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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]

Strategies that induce immunogenic cell death (ICD) or downregulate CD47 or PD-L1 expression have resulted in successful therapeutic options for tumor eradication. Several groups have reported the tumoricidal effects of human umbilical cord Wharton's jelly stem cells (hWJSCs) or its conditioned medium (hWJSC-CM) on certain cancers but the mechanisms have not been elucidated. Since hWJSCs possess immunomodulatory properties, we investigated whether one of the tumoricidal mechanisms was via ICD. We first concentrated hWJSC-CM into a 3 kDa concentrate and then exposed various concentrations of this concentrate to human lymphoma cells to find out which concentration had the greatest tumoricidal effect. We observed that a 500 µg/ml concentration of the concentrate had the greatest inhibitory effect. Thereafter, lymphoma cells were exposed to 500 µg/ml of the hWJSC-CM-3 kDa concentrate and then subjected to analysis for morphology, viability, apoptosis, mitochondrial and endoplasmic reticulum stress, danger associated molecular patterns (DAMP), extracellular HMGB1, CD47 and PD-L1 markers and dendritic cell phenotype. Extensive nuclear chromatin and mitochondrial changes with significantly decreased cell viability and increased apoptosis were observed in the treated lymphoma cells compared to controls. There were also significant increases in the release of DAMPs, extracellular HMGB1 and dendritic cell activation and maturation, with concomitant decreases in CD47 and PD-L1 expression in the treated cells compared to controls. In other ongoing studies we observed increased expression of specific tumor-suppressor molecules (miRNA-146a and miRNA-126, MCP-1, IL-6, IL-8 and IL-12) in hWJSC-CM suggesting that one or more of these molecules may be the modulators of the ICD. [ABSTRACT FROM AUTHOR]

Background: Congenital afibrinogenemia (OMIM #202400) is a rare coagulation disorder that was first described in 1920. It is transmitted as an autosomal recessive trait that is characterized by absent levels of fibrinogen (factor I) in plasma. Consanguinity in Pakistan and its neighboring countries has resulted in a higher number of cases of congenital fibrinogen deficiency in their respective populations. This study focused on the detection of mutations in fibrinogen genes using DNA sequencing and molecular modeling of missense mutations in all three genes [Fibrinogen gene alpha (FGA), beta (FGB) and gamma (FGG)] in Pakistani patients. Methods: This descriptive and cross sectional study was conducted in Karachi and Lahore and fully complied with the Declaration of Helsinki. Patients with fibrinogen deficiency were screened for mutations in the Fibrinogen alpha (FGA), beta (FGB) and gamma (FGG) genes by direct sequencing. Molecular modeling was performed to predict the putative structure functional impact of the missense mutations identified in this study. Results: Ten patients had mutations in FGA followed by three mutations in FGB and three mutations in FGG, respectively. Twelve of these mutations were novel. The missense mutations were predicted to result in a loss of stability because they break ordered regions and cause clashes in the hydrophobic core of the protein. Conclusions: Congenital afibrinogenemia is a rapidly growing problem in regions where consanguinity is frequently practiced. This study illustrates that mutations in FGA are relatively more common in Pakistani patients and molecular modeling of the missense mutations has shown damaging protein structures which has profounding effect on phenotypic bleeding manifestations in these patients. [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]

Disease-associated silent mutations are considered to affect the accurate premessenger RNA (mRNA) splicing either by influencing regulatory elements, leading to exon skipping, or by creating a new cryptic splice site. This study describes a new molecular pathological mechanism by which a silent mutation inhibits splicing and leads to intron retention. We identified a heterozygous silent mutation, c.7464C>T, in exon 44 of the von Willebrand factor (VWF) gene in a family with type 1 von Willebrand disease. In vivo and ex vivo transcript analysis revealed an aberrantly spliced transcript, with intron 44 retained in the mRNA, implying disruption of the first catalytic step of splicing at the 5' splice site (5'ss). The abnormal transcript with the retained intronic region coded a truncated protein that lacked the carboxy-terminal end of the VWF protein. Confocal immunofluorescence characterizations of blood outgrowth endothelial cells derived from the patient confirmed the presence of the truncated protein by demonstrating accumulation of VWF in the endoplasmic reticulum. In silico pre-mRNA secondary and tertiary structure analysis revealed that this substitution, despite its distal position from the 5'ss (85 bpdownstream), induces cis alterations in pre-mRNA structure that result in the formation of a stable hairpin at the 5'ss. This hairpin sequesters the 5'ss residues involved in U1 small nuclear RNA interactions, there by inhibiting excision of the pre-mRNA intronic region. This study is the first to show the allosteric-like/far-reaching effect of an exonic variation on pre-mRNA splicing that is mediated by structural changes in the pre-mRNA. [ABSTRACT FROM AUTHOR]

