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In the present work, we construct a Dunkl generalization of the modified Szász-Mirakjan operators of integral form defined by Pǎltanea [1]. We study the approximation properties of these operators including weighted Korovkin theorem, the rate of convergence in terms of the modulus of continuity, second order modulus of continuity via Steklov-mean, the degree of approximation for Lipschitz class of functions and the weighted space. Furthermore, we obtain the rate of convergence of the considered operators with the aid of the unified Ditzian-Totik modulus of smoothness and for functions having derivatives of bounded variation.

Alzheimer's disease (AD) is a global burden to the healthcare system with no viable treatment options till date. Rodents and primates have been extensively used as models for understanding AD pathogenesis and identifying therapeutic targets. However, the focus is now shifting towards developing alternate models. Zebrafish is emerging as a preferred model for neurodegenerative conditions because of its simple nervous system, highly conserved genome and short duration required to model disease condition. The present study is aimed to develop streptozotocin (STZ)-induced model of sporadic AD (sAD) in zebrafish. STZ was administered to adult zebrafish (4-6 mo) at different doses (1 to 50 mg/kg body weight, intracerebroventricularly). Kaplan-Meier survival analysis revealed time and dose dependent mortality in the zebrafish administered with STZ. Based on survival analysis, 1 to 10 mg/kg body weight of STZ was selected for behavioural, molecular and histological studies. STZ administered fish had anxiety and stress-like behaviour in novel tank and light/dark preference tests. STZ-induced cognitive and memory deficits assessed using novel object recognition and spatial alternation tests. Further, expression of markers of amyloidogenic pathway (appa and bace1) were increased in terms of mRNA and protein levels in a time and dose dependent manner following STZ administration. However, expression of non-amyloidogenic pathway mediator (adam10) was reduced at both mRNA and protein level. Histological assessment using hematoxylin and eosin, and Nissl stain revealed loss of neurons in STZ administered fish. The ratio of phosphor-tau ser396 /total-tau was increased in STZ administered fish. Based on these findings, 5 mg/kg body weight of STZ was found to be most appropriate dose to exhibit sAD phenotype. Mass spectrometric analysis confirmed the presence of amyloid beta oligomers in brains of STZ administered fish. Transmission electron microscopy also showed the presence of higher order insoluble amyloid fibrils with twists. Immunohistochemical analysis revealed amyloid beta deposits in brain of STZ administered fish. Golgi-cox staining indicated decreased number of dendrites, whereas microglia had increased density, span ratio, soma area and lacunarity. The results of the present study demonstrate presence of AD hallmarks and phenotype in zebrafish 7 days post STZ administration (5 mg/kg). The study validates the potential of STZ-induced sAD in zebrafish as a reliable model for studying pathophysiology and rapid screening of therapeutic molecules against sAD., (Copyright © 2024. Published by Elsevier Inc.)

The mevalonate pathway produces essential lipid metabolites such as cholesterol. Although this pathway is negatively regulated by metabolic intermediates, little is known of the metabolites that positively regulate its activity. We found that the amino acid glutamine is required to activate the mevalonate pathway. Glutamine starvation inhibited cholesterol synthesis and blocked transcription of the mevalonate pathway-even in the presence of glutamine derivatives such as ammonia and α-ketoglutarate. We pinpointed this glutamine-dependent effect to a loss in the ER-to-Golgi trafficking of SCAP that licenses the activation of SREBP2, the major transcriptional regulator of cholesterol synthesis. Both enforced Golgi-to-ER retro-translocation and the expression of a nuclear SREBP2 rescued mevalonate pathway activity during glutamine starvation. In a cell model of impaired mitochondrial respiration in which glutamine uptake is enhanced, SREBP2 activation and cellular cholesterol were increased. Thus, the mevalonate pathway senses and is activated by glutamine at a previously uncharacterized step, and the modulation of glutamine synthesis may be a strategy to regulate cholesterol levels in pathophysiological conditions., (© 2024. The Author(s).)

