Unleashing unprecedented activation of high-valent Ni and Fe charge dynamics in CeF3-NiFe layered double hydroxide heterostructure: Demonstrating oxygen evolution reaction at an extremely high current density.

The efficacy of any electrochemical reaction hinges on the extent of interaction achievable between reactive intermediates and the electrocatalytic active site. Any weak adsorption of these intermediates on the metal's active site results in low oxygen evolution reaction (OER) rates, mainly when catalysed by the Ni-based layered double hydroxide. To tackle this challenge, a heterojunction consisting of nickel-iron layered double hydroxide (NiFe-LDH) and cerium trifluoride (CeF3) is synthesized. Both phases were developed in-situ to have an abundance of heterointerfaces. The charge transfer amid the NiFe-LDH and CeF3 phases is brought about via these heterointerfaces. As a result, the overall charge dynamics associated with nickel (Ni) and iron (Fe) atoms are somewhat increased, and an enhanced positive charge on the metal site makes it more active in grabbing the reactive species, thereby making the entire OER process faster. The CeF3-NiFeLDH catalyst reaches a current density of 1000 mA cm-2 at an overpotential of 340 mV. Such a high current density is highly significant for the industrial-scale production of the products. The catalyst demonstrated impressive durability, maintaining stable performance for 90 h while operating at 500 mA cm-2. The charge dynamics between both phases were thoroughly examined using X-ray photoelectron spectroscopy (XPS).

Electronic redistribution through the interface of MnCo2O4-Ni3N nano-urchins prompts rapid In situ phase transformation for enhanced oxygen evolution reaction.

One of the most coveted objectives in the realm of energy conversion technologies is the development of highly efficient and economically viable electrocatalysts for the oxygen evolution reaction. The commercialization of such techniques has thus far been impeded by their slow response kinetics. One of the many ways to develop highly effective electrocatalysts is to judiciously choose a coupling interface that maximizes catalyst performance. In this study, the in situ electrochemical phase transformation of MnCo2O4-Ni3N into MnCo2O4-NiOOH is described. The catalyst has an exceptional overpotential of 224 mV to drive a current density of 10 mA cm-2. Strong interfacial contact is seen in the MnCo2O4-Ni3N catalyst, leading to a considerable electronic redistribution between the MnCo2O4 and Ni3N phases. This causes an increase in the valence state of Ni, which makes it an active site for the adsorption of *OH, O*, and *OOH (intermediates). This charge transfer facilitates the rapid phase transformation to form NiOOH from Ni3N. At a higher current density of 300 mA cm-2, the catalyst remained stable for a period of 140 h. DFT studies also revealed that the in situ-formed NiOOH on the MnCo2O4 surface results in superior OER kinetics compared to that of NiOOH alone.

Valorization of grape (Vitis vinifera) leaves for bioactive compounds: novel green extraction technologies and food-pharma applications.

Grape leaves, scientifically known as Vitis vinifera, the primary by-product obtained after the processing of grapes, are gathered in enormous amounts and disposed of as agricultural waste. For more sustainable agriculture and better food systems, it is crucial to investigate these byproducts' nutritional values. The primary bioactive compounds present in grape leaves are quercetin, resveratrol, caffeic acid, kaempferol, and gallic acid, which favour pharmacological effects on human health such as antioxidant, anti-inflammatory, anti-obesity, anti-diabetic, and hepatoprotective. Furthermore, grape leaves extract has been used as a functional ingredient for creating both food and non-food products. The aim of the current review is to review the nutritional and phytochemical composition of various varieties of grape leaves, their health-promoting characteristics and their applications. The study also highlights the various extraction techniques including conventional and non-conventional methods for extracting the various bioactive compounds present in grape leaves. Grape leaves bioactives can be extracted using environmentally safe and sustainable processes, which are in line with the rising demand for eco-friendly and healthful products worldwide. These methods are perfectly suited to the changing needs of both customers and industries since they lessen environmental effect, enhance product quality, and offer financial advantages.

Composite Classical Hodgkin Lymphoma and Mantle Cell Lymphoma: A Case Report.

