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Growing energy demands in various sectors have resulted in overusing fossil fuel sources and rise in greenhouse gases in the atmosphere. This necessitates the need for reducing greenhouse gases and shifting to cleaner, renewable energy sources like H 2. Chemical looping is one such renewable method to produce clean H 2. The efficiency of this process depends on the oxygen carrier. Generally, oxygen carriers (OC) are transition metal oxides (Fe 2 O 3 or NiO) or some complex metal oxides like spinel or perovskites, but usage of these OCs are restricted due to their availability and redox performance. One solution for selecting OCs can be using industrial waste like slag or low-grade ores because of their composition, which consists of metal oxides. One such low-grade ore is Ni-laterite ore or chromite overburden, a mining waste found in the chromite mines of Sukinda (India). In this work, we have focused on utilizing this laterite ore as an OC for the chemical looping reforming of methane to produce syngas. The reactivity analysis of laterite ore with CH 4 was performed in DSC-TG and the reaction products were analyzed in gas chromatography along with microscopy and spectroscopic techniques. Results showed the formation of H 2 and CO gases along with reduced metallic phases. The total H 2 yield at 750 °C is determined to 53.67 (±1.09) ml/g of OC which is comparable or even higher than existing CeO 2 based OCs. Further, thermodynamic calculations are presented to calculate the theoretical yield for our process and compared with the experimental H 2 yield. This study effectively demonstrates the performance of laterite ore as an OC for generating clean and renewable energy through chemical looping technique. [Display omitted] • Utilization of laterite ore as an oxygen carrier and reactivity study in TGA of laterite ore in presence of methane. • Theoretical study of reaction with CH 4 and predicting the reaction products of laterite ore reaction with methane. • Comparison of hydrogen yield obtained in experiments (53.67 ± 1.09 ml/g of OC) and theoretical calculation (61.96 ml/g of OC). [ABSTRACT FROM AUTHOR]

Sulfonylureas (SUs) are still among the mostly prescribed antidiabetic drugs with an established mode of action: release of insulin from pancreatic β-cells. In addition, effects of SUs on adipocytes by activation of the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) have been described, which might explain their insulin-sensitizing potential observed in patients. However, there is a discrepancy between the impact of SUs on antidiabetic action and their rather moderate in vitro effect on PPARγ transcriptional activity. Recent studies have shown that some PPARγ ligands can improve insulin sensitivity by blocking PPARγ Ser-273 phosphorylation without having full agonist activity. It is unknown if SUs elicit their antidiabetic effects on adipocytes by inhibition of PPARγ phosphorylation. Here, we investigated if binding of SUs to PPARγ can interfere with PPARγ Ser-273 phosphorylation and determined their antidiabetic actions in vitro in primary human white adipocytes and in vivo in high-fat diet (HFD) obese mice. Primary human white preadipocytes were differentiated in the presence of glibenclamide, glimepiride and PPARγ ligands rosiglitazone and SR1664 to compare PPARγ Ser-273 phosphorylation, glucose uptake and adipokine expression. Transcriptional activity at PPARγ was determined by luciferase assays, quantification of PPARγ Ser-273 phosphorylation was determined by Western blotting and CDK5 kinase assays. In silico modelling was performed to gain insight into the binding characteristics of SUs to PPARγ. HFD mice were administered SUs and rosiglitazone for 6 days. PPARγ Ser-273 phosphorylation in white adipose tissue (WAT), body composition, glucose tolerance, adipocyte morphology and expression levels of genes involved in PPARγ activity in WAT and brown adipose tissue (BAT) were evaluated. SUs inhibit phosphorylation of PPARγ at Ser-273 in primary human white adipocytes and exhibit a positive antidiabetic expression profile, which is characterized by up regulation of insulin-sensitizing and down regulation of insulin resistance-inducing adipokines. We demonstrate that SUs directly bind to PPARγ by in silico modelling and inhibit phosphorylation in kinase assays to a similar extend as rosiglitazone and SR1664. In HFD mice SUs reduce PPARγ phosphorylation in WAT and have comparable effects on gene expression to rosiglitazone. In BAT SUs increase UCP1 expression and reduce lipid droplets sizes. Our findings indicate that a part of SUs extra-pancreatic effects on adipocytes in vitro and in vivo is probably mediated via their interference with PPARγ phosphorylation rather than via classical agonistic activity at clinical concentrations. • Sulfonylureas (SUs) inhibit PPARγ serine 273 phosphorylation in primary human adipocytes and in adipose tissue of obese mice. • SUs exhibit a positive antidiabetic expression profile in primary human adipocytes and obese mice. • A new MoA of SUs is proposed which is mediated by inhibition of PPARγ phosphorylation rather than classical PPARγ agonism. [ABSTRACT FROM AUTHOR]

