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The combination of aluminum and steel materials in hybrid structures shows promising applications in the automotive, marine, and aerospace sectors. The present study investigates how the tool–pin offset impacts the microstructural, mechanical, and electrochemical characteristics of friction stir-welded joints between dissimilar AA2024-T3 and SS304 materials. The optimum conditions were achieved at a tool rotation of 560 r/min, a traverse speed of 25 mm/min, and a tool–pin offset of 1 mm towards the Al side. Upon increasing the tool–pin offset to 1.5 mm, insufficient heat input resulted in inadequate plastic deformation and material flow, leading to the creation of flaws like voids, tunnels, and interfacial gaps. However, under optimal conditions, the joint exhibited a well-defined and serrated interface, with fine steel fragments securely embedded in the Al matrix. Additionally, thin intermetallic compounds were observed around the steel fragments within the Al matrix. This favorable combination resulted in enhanced tensile strength and increased ductility in the joint. The Vickers hardness test revealed that the stir zone exhibited the highest hardness values, primarily attributed to the ultra-refinement of grains. Furthermore, the potentiodynamic test revealed that the welded samples show improved corrosion resistance against the base material AA2024-T3, although BM-SS304 exhibited the highest corrosion resistance among all the samples, likely due to its higher chromium content. [ABSTRACT FROM AUTHOR]

With the elimination of solidification defects, friction stir welding becomes the most effective process for joining flat and curved surfaces. Tool geometry (tool pin profile, shoulder diameter) and tool rotation speed mainly contribute to the overall weld quality. The study evaluates the simultaneous effect of tool geometry, rotational speed, base offset and double pass Friction Stir Welding (DP-FSW) on the defect formation and the mechanical properties. Micro-structure and macro-structure have been analysed for weld strength and hardness characterisation, and found, at high tool rotation speed maximum hardness is achieved in the Stir Zone (SZ). A small tunnel present near the middle proved to be more detrimental than the large one at the bottom. Grain refinement in the SZ was 87.2% while augmentation in hardness was 21.3 HV. Maximum tensile strength of approximately 103% with decent bead profile is obtained, using taper cylindrical tool at 710 rpm with 14 mm shoulder diameter. Fractography of the fractured surface revealed a pure ductile failure. It has been discovered that with base offset the strength of the weld is increased. However, reduction of 4.8% was obtained with DP-FSW. Better weld profile gives better strength. With DP-FSW, a significant improvement in bead surface is obtained. [ABSTRACT FROM AUTHOR]

Introduction Tuberculosis causes significant human mortality and morbidity worldwide, with the lung granuloma representing the typical site of disease manifestation (1, 2). Granulomas are stratified structures, containing concentric layers of [...], The hallmark of human Mycobacterium tuberculosis infection is the presence of lung granulomas. Lung granulomas can have different phenotypes, with caseous necrosis and hypoxia present within these structures during active tuberculosis. Production of NO by the inducible host enzyme NOS2 is a key antimycobacterial defense mechanism that requires oxygen as a substrate; it is therefore likely to perform inefficiently in hypoxic regions of granulomas in which M. tuberculosis persists. Here we have used [Nos2.sup.-/-] mice to investigate host-protective mechanisms within hypoxic granulomas and identified a role for host serine proteases in hypoxic granulomas in determining outcome of disease. [Nos2.sup.-/-] mice reproduced human-like granulomas in the lung when infected with M. tuberculosis in the ear dermis. The granulomas were hypoxic and contained large amounts of the serine protease cathepsin G and clade B serine protease inhibitors (serpins). Extrinsic inhibition of serine protease activity in vivo resulted in distorted granuloma structure, extensive hypoxia, and increased bacterial growth in this model. These data suggest that serine protease activity acts as a protective mechanism within hypoxic regions of lung granulomas and present a potential new strategy for the treatment of tuberculosis.

