Substrate-Induced Cooperative Ionic Catalysis: Difunctionalization of Indole Derivatives Employing Dimethyl Carbonate.

The global urge to adopt sustainable chemistry has resulted in the development of more environmentally benign strategies (EBS) that use CO2 and CO2-derived chemicals in a step-economic manner. In this context, we investigated a dual C-H methylation and (C═O)-methoxylation of indole derivatives using dimethyl carbonate (DMC) in the presence of catalytic amounts of Cs2CO3. Mechanistic insights include DMF-assisted, DMC-induced cooperative ionic catalysis, which allows DMC to act as both a nucleophilic and an electrophilic precursor, resulting in (C═O)-methoxylation and C-H methylation of N-benzylindolyl ketones.

Left Atrial Strain to Predict Postoperative Atrial Fibrillation in Patients Undergoing Off-pump Coronary Artery Bypass Graft.

OBJECTIVE: Postoperative atrial fibrillation (POAF) is associated with increased morbidity, mortality, and length of hospital stay. The objective of this study was to assess the utility of left atrial strain (LAS) to predict POAF in patients undergoing off-pump coronary artery bypass grafting (OPCABG). DESIGN: Retrospective observational study. SETTING: Tertiary care hospital. PARTICIPANTS: 103 patients undergoing OPCABG. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: In addition to comprehensive transthoracic echocardiography, LAS was measured for reservoir (R), conduction (CD), and contraction (CT) components. POAF was defined as new electrocardiographic evidence of AF requiring treatment. Logistic regression was done to assess factors associated with POAF. The diagnostic accuracy of variables in predicting POAF was assessed by receiver operating characteristic analysis. POAF was documented in 24 (23.3%) patients. There was no difference in ejection fraction, average global longitudinal strain, or proportion of left ventricular diastolic dysfunction grades between patients with POAF and patients without POAF. All three components of LAS: LAS R (19.2 ± 4.7 v 23.5 ± 4.8, p < 0.001), LAS CD (8.9 ± 3.7 v 12.3 ± 4.8, p = 0.1), and LAS CT (10.3 ± 3.9 v 12.1 ± 4.1, p = 0.04), were significantly lower among patients with POAF compared with patients without POAF, respectively. According to univariate analysis, all components of LAS were statistically significant predictors of POAF. In multivariate analysis, only age (odds ratio = 1.08, p = 0.025) and LAS R (odds ratio = 0.84, p = 0.004) were independently associated with POAF. LAS R was a better predictor of POAF, with an area under the curve (AUC) of 0.758, than LAS CD (AUC = 0.67) and LAS CT (AUC = 0.62). LAS R had an optimal cutoff of 23% with sensitivity of 95.8% (confidence interval: 78.9-99.9%) and specificity of 49.4% (37.9-60.9%) to predict POAF. CONCLUSIONS: LAS R is a significant predictor of POAF, and its use can be recommended for screening of OPCABG patients at high risk of POAF.

Exploring the Arsenal of Novel Antifungal Drug Targets for Combating Fungal Infections.

Fungal infections contribute to over 1.5 million fatalities each year, with cutaneous mycoses standing as prominent global infections. The spectrum of these mycoses varies widely, encompassing enduring afflictions like ringworm, localized infections such as tinea capitis, recurrent instances like vaginal candidiasis, and potentially fatal systemic infections impacting multiple organ systems. The escalating recognition of the health and socioeconomic ramifications associated with fungal pathogens underscores their importance in contemporary discourse. On a global scale, projections indicate that over 300 million individuals experience significant fungal infections annually, resulting in a mortality rate exceeding 1.5 million deaths per year. Alarmingly, resistance to commonly used antifungal drugs was on the rise, with some reports suggesting that over 10% of Candida bloodstream isolates worldwide were resistant to fluconazole, a commonly prescribed antifungal medication. Therefore, there is an immediate need to increase the accessibility of new antifungal medications while minimizing their costs and adverse effects. Fungi, as heterotrophic organisms, acquire nutrients through absorption. Their filamentous structure, composed of hyphae, facilitates efficient nutrient uptake by secreting enzymes that break down complex organic matter into simpler compounds. These organisms exhibit remarkable adaptability in responding to environmental cues, adjusting growth rates, and altering morphological features. Fungi regulate their metabolism intricately, undergoing various metabolic pathways for energy production and utilizing diverse substrates for respiration. Additionally, they exhibit distinctive reproductive strategies, employing both sexual and asexual modes of reproduction, contributing to their genetic diversity and resilience in diverse ecosystems. We now have more information than ever on the origins of infection as well as the physiology of fungi cells, giving us the chance to use it to produce new generations of antifungals. This review includes various novel antifungal drug targets showing their possible effects via different mechanisms aiming at vital functions like GPI synthesis, cell wall synthesis, hyphal growth, and other essential pathways responsible for fungal growth.

