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The World Health Organization has revised the cardiovascular disease (CVD) risk prediction charts in 2019 for each of the 21 Global Burden of Disease regions. These charts (non-lab and lab versions) estimate the total CVD risk in an individual, of which the non-lab is for low-resource settings. We aimed to estimate the burden of ten-year risk of fatal or non-fatal CVD event in the district of Puducherry in India using 'non-lab' and 'lab' versions of WHO CVD risk prediction charts, and to evaluate the agreement between them.We included 710 individuals aged 40-69 years who participated in a district wide non-communicable diseases survey conducted in Puducherry, India, during 2019-20. Both charts use information on age, gender, systolic blood pressure and smoking status. Additionally, lab-chart requires individual's status on diabetes mellitus and total cholesterol while non-lab requires body mass index. Population in different CVD risk levels was presented using proportions (95% confidence intervals). Agreement between lab and non-lab charts was evaluated using Cohen's Kappa (k). The lab and non-lab charts estimated 3% (95% CI: 1.7-4.2) and none of the population respectively, to have high risk (≥20%) for fatal or non-fatal CVD event over the next ten years. Both the charts showed 89.4% (95% CI:87.2%-91.7%) concordance in CVD risk prediction indicating a good level of agreement (k = 0.653).WHO updated CVD risk prediction charts are feasible to apply when data is available and there is good agreement between non-lab and lab based charts.

Purpose The purpose of this study was to elucidate the role and molecular consequences of impaired glutathione (GSH) biosynthesis on eye development. Methods GSH biosynthesis was impaired in surface ectoderm-derived ocular tissues by crossing Gclcf/f mice with hemizygous Le-Cre transgenic mice to produce Gclcf/f/Le-CreTg/- (KO) mice. Control mice included Gclcf/f and Gclcwt/wt/Le-CreTg/- mice (CRE). Eyes from all mice (at various stages of eye development) were subjected to histological, immunohistochemical, Western blot, RT-qPCR, RNA-seq, and subsequent Gene Ontology, Ingenuity Pathway Analysis and TRANSFAC analyses. PAX6 transactivation activity was studied using a luciferase reporter assay in HEK293T cells depleted of GSH using buthionine sulfoximine (BSO). Results Deletion of Gclc diminished GSH levels, increased reactive oxygen species (ROS), and caused an overt microphthalmia phenotype characterized by malformation of the cornea, iris, lens, and retina that is distinct from and much more profound than the one observed in CRE mice. In addition, only the lenses of KO mice displayed reduced crystallin (α, β), PITX3 and Foxe3 expression. RNA-seq analyses at postnatal day 1 revealed 1552 differentially expressed genes (DEGs) in the lenses of KO mice relative to those from Gclcf/f mice, with Crystallin and lens fiber cell identity genes being downregulated while lens epithelial cell identity and immune response genes were upregulated. Bioinformatic analysis of the DEGs implicated PAX6 as a key upstream regulator. PAX6 transactivation activity was impaired in BSO-treated HEK293T cells. Conclusions These data suggest that impaired ocular GSH biosynthesis may disrupt eye development and PAX6 function.