High temperature refractory materials of refractoriness above 1665°C having refractory phases such as forsterite (Mg2SiO4), periclase (MgO) and spinel can be developed from the water granulated spongy ferrochromium slag granules (90% particle) of size below 3100 micron by MgO enrichment. MgO enrichment in ferrochrome slag can be achieved by a method comprises of grinding of granulated ferrochrome slag in presence of magnesite raw material followed by compaction and sintering. The ratio of MgO/SiO2> 2.2 and MgO/(Al2O3+ Cr2O3) > 1.71 in the final composition ensures the refractoriness above 1665°C. [ABSTRACT FROM AUTHOR]

The ferrochromium slag is an important by-product of ferrochromium industries. Recycling and efficient utilization of the large volumes of slag generated by ferrochrome production process is a huge challenge for ferrochrome producers. This article reviews ferrochromium slag utilization with reference to refractory, ceramics and construction and other applications. In addition to this the development of crystal phases and the environmental aspects of ferrochromium slag in relation to its utilization are discussed. The crystalline phases evolve during solidification impart unique properties like strength, stability and refractoriness which open its opportunities as an alternative raw material for ceramic, refractory, civil construction. Chemical composition of ferrochromium slag can be altered suitably for application in high temperature refractory ceramic application. The use of ferrochromium slag in building and road making material will relieve some of the burden from natural resources. [ABSTRACT FROM AUTHOR]

The coagulation factor XIII( FXIII) is a plasma circulating heterotetrameric protransglutaminase that acts at the end of the coagulation cascade by covalently cross-linking preformed fibrin clots (to themselves and to fibrinolytic inhibitors) in order to stabilize them against fibrinolysis. It circulates in the plasma as a heterotetramer composed of two homomeric catalytic Factor XIIIA2 ( FXIIIA2) and two homomeric protective/carrier Factor XIIIB2 subunit ( FXIIIB2). Congenital deficiency of FXIII is of two types: severe homozygous/compound heterozygous FXIII deficiency which results in severe bleeding symptoms and mild heterozygous FXIII deficiency which is associated with mild bleeding (only upon trauma) or an asymptomatic phenotype. Defects in the F13B gene (Factor XIIIB subunit) occur more frequently in mild FXIII deficiency patients than in severe FXIII deficiency. We had recently reported secretion-related defects for seven previously reported F13B missense mutations. In the present study we further analyze the underlying molecular pathological mechanisms as well as the heterozygous expression phenotype for these mutations using a combination of in vitro heterologous expression (in HEK293T cells) and confocal microscopy. In combination with the in vitro work we have also performed an in silico solvated molecular dynamic simulation study on previously reported FXIIIB subunit sushi domain homology models in order to predict the putative structure-functional impact of these mutations. We were able to categorize the mutations into the following functional groups that: (1) affect antigenic stability as well as binding to FXIIIA subunit, that is, Cys5Arg, Cys316Phe, and Pro428Ser (2) affect binding to FXIIIA subunit with little or no influence on antigenic stability, that is, Ile81Asn and Val401Gln c) influence neither aspects and are most likely causality linked polymorphisms or functional polymorphisms, that is, Leu116Phe and Val217Ile. The Cys5Arg mutation was the only mutation to show a direct secretion-based defect since the mutated protein was observed to accumulate in the endoplasmic reticulum. [ABSTRACT FROM AUTHOR]

Mutations in the maternal effect gene NLRP7 cause biparental hydatidiform mole (HYDM1). HYDM1 is characterized by abnormal growth of placenta and lack of proper embryonic development. The molar tissues are characterized by abnormal methylation patterns at differentially methylated regions (DMRs) of imprinted genes. It is not known whether this occurs before or after fertilization, but the high specificity of this defect to the maternal allele indicates a possible maternal germ line-specific effect. To better understand the unknown molecular mechanism leading to HYDM1, we performed a yeast two-hybrid screen against an ovarian library using NLRP7 as bait. We identified the transcriptional repressor ZBTB16 as an interacting protein of NLRP7 and verified this interaction in mammalian cells by immunoprecipitation and confocal microscopy. Native protein analysis detected NLRP7 and ZBTB16 in a 480kD protein complex and both proteins co-localize in the cytoplasm in juxtanuclear aggregates. HYDM1-causing mutations in NLRP7 did not show altered patterns of interaction with ZBTB16. Hence, the biological significance of the NLRP7-ZBTB16 interaction remains to be revealed. However, a clear effect of harvesting ZBTB16 to the cytoplasm when the NLRP7 protein is overexpressed may be linked to the pathology of the molar pregnancy disease. [ABSTRACT FROM AUTHOR]