MiR-29 and MiR-140 regulate TRAIL-induced drug tolerance in lung cancer.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has chemotherapeutic potential as a regulator of an extrinsic apoptotic ligand, but its effect as a drug is limited by innate and acquired resistance. Recent findings suggest that an intermediate drug tolerance could mediate acquired resistance, which has made the main obstacle for limited utility of TRAIL as an anti-cancer therapeutics. We propose miRNA-dependent epigenetic modification drives the drug tolerant state in TRAIL-induced drug tolerant (TDT). Transcriptomic analysis revealed miR-29 target gene activation in TDT cells, showing oncogenic signature in lung cancer. Also, the restored TRAIL-sensitivity was associated with miR-29ac and 140-5p expressions, which is known as tumor suppressor by suppressing oncogenic protein RSK2 (p90 ribosomal S6 kinase), further confirmed in patient samples. Moreover, we extended this finding into 119 lung cancer cell lines from public data set, suggesting a significant correlation between TRAIL-sensitivity and RSK2 mRNA expression. Finally, we found that increased RSK2 mRNA is responsible for NF-κB activation, which we previously showed as a key determinant in both innate and acquired TRAIL-resistance. Our findings support further investigation of miR-29ac and -140-5p inhibition to maintain TRAIL-sensitivity and improve the durability of response to TRAIL in lung cancer.

Loss of RAB25 Cooperates with Oncogenes in the Transformation of Human Mammary Epithelial Cells (HMECs) to Give Rise to Claudin-Low Tumors.

The loss of RAB25 expression-RAS superfamily of GTPase characteristic of numerous breast cancers-corresponds with H-RAS point mutations, particularly in triple-negative breast cancers (TNBC), a subtype associated with a poor prognosis. To address the poorly understood factors dictating the progression of TNBC tumors, we examine the cooperative effects that loss of RAB25 expression in human mammary epithelial cell (HMEC) lines with H-RAS mutations confers in tumorigenesis. HMECs were immortalized by transduction with LXSN CDK4 R24C, a mutant form of cyclin-dependent kinase, followed by transduction with hTERT, a catalytic subunit of the telomerase enzyme. We found that with the loss of RAB25 and overexpression of mutant H-RAS61L, immortal HMECs transformed toward anchorage-independent growth and acquired an increased ability to migrate. Furthermore, cells express low CD24, high CD44, and low claudin levels, indicating stem-like properties upon transformation. Besides, loss of RAB25 and overexpression of H-RAS61L resulted in increased expression of transcription factors Snail and Slug that drive these cells to lose E-cadherin and undergo epithelial-mesenchymal transition (EMT). This study confirms that loss of RAB25 and overexpression of mutant H-RAS can drive HMECs toward a mesenchymal stem-like state. Our findings reveal that RAB25 functions as a tumor suppressor gene, and loss of RAB25 could serve as a novel biomarker of the claudin-low type of TNBC.

Pecto-intercostal Fascial Plane Block: A Novel Technique for Analgesia in Patients with Sternal Dehiscence.