The current coronavirus disease 2019 (COVID-19) pneumonia pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading globally at an accelerated rate, with a basic reproduction number (R0) of 2-2.5, indicating that 2-3 persons will be infected from an index patient. A serious public health emergency, it is particularly deadly in vulnerable populations and communities in which healthcare providers are insufficiently prepared to manage the infection. As of March 16, 2020, there are more than 180,000 confirmed cases of COVID-19 worldwide, with more than 7000 related deaths. The SARS-CoV-2 virus has been isolated from asymptomatic individuals, and affected patients continue to be infectious 2 weeks after cessation of symptoms. The substantial morbidity and socioeconomic impact have necessitated drastic measures across all continents, including nationwide lockdowns and border closures. Pregnant women and their fetuses represent a high-risk population during infectious disease outbreaks. To date, the outcomes of 55 pregnant women infected with COVID-19 and 46 neonates have been reported in the literature, with no definite evidence of vertical transmission. Physiological and mechanical changes in pregnancy increase susceptibility to infections in general, particularly when the cardiorespiratory system is affected, and encourage rapid progression to respiratory failure in the gravida. Furthermore, the pregnancy bias toward T-helper 2 (Th2) system dominance, which protects the fetus, leaves the mother vulnerable to viral infections, which are more effectively contained by the Th1 system. These unique challenges mandate an integrated approach to pregnancies affected by SARS-CoV-2. Here we present a review of COVID-19 in pregnancy, bringing together the various factors integral to the understanding of pathophysiology and susceptibility, diagnostic challenges with real-time reverse transcription polymerase chain reaction (RT-PCR) assays, therapeutic controversies, intrauterine transmission, and maternal-fetal complications. We discuss the latest options in antiviral therapy and vaccine development, including the novel use of chloroquine in the management of COVID-19. Fetal surveillance, in view of the predisposition to growth restriction and special considerations during labor and delivery, is addressed. In addition, we focus on keeping frontline obstetric care providers safe while continuing to provide essential services. Our clinical service model is built around the principles of workplace segregation, responsible social distancing, containment of cross-infection to healthcare providers, judicious use of personal protective equipment, and telemedicine. Our aim is to share a framework that can be adopted by tertiary maternity units managing pregnant women in the flux of a pandemic while maintaining the safety of the patient and healthcare provider at its core. [ABSTRACT FROM AUTHOR]

Coagulation factor XIII (FXIII) acts as a fine fulcrum in blood plasma that maintains the balance between bleeding and thrombosis by covalently crosslinking the pre-formed fibrin clot into an insoluble one that is resistant to premature fibrinolysis. In plasma, FXIII circulates as a pro-transglutaminase complex composed of the dimeric catalytic FXIII-A encoded by the F13A1 gene and dimeric carrier/regulatory FXIII-B subunits encoded by the F13B gene. Growing evidence accumulated over decades of exhaustive research shows that not only does FXIII play major roles in both pathological extremes of hemostasis i.e. bleeding and thrombosis, but that it is, in fact, a pleiotropic protein with physiological roles beyond coagulation. However, the current FXIII genetic-epidemiological literature is overwhelmingly derived from the bleeding pathology associated with its deficiency. In this article we review the current clinical, functional, and molecular understanding of this fascinating multifaceted protein, especially putting into the same perspective its genetic landscape. [ABSTRACT FROM AUTHOR]

This study is focused on the develop of a cost effective physicochemical beneficiation process for low grade ferruginous manganese ores to recover a valuable iron bearing by-product (Fe Oxalate or Mn Ferrite) and manganese ore concentrate. It was found the one molarity solution of oxalic acid can leach five times more Fe than Mn from ferruginous manganese ores during treatment at temperature 333 K for 2 h. Photoreduction of the leached solution with sunlight for four hours provided ferrous oxalate dihydrate of > 75 % purity which was further converted into Mn ferrite by roasting it at 773 K for 4 h. Residue samples were roasted in a controlled atmosphere tubular furnace (temperature: 573 - 973 K; time: 1, 3, 5 h) and muffle furnace (temperature: 523- 773 K; time: 2, 4, 12 h) to study the formation of maghemite coating on the surface of iron bearing particles. Chemical analysis, XRD, SEM, magnetometer tests were carried out to characterize the products recovered at different stages of the process. Davis tube magnetic separation tests were conducted using different current intensity (0.5, 1, 2 A) to establish grade and yield of the ore concentrate. The proposed process can recover 0.12-0.25 tons of iron oxalate and 0.33-0.50 tons of manganese ore concentrate (Mn: 42-55 % and Mn/Fe: 2.91-4.5) by processing of one ton of low grade ferruginous manganese ore (Mn: 19.3-31.3 % and Mn/Fe: 0.48-1.16). [ABSTRACT FROM AUTHOR]

Nitric oxide levels and NOS3 gene variants play a pivotal role in the development of vascular diseases/stroke. We attempted to determine the role of NOS3 gene variants and plasma NO levels towards the development of ischemic stroke in young Asian-Indians. Methods One hundred ischemic stroke patients and 200 age and sex matched control study subjects were screened for NOS3 gene variants using SSCP [single stranded confirmation polymorphism] and PCR based techniques. Plasma NO metabolites [NOx] were evaluated for the investigated population. Results Significantly higher NOx levels were observed in controls [controls 56.63 ± 25.92 μmol/L, patients 34.73 ± 19.88 μmol/L, p < 0.001]. The SNPs [single nucleotide polymorphisms] 894G/T, 1998C/G and 2479G/A were found associated with the disease phenotype with the most significant finding observed for 894G/T [χ² = 36.68, p < 0.001]. The SNPs 894G/T and 2479G/A were significantly associated with NOx levels [p = 0.001]. The haplotypes TCA and TGA were overrepresented in the patient population [p < 0.0001]. Conclusion Two NOS3 SNP [894G/T and 2479G/A] variants and NOx levels are associated with ischemic stroke in young Asian Indians. These NOS3 SNPs might represent genetic risk factors for ischemic stroke in young Asian Indians. However these observations need to be confirmed by larger replicate/cross-sectional studies. [ABSTRACT FROM AUTHOR]

