenile Sclerosis though rare is associated with significant morbidities and lacks a curative treatment but a reasonable quality of life to perform daily activities can be achieved using methotrexate and steroid-based immuosuppressive therapy.

Mitochondria-associated endoplasmic reticulum membrane (MAM) regulates steroidogenic activity via steroidogenic acute regulatory protein (StAR)-voltage-dependent anion channel 2 (VDAC2) interaction.

Steroid hormones are essential for carbohydrate metabolism, stress management, and reproduction and are synthesized from cholesterol in mitochondria of adrenal glands and gonads/ovaries. In acute stress or hormonal stimulation, steroidogenic acute regulatory protein (StAR) transports substrate cholesterol into the mitochondria for steroidogenesis by an unknown mechanism. Here, we report for the first time that StAR interacts with voltage-dependent anion channel 2 (VDAC2) at the mitochondria-associated endoplasmic reticulum membrane (MAM) prior to its translocation to the mitochondrial matrix. In the MAM, StAR interacts with mitochondrial proteins Tom22 and VDAC2. However, Tom22 knockdown by siRNA had no effect on pregnenolone synthesis. In the absence of VDAC2, StAR was expressed but not processed into the mitochondria as a mature 30-kDa protein. VDAC2 interacted with StAR via its C-terminal 20 amino acids and N-terminal amino acids 221-229, regulating the mitochondrial processing of StAR into the mature protein. In the absence of VDAC2, StAR could not enter the mitochondria or interact with MAM-associated proteins, and therefore steroidogenesis was inhibited. Furthermore, the N terminus was not essential for StAR activity, and the N-terminal deletion mutant continued to interact with VDAC2. The endoplasmic reticulum-targeting prolactin signal sequence did not affect StAR association with the MAM and thus its mitochondrial targeting. Therefore, VDAC2 controls StAR processing and activity, and MAM is thus a central location for initiating mitochondrial steroidogenesis.

Passenger protein determines translocation versus retention in the endoplasmic reticulum for aromatase expression.

Aromatase protein is overexpressed in the breasts of women affected with cancer. In the endoplasmic reticulum (ER), signal sequence and signal anchors (SAs) facilitate translocation and topology of proteins. To understand the function of type-I SAs (SA-Is), we evaluated translocation of aromatase, whose signal anchor follows a hydrophilic region. Aromatase SA-I mediates translocation of a short N-terminal hydrophillic domain to ER lumen and integrates the protein in the membrane, with the remainder of the protein residing in the cytosol. We showed that lack of a signal peptidase cleavage site is not responsible for the stop-transfer function of SA-I. However, SA-I could not block the translocation of a full-length microsomal secretory protein and was cleaved as part of the signal sequence. We propose that interaction between the translocon and the region after the signal anchor plays a critical role in directing the topology of the protein by SA-Is. The positive charges in the signal sequence helped it to override the function of signal anchor. Thus, when signal sequence follows SA-I immediately, the interaction with the translocon is perturbed and topology of the protein in ER is altered. If signal sequence is placed far enough from SA-I, then it does not affect membrane integration of SA-I. In summary, we conclude that it is not just the SA-I, but also the region following it, which together affect function of aromatase SA-I in ER.

Multimodality imaging probe for positron emission tomography and fluorescence imaging studies.