Herein, we report a three-component stereoselective cyclopropanation of vinyl sulfoxonium ylides with indane 1,3-dione and aldehydes under mild reaction conditions. In contrast to previous reports, the present work shows that electrophilic addition selectively takes place at the α-position of the vinyl sulfoxonium ylide. The interesting feature of this approach is that the multicomponent reaction selectively proceeds because of the difference in nucleophilic reactivity of vinyl sulfoxonium ylides and indane 1,3-dione with electrophilic partners, such as aldehydes and in situ generated arylidenes. Additionally, density functional theory (DFT) studies were conducted to investigate the difference in the reactivity of these reactants, as well as to unveil the mechanism of this three-component reaction. Furthermore, non-covalent interactions of selectivity-determining transition states explain the origin of the diastereoselectivity of cyclopropanation.

Herein, we report the synthesis of 2 H -chromenes via catalyst-controlled highly regioselective [3 + 3] annulation of vinyl sulfoxonium ylides with quinones. Under boron-catalyzed conditions, the reaction between the ylide and quinone resulted in the formation of 2 H -chromene-4-carboxylates. In contrast, a different mechanistic pathway was observed when utilizing a Ru(II) catalytic system, which led to the formation of 2 H -chromene-2-carboxylates through a furan intermediate.

Parkinson's disease (PD) is an age-related second most common progressive neurodegenerative disorder that affects millions of people worldwide. Despite decades of research, no effective disease modifying therapeutics have reached clinics for treatment/management of PD. Leucine-rich repeat kinase 2 (LRRK2) which controls membrane trafficking and lysosomal function and its variant LRRK2-G2019S are involved in the development of both familial and sporadic PD. LRRK2, is therefore considered as a legitimate target for the development of therapeutics against PD. During the last decade, efforts have been made to develop effective, safe and selective LRRK2 inhibitors and also our understanding about LRRK2 has progressed. However, there is an urge to learn from the previously designed and reported LRRK2 inhibitors in order to effectively approach designing of new LRRK2 inhibitors. In this review, we have aimed to cover the pre-clinical studies undertaken to develop small molecule LRRK2 inhibitors by screening the patents and other available literature in the last decade. We have highlighted LRRK2 as targets in the progress of PD and subsequently covered detailed design, synthesis and development of diverse scaffolds as LRRK2 inhibitors. Moreover, LRRK2 inhibitors under clinical development has also been discussed. LRRK2 inhibitors seem to be potential targets for future therapeutic interventions in the treatment and management of PD and this review can act as a cynosure for guiding discovery, design, and development of selective and non-toxic LRRK2 inhibitors. Although, there might be challenges in developing effective LRRK2 inhibitors, the opportunity to successfully develop novel therapeutics targeting LRRK2 against PD has never been greater., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Sulfoxonium ylides are important synthetic precursors in various organic transformations. Their synthetic potential was well explored in the synthesis of various bioactive natural products and pharmaceuticals. Vinyl sulfoxonium ylide is a stabilized sulfoxonium ylide containing an electron-deficient alkene at the ylidic carbon. Similar to α-keto sulfoxonium ylides, these reagents can generate vinyl carbenes in the presence of metals under suitable conditions. These vinyl carbenes can be used for various organic transformations such as X-H (X = C, N, O, S) insertions, annulations, and rearrangement reactions. Due to the dipole structure of the vinyl sulfoxonium ylide, it can undergo electrophilic addition with electrophiles at the α-position. These reagents are used as synthons for various aromatic and heteroaromatic compound syntheses. Moreover, their stability and convenient handling make them potential replacements for thermally less stable vinyl diazo compounds. Herein, we provide an overview of early efforts in this area, with particular emphasis on our own recent development of vinyl sulfoxonium ylide-mediated transformations in the presence and absence of metal catalysis, and also give personal perspectives on the challenges and future scope for improving the application of vinyl sulfoxonium ylides.