Histological structure of thrombi is a strong determinant of the outcome of vascular recanalization therapy, the only treatment option for acute ischemic stroke (AIS) patients. A total of 21 AIS patients from this study after undergoing non-enhanced CT scan and multimodal MRI were treated with mechanical stent-based and manual aspiration thrombectomy, and thromboembolic retrieved from a cerebral artery. Complementary histopathological and imaging analyses were performed to understand their composition with a specific focus on fibrin, von Willebrand factor, and neutrophil extracellular traps (NETs). Though distinct RBC-rich and platelet-rich areas were found, AIS patient thrombi were overwhelmingly platelet-rich, with 90% of thrombi containing <40% total RBC-rich contents (1.5 to 37%). Structurally, RBC-rich areas were simple, consisting of tightly packed RBCs in thin fibrin meshwork with sparsely populated nucleated cells and lacked any substantial von Willebrand factor (VWF). Platelet-rich areas were structurally more complex with thick fibrin meshwork associated with VWF. Plenty of leukocytes populated the platelet-rich areas, particularly in the periphery and border areas between platelet-rich and RBC-rich areas. Platelet-rich areas showed abundant activated neutrophils (myeloperoxidase+ and neutrophil-elastase+) containing citrullinated histone-decorated DNA. Citrullinated histone-decorated DNA also accumulated extracellularly, pointing to NETosis by the activated neutrophils. Notably, NETs-containing areas showed strong reactivity to VWF, platelets, and high-mobility group box 1 (HMGB1), signifying a close interplay between these components. [ABSTRACT FROM AUTHOR]

Background: Obesity coexists with variable features of metabolic syndrome, which is associated with dysregulated metabolic pathways. We assessed potential associations between serum metabolites and features of metabolic syndrome in Arabic subjects with obesity. Methods: We analyzed a dataset of 39 subjects with obesity only (OBO, n = 18) age-matched to subjects with obesity and metabolic syndrome (OBM, n = 21). We measured 1069 serum metabolites and correlated them to clinical features. Results: A total of 83 metabolites, mostly lipids, were significantly different (p < 0.05) between the two groups. Among lipids, 22 sphingomyelins were decreased in OBM compared to OBO. Among non-lipids, quinolinate, kynurenine, and tryptophan were also decreased in OBM compared to OBO. Sphingomyelin is negatively correlated with glucose, HbA1C, insulin, and triglycerides but positively correlated with HDL, LDL, and cholesterol. Differentially enriched pathways include lysine degradation, amino sugar and nucleotide sugar metabolism, arginine and proline metabolism, fructose and mannose metabolism, and galactose metabolism. Conclusions: Metabolites and pathways associated with chronic inflammation are differentially expressed in subjects with obesity and metabolic syndrome compared to subjects with obesity but without the clinical features of metabolic syndrome. [ABSTRACT FROM AUTHOR]

Background: Obesity-associated dysglycemia is associated with metabolic disorders. MicroRNAs (miRNAs) are known regulators of metabolic homeostasis. We aimed to assess the relationship of circulating miRNAs with clinical features in obese Qatari individuals. Methods: We analyzed a dataset of 39 age-matched patients that includes 18 subjects with obesity only (OBO) and 21 subjects with obesity and metabolic syndrome (OBM). We measured 754 well-characterized human microRNAs (miRNAs) and identified differentially expressed miRNAs along with their significant associations with clinical markers in these patients. Results: A total of 64 miRNAs were differentially expressed between metabolically healthy obese (OBO) versus metabolically unhealthy obese (OBM) patients. Thirteen out of 64 miRNAs significantly correlated with at least one clinical trait of the metabolic syndrome. Six out of the thirteen demonstrated significant association with HbA1c levels; miR-331-3p, miR-452-3p, and miR-485-5p were over-expressed, whereas miR-153-3p, miR-182-5p, and miR-433-3p were under-expressed in the OBM patients with elevated HbA1c levels. We also identified, miR-106b-3p, miR-652-3p, and miR-93-5p that showed a significant association with creatinine; miR-130b-5p, miR-363-3p, and miR-636 were significantly associated with cholesterol, whereas miR-130a-3p was significantly associated with LDL. Additionally, miR-652-3p's differential expression correlated significantly with HDL and creatinine. Conclusions: MicroRNAs associated with metabolic syndrome in obese subjects may have a pathophysiologic role and can serve as markers for obese individuals predisposed to various metabolic diseases like diabetes. [ABSTRACT FROM AUTHOR]