Our goal is to develop multimodality imaging agents for use in cell tracking studies by positron emission tomography (PET) and optical imaging (OI). For this purpose, bovine serum albumin (BSA) was complexed with biotin (histologic studies), 5(6)-carboxyfluorescein, succinimidyl ester (FAM SE) (OI studies), and diethylenetriamine pentaacetic acid (DTPA) for chelating gallium 68 (PET studies). For synthesis of BSA-biotin-FAM-DTPA, BSA was coupled to (+)-biotin N-hydroxysuccinimide ester (biotin-NHSI). BSA-biotin was treated with DTPA-anhydride and biotin-BSA-DTPA was reacted with FAM. The biotin-BSA-DTPA-FAM was reacted with gallium chloride 3 to 5 mCi eluted from the generator using 0.1 N HCl and was passed through basic resin (AG 11 A8) and 150 µCi (100 µL, pH 7-8) was incubated with 0.1 mg of FAM conjugate (100 µL) at room temperature for 15 minutes to give 68Ga-BSA-biotin-DTPA-FAM. A shaved C57 black mouse was injected with FAM conjugate (50 µL) at one flank and FAM-68Ga (50 µL, 30 µCi) at the other. Immediately after injection, the mouse was placed in a fluorescence imaging system (Kodak In-Vivo F, Bruker Biospin Co., Woodbridge, CT) and imaged (λex: 465 nm, λem: 535 nm, time: 8 seconds, Xenon Light Source, Kodak). The same mouse was then placed under an Inveon microPET scanner (Siemens Medical Solutions, Knoxville, TN) injected (intravenously) with 25 µCi of 18F and after a half-hour (to allow sufficient bone uptake) was imaged for 30 minutes. Molecular weight determined using matrix-associated laser desorption ionization (MALDI) for the BSA sample was 66,485 Da and for biotin-BSA was 67,116 Da, indicating two biotin moieties per BSA molecule; for biotin-BSA-DTPA was 81,584 Da, indicating an average of 30 DTPA moieties per BSA molecule; and for FAM conjugate was 82,383 Da, indicating an average of 1.7 fluorescent moieties per BSA molecule. Fluorescence imaging clearly showed localization of FAM conjugate and FAM-68Ga at respective flanks of the mouse, whereas only a hot spot at the expected flank (FAM-68Ga injection site) was observed in microPET imaging. Our results suggest that BSA-biotin-DTPA-FAM may function as a multiprobe for PET and fluorescence imaging. Experiments are currently in progress to demonstrate cell tracking using both optical and nuclear imaging.

Predicting the bioactive compounds of Lentinula edodes and elucidating its interaction with genes associated to obesity through network pharmacology and in-vitro cell-based assay.

Mushrooms are traditionally used for various medicinal purposes in traditional oriental medicine. The Japanese and Chinese are familiar with the medicinal macro fungus Lentinula edodes (Shiitake mushroom). This study aims to evaluate the role of chemical compounds from L. edodes using network pharmacology and in-vitro studies for management of Obesity. Bioactive compounds in extracts of L. edodes were identified by GC-MS analysis. Compounds were later screened for their drug-like property by Lipinski's rule. In addition, public databases (SEA, STP, Omim and DisGenet) were searched to identify genes associated with selected molecules and obesity, as well as genes that overlap obesity target genes with genes related to L. edodes. Additionally, analysis was performed using Enrichr KG to predict the disease targets of L. edodes. Finally, network was constructed between the overlapping genes and bioactive molecules using Rstudio. Further in-vitro studies were carried out using 3T3-L1 cell line. The genes related to the selected compounds and obesity were identified and overlapped. The disease targets of L. edodes was predicted by enrichment analysis and was found to be linked to obesity. Furthermore, the hub gene was found to be fatty acid amide hydrolase, and the key bioactive compound was hexadecanoic acid methyl ester. The in-vitro cell culture studies confirmed the inhibition of adipogenesis in mushroom extract-treated 3T3-L1 cells and the augmentation of adiponectin. The study suggests that the hub gene fatty acid amide hydrolase might alleviate obesity by inhibiting arachidonoyl ethanolamide signaling, which would enhance the action of fatty acid amide hydrolase and limit appetite in L. edodes extract.

Prevalence of Ear Disease and Associated Hearing Loss Among Government Rural Primary School Students in Patiala, Punjab: A Cross Sectional Survey.