Composite lymphoma implies the presence of two or more morphological and immunophenotypical subtypes of lymphoma in a single tissue or organ. Composite lymphoma with concurrent mantle cell lymphoma (MCL) and classical Hodgkin lymphoma is extremely rare. In this case report, we present the case of a 70-year-old male who was diagnosed with a composite of MCL and classical Hodgkin lymphoma (cHL) and achieved near-complete resolution with chemoimmunotherapy. To the best of our knowledge, this is the first case of this kind demonstrating the effectiveness of a combination chemoimmunotherapy regimen leading to complete remission in composite lymphoma involving MCL and cHL. We report the history, imaging findings, and pathology and illustrate the challenges in therapeutic decision-making in managing composite lymphoma patients involving MCL and cHL. We also review the literature on this rare entity and discuss its clinical implications.

Chemoresistance Mechanisms in Non-Small Cell Lung Cancer-Opportunities for Drug Repurposing.

Globally, lung cancer contributes significantly to the public health burden-associated mortality. As this form of cancer is insidious in nature, there is an inevitable diagnostic delay leading to chronic tumor development. Non-small cell lung cancer (NSCLC) constitutes 80-85% of all lung cancer cases, making this neoplasia form a prevalent subset of lung carcinoma. One of the most vital aspects for proper diagnosis, prognosis, and adequate therapy is the precise classification of non-small cell lung cancer based on biomarker expression profiling. This form of biomarker profiling has provided opportunities for improvements in patient stratification, mechanistic insights, and probable druggable targets. However, numerous patients have exhibited numerous toxic side effects, tumor relapse, and development of therapy-based chemoresistance. As a result of these exacting situations, there is a dire need for efficient and effective new cancer therapeutics. De novo drug development approach is a costly and tedious endeavor, with an increased attrition rate, attributed, in part, to toxicity-related issues. Drug repurposing, on the other hand, when combined with computer-assisted systems biology approach, provides alternatives to the discovery of new, efficacious, and safe drugs. Therefore, in this review, we focus on a comparison of the conventional therapy-based chemoresistance mechanisms with the repurposed anti-cancer drugs from three different classes-anti-parasitic, anti-depressants, and anti-psychotics for cancer treatment with a primary focus on NSCLC therapeutics. Certainly, amalgamating these novel therapeutic approaches with that of the conventional drug regimen in NSCLC-affected patients will possibly complement/synergize the existing therapeutic modalities. This approach has tremendous translational significance, since it can combat drug resistance and cytotoxicity-based side effects and provides a relatively new strategy for possible application in therapy of individuals with NSCLC.

Synergistic modulation in a triphasic Ni5P4-Ni2P@Ni3S2 system manifests remarkable overall water splitting.

The potential for water splitting electrocatalysts with high efficiency paves the way for a sustainable future in hydrogen energy. However, this task is challenging due to the sluggish kinetics of the oxygen evolution reaction (OER), which has a significant impact on the hydrogen evolution reaction (HER). Herein multi-heterointerface of Ni5P4-Ni2P@Ni3S2 was fabricated by a two-step synthesis procedure that consist the development of Ni5P4-Ni2P nanosheets over nickel foam followed by the electrodeposition of Ni3S2. The HR-TEM analysis shows that the Ni5P4-Ni2P@Ni3S2 nanosheets array provide numerous well-exposed diverse heterointerfaces. The electrochemical investigations conducted on the Ni5P4-Ni2P@Ni3S2 nanosheets for complete water splitting indicate that they possess an overpotential of 73 mV and 230 mV in HER and OER respectively, enabling them to generate a current density of 10 and 50 mA cm-2. The nanosheets also demonstrate Tafel slope values of 95 mV dec-1 and 83 mV dec-1 for HER and OER, respectively. The HER stability of the catalyst was conducted for 45 h using chronoamperometric technique under a current density of 20 mA cm-1, while the stability test for OER was carried out at current densities of 100 and 200 mA cm-1 for 100 h each. Furthermore, in the overall water splitting, the catalyst exhibits a cell voltage of 1.47 V@10 mA cm-2 and displayed a stability operation for 100 h at a current density of 150 mA cm-1.

Structural and molecular insights into tacrine-benzofuran hybrid induced inhibition of amyloid-ß peptide aggregation and BACE1 activity.