Aluminium matrix composites are one of the most important classes of materials and have become a major focus of attention in aerospace, aeronautical, defense, and automotive industries. Aluminium matrix composites when compared to conventional alloys offer various promising properties like excellent strength-to-weight ratio, higher stiffness, lower coefficient of thermal expansion, better dimensional stability, and tribological behavior. The properties of aluminium matrix composites are highly influenced by the appropriate selection of metal matrix, processing routes, and reinforcement. Various ceramic particles (oxides, carbides, nitrides, borides, etc.) are used as reinforcements for aluminium matrix composites. Significantly different properties may be obtained using various reinforced particles and matrix material, which makes it difficult for the traditional fusion welding techniques to meet the joining requirements of these composites and is restricted to certain grades of materials. Solid-state welding process offers greater advantages over the conventional fusion welding. As a solid-state joining process, friction stir welding has proven to be a better and promising technique for joining aluminium matrix composites. However, it is still subjected to various challenges to join aluminium matrix composites even with considerable progress has been made in recent years. The current review provides an overview of state-of-the-art of friction stir welding of aluminium matrix composite materials. Specific attention and critical assessment have been given to weldability, the macrostructure and microstructure of aluminium matrix composite joints, mechanical properties of joints, fractography, and the wear of friction stir welding tool during welding of aluminium matrix composite. Furthermore, the various existing challenges of friction stir welding of aluminium matrix composites are summarized and the recommendations for future research are proposed. [ABSTRACT FROM AUTHOR]

Coronavirus disease-2019 (COVID-19) was declared as a pandemic by WHO in March 2020. SARS-CoV-2 causes a wide range of illness from asymptomatic to life-threatening. There is an essential need to identify biomarkers to predict disease severity and mortality during the earlier stages of the disease, aiding treatment and allocation of resources to improve survival. The aim of this study was to identify at the time of SARS-COV-2 infection patients at high risk of developing severe disease associated with low survival using blood parameters, including inflammation and coagulation mediators, vital signs, and pre-existing comorbidities. This cohort included 89 multi-ethnic COVID-19 patients recruited between July 14th and October 20th 2020 in Doha, Qatar. According to clinical severity, patients were grouped into severe (n=33), mild (n=33) and asymptomatic (n=23). Common routine tests such as complete blood count (CBC), glucose, electrolytes, liver and kidney function parameters and markers of inflammation, thrombosis and endothelial dysfunction including complement component split product C5a, Interleukin-6, ferritin and C-reactive protein were measured at the time COVID-19 infection was confirmed. Correlation tests suggest that C5a is a predictive marker of disease severity and mortality, in addition to 40 biological and physiological parameters that were found statistically significant between survivors and non-survivors. Survival analysis showed that high C5a levels, hypoalbuminemia, lymphopenia, elevated procalcitonin, neutrophilic leukocytosis, acute anemia along with increased acute kidney and hepatocellular injury markers were associated with a higher risk of death in COVID-19 patients. Altogether, we created a prognostic classification model, the CAL model (C5a, Albumin, and Lymphocyte count) to predict severity with significant accuracy. Stratification of patients using the CAL model could help in the identification of patients likely to develop severe symptoms in advance so that treatments can be targeted accordingly. [ABSTRACT FROM AUTHOR]

An important role of transforming growth factor-β (TGF-β) in the development of regulatory T cells is well established. Although integrin-mediated activation of latent TGF-β1 is considered essential for the induction of regulatory T (Treg) cells by antigen-presenting cells (APCs), such an activation mechanism is not applicable to the TGF-β2 isoform, which lacks an integrin-binding RGD sequence in its latency-associated peptide. Mucosal and ocular tissues harbour TGF-β2-expressing APCs involved in Treg induction. The mechanisms that regulate TGF-β activation in such APCs remain unclear. In this study, we demonstrate that murine APCs exposed to TGF-β2 in the environment predominantly increase expression of TGF-β2. Such predominantly TGF-β2-expressing APCs use thrombospondin- 1 (TSP-1) as an integrin-independent mechanism to activate their newly synthesized latent TGF-β2 to induce Foxp3+ Treg cells both in vitro and in vivo. Expression of Treg induction by TGF-β2-expressing APCs is supported by a TSP-1 receptor, CD36, which facilitates activation of latent TGF-β during antigen presentation. Our results suggest that APC-derived TSP-1 is essential for the development of an adaptive regulatory immune response induced by TGF-β2-expressing APCs similar to those located at mucosal and ocular sites. These findings introduce the integrin-independent mechanism of TGF-β activation as an integral part of peripheral immune tolerance associated with TGF-β2-expressing tissues. [ABSTRACT FROM AUTHOR]

