Search

This study introduces an inventory system with a non-instantaneous deteriorating product with credit facility and variable demand depending on the selling price. Two different selling prices are considered in the deterioration and non-deterioration periods. Shortages are partially backlogged and dependent on the length of the customers’ waiting time upto the arrival of fresh lot. Alternative trade-credit policy is applied herein, and several cases, sub-cases and situations are investigated. The corresponding optimization problems of different cases, sub-cases and situations are solved using an interval-oriented multi-section technique with the help of interval mathematics and interval order relations. A numerical example with three different credit periods is studied and solved to validate the said problem. Also, two different case studies are investigated. Then to investigate the effect of changes of several system parameters on the optimal policy, post optimality analyses are performed.

The regulated Metal Deposition (RMD™) process is a variant of the gas metal arc welding process (GMAW), which was developed to effectively control the metal transfer in the short-circuiting mode. The process is fundamentally a modified short-circuit GMAW process wherein a uniform droplet deposition, making it easier for the welder to control the puddle and hence achieve an enhanced quality of welded joints. In the present study, the RMD technique has been established for the low alloy steel grade 2.25 Cr - 1.0 Mo particularly for depositing the root pass on a 10 mm thick joint. In addition to this, the RMD technique is attempted with metal-cored wires to enhance the deposition rates and hence productivity. The joint fill-up is further attempted with the GMAW technique using metal-cored wires and analysed. The weldments were subjected to post-weld heat treatment followed by mechanical and metallurgical characterization. Mechanical characterization such as tensile properties, impact properties, bend test as well as all weld tensile properties of the weld joint was evaluated and found to be acceptable. The ductile to brittle transition temperature (DBTT) testing was carried out by breaking series of impact specimen till negative temperatures. The DBTT temperature for the weld joint was found well below −30 °C which indicated the strength and soundness of the welded joint. Optical microscopy and scanning electron microscopy was carried out for and favourable results were achieved in microanalysis. The study proposes the use of metal-cored wires for potential applications in the welding of high thickness joints for enhancing the overall productivity.

Regulated Metal Deposition (RMD™) welding process is fundamentally a modified short-circuit gas metal arc welding (GMAW) process wherein a precisely-controlled metal transfer provides uniform droplet deposition, making it easier for the welder to control the puddle and hence achieve an enhanced quality of welded joints. RMD technique was experimented and implemented on a variety of steels such as stainless steel, carbon steels, etc. However, obtaining satisfactory welding performance is indeed a challenging task during RMD. Hence, this study aims to assess the favorable parameters settings in order to optimize welding performance characteristics such as Heat affected zone (HAZ), depth of penetration (DOP) and bead width (BW) of Regulated Metal Deposited arc weldment using grey relation analysis integrated with fuzzy inference system with Taguchi approach. From the adopted methodology the optimal parameter settings for current (135 A), voltage (14 V), and gas flow rate (13 L/min) have been achieved. The study also tells that the voltage is the most influencing parameter during RMD welding.

Objective. Present a case of a transgender and gender diverse (TGD) individual receiving gender affirming hormone therapy (GAHT) who presented with first episode bipolar mania and received electroconvulsive therapy (ECT). To understand the safety and efficacy of ECT in the TGD population including those receiving GAHT through literature review. Materials and Methods. Case report using informed consent from an individual TGD patient who received ECT. A review of the literature was conducted using PubMed, Embase, and Medline. Results. The case illustrated safe and effective ECT use in a TGD individual receiving GAHT. Eight studies were reviewed. GAHT has been reported to interfere with certain anaesthetic agents used in ECT. ECT appeared to be a safe and effective treatment in the TGD samples in those studies. Conclusion. There is limited literature on the safety and efficacy of ECT for TGD individuals receiving GAHT. More research is required to address mental health inequalities in this population and to support safe and effective gender affirming treatment modalities.