Mild FXIII deficiency is an under-diagnosed disorder because the carriers of this deficiency are often asymptomatic and reveal a phenotype only under special circumstances like surgery or induced trauma. Mutational reports from this type of deficiency have been rare. In this study, we present the phenotypic and genotypic data of nine patients showing mild FXIII-A deficiency caused by eight novel heterozygous missense mutations (Pro166Leu, Arg171Gln, His342Tyr, Gln415Arg, Leu529Pro, Gln601Lys, Arg703Gln and Arg715Gly) in the F13A1 gene. None of these variants were seen in 200 healthy controls. In silico structural analysis of the local wild-type protein structures (activated and non-activated) from X-ray crystallographic models downloaded from the protein databank identified potential structural/functional effects for the identified mutations. The missense mutations in the core domain are suggested to be directly influencing the catalytic triad. Mutations on other domains might influence other critical factors such as activation peptide cleavage or the barrel domain integrity. In vitro expression and subsequent biochemical studies in the future will be able to confirm the pathophysiological mechanisms proposed for the mutations in this article. [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]

Vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) is an enzyme localized to the endoplasmic reticulum (ER) membrane. VKORC1 catalyzes the reduction of vitamin K 2,3-epoxide to vitamin K and to vitamin K hydroquinone, the latter required by the enzyme γcarboxylase for γcarboxylation of all vitamin K-dependent (VKD) proteins. Until now, only 1 human VKORC1 mutation, p.Arg98Trp, is known to cause combined deficiency of VKD clotting factors type2 (VKCFD2), a disease phenotype reported in 3 unrelated families. VKCFD2 patients suffer from spontaneous bleeding episodes because of decreased levels of γcarboxylated VKD clotting factors. Daily supraphysioiogical vitamin K supplementation restores clotting for VKCFD2 patients and results in high serum levelsof vitamin K 2,3-epoxide, suggesting that supplemented vitamin K is reduced in vivo. Although the p.Arg98Trp mutation results in reduced vitamin K2,3-epoxidereductase activity, the molecular mechanism underlying this pathophysiology is unknown. Using a combination of in silico analysis and confocal microscopy, we demonstrate for the first time that VKORC1:p.Arg98Trp disrupts a di-arginine ER retention motif resulting in 20% ER colocalization only. As a consequence, VKORC1 exits the ER membrane by cellular quality control systems and results in the observed VKCFD2 phenotype. (Blood.2014;124(8):1354-1362) [ABSTRACT FROM AUTHOR]

We propose a method of clustering images that combines algorithmic and human input. An algorithm provides us with pairwise image similarities. We then actively obtain selected, more accurate pairwise similarities from humans. A novel method is developed to choose the most useful pairs to show a person, obtaining constraints that improve clustering. In a clustering assignment, elements in each data pair are either in the same cluster or in different clusters. We simulate inverting these pairwise relations and see how that affects the overall clustering. We choose a pair that maximizes the expected change in the clustering. The proposed algorithm has high time complexity, so we also propose a version of this algorithm that is much faster and exactly replicates our original algorithm. We further improve run-time by adding two heuristics, and show that these do not significantly impact the effectiveness of our method. We have run experiments in three different domains, namely leaf, face and scene images, and show that the proposed method improves clustering performance significantly. [ABSTRACT FROM AUTHOR]

Since the discovery of warfarin-sensitive vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1), 26 human VKORC1 (hVKORC1) missense mutations have been associated with oral anticoagulant resistance (OACR). Assessment of warfarin resistance using the "classical" dithiothreitol-driven vitamin K 2,3-epoxide reductase (VKOR) assay has not reflected clinical resistance phenotypes for most mutations. Here, we present half maximal inhibitory concentrations (IC50) results for 21 further hVKORC1 mutations obtained using a recently validated cell-based assay (J Thromb Haemost 11 (5):872). In contrast to results from the dithiothreitol-driven VKOR assay, all mutations exhibited basal VKOR activity and warfarin IC50 values that correspond well to patient OACR phenotypes. Thus, the present assay is useful for functional investigations of VKORC1 and oral anticoagulant inhibition of the vitamin K cycle. Additionally, we modeled hVKORC1 on the previously solved structure of a homologous bacterial enzyme and performed in silico docking of warfarin on this model. We identified one binding site delineated by 3 putative binding interfaces. These interfaces comprise linear sequences of the endoplasmic reticulum-lumenal loop (Ser52-Phe55) and the first (Leu22-Lys30) and fourth (Phe131-Thr137) transmembrane helices. All known OACR-associated hVKORC1 mutations are located in or around these putative interfaces, supporting our model. [ABSTRACT FROM AUTHOR]

