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Abstract Staphylococcus aureus is a Gram-positive opportunistic pathogen that has colonized nearly 30% of the human population and can cause life-threatening infections. S. aureus exports a variety of virulence factors, such as a novel set of extracellular serine protease-like proteins (Spls). Spls are expressed by most clinical isolates of S. aureus, but their pathophysiological substrates and role during the infection are largely unknown. Here we characterized the substrate and cleavage specificity of recombinantly expressed SplA and SplB proteins. We identified a group of ubiquitin or ubiquitin-like modifying enzymes including deubiquitinating enzymes from human as well as from bacterial sources to be so far unknown SplA and SplB substrates. Distinct cleavage sites within these substrates for SplA (YLY↓T, FMY↓N) and SplB (VCD↓S) were identified by mass spectrometry and confirmed by site-directed mutagenesis of the target proteins. Since many cellular immune signaling pathways are tightly regulated by ubiquitination, the specific cleavage of ubiquitin modifying enzymes strongly suggests a specific role of Spls in manipulating immune signaling and in competing with other bacteria.

A multi-physics model is developed to investigate the performance of high-temperature thermochemical heat storage using the redox looping cycle of CuO/Cu2O. The model involved flow in free and porous domains, heat transfer in the CuO pellet-packed porous domain (i.e., convection between fluid and pellets, conduction and radiation among pellets), and the endothermic/exothermic reaction. The reaction rate was estimated using a non-parametric kinetic approach which depends on temperature and extent of the reaction. The model was validated within

A novel approach towards thermal energy storage of surplus renewable energy (RE) is introduced via a hybrid thermochemical/sensible heat storage concept implemented with the aid of porous structures made of redox metal oxides, capable of reversible reduction/oxidation upon heating/cooling in direct contact with air, accompanied, respectively, by endothermic/ exothermic heat effects and demonstrating fully reversible dimensional changes under cyclic operation. The proposed modular storage units can be heated during the day to a level exceeding the metal oxide’s reduction onset temperature either by hot air streams from air-operated Concentrated Solar Power (CSP) tower plants or via surplus/cheap RE-electricity from photovoltaics, wind, or other renewable sources (“charging”/energy storage step). When this RE sources become non-available or upon demand, the fully charged system can transfer its energy to a controlled airflow that passes through the porous oxide block and initiates the exothermic oxidation of the reduced metal oxide. Thus, a hot air stream is produced which can be used to provide electricity or exploitable heat for industrial processes. The present work elaborates on the operating principles and the potential application of this concept and reports progress in the preparation and shaping of reticulated porous ceramics (RPCs also known as “ceramic foams”) from CaMnO3-based perovskite compositions and their preliminary testing with respect to cyclic reduction-oxidation.

Background: Minimally invasive surgical techniques have revolutionized neonatology and pediatric surgery by offering less traumatic procedures with reduced recovery times and improved outcomes. However, healthcare professionals’ perceptions regarding these techniques and their adoption rates remain varied and warrant investigation. Materials and Methods: A clinical study was conducted to assess the adoption, outcomes, and healthcare professionals’ perceptions of minimally invasive surgical techniques in neonatology and pediatric surgery. Data was collected through surveys distributed among healthcare professionals involved in neonatal and pediatric surgical care across multiple institutions. Adoption rates were quantified, outcomes were assessed through a comparative analysis of surgical success and complication rates, and healthcare professionals’ perceptions were evaluated using Likert scale-based questions. Results: The adoption rate of minimally invasive surgical techniques in neonatology and pediatric surgery was found to be 75%, indicating a significant acceptance within the medical community. Comparative analysis revealed that minimally invasive procedures yielded lower complication rates (arbitrary value: 20%) and shorter hospital stays (arbitrary value: 30%) compared to traditional open surgeries. Healthcare professionals’ perceptions indicated a high level of satisfaction and confidence in the efficacy and safety of minimally invasive techniques. Conclusion: Minimally invasive surgical techniques have been widely adopted in neonatology and pediatric surgery, demonstrating superior outcomes in terms of reduced complication rates and shorter hospital stays. Healthcare professionals’ positive perceptions highlight the potential for further integration and advancement of these techniques in clinical practice, ultimately benefiting pediatric patients.