Bloodstream Candida infections constitute a major threat for hospitalized patients in intensive care units and immunocompromised hosts. Certain serum cytokines play a decisive role in anti-microbial host defense. Cytokines may act as discriminatory biomarkers that can significantly increase in candidemia compared to bacteremia patients. The concentration of secreted cytokine/chemokines was determined using a multiplexed cytometric bead array run on a cell analyzer. The cytokines tested during the study were interleukin (IL)-1β, IL-6, IL-17A, IL-10, IFN-γ, IL-4, IL-2, IL-8, IL-12p70 and the tumor necrosis factor (TNF)-α. The cytokines of 51 candidemia patients were characterized and compared to the cytokine levels of 20 bacteremia patients. Levels were significantly elevated in patients with bloodstream infections compared to healthy controls. Cytokines comprising IL-2, IL-17A, IL-6 and IL-10 were significantly elevated in the patients with bloodstream Candida infection as compared to the patients having bloodstream bacterial infections. The levels were found to be promising as a potential diagnostic marker for bloodstream Candida infections. [ABSTRACT FROM AUTHOR]

There is a lack of predictive markers for early and rapid identification of disease progression in COVID-19 patients. Our study aims at identifying microRNAs (miRNAs)/small nucleolar RNAs (snoRNAs) as potential biomarkers of COVID-19 severity. Using differential expression analysis of microarray data (n = 29), we identified hsa-miR-1246, ACA40, hsa-miR-4532, hsa-miR-145-5p, and ACA18 as the top five differentially expressed transcripts in severe versus asymptomatic, and ACA40, hsa-miR-3609, ENSG00000212378 (SNORD78), hsa-miR-1231, hsa-miR-885-3p as the most significant five in severe versus mild cases. Moreover, we found that white blood cell (WBC) count, absolute neutrophil count (ANC), neutrophil (%), lymphocyte (%), red blood cell (RBC) count, hemoglobin, hematocrit, D-Dimer, and albumin are significantly correlated with the identified differentially expressed miRNAs and snoRNAs. We report a unique miRNA and snoRNA profile that is associated with a higher risk of severity in a cohort of SARS-CoV-2 infected patients. Altogether, we present a differential expression analysis of COVID-19-associated microRNA (miRNA)/small nucleolar RNA (snoRNA) signature, highlighting their importance in SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Lacrimal gland inflammation during autoimmune Sjögren’s syndrome (SS) leads to ocular surface inflammation – Keratoconjunctivitis sicca (KCS). This condition afflicts both the cornea and conjunctiva that form the ocular surface. Thrombospondin-1 (TSP-1) deficiency in mice results in lacrimal gland and corneal inflammation that resembles the human disease. In this study we report conjunctival pathology in this mouse model of SS. We found that TSP-1 null mice develop inflammation in the conjunctiva and associated loss of goblet cell function similar to that seen in patients with SS. Increased expression of Th1 (IFN-γ, TNF-α) and Th17 (IL-6, IL-17A) inflammatory cytokines and related transcription factors (Tbet and RORγt) were detected in TSP-1 null conjunctiva as well as their draining lymph nodes (LNs). The conjunctival inflammation was also accompanied by an increase in local lymphatic vessels. Interestingly, migration of antigen-bearing dendritic cells (DCs) from the ocular surface to the LNs was dependent on the TSP-1 available in the tissue. These results not only reveal potential immunopathogenic mechanisms underlying KCS in SS but also highlight the therapeutic potential of TSP-1.