This study examines the utilization of metal-cored filler wire in conjunction with the gas metal arc welding (GMAW) technique for welding high-strength S690QL steel. Since welding parameters significantly impact the bead quality and weld joint integrity, the main objective was to identify the optimal welding parameters. To achieve this, the input variables including the current (A), voltage (V), and gas flow rate (GFR), and their effects were evaluated for reinforcement (R), width (W), depth of penetration (DOP), and the width of the heat-affected zone (HAZ). For a more efficient and cost-effective investigation, a Box–Behnken design, which is based on response surface methodology, was used for bead-on-plate trials. Mathematical regression models, derived from experimental data, were rigorously validated using the analysis of variance, main effects plots, residual analysis, and the R2and Adj. R2values. Additionally, the heat transfer search (HTS) algorithm was employed for process optimization. While single-objective optimization provided optimal settings for individual responses, simultaneous optimization aimed to strike a balance between multiple, sometimes conflicting, objectives. This comprehensive approach resulted in specific values, including a reinforcement (R) of 4.285 mm, a width (W) of 9.906 mm, a DOP of 2.039 mm, and an HAZ width of 2.020 mm. These values were achieved with specific input parameters: current (221 A), voltage (24 V), and GFR (21 L·min−1). The Pareto solutions offered a nuanced selection of the most suitable configuration, taking into account the desired values for R, W, DOP, and HAZ. The close alignment between predicted and experimentally measured values for the responses highlights the precision and suitability of the HTS algorithm in estimating critical bead geometries during GMAW of S690QL plates.

In the current market situation, uncertainty in the market economy plays a significant role for proper controlling of inventory. In this situation, during an analysis of an inventory system with more realistic assumptions, it becomes a necessity to consider the imprecise behaviour of various inventory parameters. This work demonstrates a partially backlogged inventory model with interval uncertainty in which products during stock-in situation deteriorate at a certain rate. Two distinct cases are considered based on the advance payment and availability of discount. In the first case, the retailer makes full payment in advance to the corresponding supplier, and for this regard, supplier offers some price discount on the total purchasing cost. In the second case, the retailer makes partial payment in advance to the supplier but no discount facility is available. However, the retailer needs to make the rest of the payment at the time of receiving a lot from the supplier. As the inventory parameters are considered interval-valued, the objective function of the corresponding optimisation problem is converted into interval-valued, and to solve the same problem, the c-roptimisation technique is used. Two numerical examples are considered and solved using three distinct variants of QPSO to check the feasibility of the proposed model.

Introduction:Pyruvate Kinase M2 (PKM2) is a glycolytic enzyme that can translocate to the nucleus to regulate different transcription factors (TF) in different tissues or pathologic states. Although its function has been studied extensively in cancer, its biologic role in the heart and specifically terminally differentiated adult cardiomyocytes remains unresolved.Hypothesis:PKM2 may be critical in regulating cardiomyocyte(CM)-specific TF important for cardiac survival.Methods:Transverse aortic constriction (TAC) banding model was used to assess the levels and modifications of PKM2 during heart failure (HF). CM-specific PKM2-deficient and CM-specific Trim35 overexpressing(OE) mice were generated to evaluate the role of PKM2/Trim35 in adult CM. Human Dilated Left Ventricle biopsies were used to translate mechanistic findings into a clinical setting.Results:Here we show that nuclear PKM2 (S37P-PKM2) in CM interacts with several pro-survival or pro-apoptotic TF, including Gata-4, Gata-6, and p53. CM-specific PKM2-deficient mice developed age-dependent dilated cardiac dysfunction and had decreased levels of Gata-4/6, but increased levels of p53, compared to control Cre+ hearts. Mechanistically, we found that nuclear PKM2 can prevent caspase-1 dependent cleavage Gata-4/Gata-6, while also providing a platform for Mdm2-mediated ubiquitination of p53. In a preclinical HF model, nuclear PKM2, along with Gata-4/6 levels decreased, but p53 levels increased (compared to sham controls). Loss of nuclear PKM2 was ubiquitination-dependent and associated with the induction of the E3 ubiquitin-ligase TRIM35. CM-specific Trim35 OE mice had decreased S37P-PKM2 and GATA-4/6, along with increased p53 levels (compared to littermate controls) and had similar cardiac dysfunction to CM-specific PKM2-deficient mice. In a well-characterized cohort of patients with dilated left ventricles, we found a significant increase in TRIM35 levels that was associated with a decrease in S37P-PKM2, Gata-4/6 levels, but an increase in p53 levels, compared to non-failing ventricles.Conclusion:This study provides insight into a previously unrecognized biologic role for PKM2 in providing a molecular platform for TF essential for preserving cardiac survival.