Mild factor XIII deficiency is an underdiagnosed coagulation disorder. Considering the large number of coding and non-coding polymorphisms identified in the F13A1 gene, there is a possibility that some of these might result in alterations of plasma FXIII levels and cause mild FXIII deficiency. Recently, a homozygous F13A1 gene intron 1 variant (IVS1+12C>A) was found in a patient with FXIII deficiency. In vitro expression studies for this variant demonstrated its lowering effect on FXIII levels. In order to determine the impact of this variant on a population level, we analysed the prevalence of this variant in three clinically and genetically defined population cohorts: an apparently healthy control cohort C1 ( n = 102), a mild FXIII deficiency cohort C2 with no detectable F13A1 or F13B gene mutations ( n = 183) and a mild FXIII-A deficiency cohort C3 exhibiting heterozygous F13A1 mutations ( n = 37). FXIII activity was determined using photometric assay on plasma samples. The F13A1 gene intron 1 variant was analysed by direct sequencing. The C1 cohort showed a normal distribution of FXIII activity (mean 114.1 ± 20.86 %). Mean FXIII activity levels for the C2 and C3 cohorts were 54.45 ± 11.12 % and 44.21 ± 10.16 %, respectively. The frequencies of minor allele (A) were 0.07 in C1 cohort, 0.19 in C2 cohort and 0.11 in C3 cohort. The difference in minor allele frequencies for the C1 and C2 cohorts were highly significant ( p < 0.001). The greater frequency of the IVS1+12(A) variant among C2 cohort patients suggests that this polymorphism is associated with mild FXIII deficiency. [ABSTRACT FROM AUTHOR]

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 named the Bacterial Foraging Optimization Algorithm (BFOA). One of the major operators of BFOA is the reproduction phenomenon of virtual bacteria, each of which models one trial solution of the optimization problem. During reproduction, the least healthy 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. The phenomenon has a direct analogy with the selection mechanism of classical evolutionary algorithms. This paper attempts to model reproduction as a dynamics and then analyses the stability of the reproductive system very near to an equilibrium point, which in this case is an isolated optimum. It also finds conditions under which a stable reproduction event can take place, to direct a worse bacterium towards a better one. Our analysis reveals that a stable reproduction event contributes to the quick convergence of the bacterial population near optima. [Copyright &y& Elsevier]

Abstract: Background: Endothelium derived nitric oxide is formed from l-arginine by endothelial nitric oxide synthase encoded by the nitric oxide synthase 3 (NOS3) gene. Nitric oxide possesses a variety of protective effects on endothelial cells and therefore NOS3 is a logical candidate gene to be investigated for the susceptibility of deep vein thrombosis (DVT). Methods: One hundred consecutive patients (M: F=56:44) with idiopathic deep vein thrombosis and an equal number of age and sex matched healthy controls were the study subjects. All study subjects were typed for five NOS3 polymorphisms (−786C/T, −922A/G, 894G/T, Intron 4 VNTR, and Intron 23 G10T). Results: Two polymorphisms (−922A/G and 894G/T) are showing their association with DVT. −922A/G shows both genotypic (P =0.0218; χ 2 =5.25; O.R=1.94) as well as allelic association (P =0.0014; χ 2 =10.19; O.R=2.0) while 894G/T shows only allelic (P =0.04; χ 2 =3.93; O.R=3.93) association with DVT. Conclusion: Susceptibility to DVT in North Indian Asian patients may be associated with some variants of NOS3 gene. [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]

Genes involved in the hemostatic mechanism are logical candidate genes for association studies in prothrombotic conditions such as stroke. Since the underlying etiology in pediatric strokes is different than adults, looking for genetic causes would be the logical thing to do in the pediatric stroke population. Fifty-eight Asian-Indian stroke patients below 15 years of age and equal number of age- and sex-matched healthy controls were the subjects for the study. The subjects were screened for 13 polymorphisms and three mutations spread across seven different candidate genes involved in the hemostatic system. Of the 13 polymorphisms and three mutations studied, four polymorphisms, HPA-I, TAFI 147Ala>Thr, methylene tetrahydrofolate reductase (MTHFR) 677 C>T, and MTHFR 1298 A>C, showed significant association with the disease phenotype. MTHFR 677 C>T showed the strongest association and therefore may have a strong predisposing role for pediatric strokes. Gene–gene interaction studies showed a strong interaction between HPA-I and MTHFR 677 C>T polymorphism. The wild type of both these polymorphisms synergistically showed a strong protective effect [ p < 0.0001, O.R: 10.06(4.26–23.71)]. Polymorphisms in HPA-I and MTHFR may have important predisposing roles in the development of pediatric stroke. [ABSTRACT FROM AUTHOR]

Several hydrometallurgical processes have been studied for the extraction of metals from lean ores utilizing various flow sheet options. Of particular significance is the grade of the ore being treated, the energy consumed and associated costs, options for byproduct recovery, and the relative price of the products. A process scheme needs to be optimized for simultaneously maximizing metal throughput and minimizing the direct operating costs incurred within constraints set for the operating variables. This leads to a multi-objective optimization problem. The range of input grades for raw material, which a flowsheet can handle, needs to be worked out based on an optimization exercise. A lean manganese-bearing resource such as polymetallic sea nodules has been chosen in this article for the development of an optimization approach based on which the input raw nodules grades are to be treated by a particular flowsheet. Only the chemical consumption costs have been adopted in this article as a measure of direct operating costs. A linear simulation model for the flowsheet has been developed, keeping a set of design parameters constant. The solutions generated by using a sequential modular approach become inputs to an optimization procedure based on a multi-objective genetic algorithm belonging to the differential evolution family. The variables considered in the optimization task are the grade of nodules and reactivity of different species inside the reactor. A nickel equivalent (t/h function) has been suggested as a measure of productivity, as it indirectly enhances the input manganese ore grade through a price ratio effect. This productivity function was maximized with the simultaneous minimization of direct chemical costs. Pareto optimal solutions were generated with grades of nodules and reactivity in the leach reactor as decision variables. The effect of the price ratio on the Pareto optimal solutions was also investigated. The various cases investigated clarifies the methodology for choosing an appropriate ore grade range for a given process flowsheet. Appropriate decisions regarding the nature of raw material to be used for a given flowsheet are then found on the basis of the Pareto optimal solutions. [ABSTRACT FROM AUTHOR]