Replication of the mitochondrial genome and expression of the genes it encodes both depend on a sufficient supply of nucleotides to mitochondria. Accordingly, dysregulated nucleotide metabolism not only destabilises the mitochondrial genome, but also affects its transcription. Here, we report that a mitochondrial nucleoside diphosphate kinase, NME6, supplies mitochondria with pyrimidine ribonucleotides that are necessary for the transcription of mitochondrial genes. Loss of NME6 function leads to the depletion of mitochondrial transcripts, as well as destabilisation of the electron transport chain and impaired oxidative phosphorylation. These deficiencies are rescued by an exogenous supply of pyrimidine ribonucleosides. Moreover, NME6 is required for the maintenance of mitochondrial DNA when the access to cytosolic pyrimidine deoxyribonucleotides is limited. Our results therefore reveal an important role for ribonucleotide salvage in mitochondrial gene expression., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Objectives: Achieving glycemic control in patients with type 2 diabetes is important as it reduces the risk of complications and their related clinical and economic burden. Yet therapeutic inertia due to the fear of hypoglycemia, complex treatment regimens, weight gain, and therapy costs, among others, limits achieving glycemic control. This analysis aims to assess the short-term cost of control (cost per patient achieving treatment goals) with insulin degludec/liraglutide (IDegLira) versus other forms of basal insulin intensification (insulin glargine titration, basal-bolus therapy, and the combination of insulin glargine and lixisenatide: IGlarLixi) in type 2 diabetes patients not controlled with basal insulin in the Mexican private setting., Methods: The proportion of patients achieving treatment goals was obtained from DUAL V and DUAL VII studies (full trial population) and a indirect treatment comparison analyzing IDegLira versus IGlarLixi. Annual cost of treatment was estimated using unitary costs from IQVIA's Pharmaceutical Market Mexico (PMM) audit and wholesale acquisition costs (both from December 2021). The cost of control was estimated by dividing the annual cost of treatment by the proportion of patients achieving the corresponding treatment goal: glycated hemoglobin (HbA1C) < 7.0%, HbA1C < 7.0% without weight gain, HbA1C < 7.0% without hypoglycemia, and HbA1C < 7.0% without hypoglycemia and weight gain. One-way sensitivity analyses were conducted to assess how variations in the model inputs impacted cost-effectiveness outcomes., Results: The proportion of patients achieving treatment goals was higher for IDegLira versus other forms of basal insulin intensification in all endpoints assessed. The annual cost of treatment with IDegLira was similar to the cost of treatment versus IGlarLixi or versus basal-bolus therapy ($54,659 versus $55,831 MXN and $51,008 versus $52,987 MXN, respectively), and higher in comparison with insulin glargine titration ($52,186 versus $40,194 MXN). The cost of controlling one patient with IDegLira was lower than any other form of basal insulin intensification, for all treatment goals., Conclusion: When integrating the greater clinical efficacy of IDegLira with its annual cost, it can be shown that within 1 year, IDegLira is the best option in terms of value for money for payers in a private healthcare setting in Mexico in comparison with other forms of basal insulin intensification. Thus, investing in IDegLira not only represents a greater clinical benefit, but also an economical one for payers., (© 2023. The Author(s).)

New 2-oxo-chromene-7-oxymethylene acetohydrazide derivatives 4a-d were designed and synthesized with a variety of bioactive chemical fragments. The newly synthesized compounds were evaluated as acetylcholinesterase (AChE) inhibitors and antioxidant agents in comparison to donepezil and ascorbic acid, respectively. Compound 4c exhibited a promising inhibitory impact with an IC 50 value of 0.802 μM and DPPH scavenging activity of 57.14 ± 2.77%. Furthermore, biochemical and haematological studies revealed that compound 4c had no effect on the blood profile, hepatic enzyme levels (AST, ALT, and ALP), or total urea in 4c-treated rats compared to the controls. Moreover, the histopathological studies of 4c-treated rats revealed the normal architecture of the hepatic lobules and renal parenchyma, as well as no histopathological damage in the examined hepatic, kidney, heart, and brain tissues. In addition, an in vivo study investigated the amelioration in the cognitive function of AD-rats treated with 4c through the T-maze and beam balance behavioural tests. Also, 4c detectably ameliorated MDA and GSH, reaching 90.64 and 27.17%, respectively, in comparison to the standard drug (90.64% and 35.03% for MDA and GSH, respectively). The molecular docking study exhibited a good fitting of compound 4c in the active site of the AChE enzyme and a promising safety profile. Compound 4c exhibited a promising anti-Alzheimer's disease efficiency compared to the standard drug donepezil., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background Total hip arthroplasty (THA) is the most successful orthopedic elective surgical procedure for end-stage hip arthritis. THA is linked with significant blood loss, ranging from 1,188 to 1,651 mL, and a transfusion rate of 16-37%, which frequently results in postoperative blood transfusions. Postoperative blood transfusions can be avoided by using autologous blood transfusion, intraoperative blood saving, local anesthetic, hypotensive anesthesia, and antifibrinolytic medications such as tranexamic acid (TXA) administration. Methodology A double-blinded, placebo-controlled, randomized, controlled study was conducted with three prospective groups to investigate the efficacy of topical and systemic routes of a single intraoperative dose (1.5 g) of TXA. Patients were recruited from our center between October 2021 to March 2022 who were undergoing primary total hip replacement. Estimated blood loss was calculated and compared in groups, and a p-value of <0.05 was taken as significant. Results A total of 60 patients were recruited in our study. Estimated blood loss was similar in both treatment groups, 816.8 ± 219.9 mL in the systemic TXA group and 775.5 ± 107.2 mL in the topical TXA group. The placebo group had 1,066.3 ± 150.4 mL estimated blood loss, which was significantly higher compared to the treatment groups. Conclusions Administration of TXA (1.5 g) significantly lowers blood loss without increasing problems, which can eliminate concerns about intravenous TXA use. TXA reduces blood loss by 270 mL on average., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Kushwaha et al.)