Pyruvate kinase M2 (PKM2) is a glycolytic enzyme that translocates to the nucleus to regulate transcription factors in different tissues or pathologic states. Although studied extensively in cancer, its biological role in the heart remains unresolved. PKM1 is more abundant than the PKM2 isoform in cardiomyocytes, and thus, we speculated that PKM2 is not genetically redundant to PKM1 and may be critical in regulating cardiomyocyte-specific transcription factors important for cardiac survival. Here, we showed that nuclear PKM2 (S37P-PKM2) in cardiomyocytes interacts with prosurvival and proapoptotic transcription factors, including GATA4, GATA6, and P53. Cardiomyocyte-specific PKM2-deficient mice (Pkm2Mut Cre+) developed age-dependent dilated cardiac dysfunction and had decreased amounts of GATA4 and GATA6 (GATA4/6) but increased amounts of P53 compared to Control Cre+hearts. Nuclear PKM2 prevented caspase-1–dependent cleavage and degradation of GATA4/6 while also providing a molecular platform for MDM2-mediated reduction of P53. In a preclinical heart failure mouse model, nuclear PKM2 and GATA4/6 were decreased, whereas P53 was increased in cardiomyocytes. Loss of nuclear PKM2 was ubiquitination dependent and associated with the induction of the E3 ubiquitin ligase TRIM35. In mice, cardiomyocyte-specific TRIM35 overexpression resulted in decreased S37P-PKM2 and GATA4/6 along with increased P53 in cardiomyocytes compared to littermate controls and similar cardiac dysfunction to Pkm2Mut Cre+mice. In patients with dilated left ventricles, increase in TRIM35 was associated with decreased S37P-PKM2 and GATA4/6 and increased P53. This study supports a previously unrecognized role for PKM2 as a molecular platform that mediates cell signaling events essential for cardiac survival.

Supplemental Digital Content is available in the text.

Diabetic nephropathy is the most common cause of end-stage renal disease. Polymorphism in the tissue inhibitor of metalloproteinase-3 (TIMP3) gene, and the ECM-bound inhibitor of matrix metalloproteinases (MMPs), has been linked to diabetic nephropathy in humans. To elucidate the mechanism, we generated double mutant mice in which the TIMP3 gene was deleted in the genetic diabetic Akita mouse background. The aggravation of diabetic injury occurred in the absence of worsening of hypertension or hyperglycemia. In fact, myocardial TIMP3 levels were not affected in Akita hearts, and cardiac diastolic and systolic function remained unchanged in the double mutant mice. However, TIMP3 levels increased in Akita kidneys and deletion of TIMP3 exacerbated the diabetic renal injury in the Akita mouse, characterized by increased albuminuria, mesangial matrix expansion, and kidney hypertrophy. The progression of diabetic renal injury was accompanied by the upregulation of fibrotic and inflammatory markers, increased production of reactive oxygen species and NADPH oxidase activity, and elevated activity of TNF-α-converting enzyme (TACE) in the TIMP3−/−/Akita kidneys. Moreover, while the elevated phospho-Akt (S473 and T308) and phospho-ERK1/2 in the Akita mice was not detected in the TIMP3−/−/Akita kidneys, PKCβ1 (but not PKCα) was markedly elevated in the double mutant kidneys. Our data provide definitive evidence for a critical and selective role of TIMP3 in diabetic renal injury consistent with gene expression findings from human diabetic kidneys.