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]

Thrombin activatable fibrinolysis inhibitor [carboxypeptidase B2 (plasma), CPB2] is a basic carboxypeptidase, which inhibits fibrinolysis by cleaving the C-terminal lysine residues on plasmin-modified partially degraded fibrin. Plasma CPB2 concentrations have been reported to be under the control of numerous single nucleotide polymorphisms located in the regulatory and coding regions of the gene encoding CPB2 ( CPB2). High functional CPB2 levels have been found to be associated with an increased risk for ischemic stroke. The present study investigated CPB2 antigen levels and associated CPB2 polymorphisms in an acute onset non-cardioembolic stroke population compared with an age- and sex-matched healthy control population. This is, to the best of our knowledge, the first such study done in an Asian Indian population. CPB2 antigen levels were significantly associated with the disease phenotype ( P < 0·001) and with CPB2 polymorphisms ( P < 0·001). The haplotypes generated on analysis of the genotypic data accounted for 21% of the natural variation in the CPB2 antigenic levels. However none of the haplotype combinations generated showed any association with disease phenotype and therefore could not explain for the difference in CPB2 antigen levels between cases and controls. [ABSTRACT FROM AUTHOR]

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]

Abstract: Background: Deep vein thrombosis is a condition, which has several acquired as well as genetic causes. One of the most common reasons for deep vein thrombosis is activated protein C resistance caused by Factor V Leiden. Method: We examined the risk posed by Factor V Leiden, Hong Kong/Cambridge and HR2 Haplotype mutations in 155 deep vein thrombosis patients and 120 healthy controls in the background of activated protein C resistance. Result: Thirty-one of our patients showed activated protein C resistance of which only 16 carried Factor V Leiden mutation which was a far lower number than what is usually seen in Caucasian population. Factor V Leiden mutation was significantly associated with the risk of deep vein thrombosis (Yates corrected p-value=0.002; 95%CI; odds ratio: 13.7). Factor V Hong Kong/Cambridge and HR2 Haplotype were not found to be associated with the risk of deep vein thrombosis. There is a possibility that Factor V HR2 Haplotype might also be associated with activated protein C resistance even in the absence of Factor V Leiden. Conclusions: Factor V Leiden mutation was seen to contribute far less towards activated protein C resistance in Asian-Indian deep vein thrombosis patients than what has been commonly observed in Caucasians. [Copyright &y& Elsevier]

Abstract: Background: Hemophilia A is a common hereditary bleeding disorder caused mainly by mutations in the Factor VIII (FVIII) gene, which results in defective or absent FVIII protein. Most of the causative mutations arise from the germ cells, which leads to either heterozygous or hemizygous state for the mutation in the next generation. Germline or somatic mosaic may result due to a de novo mutation during early embryogenesis. Method: We analyzed 14 families of Indian origin with Hemophilia A [sporadic and severe] for the presence of mosaic individuals by employing Allele Specific PCR, mutation enrichment experiment and sequencing. Result: Nine families had point mutations, 3 families had small deletions or insertions, 2 families had splice site mutations. The origin of the de novo mutation was assigned to the patients'' mother in 8 families. For 4 families it was assigned to the maternal grandmother and to the maternal grandfather in 2 families. In a single family somatic mosaic was detected. Conclusion: The presence of somatic mosaic in families with sporadic Hemophilia A in India may confound risk estimation during genetic counseling. [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]

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]

Coagulation factor XIII (FXIII) is a protransglutaminase which plays an important role in clot stabilization and composition by cross-linking the α- and γ-chains of fibrin and increasing the resistance of the clot to mechanical and proteolytic challenges. In this study, we selected six DNA aptamers specific for activated FXIII (FXIIIa) and investigated the functional characterization of FXIIIa after aptamer binding. One of these aptamers, named FA12, efficiently captures FXIIIa even in the presence of zymogenic FXIII subunits. Furthermore, this aptamer inhibits the incorporation of FXIII and α2-antiplasmin (α2AP) into fibrin(ogen) with IC50-values of 38 nM and 17 nM, respectively. In addition to FA12, also another aptamer, FA2, demonstrated significant effects in plasma-based thromboelastometry (rotational thromboelastometry analysis, ROTEM)-analysis where spiking of the aptamers into plasma decreased clot stiffness and elasticity (p < 0.0001). The structure–function correlations determined by combining modeling/docking strategies with quantitative in vitro assays revealed spatial overlap of the FA12 binding site with the binding sites of two FXIII substrates, fibrinogen and α2AP, while FA2 binding sites only overlap those of fibrinogen. Taken together, these features especially render the aptamer FA12 as an interesting candidate molecule for the development of FXIIIa-targeting therapeutic strategies and diagnostic assays. [ABSTRACT FROM AUTHOR]