Background Deficiency of plasma glutathione peroxidase (GPx-3) has been associated with platelet-dependent thrombosis. Single-nucleotide polymorphisms (SNPs) in the promoter region of GPX3 gene have been found associated with the risk for ischemic stroke in Caucasian populations. The aim of our present study was to evaluate the impact of genetic variations in the GPX3 gene and plasma GPx-3 antigen levels on ischemic stroke in young Asian Indians. Methods One hundred patients with ischemic stroke and 200 age- and sex-matched controls were studied. Genetic analysis for the study population was done by a combination of variant screening using single-stranded conformation polymorphism and final genotyping by polymerase chain reaction–restriction fragment length polymorphism and allele-specific polymerase chain reactions. Plasma GPx-3 antigen levels were evaluated using commercial kits. Data were analyzed using genetic analysis software and statistical tools. Results Significantly higher GPx-3 levels were observed in controls compared with patients (controls 26.37 ± 3.66 μg/mL and patients 22.83 ± 4.57 μg/mL, P < .001). Only the SNP −861A/T was found associated with stroke phenotype ( P < .0001). The SNP −568T/C was observed to significantly influence plasma GPx-3 levels ( P < .05). The haplotype carrying the risk “T” allele of SNP −861A/T was significantly over-represented in patients with stroke ( P < .0001). Conclusions The T allele of −861A/T is a risk allele for the ischemic stroke phenotype. The −861A/T and −568T/C SNPs may show a statistically significant association with both plasma GPx-3 antigen levels and the stroke phenotype in a larger sample size. [ABSTRACT FROM AUTHOR]

Abstract: Mutational reports over the past two decades have accumulated an immense amount of literature for inherited Factor XIII deficiency. However, the genotype and phenotype correlations for inherited Factor XIII deficiency are complicated. While many studies clearly prove a cause and effect relationship for the reported mutations, others are lacking in this regard. The F13B gene remains an elusive component as far as inherited Factor XIII deficiencies are concerned. Also, an in-depth analysis into the heterozygous state of this deficiency is also lacking. In this review we have tried to analyze and present an exhaustive amount of mutational data from the past three decades. The source of our mutational data is our website dedicated to Factor XIII deficiencies (www.F13-database.de) as well as literature search done on the Pubmed (www.ncbi.nlm.nih.gov/pubmed). [Copyright &y& Elsevier]

Abstract: In his seminal paper published in 2002, Passino pointed out how individual and groups of bacteria forage for nutrients and how to model it as a distributed optimization process, which he called the Bacterial Foraging Optimization Algorithm (BFOA). One of the major driving forces of BFOA is the reproduction phenomenon of virtual bacteria each of which models a trial solution of the optimization problem. During reproduction, the least healthier bacteria (with a lower accumulated value of the objective function in one chemotactic lifetime) die and the other healthier bacteria each split into two, which then starts exploring the search place from the same location. This keeps the population size constant in BFOA. The phenomenon has a direct analogy with the selection mechanism of classical evolutionary algorithms. In this letter we provide a simple mathematical analysis of the effect of reproduction on bacterial dynamics. Our analysis reveals that the reproduction event contributes to the quick convergence of the bacterial population near optima. [Copyright &y& Elsevier]

Abstract: Introduction: Several prothrombotic factors – both hereditary and acquired – are known to cause stroke. Commonly investigated causes are activated protein C resistance, factor V Leiden mutation, factor VIII levels, prothrombin 20210 G-to-A mutation, coagulation inhibitors such as proteins C and S, and antiphospholipid antibodies such as β2-glycoprotein. Objective: The literature on the prevalence of hematological defects pertaining to these variables in the Asian Indian stroke population is limited to a few isolated reports. In the current study we investigate the above-mentioned variables in 120 stroke patients (non-cardioembolic acute-onset stroke) and compare their status with the hematological profile of an equal number of healthy age- and sex-matched controls. Material and Methods: Plasma and blood leukocytes were collected from all patients and controls for performing hematological assays and molecular tests respectively. The mutations were detected using standard polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) procedures. Statistical analysis was done using SPSS version 12.0. Results: Factor V Leiden (prevalence 8.3% in patients) and activated protein C resistance (prevalence 19.6% in patients) both showed a high degree of association (P <0.01) with the disease condition. However, contrary to common expectations, factor V Leiden was observed much less frequently in patients showing activated protein C resistance (10 out of 23; 43.4%) than is commonly observed in the Caucasian population (almost 90%). Post-acute-phase factor VIII levels were also found to be significantly associated with stroke: 125.6+21.1% number of profitable positions (NPP) for controls and 136.2+28.8% NPP for patients (P =0.001). Conclusion: factor V mutations, such as factor V Leiden, may be important risk factors for stroke in an Asian Indian population. Activated protein C resistance has a stronger association with stroke than factor V Leiden and may be caused by other factors such as elevated factor VIII levels in the Asian Indian population apart from factor V Leiden itself. [Copyright &y& Elsevier]