ABSTRACT: Sternal wound complications following sternotomy need a multidisciplinary approach in high-risk postoperative cardiac surgical patients. Poorly controlled pain during surgical management of such wounds increases cardiovascular stress and respiratory complications. Multimodal analgesia including intravenous opioids, non-opioid analgesics, and regional anesthesia techniques, like central neuraxial blocks and fascial plane blocks, have been described. Pecto-intercostal fascial plane block (PIFB), a novel technique, has been effectively used in patients undergoing cardiac surgery. Under ultrasound (US) guidance PIFB is performed with the aim of depositing local anesthetic between two superficial muscles, namely the pectoralis major muscle and the external intercostal muscle. The authors report a series of five cases where US-guided bilateral PIFB was used in patients undergoing sternal wound debridement. Patients had excellent analgesia intraoperatively as well as postoperatively for 24 hours with minimal requirement of supplemental analgesia. None of the patients experienced complications due to PIFB administration. The authors concluded that bilateral PIFB can be effectively used as an adjunct to multimodal analgesia with general anesthesia and as a sole anesthesia technique in selected cases of sternal wound debridement.

Synthesis of an Immunologically Active Heptamannoside of Mycobacterium tuberculosis by the [Au]/[Ag]-Catalyzed Activation of Ethynylcyclohexyl Glycosyl Carbonate Donor.

Tuberculosis (TB) is one of the most dreadful diseases, killing more than 3 million humans annually. M. tuberculosis (MTb) is the causative agent for TB and has a thick and waxy cell wall, making it an attractive target for immunological studies. In this study, a heptamannopyranoside containing 1 → 2 and 1 → 6 α-mannopyranosidic linkages has been explored for the immunological evaluations. The conjugation-ready heptamannopyranoside was synthesized by exploiting the salient features of recently discovered [Au]/[Ag]-glycosidation of ethynylcyclohexyl glycosyl carbonate donors. The glycan was conjugated to the ESAT6, an early secreted protein of MTb for further characterization as a potential subunit vaccine candidate.

Weighted single step GWAS reveals genomic regions associated with economic traits in Murrah buffaloes.

The objective of the present study was to identify genomic regions influencing economic traits in Murrah buffaloes using weighted single step Genome Wide Association Analysis (WssGWAS). Data on 2000 animals, out of which 120 were genotyped using a double digest Restriction site Associated DNA (ddRAD) sequencing approach. The phenotypic data were collected from NDRI, India, on growth traits, viz., body weight at 6M (month), 12M, 18M and 24M, production traits like 305D (day) milk yield, lactation length (LL) and dry period (DP) and reproduction traits like age at first calving (AFC), calving interval (CI) and first service period (FSP). The biallelic genotypic data consisted of 49353 markers post-quality check. The heritability estimates were moderate to high, low to moderate, low for growth, production, reproduction traits, respectively. Important genomic regions explaining more than 0.5% of the total additive genetic variance explained by 30 adjacent SNPs were selected for further analysis of candidate genes. In this study, 105 genomic regions were associated with growth, 35 genomic regions with production and 42 window regions with reproduction traits. Different candidate genes were identified in these genomic regions, of which important are OSBPL8, NAP1L1 for growth, CNTNAP2 for production and ILDR2, TADA1 and POGK for reproduction traits.

Ryanodine receptor 2 inhibition reduces dispersion of cardiac repolarization, improves contractile function, and prevents sudden arrhythmic death in failing hearts.

Sudden cardiac death (SCD) from ventricular tachycardia/fibrillation (VT/VF) is a leading cause of death, but current therapies are limited. Despite extensive research on drugs targeting sarcolemmal ion channels, none have proven sufficiently effective for preventing SCD. Sarcoplasmic ryanodine receptor 2 (RyR2) Ca2+ release channels, the downstream effectors of sarcolemmal ion channels, are underexplored in this context. Recent evidence implicates reactive oxygen species (ROS)-mediated oxidation and hyperactivity of RyR2s in the pathophysiology of SCD. We tested the hypothesis that RyR2 inhibition of failing arrhythmogenic hearts reduces sarcoplasmic Ca2+ leak and repolarization lability, mitigates VT/VF/SCD and improves contractile function. We used a guinea pig model that replicates key clinical aspects of human nonischemic HF, such as a prolonged QT interval, a high prevalence of spontaneous arrhythmic SCD, and profound Ca2+ leak via a hyperactive RyR2. HF animals were randomized to receive dantrolene (DS) or placebo in early or chronic HF. We assessed the incidence of VT/VF and SCD (primary outcome), ECG heart rate and QT variability, echocardiographic left ventricular (LV) structure and function, immunohistochemical LV fibrosis, and sarcoplasmic RyR2 oxidation. DS treatment prevented VT/VF and SCD by decreasing dispersion of repolarization and ventricular arrhythmias. Compared to placebo, DS lowered resting heart rate, preserved chronotropic competency during transient ß-adrenergic challenge, and improved heart rate variability and cardiac function. Inhibition of RyR2 hyperactivity with dantrolene mitigates the vicious cycle of sarcoplasmic Ca2+ leak-induced increases in diastolic Ca2+ and ROS-mediated RyR2 oxidation, thereby reducing repolarization lability and protecting against VT/VF/SCD. Moreover, the consequent increase in sarcoplasmic Ca2+ load improves contractile function. These potentially life-saving effects of RyR2 inhibition warrant further investigation, such as clinical studies of repurposing dantrolene as a potential new therapy for heart failure and/or SCD.