The objective of the study is to investigate the effect of Nuchal Fold (NF) in predicting Fetal Growth Restriction (FGR) using machine learning (ML), to explain the model's results using model-agnostic interpretable techniques, and to compare the results with clinical guidelines. This study used second-trimester ultrasound biometry and Doppler velocimetry were used to construct six FGR (birthweight < 3rd centile) ML models. Interpretability analysis was conducted using Accumulated Local Effects (ALE) and Shapley Additive Explanations (SHAP). The results were compared with clinical guidelines based on the most optimal model. Support Vector Machine (SVM) exhibited the most consistent performance in FGR prediction. SHAP showed that the top contributors to identify FGR were Abdominal Circumference (AC), NF, Uterine RI (Ut RI), and Uterine PI (Ut PI). ALE showed that the cutoff values of Ut RI, Ut PI, and AC in differentiating FGR from normal were comparable with clinical guidelines (Errors between model and clinical; Ut RI: 15%, Ut PI: 8%, and AC: 11%). The cutoff value for NF to differentiate between healthy and FGR is 5.4 mm, where low NF may indicate FGR. The SVM model is the most stable in FGR prediction. ALE can be a potential tool to identify a cutoff value for novel parameters to differentiate between healthy and FGR. [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]

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]

Reactive force field (ReaxFF) based molecular dynamics simulations were performed to study the interaction nature of grafted dextrin with hematite. Nature of interaction further explained by doing periodic density functional theory (DFT) calculations. It was observed that in presence of moisture, the polymer adsorbed on the hematite surface via hydrogen bond formation mediated by water. Upon heating, the interfacial water evaporated and boding interactions with the surface was were established. The oxygens present in the polymer backbone also took part in bonding interactions in addition to −COOH, −OH and −COOCH3 functional groups. The binding energies were estimated as −35.8 (Dextrin), −42.6 (Dextrin grafted with polyacrylic acid) and −38.0 kcal/mol (Dextrin grafted with polyacrylic acid and poly (methyl acrylate)) which indicated chemisorption and effect of molecular weight. Grafted dextrin, having higher molecular weight exhibited stronger interaction and it is anticipated that it will have better thermal stability. Binding energy estimated from DFT calculations as −34.8 kcal/mol. DFT charge density difference calculation showed that the oxygen present in the ring polymer structure also interacted with Fe d‐orbitals. [ABSTRACT FROM AUTHOR]

Following the publication of this article [1], the authors noted the following typographical errors. [ABSTRACT FROM AUTHOR]

Introduction and aim: Severe haemophilia B (HB) is characterized by spontaneous bleeding episodes, mostly into joints. Recurrent bleeds lead to progressive joint destruction called haemophilic arthropathy. The current concept of prophylaxis aims at maintaining the FIX level >3–5 IU/dL, which is effective at reducing the incidence of haemophilic arthropathy. Extended half‐life FIX molecules make it easier to achieve these target trough levels compared to standard FIX concentrates. We previously reported that the fusion of a recombinant FIX (rFIX) to factor XIII‐B (FXIIIB) subunit prolonged the half‐life of the rFIX‐LXa‐FXIIIB fusion molecule in mice and rats 3.9‐ and 2.2‐fold, respectively, compared with rFIX‐WT. However, the mechanism behind the extended half‐life was not known. Materials and methods: Mass spectrometry and ITC were used to study interactions of rFIX‐LXa‐FXIIIB with albumin. Pharmacokinetic analyses in fibrinogen‐KO and FcRn‐KO mice were performed to evaluate the effect of albumin and fibrinogen on in‐vivo half‐life of rFIX‐LXa‐FXIIIB. Finally saphenous vein bleeding model was used to assess in‐vivo haemostatic activity of rFIX‐LXa‐FXIIIB. Results and conclusion: We report here the key interactions that rFIX‐LXa‐FXIIIB may have in plasma are with fibrinogen and albumin which may mediate its prolonged half‐life. In addition, using the saphenous vein bleeding model, we demonstrate that rFIX‐FXIIIB elicits functional clot formation that is indistinguishable from that of rFIX‐WT. [ABSTRACT FROM AUTHOR]