Abstract: Differential evolution (DE) has recently emerged as a simple yet very powerful technique for real parameter optimization. This article describes an application of DE to the design of fractional-order proportional–integral–derivative (FOPID) controllers involving fractional-order integrator and fractional-order differentiator. FOPID controllers’ parameters are composed of the proportionality constant, integral constant, derivative constant, derivative order and integral order, and its design is more complex than that of conventional integer-order proportional–integral–derivative (PID) controller. Here the controller synthesis is based on user-specified peak overshoot and rise time and has been formulated as a single objective optimization problem. In order to digitally realize the fractional-order closed-loop transfer function of the designed plant, Tustin operator-based continuous fraction expansion (CFE) scheme was used in this work. Several simulation examples as well as comparisons of DE with two other state-of-the-art optimization techniques (Particle Swarm Optimization and binary Genetic Algorithm) over the same problems demonstrate the superiority of the proposed approach especially for actuating fractional-order plants. The proposed technique may serve as an efficient alternative for the design of next-generation fractional-order controllers. [Copyright &y& Elsevier]

Background: Homocysteine has been for a fairly long time been debated to be a risk factor for stroke. Opinions are divided as to whether raised levels of homocysteine seen in stroke patients are the cause or consequence of stroke. A large number of studies have been conducted in the Caucasian as well as on the Oriental population, which tend to suggest contradictory findings at many times. However, there have been no reports forthcoming from the Asian Indian population, which is a genetically different population than the previously studied populations. Subjects and Methods: In our present study, we looked at homocysteine levels and four commonly seen polymorphisms of homocysteine metabolizing enzymes and their respective prevalence in 120 acute onset ischemic stroke patients compared with an equal number of age and gender matched healthy population. We also tested the influence of folic acid dosage (5 mg OD) on the levels of homocysteine and the allied vitamin supplements, vitamin B12 and folate in smaller groups selected from the larger group. Results and Conclusions: We found homocysteine levels to be significantly raised in the stroke population compared with healthy controls [patients: 12 μmol/L (range: 5.3-39.1 μmol/L), controls: 11.2 μmol/L (range: 6.2-14.2 μmol/L); P =0.001]. There was an almost total response to folic acid dosage as all hyperhomocysteinemic patients showed lowering of homocysteine levels in response to the dosage. The MTHFR 677 C > T polymorphisms showed association with both homocysteine levels as well as stroke (P < 0.001). Nutritional deficiency plays a dominant role in hyperhomocysteinemic conditions in our stroke population, however. Genetic determinants of homocysteine level may also have some part in determining hyperhomocysteinemic conditions in the Asian Indian populations. Key Words : Homocysteine, vitamin supplementation, stroke, infarct, polymorphism, Asian-Indians [Copyright &y& Elsevier]

Abstract: Thrombin Activatable Fibrinolytic Inhibitor (TAFI) is a plasma protein, which inhibits fibrinolysis by removing carboxyterminal lysine residues from partially degraded fibrin thereby decreasing plasminogen binding on its surface. In this study we have investigated the antigenic level variability (Inter and Intraindividual) of Thrombin Activatable Fibrinolysis Inhibitor in 120 healthy Asian Indians since no data on this is available regarding this population. TAFI antigen levels did not show a normal distribution in our population (p <0.001). Median TAFI antigen levels were found to be 11.683 µg/ml. It ranged from 33.9–202.5%of normal pool plasma (3.9–23.5 µg/ml). TAFI antigenic level showed high level of variability in the Indian population (coefficient of variation: 37.4%). TAFI antigenic levels were stable intraindividually (p =0.218). [Copyright &y& Elsevier]

The study aimed to assess the possible differences in effects of Implanon® and Norplant® implants on liver function over 2 years of use.This is a 2-year open randomized study of 80 implant (Implanon® and Norplant®) acceptors. Selected parameters of liver function were tested in the serum before implant insertion and at 6, 12 and 24 months after implant insertion.In both the implant groups, the mean total and unconjugated bilirubin and the gamma-glutaryl transferase levels were significantly raised during implant use. For none of the subjects, at any sampling period, did the levels exceed the normal range in our population. There was no significant elevation of any other liver enzymes in either group.It appears that there may be mild hepatocellular dysfunction associated with the use of both Implanon® and Norplant®, which is possibly of no clinical significance to the healthy acceptor. [Copyright &y& Elsevier]

The objective of this study was to assess the possible differences in effects of Implanon® (etonogestrel 68 mg, single-rod) and Norplant® (levonorgestrel 36 mg, six capsules) implants on serum lipids over 2 years of use. In this 2-year open randomized study of 80 implant acceptors, selected serum lipids were tested before implant insertion and at 6, 12 and 24 months after implant insertion. The lipid parameters evaluated were: total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, apolipoprotein A-I and apolipoprotein B. During the 2 years, the serum lipid pattern in the Implanon users was not significantly different from that of the Norplant users. There was slight decrease in HDL-C levels in both the groups but there were no significant changes in the HDL/TC ratio and the HDL/LDL ratio. Although it was statistically significant, the magnitude of decrease in HDL-C from preinsertion levels in Implanon users was only 5.8% at the end of 2 years. [Copyright &y& Elsevier]