Each year, more than 300,000 people experience cardiac arrest or sudden cardiac death. Sudden cardiac death is caused by irregular heartbeats known as ventricular tachycardia or ventricular fibrillation, which prevent the heart from pumping blood. During a regular heart rhythm, the heart muscles contract and relax, regulated by a coordinated rise and fall of calcium ions within heart cells. In the cells of diseased hearts, on the other hand, calcium leaks out of a compartment known as the sarcoplasmic reticulum in an uncontrolled manner. This happens because an ion channel in the membrane of the sarcoplasmic reticulum known as ryanodine receptor 2 becomes hyperactive and releases calcium in an uncontrolled manner. This abnormal calcium release leads to irregular calcium waves, which can make the heart's electrical properties unstable, causing ventricular tachycardia, ventricular fibrillation and sudden cardiac death. Joshi et al. tested whether dantrolene, a molecule that blocks ryanodine receptor 2, can stop calcium leaks from the sarcoplasmic reticulum and prevent lethal arrhythmias and sudden cardiac death in failing hearts. To investigate this, Joshi et al. induced heart failure in guinea pigs that have abnormal heart calcium signalling similar to human heart failure, and then treated the animals with either dantrolene or a placebo. The results indicate that blocking ryanodine receptor 2 hyperactivity with dantrolene prevents lethal arrhythmias and sudden cardiac death by blocking calcium leaks and by preventing the instability of the electrical properties of the heart. Additionally, Joshi et al. found that dantrolene also improved the diseased heart's ability to pump adequate amounts of blood, allowing failing hearts to meet increased cardiovascular demands, and thereby improving the heart's overall function. The proposed studies come from a strong clinical need to improve bad outcomes in people who keep having fatal heart rhythm episodes despite getting the best medical care. Many heart failure patients are plagued by recurrent defibrillator shocks to abort sudden cardiac death from relentless lethal heart rhythms. These shocks are painful, injure the heart, and worsen the quality of life. Unfortunately, management options are extremely limited for these patients. The findings of Joshi et al. indicate that dantrolene may be a potential treatment for people with fatal heart rhythms who are at risk of sudden cardiac death and could have a positive impact on these people's quality of life. However, before this can happen, dantrolene will first have to be thoroughly tested to ensure effectivity and safety in humans. In any case, Joshi et al. have opened a new avenue in the search for medications to treat deadly arrhythmias and sudden cardiac death.

Impact of the -1T>C single-nucleotide polymorphism of the CD40 gene on the development of endothelial dysfunction in a pro-diabetic microenvironment.