Background: The transplantation of human umbilical cord blood (UCB) CD34+ cells has been successfully used to treat hematological disorders but one major limitation has been the low cell numbers available. Mesenchymal stem cells (MSCs) lying within the bone marrow in vivo behave like a scaffold on which CD34+ cells interact and proliferate. We therefore evaluated the use of allogeneic MSCs from the human UC Wharton's jelly (hWJSCs) as stromal support for the ex vivo expansion of CD34+ cells. Methods: We performed an in-depth evaluation of the primitiveness, migration, adhesion, maturation, mitochondrial behavior, and pathway mechanisms of this platform using conventional assays followed by the evaluation of engraftment potential of the expanded CD34+ cells in an in vivo murine model. Results: We demonstrate that hWJSCs and its conditioned medium (hWJSC-CM) support the production of significantly high fold changes of CD34+, CD34+CD133+, CD34+CD90+, CD34+ALDH+, CD34+CD45+, and CD34+CD49f+ cells after 7 days of interaction when compared to controls. In the presence of hWJSCs or hWJSC-CM, the CD34+ cells produced significantly more primitive CFU-GEMM colonies, HoxB4, and HoxA9 gene expression and lower percentages of CD34+CXCR4+ cells. There were also significantly higher N-cadherin+ cell numbers and increased cell migration in transwell migration assays. The CD34+ cells expanded with hWJSCs had significantly lower mitochondrial mass, mitochondrial membrane potential, and oxidative stress. Green Mitotracker-tagged mitochondria from CD34+ cells were observed lying within red CellTracker-tagged hWJSCs under confocal microscopy indicating mitochondrial transfer via tunneling nanotubes. CD34+ cells expanded with hWJSCs and hWJSC-CM showed significantly reduced oxidative phosphorylation (ATP6VIH and NDUFA10) and increased glycolytic (HIF-1a and HK-1) pathway-related gene expression. CD34+ cells expanded with hWJSCs for 7 days showed significant greater CD45+ cell chimerism in the bone marrow of primary and secondary irradiated mice when transplanted intravenously. Conclusions: In this report, we confirmed that allogeneic hWJSCs provide an attractive platform for the ex vivo expansion of high fold numbers of UCB CD34+ cells while keeping them primitive. Allogeneic hWJSCs are readily available in abundance from discarded UCs, can be easily frozen in cord blood banks, thawed, and then used as a platform for UCB-HSC expansion if numbers are inadequate. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells from Wharton's jelly of the human umbilical cord (hWJSCs), and the conditioned medium (hWJSC-CM) prepared from them, were shown to be tumoricidal on many cancers. However, these tumoricidal effects were observed in hWJSCs grown under normoxic conditions of 21% oxygen in the laboratory. Since oxygen concentrations in the stem cell niche or physiological microenvironment are hypoxic and help to maintain stemness properties, the objective of this work was to evaluate whether there were differences in the tumoricidal properties of hWJSC-CM grown in 21% O2 (normoxic) or 5% O2 (hypoxic) environments. The results showed that hWJSCs grown under normoxic or hypoxic conditions showed no distinct morphological differences in culture and remained positive in trilineage differentiation into adipocytes, osteocytes, and chondrocytes. Hypoxic hWJSCs expressed the mesenchymal stem cell surface markers CD105, CD90, CD73, CD146, and CD108 similar to normoxic hWJSCs but were negative for the hematopoietic markers CD14, CD19, CD34, CD45, CD117, and HLA-DR. Hypoxic hWJSC-CM produced a significantly greater reduction in cell viability and a significantly greater increase in apoptosis, oxidative stress, and lipid peroxidation in human lymphoma cells compared to normoxic hWJSC-CM. Hypoxic hWJSC-CM also produced significantly greater expression of immunogenic cell death (ICD) hallmarks such as surface-bound calreticulin, HSP70, HSP90, and high mobility group binding 1 proteins and significantly decreased expression of the defense molecules CD47 and PD-L1. This study showed that the tumoricidal effect of hypoxic hWJSC-CM was superior to normoxic hWJSC-CM and should be the preferred choice of preparing hWJSC-CM for the induction of ICD on lymphoma cells. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) has been associated with an increased risk of maternal and neonatal morbidity. The Wharton's jelly (WJ) of the umbilical cord (UC) is a useful indicator of the deleterious effects of hyperglycemia on fetal tissues as it represents the fetus embryologically, physiologically and genetically. We studied WJ mesenchymal stem cells (hWJSCs) from UC from mothers without GDM (Normal; n = 3); insulin-controlled GDM mothers (GDMi; n = 3) and diet-controlled GDM mothers (GDMd; n = 3)]. Cell proliferation, stemness markers, telomerase, osteogenic and chondrogenic differentiation, antioxidant enzymes and gene expression for mitochondrial function (ND2, TFAM, PGC1α, and NDUFB9) were significantly lower in GDMi-hWJSCs and GDMd-hWJSCs compared to normal hWJSCs (P < 0.05). On the other hand, cell cycle inhibitors (p16, p21, p27) and p53 were remarkably up-regulated in GDMi-hWJSCs and GDMd-hWJSCs compared to normal hWJSCs. The results from this study confirmed that maternal hyperglycemia even though managed with insulin or diet, induced changes in the properties of the WJ and its cells. These changes may also be observed in fetal tissues and if true, prevention of the onset of gestational diabetes should be a priority over management. Generation of tissues that simulate those of the fetus such as pancreatic and cardiovascular cells from GDM-hWJSCs by direct differentiation or via induced pluripotent stem cell reprogramming provide possible platforms to evaluate the effects of glucose on specific fetal organ. [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]