Pointed gourd (Trichosanthes dioica Roxb.) is one of the most nutritive cucurbitaceous vegetable crops cultivated in tropical and subtropical regions around the world. Poor characterization of the available germplasm, vegetative means of propagation and dioecy are the main constraints in developing a systematic breeding programme in pointed gourd. In this investigation, genetic variability of pointed gourd accessions belonging to four agro-climatic zones of Bengal region of India was evaluated by employing polymerase chain reaction (PCR) based single primer amplification reaction (SPAR) methods, viz., random amplified polymorphic DNA (RAPD), inter-simple sequence repeats (ISSR) and directed amplification of minisatellite DNA (DAMD). Percentage of polymorphic loci, Nei's gene diversity index (h) and Shannon's Information index (I) indicated a moderate level of genetic heterogeneity in studied germplasm. The mean coefficient of genetic differentiation (Gst) between populations for RAPD, ISSR and DAMD were 0.419, 0.305 and 0.315 respectively, indicating that 58.1%, 69.5% and 68.5% of genetic variability prevailed within the population. Similarly, analysis of molecular variance (AMOVA) revealed that majority of the genetic variation were partitioned among the individuals within a population. Gene flow estimate (Nm) calculated for RAPD, ISSR and DAMD marker were 0.692, 1.139 and 1.086 respectively indicating a moderate gene flow among the populations. The clustering pattern based on the combined marker systems was primarily related to the geographical distribution of the accessions. This study clearly demonstrates the efficiency of single primer based amplification reactions (SPARs) in duplicate identification, core collection and improvement of pointed gourd germplasm. • Genetic variation of the pointed gourd germplasm was assessed using SPAR methods. • SPAR methods revealed a moderate level of genetic diversity across the accessions. • Higher level of genetic variation was observed within populations than among populations. • The UPGMA dendrogram generated using cumulative data showed significant relationships among the accessions. • This study will help to catalogue the pointed gourd accessions for efficient breeding. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019, caused by the severe acute respiratory syndrome coronavirus 2, has been declared a pandemic by the World Health Organization. As the pandemic evolves rapidly, there are data emerging to suggest that pregnant women diagnosed as having coronavirus disease 2019 can have severe morbidities (up to 9%). This is in contrast to earlier data that showed good maternal and neonatal outcomes. Clinical manifestations of coronavirus disease 2019 include features of acute respiratory illnesses. Typical radiologic findings consists of patchy infiltrates on chest radiograph and ground glass opacities on computed tomography scan of the chest. Patients who are pregnant may present with atypical features such as the absence of fever as well as leukocytosis. Confirmation of coronavirus disease 2019 is by reverse transcriptase-polymerized chain reaction from upper airway swabs. When the reverse transcriptase-polymerized chain reaction test result is negative in suspect cases, chest imaging should be considered. A pregnant woman with coronavirus disease 2019 is at the greatest risk when she is in labor, especially if she is acutely ill. We present an algorithm of care for the acutely ill parturient and guidelines for the protection of the healthcare team who is caring for the patient. Key decisions are made based on the presence of maternal and/or fetal compromise, adequacy of maternal oxygenation (SpO2 >93%) and stability of maternal blood pressure. Although vertical transmission is unlikely, there must be measures in place to prevent neonatal infections. Routine birth processes such as delayed cord clamping and skin-to-skin bonding between mother and newborn need to be revised. Considerations can be made to allow the use of screened donated breast milk from mothers who are free of coronavirus disease 2019. We present management strategies derived from best available evidence to provide guidance in caring for the high-risk and acutely ill parturient. These include protection of the healthcare workers caring for the coronavirus disease 2019 gravida, establishing a diagnosis in symptomatic cases, deciding between reverse transcriptase-polymerized chain reaction and chest imaging, and management of the unwell parturient. [ABSTRACT FROM AUTHOR]

The authors detected a printing error related to Fig. 5 (Effect of input burden basicity on calculated alloy composition) shown below is to be considered while reading the published paper. Effect of input burden basicity on calculated alloy composition. [Extracted from the article]

Blood disorders, such as sickle cell disease, and other clinical conditions are often accompanied by intravascular hemolytic events along with the development of severe coagulopathies. Hemolysis, in turn, leads to the accumulation of Fe(II/III)-protoporphyrin IX (heme) in the intravascular compartment, which can trigger a variety of proinflammatory and prothrombotic reactions. As such, heme binding to the blood coagulation proteins factor VIII (FVIII), fibrinogen, and activated protein C with functional consequences has been demonstrated earlier. We herein present an in-depth characterization of the FVIII-heme interaction at the molecular level and its (patho-)physiological relevance through the application of biochemical, biophysical, structural biology, bioinformatic, and diagnostic tools. FVIII has a great heme-binding capacity with seven heme molecules associating with the protein. The respective binding sites were identified by investigating heme binding to FVIII-derived peptides in combination with molecular docking and dynamic simulation studies of the complex as well as cryo-electron microscopy, revealing three high-affinity and four moderate heme-binding motifs (HBMs). Furthermore, the relevance of the FVIII-heme complex formation was characterized in physiologically relevant assay systems, revealing a ~ 50 % inhibition of the FVIII cofactor activity even in the protein-rich environment of blood plasma. Our study provides not only novel molecular insights into the FVIII-heme interaction and its physiological relevance, but also strongly suggests the reduction of the intrinsic pathway and the accentuation of the final clotting step (by, for example, fibrinogen crosslinking) in hemolytic conditions as well as a future perspective in the context of FVIII substitution therapy of hemorrhagic events in hemophilia A patients. [Display omitted] • Coagulation factor VIII (FVIII) binds rapidly up to seven heme molecules. • Heme binds to sequence stretches of functional relevance for FVIII. • Labile heme causes distinct structural changes in FVIII, including increased flexibility. • FVIII cofactor function is significantly impaired by heme in blood plasma. [ABSTRACT FROM AUTHOR]

