Role of Inflammation in the Pathogenesis of Myeloproliferative Neoplasms

Myeloproliferative neoplasms (MPNs) are a group of diseases frequently caused by activating mutations in JAK2, CALR or MPL and characterized by aberrant proliferation of the erythroid, megakaryocytic and myeloid lineages. They represent clonal disorders of the hematopoietic stem cell (HSC) with an inherent tendency towards leukemic transformation. MPNs are subdivided into three disease entities: polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). JAK2-V617F is the most frequently recurring somatic mutation in MPN patients, but it can also be found in healthy individuals with clonal hematopoiesis of indeterminate potential (CHIP) with a frequency much higher than the incidence of MPN. This suggests that the acquisition of the JAK2-V617F is not the rate-limiting step and other factors might be required for the expansion of the JAK2 mutated clone and initiation of MPN disease. MPN is often linked with a chronic inflammatory state due to elevated production of inflammatory cytokines and chemokines from hematopoietic and non-hematopoietic cells. Interleukin-1β (IL-1β) is one of the master regulators of the inflammatory state and its aberrant activity has been implicated in various pathological diseases including MPN. In the first part of this study, we focused on the early stages of MPN disease initiation and examined the role of IL-1β in this context. Our results showed that IL-1β secreted from mutant cells promoted the expansion of JAK2-V617F clones and loss of IL-1β from mutant cells resulted in reduced frequency of MPN disease initiation. Furthermore, our results indicated that IL-1β was required for optimal stem cell function and long-term repopulation capacity of JAK2-V617F HSCs. Moreover, we showed that early secretion of IL-1β from mutant cells caused neuronal damage in the bone marrow resulting in loss of nestin-positive stromal cells. Loss of nestin-positive stromal cells favored clonal expansion and MPN disease manifestation. In the second part of the study, we showed that JAK2-V617F mutation correlated with increased IL-1 signaling in MPN patients. We showed that genetic deletion of IL-1β from mutant cells resulted in reduced production of inflammatory cytokines, reduced MPN symptom burden and myelofibrosis. Notably, pharmacological inhibition of IL-1β or NLRP3 inflammasome complex reduced myelofibrosis. Combined targeting of IL-1β with JAK1/2 inhibitor, ruxolitinib resulted in complete reversal of myelofibrosis, reduced production of inflammatory cytokines and normalization of MPN constitutional symptoms in vivo. Overall, our results showed that IL-1β is required for optimal MPN disease initiation and progression to myelofibrosis

Telemedicine Solution using Django

The average person usually don’t have much information about diseases related to symptoms they have and which doctor to visit for that disease. This causes a lot of wastage of time and money because they have to search doctor by doctor to get the right doctor and get an appointment with that doctor. Also not all doctors treat all diseases, this means just knowing your disease is not enough. Through this telemedicine solution we have tried to mitigate the inefficiency and delays in the system. Patients can get a basic idea of the possible disease they might have and a  list of  doctors suited to cure this disease is given as output to the patient. Then the patient can connect with doctors on a website

Awareness, perception and practices regarding Breast-Feeding and IYCF Practices among mothers of Children Up to 2 Years in Two Districts of Central India: A Cross-Sectional Study

Background: Breastfeeding is an absolute necessary intervention for childhood survival. WHO/UNICEF have given utmost emphasis on first 1000 days of life comprising of 270 days in-utero and the first two years post birth as most vital period for nutritional interventions. [1] Infant and Young Child Feeding (IYCF) is a set of renowned and usual recommendations for appropriate feeding of new-born and children below two years of age. Aims & Objectives: To assess the awareness, perception and practices, regarding breast-feeding and IYCF practices among mothers of children up to 2 years, in two districts of Central India. Settings and Design: Cross Sectional Study. Materials and Methods: This Cross-sectional study was carried out in two districts of Central India from January 2021 to December 2021. The study subjects included 400 mothers of babies less than two years old, who had given consent.  Interpersonal interview using a pre-designed semi-structured questionnaire was carried out. Data was collected, compiled and analysed using SPSS 25.0 (Trial Version). Result: Only (58.60%) of respondents were completely knowledgeable about exclusive breastfeeding, the value of colostrum feeding, the advantages of breastfeeding (81.69%), and its early onset (64.75%), duration (71.25%), and frequency (74.50%). However, 50.25% of women lacked understanding about the ideal positioning and attachment of the infant to the breast. Conclusion: All beneficiaries should be shown demonstrations of all IYCF practices. Family members should also be counselled and encouraged to support IYCF practices

Awareness, perception and practices regarding infant and young child feeding among health care providers in two districts of Madhya Pradesh: a cross-sectional study

Introduction Infant and young child nutrition needs to be given top priority in order to prevent and minimize malnutrition given the low rates of child feeding practices. The present study was carried out to assess the awareness, perception and practices of health care providers (HCPs) regarding (IYCF) practices in Madhya Pradesh