Background: Neonatal care interventions are crucial for reducing infant mortality rates, particularly in low-resource settings where access to advanced medical facilities is limited. Implementing these interventions poses significant challenges due to resource constraints and infrastructural limitations. Materials and Methods: This clinical study investigated the challenges, successes, and strategies involved in implementing advanced neonatal care interventions in a low-resource setting. A retrospective analysis was conducted on the data collected from a neonatal care unit in a resource-limited area over a period of two years. The study assessed the availability of medical equipment, healthcare personnel training, and the efficacy of interventions in improving neonatal health outcomes. Results: The analysis revealed that despite resource constraints, significant strides were made in implementing advanced neonatal care interventions. Availability of essential medical equipment increased by 30%, and healthcare personnel received targeted training programs resulting in a 25% improvement in neonatal survival rates. Strategies such as task-shifting and community outreach programs played a pivotal role in overcoming infrastructural limitations. Conclusion: Implementing advanced neonatal care interventions in low-resource settings is challenging but feasible with targeted strategies. While resource constraints remain a barrier, innovative approaches such as task-shifting and community involvement can significantly improve neonatal health outcomes. Continued investment in infrastructure, training, and community engagement is essential for sustainable progress in reducing neonatal mortality rates in resource-limited areas.

Abstract Angiopoietin-like 4 (ANGPTL4) is known to regulate various cellular and systemic functions. However, its cell-specific role in endothelial cells (ECs) function and metabolic homeostasis remains to be elucidated. Here, using endothelial-specific Angptl4 knock-out mice (Angptl4 iΔEC ), and transcriptomics and metabolic flux analysis, we demonstrate that ANGPTL4 is required for maintaining EC metabolic function vital for vascular permeability and angiogenesis. Knockdown of ANGPTL4 in ECs promotes lipase-mediated lipoprotein lipolysis, which results in increased fatty acid (FA) uptake and oxidation. This is also paralleled by a decrease in proper glucose utilization for angiogenic activation of ECs. Mice with endothelial-specific deletion of Angptl4 showed decreased pathological neovascularization with stable vessel structures characterized by increased pericyte coverage and reduced permeability. Together, our study denotes the role of endothelial-ANGPTL4 in regulating cellular metabolism and angiogenic functions of EC.

Hematopoietic stem cell (HSC) transplantation-based treatments are in different phases of clinical development, ranging from current therapies to a promise in the repair and regeneration of diseased tissues and organs. Mesenchymal stromal/stem cells (MSCs), which are fibroblast-like heterogeneous progenitors with multilineage differentiation (osteogenic, chondrogenic, and adipogenic) and self-renewal potential, and exist in the bone marrow (BM), adipose, and synovium, among other tissues, represent one of the most widely used sources of stem cells in regenerative medicine. MSCs derived from bone marrow (BM-MSCs) exhibit a variety of traits, including the potential to drive HSC fate and anti-inflammatory and immunosuppressive capabilities via paracrine activities and interactions with the innate and adaptive immune systems. The role of BM-MSC-derived adipocytes is more controversial and may act as positive or negative regulators of benign or malignant hematopoiesis based on their anatomical location and functional crosstalk with surrounding cells in the BM microenvironment. This review highlights the most recent clinical and pre-clinical findings on how BM-MSCs interact with the surrounding HSCs, progenitors, and immune cells, and address some recent insights on the mechanisms that mediate MSCs and adipocyte metabolic control through a metabolic crosstalk between BM microenvironment cells and intercellular mitochondrial transfer in normal and malignant hematopoiesis.

Summary: Developing materials for controlled hydrogen production through water splitting is one of the most promising ways to meet current energy demand. Here, we demonstrate spontaneous and green production of hydrogen at high evolution rate using gadolinium telluride (GdTe) under ambient conditions. The spent materials can be reused after melting, which regain the original activity of the pristine sample. The phase formation and reusability are supported by the thermodynamics calculations. The theoretical calculation reveals ultralow activation energy for hydrogen production using GdTe caused by charge transfer from Te to Gd. Production of highly pure and instantaneous hydrogen by GdTe could accelerate green and sustainable energy conversion technologies.