Coenzyme Q (or ubiquinone) is a redox-active lipid that serves as universal electron carrier in the mitochondrial respiratory chain and antioxidant in the plasma membrane limiting lipid peroxidation and ferroptosis. Mechanisms allowing cellular coenzyme Q distribution after synthesis within mitochondria are not understood. Here we identify the cytosolic lipid transfer protein STARD7 as a critical factor of intracellular coenzyme Q transport and suppressor of ferroptosis. Dual localization of STARD7 to the intermembrane space of mitochondria and the cytosol upon cleavage by the rhomboid protease PARL ensures the synthesis of coenzyme Q in mitochondria and its transport to the plasma membrane. While mitochondrial STARD7 preserves coenzyme Q synthesis, oxidative phosphorylation function and cristae morphogenesis, cytosolic STARD7 is required for the transport of coenzyme Q to the plasma membrane and protects against ferroptosis. A coenzyme Q variant competes with phosphatidylcholine for binding to purified STARD7 in vitro. Overexpression of cytosolic STARD7 increases ferroptotic resistance of the cells, but limits coenzyme Q abundance in mitochondria and respiratory cell growth. Our findings thus demonstrate the need to coordinate coenzyme Q synthesis and cellular distribution by PARL-mediated STARD7 processing and identify PARL and STARD7 as promising targets to interfere with ferroptosis., (© 2023. The Author(s).)

During embryonic development, cardiomyocytes undergo differentiation and maturation, processes that are tightly regulated by tissue-specific signaling cascades. Although redox signaling pathways involved in cardiomyogenesis are established, the exact sources responsible for reactive oxygen species (ROS) formation remain elusive. The present study investigates whether ROS produced by the mitochondrial flavoenzyme monoamine oxidase A (MAO-A) play a role in cardiomyocyte differentiation from human induced pluripotent stem cells (hiPSCs). Wild type (WT) and MAO-A knock out (KO) hiPSCs were generated by CRISPR/Cas9 genome editing and subjected to cardiomyocyte differentiation. Mitochondrial ROS levels were lower in MAO-A KO compared to the WT cells throughout the differentiation process. MAO-A KO hiPSC-derived cardiomyocytes (hiPSC-CMs) displayed sarcomere disarray, reduced α- to β-myosin heavy chain ratio, GATA4 upregulation and lower macroautophagy levels. Functionally, genetic ablation of MAO-A negatively affected intracellular Ca 2+ homeostasis in hiPSC-CMs. Mechanistically, MAO-A generated ROS contributed to the activation of AKT signaling that was considerably attenuated in KO cells. In addition, MAO-A ablation caused a reduction in WNT pathway gene expression consistent with its reported stimulation by ROS. As a result of WNT downregulation, expression of MESP1 and NKX2.5 was significantly decreased in MAO-A KO cells. Finally, MAO-A re-expression during differentiation rescued expression levels of cardiac transcription factors, contractile structure, and intracellular Ca 2+ homeostasis. Taken together, these results suggest that MAO-A mediated ROS generation is necessary for the activation of AKT and WNT signaling pathways during cardiac lineage commitment and for the differentiation of fully functional human cardiomyocytes., (© 2023. The Author(s).)