Amyloid-ß (Aß) aggregation and ß-amyloid precursor protein cleaving enzyme 1 (BACE1) are the potential therapeutic drug targets for Alzheimer's disease (AD). A recent study highlighted that tacrine-benzofuran hybrid C1 displayed anti-aggregation activity against Aß42 peptide and inhibit BACE1 activity. However, the inhibition mechanism of C1 against Aß42 aggregation and BACE1 activity remains unclear. Thus, molecular dynamics (MD) simulations of Aß42 monomer and BACE1 with and without C1 were performed to inspect the inhibitory mechanism of C1 against Aß42 aggregation and BACE1 activity. In addition, a ligand-based virtual screening followed by MD simulations was employed to explore potent new small-molecule dual inhibitors of Aß42 aggregation and BACE1 activity. MD simulations highlighted that C1 promotes the non aggregating helical conformation in Aß42 and destabilizes D23-K28 salt bridge that plays a vital role in the self-aggregation of Aß42. C1 displays a favourable binding free energy (-50.7 ± 7.3 kcal/mol) with Aß42 monomer and preferentially binds to the central hydrophobic core (CHC) residues. MD simulations highlighted that C1 strongly interacted with the BACE1 active site (Asp32 and Asp228) and active pockets. The scrutiny of interatomic distances among key residues of BACE1 highlighted the close flap (non-active) position in BACE1 on the incorporation of C1. The MD simulations explain the observed high inhibitory activity of C1 against Aß aggregation and BACE1 in the in vitro studies. The ligand-based virtual screening followed by MD simulations identified CHEMBL2019027 (C2) as a promising dual inhibitor of Aß42 aggregation and BACE1 activity.Communicated by Ramaswamy H. Sarma.

Deep neural network for food image classification and nutrient identification: A systematic review.

Technology impacts human life in both the aspects such as positive and negative, which helps in better communication and eliminating geographical boundaries. However, social media and mobile devices may lead to severe health conditions such as sleep problems, depression, obesity, etc. A systematic review is conducted to analyze health issues by tracking food intake by considering positive aspects using Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) Guidelines. The major scientific databases (such as Web of Science, Scopus, and IEEE explore) are explored to search the image recognition and analysis articles. The search query is applied to the databases using keywords like "Food Image," "Food Image Classification," "Nutrient Identification," "Nutrient Estimation," and using "Machine Learning," etc. 771 articles are extracted from these databases, and 56 are identified for final consideration after rigorous screening. A few investigations are extracted based on available food image datasets, hyperparameters tuning, a technique used, performance metrics, and challenges of Food Image Classification (FIC). This study discusses different investigations with their proposed FIC and nutrient estimation solution. Finally, this intensive research presents a case study using FIC and object detection techniques to estimate nutrition with food image analysis.

Comparative evaluation of phenotypic and genotypic methods for the rapid and cost-effective detection of carbapenemases in extensively drug resistant Klebsiella pneumoniae.

PURPOSE: Carbapenemases are the enzymes that can hydrolyze carbapenems and other ß-lactam antibiotics. These enzymes confer resistance to multiple antibiotics and act as a stumbling block in the treatment of infections caused by gram-negative bacteria. Therefore, rapid and specific detection of these enzymes is crucial for deciding the course of treatment and better clinical outcomes. MATERIAL AND METHODS: This study was conducted to compare various phenotypic and PCR based methods for the detection of carbapenemases in carbapenem- and colistin-resistant Klebsiella pneumoniae. One hundred clinical isolates of extensively resistant Klebsiella pneumoniae were included in the study. Phenotypic detection for carbapenemases was performed by Rapidec® Carba NP (Biomerieux), modified carbapenem inactivation method (mCIM), imipenem-ethylenediaminetetraacetic acid disk synergy (EDS), double disk synergy test using mercaptopropionic acid (DDST-MPA), and combined disk method (CD) and for colistin by microbroth dilution method. Genotypic detection for carbapenemases and colistin resistance was performed by targeted PCR. RESULTS: The sensitivity of Carba NP test and mCIM were positive in 95% and 96% respectively and specificity was 100% for both methods. The sensitivity of EDS, DDST-MPA, and CD were 55.6%, 88.9% and 54.5% respectively. Among the carbapenem resistance genes, blaOXA-48 (82%) genes were the most prevalent. Among metallo-beta lactamases, blaVIM (56%) was most common followed by blaNDM (54%) and blaIMP (20%). The mcr-1 gene for colistin resistance was not detected in any isolate. CONCLUSION: Among the five phenotypic assays analyzed, the mCIM is the most simple, inexpensive, accurate and reproducible method for carbapenemase detection in Klebsiella pneumoniae. The DDST-MPA test provides the best sensitivity for the detection of carbapenemases, although specificity is low. These tests, when applied in a clinical laboratory and assessed by the microbiologist, can help in guiding the course of treatment.