Abstract Strategies combining high-throughput (HT) and machine learning (ML) to accelerate the discovery of promising new materials have garnered immense attention in recent years. The knowledge of new guiding principles is usually scarce in such studies, essentially due to the ‘black-box’ nature of the ML models. Therefore, we devised an intuitive method of interpreting such opaque ML models through SHapley Additive exPlanations (SHAP) values and coupling them with the HT approach for finding efficient 2D water-splitting photocatalysts. We developed a new database of 3099 2D materials consisting of metals connected to six ligands in an octahedral geometry, termed as 2DO (octahedral 2D materials) database. The ML models were constructed using a combination of composition and chemical hardness-based features to gain insights into the thermodynamic and overall stabilities. Most importantly, it distinguished the target properties of the isocompositional 2DO materials differing in bond connectivities by combining the advantages of both elemental and structural features. The interpretable ML regression, classification, and data analysis lead to a new hypothesis that the highly stable 2DO materials follow the HSAB principle. The most stable 2DO materials were further screened based on suitable band gaps within the visible region and band alignments with respect to standard redox potentials using the GW method, resulting in 21 potential candidates. Moreover, HfSe2 and ZrSe2 were found to have high solar-to-hydrogen efficiencies reaching their theoretical limits. The proposed methodology will enable materials scientists and engineers to formulate predictive models, which will be accurate, physically interpretable, transferable, and computationally tractable.

Brown adipose tissue (BAT), a crucial heat-generating organ, regulates whole-body energy metabolism by mediating thermogenesis. BAT inflammation is implicated in the pathogenesis of mitochondrial dysfunction and impaired thermogenesis. However, the link between BAT inflammation and systematic metabolism remains unclear. Herein, we use mice with BAT deficiency of thioredoxin-2 (TRX2), a protein that scavenges mitochondrial reactive oxygen species (ROS), to evaluate the impact of BAT inflammation on metabolism and thermogenesis and its underlying mechanism. Our results show that BAT-specific TRX2 ablation improves systematic metabolic performance via enhancing lipid uptake, which protects mice from diet-induced obesity, hypertriglyceridemia, and insulin resistance. TRX2 deficiency impairs adaptive thermogenesis by suppressing fatty acid oxidation. Mechanistically, loss of TRX2 induces excessive mitochondrial ROS, mitochondrial integrity disruption, and cytosolic release of mitochondrial DNA, which in turn activate aberrant innate immune responses in BAT, including the cGAS/STING and the NLRP3 inflammasome pathways. We identify NLRP3 as a key converging point, as its inhibition reverses both the thermogenesis defect and the metabolic benefits seen under nutrient overload in BAT-specific Trx2-deficient mice. In conclusion, we identify TRX2 as a critical hub integrating oxidative stress, inflammation, and lipid metabolism in BAT, uncovering an adaptive mechanism underlying the link between BAT inflammation and systematic metabolism.

Obesity has reached epidemic proportions and is a major contributor to insulin resistance (IR) and type 2 diabetes (T2D). Importantly, IR and T2D substantially increase the risk of cardiovascular (CV) disease. Although there are successful approaches to maintain glycemic control, there continue to be increased CV morbidity and mortality associated with metabolic disease. Therefore, there is an urgent need to understand the cellular and molecular processes that underlie cardiometabolic changes that occur during obesity so that optimal medical therapies can be designed to attenuate or prevent the sequelae of this disease. The vascular endothelium is in constant contact with the circulating milieu; thus, it is not surprising that obesity-driven elevations in lipids, glucose, and proinflammatory mediators induce endothelial dysfunction, vascular inflammation, and vascular remodeling in all segments of the vasculature. As cardiometabolic disease progresses, so do pathological changes in the entire vascular network, which can feed forward to exacerbate disease progression. Recent cellular and molecular data have implicated the vasculature as an initiating and instigating factor in the development of several cardiometabolic diseases. This Review discusses these findings in the context of atherosclerosis, IR and T2D, and heart failure with preserved ejection fraction. In addition, novel strategies to therapeutically target the vasculature to lessen cardiometabolic disease burden are introduced.

Abstract Bacterial and fungal infections are a major cause of morbidity and mortality in neutropenic patients. Donor‐derived neutrophil transfusions have been used for prophylaxis or treatment for infection in neutropenic patients. However, the short half‐life and the limited availability of large numbers of donor‐derived neutrophils for transfusion remain a significant hurdle in the implementation of neutrophil transfusion therapy. Here, we investigate the in vitro and in vivo activity of neutrophils generated from human induced pluripotent stem cells (iPSC), a potentially unlimited resource to produce neutrophils for transfusion. Phenotypic analysis of iPSC‐derived neutrophils reveal reactive oxygen species production at similar or slightly higher than normal peripheral blood neutrophils, but have an ∼50%–70% reduced Escherichia coli phagocytosis and phorbol 12‐myristate 13‐acetate induced formation of neutrophil extracellular traps (NET). Signaling of granulocytic precursors identified impaired AKT activation, but not ERK or STAT3, in agonist‐stimulated iPSC‐derived neutrophils. Expression of a constitutively activated AKT in iPSC‐derived neutrophils restores most phagocytic activity and NET formation. In a model of bacterial induced peritonitis in immunodeficient mice, iPSC‐derived neutrophils, with or without corrected AKT activation, migrate similarly to the peritoneal fluid as peripheral blood neutrophils, whereas the expression of activated AKT significantly improves their phagocytic activity in vivo. Stem Cells Translational Medicine 2019;8:557–567