Liver X Receptors (LXRs) are members of the nuclear receptor superfamily that regulate cholesterol metabolism. LXRs have been suggested as promising targets against many neurodegenerative diseases (NDDs). The present study was aimed to identify novel non-steroidal molecules that may potentially modulate LXR activity. The structure-based virtual screening (SBVS) was used to search for suitable compounds from the Asinex library. The top hits were selected and filtered based on their binding affinity for LXR α and β isoforms. Based on molecular docking and scoring results, 24 compounds were selected that had binding energy in the range of - 13.9 to - 12 for LXRα and - 12.5 to - 11 for LXRβ, which were higher than the reference ligands (GW3965 and TO901317). Further, the five hits referred to as model 29, 64, 202, 250, 313 were selected by virtue of their binding interactions with amino acid residues at the active site of LXRs. The selected hits were then subjected to absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis and blood-brain permeability prediction. It was observed that the selected hits had better pharmacokinetic properties with no toxicity and could cross blood-brain barrier. Further, the selected hits were analysed for dynamic evolution of the system with LXRs by molecular dynamics (MD) simulation at 100 ns using GROMACS. The MD simulation results validated that selected hits possess a remarkable amount of flexibility, stability, compactness, binding energy and exhibited limited conformational modification. The root mean square deviation (RMSD) values of the top-scoring hits complexed with LXRα and LXRβ were 0.05-0.6 nm and 0.05-0.45 nm respectively, which is greater than the protein itself. Altogether the study identified potential non-steroidal LXR modulators that appear to be effective against various neurodegenerative conditions involving perturbed cholesterol and lipid homeostasis., Competing Interests: Conflict of interest None, (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Reactive oxygen species (ROS) have been correlated with almost every human disease. Yet clinical exploitation of these hypotheses by pharmacological modulation of ROS has been scarce to nonexistent. Are ROS, thus, irrelevant for disease? No. One key misconception in the ROS field has been its consideration as a rather detrimental metabolic by-product of cell metabolism, and thus, any approach eliminating ROS to a certain tolerable level would be beneficial. We now know, instead, that ROS at every concentration, low or high, can serve many essential signaling and metabolic functions. This likely explains why systemic, nonspecific antioxidants have failed in the clinic, often with neutral and sometimes even detrimental outcomes. Recently, drug development has focused, instead, on identifying and selectively modulating ROS enzymatic sources that in a given constellation cause disease while leaving ROS physiologic signaling and metabolic functions intact. As sources, the family of NADPH oxidases stands out as the only enzyme family solely dedicated to ROS formation. Selectively targeting disease-relevant ROS-related proteins is already quite advanced, as evidenced by several phase II/III clinical trials and the first drugs having passed registration. The ROS field is expanding by including target enzymes and maturing to resemble more and more modern, big data-enhanced drug discovery and development, including network pharmacology. By defining a disease based on a distinct mechanism, in this case ROS dysregulation, and not by a symptom or phenotype anymore, ROS pharmacology is leaping forward from a clinical underperformer to a proof of concept within the new era of mechanism-based precision medicine. SIGNIFICANCE STATEMENT: Despite being correlated to almost every human disease, nearly no ROS modulator has been translated to the clinics yet. Here, we move far beyond the old-fashioned misconception of ROS as detrimental metabolic by-products and suggest 1) novel pharmacological targeting focused on selective modulation of ROS enzymatic sources, 2) mechanism-based redefinition of diseases, and 3) network pharmacology within the ROS field, altogether toward the new era of ROS pharmacology in precision medicine., (Copyright © 2020 by The Author(s).)

Mitochondria are essential metabolic hubs that dynamically adapt to physiological demands. More than 40 proteases residing in different compartments of mitochondria, termed mitoproteases, preserve mitochondrial proteostasis and are emerging as central regulators of mitochondrial plasticity. These multifaceted enzymes limit the accumulation of short-lived, regulatory proteins within mitochondria, modulate the activity of mitochondrial proteins by protein processing, and mediate the degradation of damaged proteins. Various signaling cascades coordinate the activity of mitoproteases to preserve mitochondrial homeostasis and ensure cell survival. Loss of mitoproteases severely impairs the functional integrity of mitochondria, is associated with aging, and causes pleiotropic diseases. Understanding the dual function of mitoproteases as regulatory and quality control enzymes will help unravel the role of mitochondrial plasticity in aging and disease.