Activation of the renin-angiotensin and sympathetic nervous systems may alter the cardiac energy substrate preference, thereby contributing to the progression of heart failure with normal ejection fraction. We assessed the qualitative and quantitative effects of angiotensin II (Ang II) and the -adrenergic agonist, phenylephrine (PE), on cardiac energy metabolism in experimental models of hypertrophy and diastolic dysfunction and the role of the Ang II type 1 receptor.

An epithelial-to-mesenchymal transition (EMT) phenotype with cancer stem cell-like properties is a critical feature of aggressive/metastatic tumors, but the mechanism(s) that promote it and its relation to metabolic stress remain unknown. Here we show that Collapsin Response Mediator Protein 2A (CRMP2A) is unexpectedly and reversibly induced in cancer cells in response to multiple metabolic stresses, including low glucose and hypoxia, and inhibits EMT/stemness. Loss of CRMP2A, when metabolic stress decreases (e.g., around blood vessels in vivo) or by gene deletion, induces extensive microtubule remodeling, increased glutamine utilization toward pyrimidine synthesis, and an EMT/stemness phenotype with increased migration, chemoresistance, tumor initiation capacity/growth, and metastatic potential. In a cohort of 27 prostate cancer patients with biopsies from primary tumors and distant metastases, CRMP2A expression decreases in the metastatic versus primary tumors. CRMP2A is an endogenous molecular brake on cancer EMT/stemness and its loss increases the aggressiveness and metastatic potential of tumors.

Background: The elderly are a vulnerable section of the population who are prone to physical, mental, social, and economic deprivation. The effect of COVID-19 had a worldwide impact on all age groups, with a particularly higher mortality and morbidity rate among the elderly population. The present study was undertaken to know about the psychological morbidity in the geriatric population during the period of the COVID-19 pandemic. The study was cross-sectional and was done through a telephonic survey. Eligible elderly subjects were contacted telephonically, and the Geriatric Anxiety Scale and the Geriatric Depression Scale were administered. To evaluate the functional ability of elderly subjects, the Everyday Abilities Scale for India (EASI) scale was administered. For the telephonic survey, verbal consent was sought. Results: A total of 92 elderly subjects were included. Male outnumbered the females with a ratio of 1.8:1. Spouse and children were primary caregivers in 83.7% of the subjects. 90.2% were married, and 66.3% had earned a graduate/professional level of education. Chronic illness was present in 50% of subjects. The most common co-morbidities were hypertension (27.2%) and diabetes (21.7%). The proportion of elderly with anxiety and depression was 8.7% and 15.2% respectively. Conclusion: The elderly showed lower levels of anxiety and depression. Higher resilience among the elderly and good family support may be the reasons for such an unexpected finding. However, more studies are required to validate the findings of the current study.