Both protein kinase C (PKC) and reactive oxygen species (ROS) are well-known signaling messengers cross-talking with each other to activate mitogen-activated protein kinases (MAPKs) for progression of hepatocellular carcinoma (HCC). However, the underlying mechanisms are not well elucidated. Especially, whether mitochondrial ROS (mtROS) is involved and how it triggers MAPK signaling are intriguing. In this study, we found mtROS generation and phosphorylation of MAPKs were mediated by PKCδ in HCCs treated with the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Heat shock protein 60 (HSP60), one of the chaperones in mitochondria was the major protein oxidized in TPA-treated HCCs. Moreover, depletion of HSP60 or expression of HSP60 cysteine mutant prevented TPA-induced phosphorylation of MAPKs. To delineate how HSP60 mediated MAPK activation, the role of Raf kinase inhibitor protein (RKIP), a negative regulator of MAPK, was investigated. TPA dissociated RKIP from HSP60 in both mitochondria and cytosol, concurrently with translocation of HSP60 and MAPK from mitochondria to cytosol, which was associated with robust phosphorylation of MAPKs in the cytosol. Moreover, TPA induced opposite phenotypical changes of HCCs, G1 cell cycle arrest, and cell migration, which were prevented by mtROS scavengers and depletion of PKCδ and HSP60. Consistently, TPA increased the migration-related genes, hydrogen peroxide inducible clone5, matrix metalloproteinase-1/3, lamininγ2, and suppressed the cell cycle regulator cyclin E1 (CCNE1) via PKCδ/mtROS/HSP60/MAPK-axis. Finally, c-jun and c-fos were required for TPA-induced expression of the migration-related genes and a novel microRNA, miR-6134, was responsible for TPA-induced suppression of CCNE1. In conclusion, PKCδ cross-talked with mtROS to trigger HSP60 oxidation for release of RKIP to activate MAPK, regulating gene expression for migration, and G1 cell cycle arrest in HCC. Targeted therapy aiming at key players like PKCδ, RKIP, and HSP60 is promising for preventing HCC progression.

With the rapid growing popularity of Additive Manufacturing (AM) processes throughout the globe, researchers, enthusiasts and industries are using it in the manufacturing of complex shapes and parts. In Fused Deposition Modelling (FDM) process, apart from Acrylonitrile Butadiene Styrene (ABS), Polylactic Acid (PLA) is one of the most favoured materials for the manufacturing of various prototypes. However, the usage of FDM printed parts in practical applications is still not so popular due to several reasons. This paper presents a successful testament showcasing implementation of a 3D printed component made of PLA material in a practical application. To demonstrate this, body casing of a GSB 13RE professional hand drill has been successfully 3D printed using PLA material in FDM process. Thereafter, the 3D printed hand drill body casing has been evaluated through assembly and functional testing. It is observed that the body casing perfectly encases the parts of original hand drill as well as performs drilling of holes satisfactorily without any problems. Functional tests have been performed on the assembled model to check for its durability.

The energy consumption of the buildings for cooling, especially during the days of high solar exposure is large due to the increased indoor temperature. The roof of the building contributes more for this cause by allowing a large quantity of heat during day hours. Further, the single storey buildings with the metal roof would help to penetrate a greater quantity of heat and increase the total heat gain of the building. In this way, they could increase the cooling load to attain the human comfort. In this current work, an experimental investigation was carried-out to reduce the indoor temperature of the metal roof single storey industrial building with the help of paraffin based phase changing material (PCM). In this fashion, an attempt was made to reduce the total cooling load of the building which can diminish a greater quantity of conventional power requirement. A scale model of the proposed building was fabricated and tested for the analysis. The experiments conducted in two modes such as the first case without any PCM in the roof (Plain Roof) and next case with encapsulated paraffin as PCM within the roof (PCM Roof). The test results proved that the encapsulation of PCM within the metal roof of the single storey building reduced the temperature of the outer roof, inner roof and consequently the indoor temperature of the building space to a vast extent. Quantitatively, the daily average indoor temperature was dropped by 5 °C and peak indoor temperature was reduced by 9.5 °C with the help of PCM.

Additive Manufacturing of ahuman mandible physical model is developedfrom thepatient having missing teeth at first molar position usingFDM (Fused Deposition Modelling) technique. These physical models are helpful for the surgeons to perform pre-operative procedure to improve the success rates of the surgery. Genesis AKTIV implant is Modelled using CATIA V5 software by considering DICOM Datain NNT viewer software. Finite element analysis is performed on implant with occlusal force and torque. For this initially DICOM data of mandible is extracted from CT Scan and converted to STL format using InVesalius medical modelling software. Modelling of fixture, abutment and screw are developed with IMPLANT GENESIS AKTIV implant standards using CAD software. Depending on the NNT Viewer results suitable parameters are chosen to develop fixture. STL file attained from medical modelling software is further processed and converted to STEP format for performing analysis. Analysis is performed to check deformation and vonmises stress using ANSYS software. Finite element analysis results shown that the von mises stresses does not surpass the yield strength and all the stresses generated are permissible to the mandible.