AIE+ESIPT Active Hydroxybenzothiazole for Intracellular Detection of Cu2+: Anticancer and Anticounterfeiting Applications.

Here, in the present work, a new hydroxybenzothiazole derivative (HBT 2) with AIE+ESIPT features was synthesized by Suzuki-Miyora coupling of HBT 1 with 4-formylphenylboronic acid. The AIE and ESIPT features were confirmed by optical, microscopic (AFM) and dynamic light scattering (DLS) techniques. The yellow fluorescent aggregates of HBT 2 can specifically detect Cu2+/Cu+ ions with limits of detection as low as 250 nM and 69 nM. The Job's plot revealed the formation of a 1:1 complex. The Cu2+ complexation was further confirmed by optical, NMR, AFM and DLS techniques. HBT 2 was also used for the detection of Cu2+ ions in real water samples collected from different regions of Punjab. HBT 2 was successfully used for the bio-imaging of Cu2+ ions in live A549 and its anticancer activity was checked on different cancer cell lines, such as MG63, and HeLa, and normal cell lines such as L929. We successfully utilized HBT 2 to develop security labels for anticounterfeiting applications.

Predicting risk of obesity and meal planning to reduce the obese in adulthood using artificial intelligence.

BACKGROUND: An unhealthy diet or excessive amount of food intake creates obesity issues in human beings that further may cause several diseases such as Polycystic Ovary Syndrome (PCOS), Cardiovascular disease, Diabetes, Cancers, etc. Obesity is a major risk factor for PCOS, which is a common disease in women and is significantly correlated with weight gain. METHODS: This study is providing a one-step solution for predicting the risk of obesity using different Machine Learning (ML) algorithms such as Gradient Boosting (GB), Bagging meta-estimator (BME), XG Boost (XGB), Random Forest (RF), Support Vector Machine (SVM), and K Nearest Neighbour (KNN). A dataset is collected from the UCI ML repository having features of physical description and eating habits of individuals to train the proposed model. RESULTS: The model has been experimented with different training and testing data ratios such as (90:10, 80:20, 70:30,60:40). At a data ratio of 90:10, the GB classifier achieved the highest accuracy i.e., 98.11%. Further, at the 80:20 ratio, the GB and XGB provide the same result i.e., 97.87%. For the 70:30 data ratio, XGB achieves the highest accuracy i.e., 97.79%. Further, the Nearest Neighbour (NN) learning method is applied to meal planning to overcome obesity. CONCLUSION: This method predicts the meal which includes breakfast, morning snacks, lunch, evening snacks, and dinner for the individual as per caloric and macronutrient requirements. The proposed research work can be used by practitioners to check obesity levels and to suggest meals to reduce the obese in adulthood.

Identification of novel pathogenic variants in the GCDH gene and assessment of neurodevelopmental outcomes in 24 children with glutaric aciduria type 1.

AIM: To evaluate the pathogenic variants in GCDH gene and to assess the neurodevelopmental outcomes in children with Glutaric aciduria type 1 (GA-1). METHOD: Cross-sectional observational study between January 2019 and June 2020 in consecutive North Indian children with a clinical and biochemical suspicion of GA-1. Variants in the coding regions of GCDH gene were identified through Sanger sequencing. Neurodevelopmental and quality of life assessment was done using standardized scales. RESULTS: 24 children with GA-1 were identified. The median age at diagnosis was 12 months and the median delay in diagnosis was 3 months. Genetic analysis was done in 14 cases. It revealed 12 variants (11 missense and one nonsense) from 13 patients. Most of the pathogenic variants were in exon 9 and exon 5. Three novel variants were identified in three patients: two missense variants c.169G > A (p.Glu57Lys), c.1048T > C (p.Cys350Arg) and one nonsense variant c.331C > T (p.Lys111Ter). On neurodevelopmental assessment, majority of children with GA-1 were non ambulatory (62.5%), had limited hand skills (58.3%) and impaired communication (58.3%). Overall, poor global development was noted in 43.7%. A pre-existing developmental delay was significantly associated with impaired communication skills (p = 0.03), and the number of episodes of encephalopathy were significantly associated with impaired gross motor skill (p = 0.02). Presence of encephalopathy was significantly associated with poor performance in social emotional (p = 0.01) and cognitive (p = 0.03) domains of Developmental Profile-III scale and development of severe dystonia (p = 0.01). CONCLUSION: Our findings highlight the clinical, biochemical, radiological and genetic spectrum of GA-1 in children in North India and report the presence of novel pathogenic variations.