Ferruginous manganese ores contain high concentrations of iron and having low Mn/Fe ratio and are not suitable to produce standard grade of silicomanganese. Thermochemical calculations based on available thermodynamics databases were used to understand the smelting behavior of the ore mix consisting of ferruginous manganese ore and slag from high carbon ferromanganese. A basicity map was constructed in terms of input burden material basicity B (= (CaO wt%+MgO wt%)/SiO 2 wt%) and input R (= (CaO wt%+ MgO wt%)/Al 2 O 3 wt%) value for estimating the optimum operating basicity window for low manganese and silicon partition ratio or high alloy recovery. Various experiments were conducted to check the maximum grade and recovery of the alloy based on the thermochemical equilibrium simulation study. The present study reveals usefulness of preliminary thermochemical calculations to facilitate process design and development of silicomanganese smelting using ore mix consisting of ferruginous manganese ore and slag from high carbon ferromanganese. [ABSTRACT FROM AUTHOR]

Human Wharton's jelly–derived mesenchymal stromal cells (hWJSCs) have gained considerable attention for their use in cell therapy. Many of these applications would require manufacturing of millions of hWJSCs. It is, therefore, necessary to develop a Good Manufacturing Practice (GMP)-compliant hWJSC expansion protocol, allowing the generation of a large quantity of cells to meet both clinical and regulatory requirements. Here, we compared human platelet lysate (HPL) and human serum (HS) in supporting clinical-grade hWJSC expansion. hWJSCs were successfully isolated from six different umbilical cords using GMP-compliant dissociation enzymes. Freshly isolated hWJSCs were cultured in media supplemented with 10% of one of the following sera: fetal bovine serum (FBS), HPL and HS. Properties of the expanded hWJSCs were analyzed. We showed that GMP-compliant dissociation enzymes were as efficient as research-grade dissociation enzymes in isolating hWJSCs. hWJSC fresh cell yield and cell viability using HPL and HS supplementations were at greater advantages than FBS. Moreover, hWJSCs expanded in HPL and HS supplementations not only preserved classical MSCs phenotypes and differentiation potential to adipocytes, osteocytes and chondrocytes, they also enhanced the migration of skin fibroblasts. However, HS, unlike HPL, did not alter immunogenicity properties of hWJSCs. hWJSCs expanded in HS supplementation also exerted greater immunosuppressive action in inhibiting T-cell proliferation and increased extracellular matrix (ECM) gene expression, making them useful in tissue repair clinical application. Our findings indicate that HS can be considered as a promising and safer alternative to FBS, and should be recommended for clinical-grade expansion of hWJSCs. [ABSTRACT FROM AUTHOR]

• First time to explore the possibility using industrial materials naturally containing ferrite spinel structure as oxygen carriers. • Reactivity and stability are almost the same between synthetic materials and industrial materials with the same kind of spinel structures. • The Fe-Mn based material showed excellent conversion towards CH 4 and syngas. • The Fe-Cr based materials may be desirable for hydrogenation, gasification, and cracking processes. Spinel ferrites (M x Fe 3-x O 4) as oxygen carriers (OC) in chemical looping combustion (CLC) process have drawn significant interest owing to unique lattice structure and oxygen transfer properties. However, their employment in practice is likely cost prohibitive due to the complicated synthesis processes compared to natural occurring materials. In the work, several of the low-cost industrial materials naturally containing ferrite spinel structure (M x Fe 3-x O 4 , M = Cr and Mn) were, for the first time, investigated to explore the possibility as an alternative of synthetic OCs. The reactivity and their cyclic performance during the chemical looping combustion were examined by lab-scale fluidized bed and TGA. It was demonstrated that all the tested materials contain spinel structures, especially after CLC cycles. They exhibited almost the same reactivity and stability, and less agglomeration occurred when compared to the synthetic materials contain the same kind of spinel structure. But the tested materials presented lower oxygen transport capacity than the synthetic ones. Specifically, the FM1 material containing MnFe 2 O 4 showed best reactivity towards CH 4 and syngas conversion, which may attribute to the oxygen uncoupling ability of Mn based species and the formation of spinel ferromanganese structure. But the stability was not good enough. It may because of the cracked particles attributing to the shrinking during the reduction of Mn 2 O 3 to Mn 3 O 4. The Fe-Cr based sample showed more superior stability and improved performance due to the formation of (Fe,Mg)(Cr,Fe) 2 O 4 spinel structure. The Fe-Cr based samples exhibit poor performance for complete combustion of fuel; however, it appears to convert more CH 4 to CO which may be desirable for hydrogenation, gasification, and cracking processes. It is worth noting that these industrial materials did not show significant difference in reactivity and stability when compared to the same kind of synthetic materials, presenting a possibility of potential substitution, especially taking its low cost into account. [ABSTRACT FROM AUTHOR]