Background:Pyruvate Kinase M2 (PKM2) is a glycolytic enzyme that can translocate to the nucleus and regulate different transcription factors (TF). Although its function has been studied extensively in cancer, its biologic role in the heart, and specifically terminally differentiated adult cardiomyocytes (CM), remains elusive.Hypothesis:Because PKM1 is the more abundant isoform in CM, we speculated that PKM2 would not have a genetically redundant role to PKM1 and may instead be critical in regulating CM-specific TF.Methods:Transverse aortic constriction (TAC) banding model was used to assess the levels and modifications of PKM2 during heart failure (HF). CM-specific PKM2-deficient mice were generated to evaluate the biological role of PKM2 in adult CM. Unbiased RNA sequencing was utilized to assess novel PKM2-induced signaling pathways in adult CM. Induced pluripotent stem cells (iPSCs) were used to translate mechanistic findings to mature human CM.Results:PKM2 levels were lower, but serine-37 phosphorylated PKM2 (S37P-PKM2) was higher in terminally differentiated tissues. Cell-specific analysis showed S37P-PKM2 was preferentially localized in the nucleus of CM, compared to cardiac fibroblasts (CF) (where PKM2 was mainly cytoplasmic). During TAC-induced HF, PKM2 levels increased in CF but correspondingly decreased in CM, in comparison to sham controls. CM-specific PKM2-deficient mice developed age-dependent cardiac dysfunction with decreased survival, compared to their control littermates. Unbiased RNA sequencing revealed a decrease in cardiac energetic, stress response, angiogenesis, repair and regeneration, and survival pathways from PKM2-deficient CM. In keeping, PKM2-deficient hearts had decreased levels of the cardiomyocyte-specific TF GATA4 and GATA6, compared to control hearts. Finally, the E3 ubiquitin-ligase TRIM35, which was induced during TAC-induced heart failure, ubiquitinated and degraded PKM2, along with GATA4 and GATA6 in primary adult mouse or human iPSC-derived CM.Conclusions:This study shows a new and previously unrecognized role for PKM2 in the regulation of cardiomyocyte-specific transcription factors and identifies a novel therapeutic target (TRIM35) in heart failure.

The present study aims to highlight the effect of the governing variables in regulated metal deposition (RMD™) on the mechanical properties and weld quality of low alloy steel. Current, voltage, and gas flow rate have been considered as main (RMD™) parameters, whereas heat-affected zone, depth of penetration, bead width, and bead height have been taken into account as welding performance characteristics. Signal to noise has been utilized in order to determine the optimal welding parameters, while analysis concerning the significant level of determination has been assessed using analysis of variance. Furthermore, the exploration of principal component analysis and combined quality loss concept integrated with the Taguchi method has been introduced to assess the favorable welding condition. The optimal favorable machine combination has been obtained as current = 100 A, V= 13 V, and gas flow rate = 21 L/min using both the methods.

ObjectivePopulation-based information on causes of death (CoD) by age, sex, and area is critical for countries with limited resources to identify and address key public health issues. This study analysed the demographic surveillance and verbal autopsy (VA) data to estimate age- and sex-specific mortality rates and cause-specific mortality fractions in two well-defined rural populations within the demographic surveillance system in Abhoynagar and Mirsarai subdistricts, located in different climatic zones.DesignDuring 2004–2010, the sample demographic surveillance system registered 1,384 deaths in Abhoynagar and 1,847 deaths in Mirsarai. Trained interviewers interviewed the main caretaker of the deceased with standard VA questionnaires to record signs and symptoms of diseases or conditions that led to death and health care experiences before death. The computer-automated InterVA-4 method was used to analyse VAs to determine probable CoD.ResultsAge- and sex-specific death rates revealed a higher neonatal mortality rate in Abhoynagar than Mirsarai, and death rates and sex ratios of male to female death rates were higher in the ages after infancy. Communicable diseases (CDs) accounted for 16.7% of all deaths in Abhoynagar and 21.2% in Mirsarai – the difference was due mostly to more deaths from acute respiratory infections, pneumonia, and tuberculosis in Mirsarai. Non-communicable diseases (NCDs) accounted for 56.2 and 55.3% of deaths in each subdistrict, respectively, with leading causes being stroke (16.5–19.3%), neoplasms (13.2% each), cardiac diseases (8.9–11.6%), chronic obstructive pulmonary diseases (5.1–6.3%), diseases of the digestive system (3.1–4.1%), and diabetes (2.8–3.5%), together accounting for 49.2–51.2% points of the NCD deaths in the two subdistricts. Injury and other external causes accounted for another 7.5–7.7% deaths, with self-harm being higher among females in Abhoynagar.ConclusionsThe computer-automated coding of VA to determine CoD reconfirmed that NCDs were the leading CoD with some differences between the sites. Incorporating VA into the national sample vital registration system can help policy makers to identify the leading CoDs for public health planning.