Electrocardiogram (ECG) is a non-invasive technique used to detect various cardiac disorders. One of the major causes of cardiac arrest is an arrhythmia. Furthermore, ECG beat classification is essential to detect life-threatening cardiac arrhythmias. The major limitations of the traditional ECG beat classification systems are the requirement of an extensive training dataset to train the model and inconsistent performance for the detection of ventricular and supraventricular ectopic (V and S) beats. To overcome these limitations, a system denoted as SpEC is proposed in this work based on Stockwell transform (ST) and two-dimensional residual network (2D-ResNet) for improvement of ECG beat classification technique with a limited amount of training data. ST, which is used to represent the ECG signal into a time-frequency domain, provides frequency invariant amplitude response and dynamic resolution. The resultant ST images are applied as input to the proposed 2D-ResNet to classify five different types of ECG beats in a patient-specific way as recommended by the Association for the Advancement of Medical Instrumentation (AAMI). The proposed SpEC system achieved an overall accuracy (Acc) of 99.73%, sensitivity (Sen) = 98.84%, Specificity (Spe) = 99.50%, Positive predictivity (Ppr) = 98.20% on MIT-BIH arrhythmia database, and shows an overall Acc of 89.87% on real-time acquired ECG dataset with classification time of single ECG beat image = 0.2365 (s) in detecting of five arrhythmia classes. The proposed method shows better performance on both the database compared to the earlier reported state-of-art techniques.

Several members of the aldehyde dehydrogenase (ALDH) family, especially ALDH1 isoenzymes, have been identified as biomarkers of cancer stem cells (CSCs), a small subpopulation of oncogenic cells with self-renewal and multipotency capability. Consistent with this contention, cell populations with high ALDH enzymatic activity exhibit greater carcinogenic potential. It has been reported that ALDH1, especially ALDH1A1, serves as a valuable biomarker for colon CSCs. However, the functional roles of ALDHs in CSCs and solid tumors of the colon tissue is not fully understood. The aim of the present study was to identify molecular signature associated with high ALDH activity in human colorectal adenocarcinoma (COLO320DM) cells by proteomics profiling. Aldefluor(™) assay was performed to sort COLO320DM cells exhibiting high (ALDH(high)) and low (ALDH(low)) ALDH activity. Label-free quantitative proteomics analyses were conducted on these two cell populations. Proteomics profiling revealed a total of 229 differentially expressed proteins (DEPs) in ALDH(high) relative to ALDH(low) cells, of which 182 were down-regulated and 47 were up-regulated. In agreement with previous studies, ALDH1A1 appeared to be the principal ALDH isozyme contributing to the Aldefluor(™) assay activity in COLO320DM cells. Ingenuity pathway analysis of the proteomic datasets indicated that DEPs were associated with mitochondrial dysfunction, sirtuin signaling, oxidative phosphorylation and nucleotide excision repair. Our proteomics study predicts that high ALDH1A1 activity may be involved in these cellular pathways to promote a metabolic switch and cellular survival of CSCs.