Ear disease in children are a major public health problem in developing countries and if left untreated, it may result in various social and psychological problems for affected children. Among all ear diseases, ear infections are a common but treatable cause of morbidity in children. Long term consequences of persistent severe ear infection can result in speech development disorders, poor academic and educational development and overall lower quality of life. Most of ear diseases leading to hearing loss are preventable if diagnosed and treated early. A cross sectional study was conducted in Government Rural Primary School students, 2160 students in Patiala district of Punjab state in India with aim to study the prevalence of ear disease and associated hearing loss in students and their relationship with socioeconomic status. The data was collected, compiled and analysed statistically.

Cholesterol-mediated conformational changes in the steroidogenic acute regulatory protein are essential for steroidogenesis.

Although the mechanism by which the steroidogenic acute regulatory protein (StAR) promotes steroidogenesis has been studied extensively, it remains incompletely characterized. Because structural analysis has revealed a hydrophobic sterol-binding pocket (SBP) within StAR, this study sought to examine the regulatory role of cholesterol concentrations on protein folding and mitochondrial import. Stopped-flow analyses revealed that at low concentrations, cholesterol promotes StAR folding. With increasing cholesterol concentrations, an intermediate state is reached followed by StAR unfolding. With 5 µg/mL cholesterol, the apparent binding was 0.011 s(-1), and the unfolding time (t1/2) was 63 s. The apparent binding increased from 0.036 to 0.049 s(-1) when the cholesterol concentration was increased from 50 µg/mL to 100 µg/mL while t1/2 decreased from 19 to 14 s. These cholesterol-induced conformational changes were not mediated by chemical chaperones. Protein fingerprinting analysis of StAR in the absence and presence of cholesterol by mass spectrometry revealed that the cholesterol binding region, comprising amino acids 132-188, is protected from proteolysis. In the absence of cholesterol, a longer region of amino acids from position 62 to 188 was protected, which is suggestive of organization into smaller, tightly folded regions with cholesterol. In addition, rapid cholesterol metabolism was required for the import of StAR into the mitochondria, suggesting that the mitochondria have a limited capacity for import and processing of steroidogenic proteins, which is dependent on cholesterol storage. Thus, cholesterol regulates StAR conformation, activating it to an intermediate flexible state for mitochondrial import and its enhanced cholesterol transfer capacity.

Purinergic signaling: Diverse effects and therapeutic potential in cancer.

Regardless of improved biological insights and therapeutic advances, cancer is consuming multiple lives worldwide. Cancer is a complex disease with diverse cellular, metabolic, and physiological parameters as its hallmarks. This instigates a need to uncover the latest therapeutic targets to advance the treatment of cancer patients. Purines are building blocks of nucleic acids but also function as metabolic intermediates and messengers, as part of a signaling pathway known as purinergic signaling. Purinergic signaling comprises primarily adenosine triphosphate (ATP) and adenosine (ADO), their analogous membrane receptors, and a set of ectonucleotidases, and has both short- and long-term (trophic) effects. Cells release ATP and ADO to modulate cellular function in an autocrine or paracrine manner by activating membrane-localized purinergic receptors (purinoceptors, P1 and P2). P1 receptors are selective for ADO and have four recognized subtypes-A1, A2A, A2B, and A3. Purines and pyrimidines activate P2 receptors, and the P2X subtype is ligand-gated ion channel receptors. P2X has seven subtypes (P2X1-7) and forms homo- and heterotrimers. The P2Y subtype is a G protein-coupled receptor with eight subtypes (P2Y1/2/4/6/11/12/13/14). ATP, its derivatives, and purinoceptors are widely distributed in all cell types for cellular communication, and any imbalance compromises the homeostasis of the cell. Neurotransmission, neuromodulation, and secretion employ fast purinergic signaling, while trophic purinergic signaling regulates cell metabolism, proliferation, differentiation, survival, migration, invasion, and immune response during tumor progression. Thus, purinergic signaling is a prospective therapeutic target in cancer and therapy resistance.