BACKGROUND AND AIMS: Hyperglycemia reinforces pro-inflammatory conditions that enhance CD40 expression in endothelial cells (EC). Thymine to cytosine transition (-1T > C) in the promoter of the CD40 gene (rs1883832) further increases the abundance of CD40 protein on the EC surface. This study examines potential associations of the -1T > C SNP of the CD40 gene with type 1 (T1D) or type 2 (T2D) diabetes. Moreover, it investigates the impact of a pro-inflammatory diabetic microenvironment on gene expression in human cultured umbilical vein EC (HUVEC) derived from CC- vs. TT-genotype donors. METHODS: Tetra-ARMS-PCR was used to compare genotype distribution in 252 patients with diabetes. Soluble CD40 ligand (sCD40L) and soluble CD40 receptor (sCD40) plasma levels were monitored using ELISA. RNA-sequencing was performed with sCD40L-stimulated CC- and TT-genotype HUVEC. Quantitative PCR, Western blot, multiplex-sandwich ELISA array, and immunocytochemistry were used to analyse changes in gene expression in these cells. RESULTS: Homozygosity for the C-allele was associated with a significant 4.3-fold higher odds of developing T2D as compared to individuals homozygous for the T-allele. Inflammation and endothelial-to-mesenchymal transition (EndMT) driving genes were upregulated in CC-genotype but downregulated in TT-genotype HUVEC when exposed to sCD40L. Expression of EndMT markers significantly increased while that of endothelial markers decreased in HUVEC following exposure to hyperglycemia, tumour necrosis factor-α and sCD40L. CONCLUSIONS: The -1T > C SNP of the CD40 gene is a risk factor for T2D. Depending on the genotype, it differentially affects gene expression in human cultured EC. CC-genotype HUVEC adopt a pro-inflammatory and intermediate EndMT-like phenotype in a pro-diabetic microenvironment.

Ryanodine receptor 2 inhibition reduces dispersion of cardiac repolarization, improves contractile function and prevents sudden arrhythmic death in failing hearts.

Introduction: Sudden cardiac death (SCD) from ventricular tachycardia/fibrillation (VT/VF) are a leading cause of death, but current therapies are limited. Despite extensive research on drugs targeting sarcolemmal ion channels, none have proven sufficiently effective for preventing SCD. Sarcoplasmic ryanodine receptor 2 (RyR2) Ca 2+ release channels, the downstream effectors of sarcolemmal ion channels, are underexplored in this context. Recent evidence implicates reactive oxygen species (ROS)- mediated oxidation and hyperactivity of RyR2s in the pathophysiology of SCD. Objective: To test the hypothesis that RyR2 inhibition of failing arrhythmogenic hearts reduces sarcoplasmic Ca 2+ leak and repolarization lability, mitigates VT/VF/SCD and improves contractile function. Methods: We used a guinea pig model that replicates key clinical aspects of human nonischemic HF, such as a prolonged QT interval, a high prevalence of spontaneous arrhythmic SCD, and profound Ca 2+ leak via a hyperactive RyR2. HF animals were randomized to receive dantrolene (DS) or placebo in early or chronic HF. We assessed the incidence of VT/VF and SCD (primary outcome), ECG heart rate and QT variability, echocardiographic left ventricular (LV) structure and function, immunohistochemical LV fibrosis, and sarcoplasmic RyR2 oxidation. Results: DS treatment prevented VT/VF and SCD by decreasing dispersion of repolarization and ventricular arrhythmias. Compared to placebo, DS lowered resting heart rate, preserved chronotropic competency during transient ß-adrenergic challenge, and improved heart rate variability and cardiac function. Conclusion: Inhibition of RyR2 hyperactivity with dantrolene mitigates the vicious cycle of sarcoplasmic Ca 2+ leak-induced increases in diastolic Ca 2+ and ROS-mediated RyR2 oxidation, thereby increasing repolarization lability and protecting against VT/VF/SCD. Moreover, the consequent increase in sarcoplasmic Ca 2+ load improves contractile function. These potentially life-saving effects of RyR2 inhibition warrant further investigation, such as clinical studies of repurposing dantrolene as a potential new therapy for heart failure and/or SCD.

Perception of care givers regarding danger signs of illness and practices followed in young infants (0-2 months) as per IMNCI at selected areas of Amritsar, Punjab: A qualitative study.

Background: In India, neonatal mortality contributes to over 64% of infant deaths, mostly occurring during the first week of life. Mortality rate in second month of life is also higher than at later ages. Delay in identification of warning signs of neonatal illness naturally postpones the initiation of treatment and referral to hospital. Materials and Methods: The study aimed to explore the perception of care givers regarding danger signs of illness and practices followed in young infants. Care givers who cared for the sick young infants during last six months were recruited using a convenient sampling technique and qualitative research approach. Five semi-structured interviews and one FGD were conducted using an interview and FGD guide. Data was analyzed manually by reading and rereading the transcribed verbatim leading to the emergence of themes, subthemes, and codes. Results: Data explored that excessive crying was perceived as a danger sign by entire mothers, and many of them were unable to recognize important warning signs. The delay in decision making for medical care-seeking also shows dwindling awareness. Additionally, mothers were adapting few unhygienic practices as home remedies leading to worsening the symptoms and making a call for additional infections which needs to be addressed by the health authorities at community level. Conclusion: Pronounced efforts are expected to raise mindfulness of mothers toward the significance of early identification of neonatal danger signs to stave off the high magnitude of neonatal mortality. Inclusion of excessive crying as neonatal danger sign is recommended as well.