Adipose tissue is the largest endocrine organ. When activated by cancer cells, adipocytes secrete adipocytokines and release fatty acids, which are then transferred to cancer cells and used for structural and biochemical support. How this metabolic symbiosis between cancer cells and adipocytes affects skeletal muscle and thermogenesis during cancer cachexia is unknown. Cancer cachexia is a multiorgan syndrome and how the communication between tissues is established has yet to be determined. We investigated adipose tissue secretory factors and explored their role in crosstalk of adipocytes, muscle, and tumor during pancreatic cancer cachexia.We used a pancreatic cancer cachexia mouse model generated by syngenic implantation of pancreatic ductal adenocarcinoma (PDAC) cells (KPC) intraperitoneally into C57BL/6 mice and Lcn2-knockout mice. For in vitro studies, adipocytes (3T3-L1 and primary adipocytes), cachectic cancer cells (Panc0203), non-cachectic cancer cells (Du145 cells), and skeletal muscle cells (C2C12 myoblasts) were used.To identify molecules involved in the crosstalk of adipose tissue with muscle and tumors, we treated 3T3-L1 adipocytes with conditioned medium (CM) from cancer cells. Upon screening the secretomes from PDAC-induced adipocytes, several adipocytokines were identified, including lipocalin 2 (Lcn2). We investigated Lcn2 as a potential mediator of cachexia induced by adipocytes in response to PDAC. During tumor progression, mice exhibited a decline in body weight gain, which was accompanied by loss of adipose and muscle tissues. Tumor-harboring mice developed drastic hypothermia because of a dramatic loss of fat in brown adipose tissue (BAT) and suppression of the thermogenesis pathway. We inhibited Lcn2 with an anti-Lcn2 antibody neutralization or genomic ablation in mice. Lcn2 deficiency significantly improved body temperature in tumor-bearing mice, which was supported by the increased expression of Ucp1 and β3-adrenergic receptor in BAT. In addition, Lcn2 inhibition abrogated the loss of fat and muscle in tumor-bearing mice. In contrast to tumor-bearing WT mice, the corresponding Lcn2-knockout mice showed reduced ATGL expression in iWAT and decreased the expression of muscle atrophy molecular markers MuRF-1 and Fbx32.This study showed that Lcn2 is causally involved in the dysregulation of adipose tissue-muscle-tumor crosstalk during pancreatic cancer cachexia. Therapeutic targets that suppress Lcn2 may minimize the progression of cachexia.