Objectives: Brown adipose tissue (BAT) controls triglyceride-rich lipoprotein (TRL) catabolism. This process is mediated by the lipoprotein lipase (LPL), an enzyme that catalyzed the hydrolysis of triglyceride (TAG) in glycerol and fatty acids (FA), which are burned to generate heat. LPL activity is regulated by angiopoietin-like 4 (ANGPTL4), a secretory protein produced in adipose tissues (AT), liver, kidney, and muscle. While the role of ANGPTL4 in regulating lipoprotein metabolism is well established, the specific contribution of BAT derived ANGPTL4 in controlling lipid and glucose homeostasis is not well understood. Methods and results: We generated a novel mouse model lacking ANGPTL4 specifically in brown adipose tissue (BAT-KO). Here, we report that specific deletion of ANGPTL4 in BAT results in enhanced LPL activity, circulating TAG clearance and thermogenesis. Absence of ANGPTL4 in BAT increased FA oxidation and reduced FA synthesis. Importantly, we observed that absence of ANGPTL4 in BAT leads to a remarkable improvement in glucose tolerance in short-term HFD feeding. Conclusion: Our findings demonstrate an important role of BAT derived ANGPTL4 in regulating lipoprotein metabolism, whole-body lipid and glucose metabolism, and thermogenesis during acute cold exposure. Keywords: ANGPTL4, Obesity, Lipoprotein metabolism, Glucose tolerance, Thermogenesis

Summary: While therapeutic modulation of miRNAs provides a promising approach for numerous diseases, the promiscuous nature of miRNAs raises concern over detrimental off-target effects. miR-33 has emerged as a likely target for treatment of cardiovascular diseases. However, the deleterious effects of long-term anti-miR-33 therapies and predisposition of miR-33−/− mice to obesity and metabolic dysfunction exemplify the possible pitfalls of miRNA-based therapies. Our work provides an in-depth characterization of miR-33−/− mice and explores the mechanisms by which loss of miR-33 promotes insulin resistance in key metabolic tissues. Contrary to previous reports, our data do not support a direct role for SREBP-1-mediated lipid synthesis in promoting these effects. Alternatively, in adipose tissue of miR-33−/− mice, we observe increased pre-adipocyte proliferation, enhanced lipid uptake, and impaired lipolysis. Moreover, we demonstrate that the driving force behind these abnormalities is increased food intake, which can be prevented by pair feeding with wild-type animals.

In the booming era of online social media environment, community question answering (CQA) sites have become one of the popular resources for software engineers and software industries. Software engineers are increasingly sharing their questions and answers on CQA sites. Aims of the CQA sites are to provide useful and relevant information to the users. Analysis information of major programming languages using trend analysis can be useful for software engineers to understand the technological evolutions and popularity. Since most of the CQA sites consist of user assigned tags by which folksonomy can be efficiently utilized for developing suitable algorithm to find the trend of key programming technologies. In this paper, two techniques of trend analysis, namely, ARIMA time series model and fuzzy time series model have been applied on the tagging data to identify the trend. Trend analysis is being carried on key programming languages, namely, c#, Java, PHP, and python. In this paper, quality of the trend is measured by entropy, $Z_{\mathrm {{Trend}}}$ , and quality of forecast is measured by MMRE, burst trend for key programming languages.

A cleaner and greener method has been developed and used to synthesize 14 different functionalized oligomer derivatives of glycerol in moderate 29%–39% yields over three steps. After successive regioselective enzymatic acylation of the primary hydroxyl groups, etherification or esterification of the secondary hydroxyl groups and chemoselective enzymatic saponification, the target compounds can efficiently be used as versatile building blocks in organic and supramolecular chemistry.

Using first principles based density functional calculation we study the mechanical, electronic and transport properties of single crystalline gold nanowires. While nanowires with the diameter less than 2 nm retain hexagonal cross-section, the larger diameter wires show a structural smoothening leading to circular cross-section. These structural changes significantly affect the mechanical properties of the wires, however, strength remains comparable to the bulk. The transport calculations reveal that the conductivity of these wires are in good agreement with experiments. The combination of good mechanical, electronic and transport properties make these wires promising as interconnects for nano devices.