Detection of IEMs by Mass Spectrometry Techniques in High-Risk Children: A Pilot Study.

OBJECTIVES: To determine the incidence and types of inborn errors of metabolism (IEMs) in high-risk children using mass spectrometry techniques. METHODS: Children considered high-risk for IEM were screened for metabolic diseases during a 3-y period. Dried blood spots and urine samples were analyzed by tandem mass spectrometry (LC-MS/MS) and gas chromatograph-mass spectrometry (GCMS). Samples with abnormal amino acids were confirmed by high-performance liquid chromatography (HPLC). RESULTS: Eight hundred and twenty-two suspected cases were evaluated; of which, 87 possible cases of IEMs were identified. Homocystinuria (n = 51) was the most common IEM detected followed by biotinidase deficiency (n = 7), glutaric aciduria type 1 (n = 7), and carnitine uptake defect (n = 6). Overall, there were 45 (51.7%) cases of organic acidemia, 31 cases (35.6%) of amino acid defect, 9 (10.3%) cases of fatty-acid oxidation disorders, and 2 (2.3%) cases of probable mitochondrial disorder. CONCLUSION: IEMs are common in India, with a hospital-based incidence of 1 in approximately 6642 among high-risk children. Screening of high-risk children by mass spectrometry techniques is a valuable strategy for early diagnosis of IEMs where universal newborn screening is not yet available.

Pharmacokinetic-Pharmacodynamic Study of Ampicillin-Cloxacillin Combination in Indian Thoroughbred Horses (Equus caballus) and Safety Evaluation of the Computed Dosage Regimen.

The pharmacokinetics of ampicillin-cloxacillin, given as single intravenously dose of 10 mg.kg-1 (5 mg.kg-1 of ampicillin plus 5 mg.kg-1 of cloxacillin) was examined in clinically presented Indian thoroughbred horses (n = 6) in order to design appropriate dosing strategies. Drug concentrations in plasma were determined by high performance liquid chromatography (HPLC) and pharmacokinetic parameters were derived by non-compartmental analysis using WinNonlin software. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of ampicillin-cloxacillin against quality control strains of Escherichia coli and Staphylococcus aureus, grown in Muller Hinton Broth, were determined by broth microdilution method. For ampicillin, area under plasma drug concentration time curve (AUC) was 15.2 ± 0.54 µg.h.ml-1, mean residence time (MRT) was 1.33 ± 0.06 h and clearance (Cl) was 0.33 ± 0.01 L.h-1.kg-1. For cloxacillin, AUC was 18.0 ± 0.9 µg.h.ml-1, MRT was 1.28 ± 0.02 h and Cl was 0.28 ± 0.01 L.h-1.kg-1. MIC of ampicillin-cloxacillin combination against E. coli and S. aureus was determined to be 0.4 µg.ml-1. PK-PD integration indicated that to maintain %T > MIC value 50% for bacteria with MIC ≤ 0.4 µg.ml-1, an appropriate intravenous dosage regimen of ampicillin-cloxacillin combination in horses would be 15 mg.kg-1 (i.e. 7.5 mg.kg-1 of ampicillin plus 7.5 mg.kg-1 of cloxacillin), to be repeated at 12 h intervals. Safety profile of the recommended regimen did not significantly alter any of the 16 biochemical or haematological parameters studied.

Protective effect of rosuvastatin pretreatment against acute myocardial injury by regulating Nrf2, Bcl-2/Bax, iNOS, and TNF-α expressions affecting oxidative/nitrosative stress and inflammation.