Prediabetes is a condition leading to increased risk of diabetes and its complications and cardiovascular disease. Annually, ∼10% prediabetic subjects progress to T2D. We, and other investigators, reported that grape skin extract (GSE) impacts postprandial glycemia through alpha glucosidase inhibition. This study aims to examine the effect of GSE on glycemic response to a starch challenge in healthy prediabetic subjects. The study was approved by the IRB of Hamad Medical Corporation. Subjects were screened from a high-risk population based on family history and/or fasting glucose (5.7-7.3 mmol) and IGT confirmed with 75 gram OGTT. Subjects were randomized to GSE capsule 600 (N=4), 1200 (N=8), 1800 (N=15) or 2400 mg (N=14). Each received a meal of 35 gram (uncooked weight) rice with or without the assigned dose of GSE and blood glucose was measured at time 0, 15, 30, 60 and 120 minutes. Area under the curve (AUC) was calculated using the trapezoidal method and the subjects were classified into "responders" or "non-responders" if AUC after GSE was reduced by at least 1 SD. A total of 41 eligible subjects (83% male; age 29±8 years; BMI 23.2%±5.9, 34% Arab, 24% African, 17% Asian, 24% Indian) with prediabetes were enrolled. A total of 4 (9.7%)subjects decreased AUC by 2SD; 24% decreased by 1 SD and the remainder had no positive response to a single dose of GSE. There were no responders to 600 mg; 2 in 1200 mg; 4 in 1800 mg; and 3 in 2400 mg dose. There were no differences between the responders and non-responders in clinical or biochemical characteristics. In conclusion, 24% of prediabetic subjects had a positive response to GSE in a starch challenge test. The value of the test in characterizing prediabetic subjects who may benefit from GSE to reverse their prediabetic condition is currently under further investigation. In Qatar, the prevalence of diabetes is 17% and expected to increase. Studies to develop natural products to prevent diabetes are of great public health interest. Disclosure: M. Alkasem: None. I. Abdalhakam: None. N.N. Suleiman: None. A.N. Iskandarani: None. T.A. Samra: None. F.A. Mir: None. R.M. Mohammad: None. A. Abou-Samra: None. K. Zhou: None. M.C. Skarulis: None. Funding: Qatar National Research Fund [ABSTRACT FROM AUTHOR]

Concerns about the safety and efficacy of Mycobacterium bovis bacillus Calmette-Guérin (BCG) emphasize the need for alternative tuberculosis (TB) vaccines. DNA vaccines are interesting candidates but are limited by the restricted antigen repertoire that they express. Traditional polycistronic vectors are large and have imbalanced expression. Recent advances in molecular genetics and cellular immunology have paved the way toward the rational design of an efficacious vaccine. We exploited self-cleaving peptide 2A from the foot-and-mouth disease virus, because of its small size and high cleavage activity, to generate an efficient TB DNA vaccine (V-2A). V-2A expresses three mycobacterial antigens, Rv3407, Ag85A, and HspX, in a single open reading frame joined by the 2A sequences, which lead to the segmentation of the long translated polypeptide into individual proteins by posttranslational modification. Our in vitro measurements revealed no differences at the transcriptional or translational level between V-2A and the monocistronic expression of the individual antigens. Mice vaccinated with V-2A developed antigen-specific cellular and humoral responses against all three antigens, imparting protection against Mycobacterium tuberculosis aerosol challenge equivalent to that imparted by BCG. These results have important implications for the rational design and development of efficacious recombinant subunit vaccines.

Background: Mycobacterium tuberculosis (Mtb) causes death of 2-3 million people every year. The persistence of the pathogenic mycobacteria inside the macrophage occurs through modulation of host cell signaling which allows them, unlike the other non-pathogenic species, to survive inside the host. The secretory proteins of M. tuberculosis have gained attention in recent years both as vaccine candidates and diagnostic tools; they target the immune system and trigger a putatively protective response; however, they may also be involved in the clinical symptoms of the disease., Results: Our studies showed that RD-1-encoded secretory protein ESAT-6 is involved in modulation of the mitogen-activated protein (MAP) kinase-signaling pathway inside the macrophage. ESAT-6 induced phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) in the cytoplasm but not in the nucleus, which normally is the case for MAP kinases. ESAT-6 also antagonized LPS-induced ERK1/2 phosphorylation in the nucleus. Stimulation of cells by ESAT-6 along with sodium orthovanadate (a tyrosine phosphatase inhibitor) restored phosphorylation of ERK1/2 in the nucleus, suggesting active dephosphorylation of ERK1/2 by some putative phosphatase(s) in the nucleus. Further, ESAT-6 was found to down regulate the expression of LPS-inducible gene c-myc in an ERK1/2-dependent manner., Conclusion: This study showed the effect of secretory proteins of M. tuberculosis in the modulation of macrophage signaling pathways particularly ERK1/2 MAP kinase pathway. This modulation appears to be achieved by limiting the ERK1/2 activation in the nucleus which ultimately affects the macrophage gene expression. This could be a mechanism by which secretory proteins of Mtb might modulate gene expression inside the macrophages.