Major hemoglobinopathies place tremendous strain on global resources. Intrauterine hemopoietic cell transplantation (IUHCT) and gene transfer (IUGT) can potentially reduce perinatal morbidities with greater efficacy than postnatal therapy alone. We performed both procedures in the thalassemic HbbTh3/+ mouse. Intraperitoneal delivery of co-isogenic cells at embryonic days13-14 produced dose-dependent chimerism. High-dose adult bone marrow (BM) cells maintained 0.2–3.1% chimerism over ~24 weeks and treated heterozygotes (HET) demonstrated higher chimerism than wild-type (WT) pups (1.6% vs. 0.7%). Fetalliver (FL) cells produced higher chimerism than BM when transplanted at thesame doses, maintaining 1.8–2.4% chimerism over ~32 weeks. We boosted transplanted mice postnatally with BM cells after busulfan conditioning. Engraftment was maintained at >1% only in chimeras. IUHCT-treated nonchimeras and non-IUHCT mice showed microchimerism or no chimerism. Improved engraftment was observed with a higher initial chimerism, in HET mice and with the addition of fludarabine. Chimeric HET mice expressed 2.2–15.1% engraftment with eventual decline at 24 weeks (vs. <1% in nonchimeras) and demonstrated improved hematological indices and smaller spleens compared with untreated HETmice. Intravenous delivery of GLOBE lentiviral-vector expressing human β-globin (HBB) resulted in a vector concentration of 0.001–0.6 copies/cell. Most hematological indices were higher in treated than untreated HET mice, including hemoglobin and mean corpuscular volume, but were still lower than in WT. Therefore, direct IUGT and IUHCT strategies can be used to achieve hematological improvement but require further dose optimization. IUHCT will be useful combined with postnatal transplantation to further enhance engraftment. [ABSTRACT FROM AUTHOR]

Intrauterine growth restriction is a prevalent disease in pregnancy in which placental insufficiency leads to 5 to 10 times higher mortality and lifelong morbidities. The current detection rate is poor, and recently, ultrasound strain elastography (USEL) was proposed as a new diagnostic technique. Currently, placental USEL uses maternal subcutaneous fat as the reference layer, but this is not ideal as fat tissue stiffness can vary widely between subjects. Current USEL also uses manual palpation, and under different compression depths and rates, viscoelastic tissues such as placenta can yield different stiffness results. In the study described here, we strove to improve placental USEL by (i) using an external polymeric pad of known stiffness as the reference layer and (ii) adopting motorized control of the transducer during USEL to standardize palpation motion. Results indicated that motorized USEL reduced measurement variability by 67% compared with freehand USEL. Satisfactory and statistically significant correlations between USEL measurements and mechanical testing validation results were obtained for our new USEL protocol. Placental tissues were found to be non-linear and viscoelastic in nature and, thus, differed in stiffness at different compression rates and depths. Our study also revealed that there was a specific compression depth and rate during USEL that provided better correlation to mechanical testing, and should be considered in clinical placental USEL. [ABSTRACT FROM AUTHOR]

Background Intrauterine Growth Restriction (IUGR) is a disease where the placenta is unable to transfer enough nutrients to the fetus, limiting its growth, and resulting in high mortality and life-long morbidities. Current detection rates of IUGR are poor, resulting in limited disease management. Elastography is a promising non-invasive tool for the detection of IUGR, and works by detecting changes in the mechanical properties of the placenta. To date, however, it is not known whether IUGR placentas have different mechanical properties from normal ones, and thus investigating this is the first focus of the current study. The second focus is to evaluate and model the viscoelastic properties of the normal and IUGR placenta, so that it may be possible to improve elastography in the future by incorporating viscoelasticity. Methods Cyclic uniaxial mechanical compression testing was conducted on post-delivery human placenta samples. 18 samples from 5 normal placentae and 12 samples from 3 IUGR placentae were tested. Viscoelastic models were fitted to the resulting experimental data. Results Mechanical testing showed that IUGR placentae have reduced stiffness and viscosity compared to normal placentae. Linear viscoelastic models were unable to provide a good fit to the data, but non-linear viscoelastic solid (NVS) models could do so. The best performing model was a five parameters bi-exponential NVS model. Two of the five parameters appear to capture the differences between normal and diseased samples. Discussion Our results demonstrate that IUGR placentae have different mechanical properties from normal placentae, and a five parameter bi-exponential NVS model can effectively describe the mechanical properties of the placenta in health and disease. [ABSTRACT FROM AUTHOR]

Abstract: Idiopathic carpal tunnel syndrome (CTS) is a common neuropathy, yet the pathologic changes do not explain the fleeting dynamic symptoms. Dynamic nerve-tendon interaction may be a contributing factor. Based on dynamic ultrasonographic examination of the carpal tunnel, we quantified nerve-tendon movement in thumb, index finger and middle finger flexion in normal subjects and those with mild-idiopathic CTS. Predominant motion patterns were identified. The nerve consistently moves volar-ulnarly. In thumb and index finger flexion, the associated tendons move similarly, whereas the tendon moves dorsoradially in middle finger flexion. Nerve displacement and deformation increased from thumb to index finger to middle finger flexion. Predomination motion patterns may be applied in computational simulations to prescribe specific motions to the tendons and to observe resultant nerve pressures. By identification of the greatest pressure-inducing motions, CTS treatment may be better developed. Symptomatic subjects displayed reduced nerve movement and deformation relative to controls, elucidating the physiologic changes that occur during mild CTS. [Copyright &y& Elsevier]