Cardiovascular disorders are the leading cause of death globally. Rosuvastatin is a member of statins (inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase) with many pleiotropic properties. This study investigated cardioprotective effects of rosuvastatin in isoprenaline-induced myocardial injury. Male rats were given rosuvastatin (1, 5, or 10 mg/kg, oral) daily for 1 week and on seventh and eighth day isoprenaline (150 mg/kg, subcutaneous) was given to induce cardiac injury. On ninth day, rats were euthanized and different samples were harvested for analysis. Isoprenaline administration resulted in increased cardiac mass, increased cardiac injury marker levels (cTnI, CK-MB, ALT, and AST), increased lipid/protein oxidation, and increased cardiac nitrite levels. It also decreased superoxide dismutase, CAT, GST, and glutathione reductase activities, and total antioxidant activity. Isoprenaline also increased TNF-α and IL-6 levels. Decreased mRNA expression of Nrf2 and Bcl-2 along with increased mRNA expression of Bax, eNOS and iNOS genes was observed in isoprenaline treated animals. Histopathological evaluations of rosuvastatin pre-treated groups showed reduction of myocardial necrosis. Pretreatment with rosuvastatin (5 and 10 mg/kg) reduced many of these pathological changes. The current study showed that rosuvastatin significantly reduces myocardial injury induced by isoprenaline.

Neurodegeneration and Early Infantile Epilepsy Associated with ITPA Variants: A Case Series and Review of Literature.

BACKGROUND: Inosine triphosphate pyrophosphohydrolase (ITPase) deficiency associated with mutations in the ITPA gene is a recently characterized purine pathway defect that presents with early infantile epileptic encephalopathy and lethal course. This disorder is rare, and only 12 cases are reported worldwide. METHODS: We report two additional cases of ITPA-associated neurodegeneration and two pathogenic compound heterozygous variants. We also reviewed the previously published cases of ITPA-associated encephalopathy. RESULTS: Both cases presented with progressive infantile-onset encephalopathy, severe developmental delay, microcephaly, facial dysmorphism, and epilepsy. Together with the presented two cases, 14 cases were available for analysis. The mean age of presentation was 16.7 ± 12.4 months (range 3-48 m). The most common clinical features at presentation were developmental delay, seizures, microcephaly, and hypotonia, seen in all 14 (100%) patients. The mean age of seizure onset was 4.75 months (range 2-14 m). Cardiomyopathy was noted in 42% of patients where it was explicitly evaluated (n = 5/12). Consanguinity was reported in 77% of the cases. The cardinal neuroradiological features are T2-signal abnormalities and diffusion restriction in the long tracts, especially the posterior limb of the internal capsule and the optic radiation. The majority of the patients died before 4 years of age (85.7%). CONCLUSION: ITPA-related encephalopathy presents with infantile-onset neurodegeneration, progressive microcephaly, and epilepsy. Progressive brain atrophy and diffusion restriction in the white matter tracts are important radiological clues.

Metabolic epilepsy in hyperprolinemia type II due to a novel nonsense ALDH4A1 gene variant.

Hyperprolinemia type II (HPII) is a rare autosomal recessive disorder of proline degradation pathway due to deficiency of delta-1-pyrroline-5-carboxylate dehydrogenase. Pathogenic variants in the ALDH4A1 gene are responsible for this disorder. We here describe an 11-month-old infant with recurrent seizures refractory to multiple antiepileptic drugs. She was hospitalized in view of acute-onset encephalopathy, exacerbation of generalized seizures following an upper respiratory infection. Laboratory investigation revealed significantly elevated proline levels in dried blood spots. DNA sample of the child was subjected to a targeted next-generation sequencing gene panel for hyperprolinemias. We detected a novel nonsense homozygous variant in the ALDH4A1 gene in the child and the heterozygous variant of the same in both the parents. Based on the location of the variant i.e. in the last exon, truncated protein is expected to be expressed by skipping nonsense-mediated decay and such point-nonsense variants could be an ideal target for readthrough drugs to correct genetic defects.

A high frequency and geographical distribution of MMACHC R132* mutation in children with cobalamin C defect.