Optimization of test day for milk yield recording and sire evaluation in Murrah buffaloes.

In the present study, random regression models (RRM) were used to estimate genetic parameters for test-day milk yield in Murrah buffaloes using Legendre polynomial function (LP), with the objective to find the best combination of "minimum test-day model," which would be essential and sufficient to evaluate the trait successfully. Data included for analysis were 10,615 first lactation monthly test-day milk yield records (5th, 35th, 65th, …, 305th) from 965 Murrah buffaloes for the period 1975-2018. Cubic to octic-order orthogonal polynomials with homogeneous residual variances were used for the estimation of genetic parameters. Random regression models with sixth-order were selected based on goodness of fit criteria like lower AIC, BIC and residual variance. Heritability estimates ranged from 0.079 (TD6) to 0.21(TD10). For both ends of lactation, the additive genetic and environmental variances were higher and ranged from 0.21 ± 0.12 (TD6) to 0.85 ± 0.35 kg2 (TD1) and 3.74 ± 0.36 (TD11) to 1.36 ± 0.14 kg2 (TD9), respectively. Between adjacent test-day records, genetic correlation estimates ranged from 0.09 ± 0.31 (TD1 and TD2) to 0.97 ± 0.03 (TD3 and TD4; TD4 and TD5), but values gradually declined as the distance between test days increased. Negative genetic correlations were also obtained between TD1 with TD3 to TD9, TD2 with TD9 and TD10, and TD3 with TD10. On the basis of genetic correlations, models with 5 and/or 6 test-days combination were able to account for 86.1%-98.7% of variation along the lactation. Models with fourth and fifth-order LP functions were considered to account for variance with combinations of 5 and/or 6 test-day milk yields. The model with 6 test-day combinations had a higher rank correlation (0.93) with model using 11 monthly test-day milk yield records. On the basis of relative efficiency, the model with 6 monthly test day combinations with fifth-order was more efficient (maximum 99%) than the model using 11 monthly test-day milk yield records. Looking into the similar accuracy with the 11TD model, and the low resources requirement, we recommend the use of the "6 test-day combination model" for sire evaluation. These models may help in reducing the cost and time for data recording of milk yield.

Elastic recoil signal on tissue doppler imaging of mitral annulus as a qualitative test to identify left ventricular diastolic function.

Introduction: Left ventricular (LV) diastolic dysfunction is common on preoperative screening among patients undergoing surgery. There is no simple screening test at present to suspect LV diastolic dysfunction. This study was aimed to test the hypothesis, whether elastic recoil signal (ERS) on tissue Doppler imaging of mitral annulus (MA TDI) can be used as a qualitative test to differentiate patients from normal LV diastolic function versus patients with LV diastolic dysfunction. Methods: This was a prospective cross-sectional observational study of patients admitted for elective surgeries. Normal diastolic function and categorization of LV diastolic dysfunction into severity grades I, II, or III were performed as per the American Society of Echocardiography/ European Associationof Cardio Vascular Imaging (ASE/EACVI) recommendations for LV diastolic dysfunction. Results: There were 41 (61%) patients with normal LV diastolic function and 26 (39%) patients with various grades of LV diastolic dysfunction. In 38 out of 41 patients with normal LV diastolic function, the characteristic ERS was identified. The ERS was absent in all the patients with any grade of LV diastolic dysfunction. Consistency of identification of ERS on echocardiography was tested with a good interobserver variability coefficient of 0.94 (P-value <0.001). The presence of ERS demonstrated an excellent differentiation to rule out any LV diastolic dysfunction with an area under the receiver operating characteristics curve (AUROC) of 0.96 (CI 0.88-0.99; P value <0.001). Conclusions: To conclude, in a mixed surgical population, the anesthetist could successfully assess LV diastolic dysfunction in the preoperative period and the characteristic ERS on MA TDI signal can be used as a qualitative test to differentiate patients from normal LV diastolic function versus patients with LV diastolic dysfunction using the transthoracic echocardiography (TTE).