Reactive oxygen species (ROS) have an equivocal role in myocardial ischaemia reperfusion injury. Within the cardiomyocyte, mitochondria are both a major source and target of ROS. We evaluate the effects of a selective, dose-dependent increase in mitochondrial ROS levels on cardiac physiology using the mitochondria-targeted redox cycler MitoParaquat (MitoPQ). Low levels of ROS decrease the susceptibility of neonatal rat ventricular myocytes (NRVMs) to anoxia/reoxygenation injury and also cause profound protection in an in vivo mouse model of ischaemia/reperfusion. However higher doses of MitoPQ resulted in a progressive alteration of intracellular [Ca 2+ ] homeostasis and mitochondrial function in vitro, leading to dysfunction and death at high doses. Our data show that a primary increase in mitochondrial ROS can alter cellular function, and support a hormetic model in which low levels of ROS are cardioprotective while higher levels of ROS are cardiotoxic., (Copyright © 2019. Published by Elsevier Inc.)

Monoamine oxidase (MAO) inhibitors ameliorate contractile function in diabetic animals, but the mechanisms remain unknown. Equally elusive is the interplay between the cardiomyocyte alterations induced by hyperglycemia and the accompanying inflammation. Here we show that exposure of primary cardiomyocytes to high glucose and pro-inflammatory stimuli leads to MAO-dependent increase in reactive oxygen species that causes permeability transition pore opening and mitochondrial dysfunction. These events occur upstream of endoplasmic reticulum (ER) stress and are abolished by the MAO inhibitor pargyline, highlighting the role of these flavoenzymes in the ER/mitochondria cross-talk. In vivo, streptozotocin administration to mice induced oxidative changes and ER stress in the heart, events that were abolished by pargyline. Moreover, MAO inhibition prevented both mast cell degranulation and altered collagen deposition, thereby normalizing diastolic function. Taken together, these results elucidate the mechanisms underlying MAO-induced damage in diabetic cardiomyopathy and provide novel evidence for the role of MAOs in inflammation and inter-organelle communication. MAO inhibitors may be considered as a therapeutic option for diabetic complications as well as for other disorders in which mast cell degranulation is a dominant phenomenon.

Purpose: Breast and/or ovarian cancers are among the most common cancers in women across the world. In the Indian population, the healthcare burden of breast and/or ovarian cancers has been steadily rising, thus stressing the need for early detection, surveillance, and disease management measures. However, the burden attributable to inherited mutations is not well characterized., Methods: We sequenced 1010 unrelated patients and families from across India with an indication of breast and/or ovarian cancers, using the TruSight Cancer panel which includes 14 genes, strongly associated with risk of hereditary breast and/or ovarian cancers. Genetic variations were identified using the StrandNGS software and interpreted using the StrandOmics platform., Results: We were able to detect mutations in 304 (30.1%) cases, of which, 56 mutations were novel. A majority (84.9%) of the mutations were detected in the BRCA1/2 genes as compared to non-BRCA genes (15.1%). When the cases were stratified on the basis of age at diagnosis and family history of cancer, the high rate of 75% of detection of hereditary variants was observed in patients whose age at diagnosis was below 40 years and had first-degree family member(s) affected by breast and/or ovarian cancers. Our findings indicate that in the Indian population, there is a high prevalence of mutations in the high-risk breast cancer genes: BRCA1, BRCA2, TP53, and PALB2., Conclusion: In India, socioeconomic inequality limiting access to treatment is a major factor towards increased cancer burden; therefore, incorporation of a cost-effective and comprehensive multi-gene test will be helpful in ensuring widespread implementation of genetic screening in the clinical practice for hereditary breast and/or ovarian cancers.

Reactive oxygen species (ROS) are involved in both physiological and pathological processes. This widely accepted concept is based more on the effects of antioxidant interventions than on reliable assessments of rates and sites of intracellular ROS formation. This argument applies also to mitochondria that are generally considered the major site for ROS formation, especially in skeletal and cardiac myocytes.Detection of oxidative modifications of intracellular or circulating molecules is frequently used as a marker of ROS formation. However, this approach provides limited information on spatiotemporal aspects of ROS formation that have to be defined in order to elucidate the role of ROS in a given pathophysiological condition. This information can be obtained by means of fluorescent probes that allow monitoring ROS formation in cell-free extracts and isolated cells. Thus, this approach can be used to characterize ROS formation in both isolated mitochondria and mitochondria within intact cells. This chapter describes three major examples of the use of fluorescent probes for monitoring mitochondrial ROS formation. Detailed methods description is accompanied by a critical analysis of the limitations of each technique, highlighting the possible sources of errors in performing the assay and results interpretation.