Tumorigenesis is the major obstacle of tissues derived from human embryonic stem cells (ESC) and human induced pluripotent stem cell (IPSC) for transplantation therapy. This prompted a search for other sources of ESC. This study isolated and characterized stem cells from the extra-embryonic human umbilical cord Wharton's jelly (WJSC). These cells are non-controversial, available in abundance, proliferative, multipotent and hypoimmunogenic. However, their tumorigenic potential has not been property addressed. Their tumour-producing capabilities were compared with human ESC using the immunodeficient mouse model. Unlabelled human ESC + matrigel (2 x 106 cells/site), labelled human WJSC (red fluorescent protein; 5 x 106 cells/site) and unlabelled human WJSC + matrigel (5 x 106 cells/site) were injected via three routes (s.c., i.m. and i.p.). Animals that received human ESC + matrigel developed teratomas in 6 weeks (s.c. 85%; i.m. 75%; i.p. 100%) that contained tissues of ectoderm, mesoderm and endoderm. No animal that received human WJSC developed tumours or inflammatory reactions at the injection sites when maintained for a prolonged period (20 weeks). Human WJSC produced increases in anti-inflammatory cytokines in contrast to human ESC, which increased pro-inflammatory cytokines. Human WJSC, being hypoimmunogenic and non-tumorigenic, have the potential for safe cell-based therapies. [ABSTRACT FROM AUTHOR]

Intrauterine gene transfer (IUGT) offers ontological advantages including immune naiveté mediating tolerance to the vector and transgenic products, and effecting a cure before development of irreversible pathology. Despite proof-of-principle in rodent models, expression efficacy with a therapeutic transgene has yet to be demonstrated in a preclinical nonhuman primate (NHP) model. We aimed to determine the efficacy of human Factor IX (hFIX) expression after adeno-associated-viral (AAV)-mediated IUGT in NHP. We injected 1.0-1.95 × 1013 vector genomes (vg)/kg of self-complementary (sc) AAV5 and 8 with a LP1-driven hFIX transgene intravenously in 0.9G late gestation NHP fetuses, leading to widespread transduction with liver tropism. Liver-specific hFIX expression was stably maintained between 8 and 112% of normal activity in injected offspring followed up for 2-22 months. AAV8 induced higher hFIX expression (P = 0.005) and milder immune response than AAV5. Random hepatocellular integration was found with no hotspots. Transplacental spread led to low-level maternal tissue transduction, without evidence of immunotoxicity or germline transduction in maternal oocytes. A single intravenous injection of scAAV-LP1-hFIXco to NHP fetuses in late-gestation produced sustained clinically-relevant levels of hFIX with liver-specific expression and a non-neutralizing immune response. These data are encouraging for conditions where gene transfer has the potential to avert perinatal death and long-term irreversible sequelae. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This study was conducted to evaluate the prognostic significance of haptoglobin levels in the overall survival of patients presenting with various stages of epithelial ovarian cancer. MATERIALS AND METHODS: We employed an in-house sandwich enzyme-linked immunosorbent assay method to determine the concentrations of preoperative haptoglobin and C-reactive protein (CRP) in sera samples obtained from 66 malignant tumors, 60 benign tumors, and 10 normal healthy women. RESULTS: Levels of serum haptoglobin significantly correlated with tumor type (P < .001) and International Federation of Gynecology and Obstetrics stage (P < .05). A significant correlation was observed between clinical stage and patient survival (r = 5.99, P = .026). Our data also indicated that elevated serum haptoglobin levels were associated with poor outcome for overall survival using both univariate and multivariate analyses (P = .048 and P = .036 respectively). Using Pearson's correlation, we have noted that serum CRP concentrations significantly correlated with haptoglobin levels (r² = 0.22, P < .001). Immunohistochemical findings and Western blot analyses were compatible with sera levels of haptoglobin in which a higher intensity of staining occurred in late-stage epithelial ovarian cancers. CONCLUSION: This study provides evidence that preoperative serum levels of haptoglobin could serve as an independent prognostic factor in patients presenting with epithelial ovarian cancer. [ABSTRACT FROM AUTHOR]

Tridegin is a 66mer cysteine-rich coagulation factor XIIIa (FXI-IIa) inhibitor from the giant amazon leech Haementeria ghilianii of yet unknown disulfide connectivity. This study covers the structural and functional characterization of five different 3-disulfide-bonded tridegin isomers. In addition to three previously identified isomers, one isomer containing the inhibitory cystine knot (ICK, knottin) motif, and one isomer with the leech antihemostatic protein (LAP) motif were synthesized in a regioselective manner. A fluorogenic enzyme activity assay revealed a positive correlation between the constriction of conformational flexibility in the N-terminal part of the peptide and the inhibitory potential towards FXI-IIa with clear differences between the isomers. This observation was supported by molecular dynamics (MD) simulations and subsequent molecular docking studies. The presented results provide detailed structure-activity relationship studies of different tridegin disulfide isomers towards FXI-IIa and reveal insights into the possibly existing native linkage compared to non-native disulfide tridegin species. Image 1 • Synthesis and characterization of five disulfide isomers of FXIIIa inhibitor tridegin. • Differential potency of distinct 3-disulfide-bonded tridegin isomers towards FXIIIa. • Selective inhibition of FXIIIa over TGase2. • Confirmation of postulated tridegin sequence in native material. • Further studies on tridegin should focus on 2-disulfide-bonded analogues. [ABSTRACT FROM AUTHOR]