Cardiac sympathetic denervation prevents sudden cardiac arrest and improves cardiac function by enhancing mitochondrial-antioxidant capacity.

RATIONALE: Sudden cardiac arrest (SCA) and heart failure (HF) are leading causes of death. The underlying mechanisms are incompletely understood, limiting the design of new therapies. Whereas most autonomic modulation therapies have not shown clear benefit in HF patients, growing evidence indicates cardiac sympathetic denervation (CSD) exerts cardioprotective effects. The underlying molecular and cellular mechanisms remain unexplored. OBJECTIVE: Based on the hypothesis that mitochondrial reactive oxygen species (mROS) drive the pathogenesis of HF and SCA, we investigated whether CSD prevents SCA and HF by improving mitochondrial antioxidant capacity and redox balance, to correct impaired Ca2+ handling and repolarization reserve. METHODS AND RESULTS: We interrogated CSD-specific responses in pressure-overload HF models with spontaneous SCA using in vivo echocardiographic and electrocardiographic studies and in vitro biochemical and functional studies including ratiometric measures of mROS, Ca2+ and sarcomere dynamics in left ventricular myocytes. Pressure-overloaded HF reduced mitochondrial antioxidant capacity and increased mROS, which impaired ß-adrenergic signaling and caused SR Ca2+ leak, reducing SR Ca2+ and increasing diastolic Ca2+, impaired myofilament contraction and further increased the sympathetic stress response. CSD improved contractile function and mitigated mROS-mediated diastolic Ca2+ overload, dispersion of repolarization, triggered activity and SCA by upregulating mitochondrial antioxidant and NADPH-producing enzymes. CONCLUSIONS: Our findings support a fundamental role of sympathetic stress-induced downregulation of mROS scavenging enzymes and RyR-leak mediated diastolic Ca2+ overload in HF and SCA pathogenesis that are mitigated by CSD. This first report on the molecular and cellular mechanisms of CSD supports its evaluation in additional high-risk patient groups.

Formic acid, an organic acid food preservative, induces viable-but-non-culturable state, and triggers new Antimicrobial Resistance traits in Acinetobacter baumannii and Klebsiella pneumoniae.

Numerous human pathogens, especially Gram-negative bacteria, are able to enter the viable-but-non-culturable (VBNC) state when they are exposed to environmental stressors and pose the risk of being resuscitated and causing infection after the removal of the trigger. Widely used food preservatives like weak organic acids are potential VBNC inducers in food processing and packaging facilities but have only been reported for food-borne pathogens. In the present study, it is demonstrated for the first time that one such agent, formic acid (FA), can induce a VBNC state at food processing, storage, and distribution temperatures (4, 25, and 37°C) with a varied time of treatment (days 4-10) in pathogenic Gram-negative bacteria Acinetobacter baumannii and Klebsiella pneumoniae. The use of hospital-associated pathogens is critical based on the earlier reports that demonstrated the presence of these bacteria in hospital kitchens and commonly consumed foods. VBNC induction was validated by multiple parameters, e.g., non-culturability, metabolic activity as energy production, respiratory markers, and membrane integrity. Furthermore, it was demonstrated that the removal of FA was able to resuscitate VBNC with an increased expression of multiple virulence and Antimicrobial Resistance (AMR) genes in both pathogens. Since food additives/preservatives are significantly used in most food manufacturing facilities supplying to hospitals, contamination of these packaged foods with pathogenic bacteria and the consequence of exposure to food additives emerge as pertinent issues for infection control, and control of antimicrobial resistance in the hospital setting.

Intramolecular C-N bond activation by a geometrically constrained PIII-centre.

In this work the first examples of C-N bond activation by insertion into a geometrically constrained PIII-centre are shown. The mechanisms of these activation processes leading to new PV species were studied both experimentally and computationally. Interestingly, in the case of insertion of the PIII-centre into an N-C(O)H bond, an unstable phosphoranyl-formaldehyde intermediate is probably formed, which undergoes decarbonylation in the presence of a catalytic amount of HCl producing a hydrophosphorane.