In the past decade, accumulating evidence highlighted the role of monoamine oxidases (MAOs) in cardiovascular disease (CVD). MAOs are flavoenzymes located in the outer mitochondrial membrane, responsible for the degradation of neurotransmitters and biogenic amines. During this process they generate hydrogen peroxide, aldehydes and ammonia, species that can target mitochondria and induce mitochondrial dysfunction and cardiomyocyte death. Indeed, MAO inhibition affords cardioprotection in several models of CVD, such as ischemia/reperfusion, heart failure and diabetes. Importantly, a few studies provided encouraging results suggesting that MAO inhibition might be beneficial also in patients with CVD. Thus, selective and reversible MAO inhibitors, currently used as therapy for depression and neurodegenerative disorders, might be considered as candidate drugs for the treatment of CVD., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

In this paper, we construct a sequence of modified Stancu-Baskakov operators for a real valued function bounded on [Formula: see text], based on a function [Formula: see text]. This function [Formula: see text] is infinite times continuously differentiable on [Formula: see text] and satisfy the conditions [Formula: see text] and [Formula: see text] is bounded for all [Formula: see text]. We study the degree of approximation of these operators by means of the Peetre K-functional and the Ditzian-Totik modulus of smoothness. The quantitative Voronovskaja-type theorems are also established in terms of the first order Ditzian-Totik modulus of smoothness.

Breast and/or ovarian cancer (BOC) are among the most frequently diagnosed forms of hereditary cancers and leading cause of death in India. This emphasizes on the need for a cost-effective method for early detection of these cancers. We sequenced 141 unrelated patients and families with BOC using the TruSight Cancer panel, which includes 13 genes strongly associated with risk of inherited BOC. Multi-gene sequencing was done on the Illumina MiSeq platform. Genetic variations were identified using the Strand NGS software and interpreted using the StrandOmics platform. We were able to detect pathogenic mutations in 51 (36.2%) cases, out of which 19 were novel mutations. When we considered familial breast cancer cases only, the detection rate increased to 52%. When cases were stratified based on age of diagnosis into three categories, ⩽40 years, 40-50 years and >50 years, the detection rates were higher in the first two categories (44.4% and 53.4%, respectively) as compared with the third category, in which it was 26.9%. Our study suggests that next-generation sequencing-based multi-gene panels increase the sensitivity of mutation detection and help in identifying patients with a high risk of developing cancer as compared with sequential tests of individual genes.

Reactive oxygen species (ROS) formation and signaling are of major importance and regulate a number of processes in physiological conditions. A disruption in redox status regulation, however, has been associated with numerous pathological conditions. In recent years it has become increasingly clear that oxidative and reductive modifications are confined in a spatio-temporal manner. This makes ROS signaling similar to that of Ca(2+) or other second messengers. Some subcellular compartments are more oxidizing (such as lysosomes or peroxisomes) whereas others are more reducing (mitochondria, nuclei). Moreover, although more reducing, mitochondria are especially susceptible to oxidation, most likely due to the high number of exposed thiols present in that compartment. Recent advances in the development of redox probes allow specific measurement of defined ROS in different cellular compartments in intact living cells or organisms. The availability of these tools now allows simultaneous spatio-temporal measurements and correlation between ROS generation and organelle and/or cellular function. The study of ROS compartmentalization and microdomains will help elucidate their role in physiology and disease. Here we will examine redox probes currently available and how ROS generation may vary between subcellular compartments. Furthermore, we will discuss ROS compartmentalization in physiological and pathological conditions focusing our attention on mitochondria, since their vulnerability to oxidative stress is likely at the basis of several diseases.

Bumblebees, amongst the most important of pollinators, are under enormous population pressures. One of these is disease. The bumblebee and its gut trypanosome Crithidia bombi are one of the fundamental models of ecological immunology. Although there is previous evidence of increased immune gene expression upon Crithidia infection, recent work has focussed on the bumblebee's gut microbiota. Here, by knocking down gene expression using RNAi, we show for the first time that antimicrobial peptides (AMPs) have a functional role in anti-Crithidia defense., (Copyright © 2013 Elsevier Ltd. All rights reserved.)