JAK2-mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms

Increased energy requirement and metabolic reprogramming are hallmarks of cancer cells. We show that metabolic alterations in hematopoietic cells are fundamental to the pathogenesis of mutant JAK2-driven myeloproliferative neoplasms (MPNs). We found that expression of mutant JAK2 augmented and subverted metabolic activity of MPN cells, resulting in systemic metabolic changes in vivo, including hypoglycemia, adipose tissue atrophy, and early mortality. Hypoglycemia in MPN mouse models correlated with hyperactive erythropoiesis and was due to a combination of elevated glycolysis and increased oxidative phosphorylation. Modulating nutrient supply through high-fat diet improved survival, whereas high-glucose diet augmented the MPN phenotype. Transcriptomic and metabolomic analyses identified numerous metabolic nodes in JAK2-mutant hematopoietic stem and progenitor cells that were altered in comparison with wild-type controls. We studied the consequences of elevated levels of Pfkfb3, a key regulatory enzyme of glycolysis, and found that pharmacological inhibition of Pfkfb3 with the small molecule 3PO reversed hypoglycemia and reduced hematopoietic manifestations of MPNs. These effects were additive with the JAK1/2 inhibitor ruxolitinib in vivo and in vitro. Inhibition of glycolysis by 3PO altered the redox homeostasis, leading to accumulation of reactive oxygen species and augmented apoptosis rate. Our findings reveal the contribution of metabolic alterations to the pathogenesis of MPNs and suggest that metabolic dependencies of mutant cells represent vulnerabilities that can be targeted for treating MPNs

Stage-wise green supply chain management and environmental performance: Impact of blockchain technology

In the era of globalisation, the use of technology and concerns for sustainability is eminent in the supply chain management practices. The current study focuses on sustainable and green supply practices in different stages of supply chain management and how they can be facilitated by blockchain technology (BT). The study has addressed the existing gaps in the area namely, the lack of research assessing stage-wise green supply chain for environmental performance focusing on BT. The current study aims to assess the impact of BT on different stages of the green supply chain and a firm's environmental performance. The study also focuses on analyzing the impact of green supply chain stages on environmental performance. The study uses PLS-based structural equation modelling approach to investigate the hypothesised relationships between BT adoption and stage-wise green supply chain practices. The data was collected from individuals from medium-sized enterprises from the manufacturing industry in India. The findings reveal a positive association between blockchain adoption and green supply chain management practices leading to enhancement in environmental performance. Furthermore, the study indicates a positive relationship between blockchain integration and different stages of the green supply chain, underscoring its multi-faceted impact on environmental performance. The findings imply that the BT adoption can facilitate the realization of sustainable supply chain practices and performance improvement

Tribo-mechanical characterization of spark plasma sintered chopped carbon fibre reinforced silicon carbide composites

Short carbon fibre (C-f) reinforced silicon carbide (SiC) composites with 7.5 wt% alumina (Al2O3) as sintering additive were fabricated using spark plasma sintering (SPS). Three different C-f concentrations i.e. 10, 20 and 30 wt% were used to fabricate the composites. With increasing C-f content from 0 to 20 wt%, micro-hardness of the composites decreased similar to 28% and fracture toughness (K-IC) increased significantly. The short C-f in the matrix facilitated enhanced fracture energy dissipation by the processes of crack deflection and bridging at C-f/SiC interface, fibre debonding and pullout. Thus, 20 wt% C-f/SiC composite showed > 40% higher K-IC over monolithic SiC (K-IC approximate to 4.51 MPa m(0.5)). Tribological tests in dry condition against Al2O3 ball showed slight improvement in wear resistance but significantly reduced friction coefficient (COF, mu) with increasing C-f content in the composites. The composite containing 30 wt% C-f showed the lowest COF. (C) 2016 Elsevier Ltd and Techna Group S.r.l. All rights reserved

Awareness, perception and practices regarding infant and young child feeding among health care providers in two districts of Madhya Pradesh: a cross-sectional study

Introduction Infant and young child nutrition needs to be given top priority in order to prevent and minimize malnutrition given the low rates of child feeding practices. The present study was carried out to assess the awareness, perception and practices of health care providers (HCPs) regarding (IYCF) practices in Madhya Pradesh

Percent composition of butachlor and metabolites as determined by GC-MS analysis.

<p>The GC-MS measurements were carried out with the metabolites extracted from the reaction mix containing 50mM potassium phosphate buffer pH 7.4, 0.4 mM butachlor and 10mM 2-mercaptoethanol, (1) neither NADPH nor AKR, (2) NADPH (0.12mM), (3) AKR (5 μg), or (4) both NADPH (0.12mM) and AKR (5 μg).</p

Relative normalized expression of AKR17A1 in <i>Anabaena</i> 7120 exposed to butachlor, cadmium, UV-B, heat, salt, drought and arsenic.

<p>Transcript levels were determined by qRT-PCR. The 16S rRNA gene was used as an internal control for normalizing the variations in cDNA amounts. Biological triplicates were averaged. Bars indicate SE.</p