Estimation of genetic parameters of growth traits for direct and maternal effects in Murrah buffalo.

An understanding of genetic principles and environmental factors affecting the growth traits is essential to implement optimal breeding and selection programs. Early growth is an indicator of future success in production and reproduction status of dairy animals. In this study, a total of 18,989 records of body weight were used to estimate genetic parameters of body weight at birth (BW), 3 months (3BW), 6 months (6BW), 9 months (9BW),12 months (12BW), 18 months (18BW), 24 months (24 BW), 30 months (3BW), and 36 months (36BW) in Murrah buffalo at ICAR-NDRI Karnal, Haryana, for the period 1974-2019. The genetic parameters were estimated using the average information restricted maximum likelihood (AIREML) procedure by excluding or including maternal effects. Six analytical models were fitted in order to optimize the model for each trait. The most appropriate univariate model was selected based on the log likelihood ratio test (LRT). Influencing factors like calf sex, period of birth, season of birth, and dam's parity were investigated. The results showed that the maternal genetic effects, in addition to direct additive effects, were important for unbiased and accurate genetic parameter estimates of growth traits in Murrah buffaloes. Total heritability estimates h2T1 for BW, 3BW, 6BW, 9BW, 12BW, 18BW, 24BW, 30BW, and 36BW were 0.25, 0.04, 0.14, 0.16, 0.10, 0.15, 0.21, 0.24, and 0.23, respectively. Maternal effect was significant for birth weight and accounted for 13% variation through maternal genetic and 5% variability through maternal permanent environmental effect. Maternal genetic effect was also important for other traits. However, it interfered with the estimates of variance ratios in live weight traits owing to large and negative covariance between direct and maternal genetic effects. Direct genetic correlations between body weight traits were positive and high ranging from 0.10 to 0.94. Results revealed that the Murrah herd has a sizable genetic variability for growth traits and hence, there is sufficient scope for selection for achieving better growth rate if selection in this direction is applied. Owing to higher positive genetic correlation of 6BW with later ages, the scope of indirect selection for optimum growth in later ages can be aimed at by selecting animals for their higher 6-month live weight.

Associations between polymorphisms of LAP3 and SIRT1 genes with clinical mastitis and milk production traits in Sahiwal and Karan Fries dairy cattle.

BACKGROUND: Bovine mastitis continues to remain as the most challenging disease in dairy cattle, as a result improvement of selection methods has great economic relevance while a deeper understanding of the genetic mechanisms regulating milk production traits and mastitis is of general scientific interest. OBJECTIVES: This study aimed to evaluate the association of SNPs of the LAP3 and SIRT1 genes with estimated breeding values (EBVs) of milk production traits and clinical mastitis in dairy cattle of Indian origin. METHODS: DNA samples from 263 animals (Sahiwal and Karan Fries cattle) were genotyped by PCR-RFLP to assess their pattern of genetic variation. EBVs of milk production traits and phenotypic records of incidences of clinical mastitis were used for association analysis. RESULTS: A total of 9 SNPs were identified, including three (rs110932626: A>G, rs716493845: C>T and rs43702363: C>T) in intron 12, four (g.24904G>C, rs110839532: G>T, rs43702361: T>C and rs41255599: C>T) in exon 13 and within 3'UTR of LAP3 gene and two (rs110250233: G>A and rs42140046: C>G) in the promoter region of SIRT1 gene. Eight of these identified SNPs were chosen for subsequent genotyping and association analyses. Association analysis revealed that SNP rs41255599: C>T was significantly associated with lactation milk yield, 305-day milk yield, 305-day fat yield, 305-day solid not fat yield, lactation length and incidence of clinical mastitis (p < 0.05) in Sahiwal cattle. For Karan Fries cattle, two SNPs including rs110932626: A>G and rs43702363: C>T showed significant association with 305-day milk yield. CONCLUSION: Overall, these findings provide evidence for association of the LAP3 gene with milk production traits and clinical mastitis in dairy cattle, indicating the potential role of LAP3 variants in these traits.