Colorectal cancer (CRC) is the third most common cancer worldwide and one of the most common diseases diagnosed in the USA among both men and women [1]. Interestingly, the incidence and mortality rates have been declining in the United States over the past decades for those aged over 50, with the pace accelerating to 3% annually from 2003 to 2012. However, there has been an alarming increase (51%) in colorectal cancer incidence in those under 50 since 1994 [2–4]. The reasons for this increase are not fully understood. Known risk factors, such as obesity, alcohol, smoking and a sedentary lifestyle, are likely to underlie early-onset cancers [3]. Genetic predisposition and epigenetic alterations are likely to contribute to this increase. Both play an important role in the disruption of several oncogenic signaling pathways which have been identified in colorectal cancer. Numerous reports have highlighted the importance of early mutations in the adenomatous polyposis coli (APC) tumor suppressor gene and in the CTNNB1 (β-catenin) gene; both of these genes influence the Wnt/β pathway signaling by preventing axin-dependent phosphorylation and degradation of β-catenin [5–8]. In addition to these mutations, a synergistic interaction between the genetic and epigenetic alterations is believed to contribute in the development of CRC [8]. Methylations, such as H3K9 and H3K27, have been found to contribute to the regulation of gene expression in both embryonic stem cells and adult stem cells by silencing genes. On the other hand, H3K4 methylation is critical for gene activation [9]. Another mechanism, which is the subject of intensive research, is the one activated by aldehyde dehydrogenase (ALDH) and that promotes tumor growth. ALDH catalytic activity has been identified as a biomarker of many cancers and cancer stem cells [10]. Our group has recently shown that high ALDH1B1 expression was observed throughout the cells of human colon adenocarcinomas, suggesting a close association between ALDH1B1 presence and activation of Wnt/β-catenin [11, 12]. However, other groups have suggested the ALDH1A1 isozyme to be present in CRC [13, 14]. However, the mechanism by which ALDH1A1 contributes to CRC has not been elucidated. Athough important signaling pathways and genes have been identified as playing a role in CRC, identification of new prognostic biomarkers continues to be a challenge, because it is a highly heterogeneous cancer, with various molecular alterations taking place throughout the natural course of the disease [15]. Evaluation of the transcriptome allows investigation of alterations in the molecular constituents of the cells and tissues induced by disease. RNA-Seq is one approach that uses deep-sequencing technologies to measure the levels of transcripts and their isoforms, thereby providing a detailed insight into the transcriptome [16]. By identify cellular proteins, proteomics provides additional insights into cellular changes that are downstream of the transcriptome. Metabolite profiling (or metabolomics) provides information about the biochemical consequences of changes in protein expression. This is a powerful approach that measures and identifies small molecules that change during a disease, providing valuable insights into how biochemistry is linked to cell metabolism [17]. Each one of these approaches contributes in a different way in advancing to our understanding of the molecular basis and cellular changes occurring in diseases, such as CRC. They also facilitate the discovery novel biomarkers. For example, transcriptomics can identify the differences in gene expression profiles in key oncogenes and tumor suppressors CRC cells. Proteomics can provide insight into changes in proteins involved in molecular pathways contributing to the development and progression of CRC. Metabolomics can elucidate the biochemical pathways that are altered in the tumor tissue. Each of these approaches enhance our understanding of CRC biology. Recent advances in biocomputational tools make it feasible to (i) analyze large data sets from transcriptomic, proteomic and metabolomic studies, (ii) efficiently integrate them, and (iii) generate a comprehensive systems biology analysis of the disease [18–20]. The use of a multilayer “omics” approach that integrates transcriptomics, proteomics and metabolomics has the potential to greatly increase our understanding of the mechanisms underlying disease. The changes in the metabolome can be linked to alterations in enzymes identified with proteomics, and when combined with transcriptomics data, can enhance the interpretation of the genetic background of thedisease, leading to a more comprehensive molecular view of CRC. The end result of the multi “omics’” approaches to a disease should improve prognosis, and ultimately lead to improved treatment and patient outcomes. Using a multi-omics approach, we have investigated the impact of genetic suppression (shRNA) of ALDH1A1 expression on transcriptomics, proteomics and untargeted metabolomics analyses in a human colon cancer cell line (COLO320) which has a high constitutive expression of ALDH1A1. The present study (i) generates an integrative omic profile of scramble shRNA vs. ALDH1A1 shRNA COLO320 cells, and (ii) identifies possible alterations in biological pathways caused by suppression of ALDH1A1 expression.

Background COVID-19 is associated with both venous and arterial thrombotic complications. While prophylactic anticoagulation is now widely recommended for hospitalized patients with COVID-19, the effectiveness and safety of thromboprophylaxis in outpatients with COVID-19 has not been established. Study Design PREVENT-HD is a double-blind, placebo-controlled, pragmatic, event-driven phase 3 trial to evaluate the efficacy and safety of rivaroxaban in symptomatic outpatients with laboratory-confirmed COVID-19 at risk for thrombotic events, hospitalization, and death. Several challenges posed by the pandemic have necessitated innovative approaches to clinical trial design, start-up, and conduct. Participants are randomized in a 1:1 ratio, stratified by time from COVID-19 confirmation, to either rivaroxaban 10 mg once daily or placebo for 35 days. The primary efficacy end point is a composite of symptomatic venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, non-central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality. The primary safety end point is fatal and critical site bleeding according to the International Society on Thrombosis and Haemostasis definition. Enrollment began in August 2020 and is expected to enroll approximately 4,000 participants to yield the required number of end point events. Conclusions PREVENT-HD is a pragmatic trial evaluating the efficacy and safety of the direct oral anticoagulant rivaroxaban in the outpatient setting to reduce major venous and arterial thrombotic events, hospitalization, and mortality associated with COVID-19.