Cobalamin C defect is caused by pathogenic variants in the MMACHC gene leading to impaired conversion of dietary vitamin B12 into methylcobalamin and adenosylcobalamin. Variants in the MMACHC gene cause accumulation of methylmalonic acid and homocysteine along with decreased methionine synthesis. The spectrum of MMACHC gene variants differs in various populations. A total of 19 North Indian children (age 0-18 years) with elevated methylmalonic acid and homocysteine were included in the study, and their DNA samples were subjected to Sanger sequencing of coding exons with flanking intronic regions of MMACHC gene. The genetic analysis resulted in the identification of a common pathogenic nonsense mutation, c.394C > T (R132*) in 85.7% of the unrelated cases with suspected cobalamin C defect. Two other known mutations c.347T > C (7%) and c.316G > A were also detected. Plasma homocysteine was significantly elevated (> 100 µmol/L) in 75% of the cases and methionine was decreased in 81% of the cases. Propionyl (C3)-carnitine, the primary marker for cobalamin C defect, was found to be elevated in only 43.75% of cases. However, the secondary markers such as C3/C2 and C3/C16 ratios were elevated in 87.5% and 100% of the cases, respectively. Neurological manifestations were the most common in our cohort. Our findings of the high frequency of a single MMACHC R132* mutation in cases with combined homocystinuria and methylmalonic aciduria may be proven helpful in designing a cost-effective and time-saving diagnostic strategy for resource-constraint settings. Since the R132* mutation is located near the last exon-exon junction, this is a potential target for the read-through therapeutics.

Investigating the role of nitric oxide in stress adaptive process in electric foot shock stress-subjected mice.

AIM: The present study was designed to investigate the role of nitric oxide (NO) in the non-development of stress adaptation in high-intensity foot-shock stress (HIFS) subjected mice. METHODS: Mice were subjected to low-intensity shocks (LIFS i.e. 0.5 mA) or HIFS (1.5 mA) for 5 days. Stress-induced behavioral changes were assessed by actophotometer, hole board, open field and social interaction tests. Biochemically, the serum corticosterone levels were measured as a marker of stress. L-arginine (100 mg/kg and 300 mg/kg), as NO donor, and L-NAME (10 mg/kg and 30 mg/kg), as nitric oxide synthase (NOS) inhibitor, were employed as pharmacological agents. RESULTS: A single exposure of LIFS and HIFS produced behavioral and biochemical alterations. However, there was the restoration of behavioral and biochemical alterations on 5th day in response to repeated LIFS exposure suggesting the development of stress adaptation. However, no stress adaptation was observed in HIFS subjected mice. Administration of L-arginine (300 mg/kg) abolished the stress adaptive response in LIFS-subjected mice, while L-NAME (30 mg/kg) induced the development of stress adaptation in HIFS subjected mice. CONCLUSION: It is concluded that an increase in the NO release may possibly impede the process of stress adaptation in HIFS-subjected mice.

Bioaccumulation of pesticide contaminants in tissue matrices of dogs suffering from malignant canine mammary tumors in Punjab, India.

The unprecedented application of pesticides in Punjab, India during green revolution has lead to an environmental crisis due to the accumulation of persistent organic and pesticide pollutants in the environment and biota of this region. The present study aimed at estimating the abundance of pesticide contaminants in three biological matrices of 36 dogs suffering from malignant canine mammary tumor (mCMT) and 6 tumor free control dogs from Punjab, India. Presence of individual and total pesticides in canine biological samples, age and bodyweight of canine patients was assessed as a potential risk factor for mCMT using logistic regression analysis. Chi-square test was employed to determine tissue-specific accumulations of individual pesticides. Spearman's correlation coefficient was estimated to determine the association between the levels of total pesticides in different tissue matrices and with age and bodyweight of mCMT cases. Gas chromatography-ECD analysis of serum, mammary tissue and adjoining mammary adipose tissue revealed fourteen different pesticides including γ-HCH, α-HCH, dieldrin, aldrin, heptachlor, butachlor, p,p-DDT, o,p-DDT, p,p-DDD, p,p-DDE, L-cyhalothrin, permethrin, fipronil, and fenitrothion. Heptachlor, γ-HCH, aldrin and p,p-DDT were more frequently detected, whereas, p,p-DDE and o,p-DDT were the least common. Differential accumulation of pesticides in tissue matrices, particularly between serum and mammary tissue/adipose tissue was observed. We could not find any association between the total pesticide concentrations among serum, mammary tissue and mammary adipose tissue in mCMT cases. We found that the odds for individual pesticide for serum, mammary tissue and adipose tissue were associated with high uncertainties; however, the total pesticide concentration in mammary tissue was near non-significantly associated with higher risk of mCMT with low uncertainty. Statistically non-significant higher odds of CMT occurrence with increase in age was noticed No association between the concentration of total pesticides in different matrices and age and bodyweight of canine subjects was found.