Objectives: To evaluate the association of interleukin 6 (IL-6) levels with deep vein thrombosis (DVT) and to assess the impact of IL-6 promoter polymorphisms (−174G > C, −572G > C and −597G > A) on its plasma levels and their influence in the development of DVT in India. Methods: One hundred DVT patients and 100 age and sex-matched healthy controls were study subjects. IL-6 polymorphisms were identified by polymerase chain reaction-restriction fragment length polymorphism. IL-6 levels were detected by enzyme-linked immunosorbent assay. Results: Significantly raised IL-6 levels were observed in patients as compared to controls. (Patients: 13.73 ± 6.30 pg/ml, Controls: 11.83 ± 4.47 pg/ml, p = 0.014). The prevalence of C allele of −572G > C polymorphism was significantly higher in patients than controls (Patients: 39.5%, Controls: 27.5%, p = 0.011, χ2=6.463). Subjects with GC and CC genotype had significantly higher IL-6 levels than GG genotype (p=<0.001). Patients with GC and CC genotype increased the DVT risk by 1.39 fold (ORa: 1.39, CI: 0.74-2.62) and 2.69 fold (ORa: 2.42, CI: 1.08-6.70), respectively. IL-6 −174G > C and −597G > A polymorphisms were not associated with raised IL-6 levels and nor with thrombotic risk (−174G > C: p = 0.823 χ2=0.369; −597G > A: p = 0.678 χ2=1.08). Conclusion: Our study emphasizes the importance of −572G > C polymorphism in increasing IL-6 levels, thereby showing its significant role in DVT in India. IL-6 −174G > C and −597G > A were neither associated with raised plasma IL-6 levels nor with thrombotic risk. Thus −572G > C polymorphism detection may be one of the connecting links between IL-6 and thrombotic risk in Indian DVT patients. [ABSTRACT FROM AUTHOR]

Presents a case of a pregnant woman with complications of pancreatic adenocarcinoma. Description of the condition of the patient as revealed by magnetic resonance retrograde cholangiopancreatography; Decision of the couple to terminate the pregnancy; Other factors complicating pregnancy.

Advanced mitochondrial multi-omics indicate a multi-facet involvement of mitochondria in the physiology of the cell, changing the perception of mitochondria from being just the energy-generating organelles to organelles that highly influence cell structure, function, signaling, and cell fate. This sets mitochondrial dysfunction in the centerstage of numerous acquired and genetic diseases. Sickle cell disease is also being increasingly associated with mitochondrial anomalies and the pathophysiology of sickle cell disease finds mitochondria at crucial intersections in the pathological cascade. Altered mitophagy, increased ROS, and mitochondrial DNA all contribute to the condition and its severity. Such mitochondrial aberrations lead to consequent mitochondrial retention in red blood cells in sickle cell diseases, increased oxidation in the cellular environment, inflammation, worsened vaso-occlusive crisis, etc. There are increasing studies indicating mitochondrial significance in sickle cell disease, consequently providing an opportunity to target it for improving the outcomes of treatment. Identification of the impaired mitochondrial attributes in sickle cell disease and their modulation by therapeutic interventions can impart a better management of the disease. This review aims to describe the mitochondria in the perspective of sicke cell disease so as to provide the reader an overview of the emerging mitochondrial stance in sickle cell disease. [ABSTRACT FROM AUTHOR]

The endothelial cells of the umbilical vessels are frequently used in mechanobiology experiments. They are known to respond to wall shear stress (WSS) of blood flow, which influences vascular growth and remodeling. The in vivo environment of umbilical vascular WSS, however, is not well characterized. In this study, we performed detailed characterization of the umbilical vascular WSS environments using clinical ultrasound scans combined with computational simulations. Doppler ultrasound scans of 28 normal human fetuses from 32nd to 33rd gestational weeks were investigated. Vascular cross-sectional areas were quantified through 3D reconstruction of the vascular geometry from 3D B-mode ultrasound images, and flow velocities were quantified through pulse wave Doppler. WSS in umbilical vein was computed with Poiseuille's equation, whereas WSS in umbilical artery was obtained via computational fluid dynamics simulations of the helical arterial geometry. Results showed that blood flow velocity for umbilical artery and vein did not correlate with vascular sizes, suggesting that velocity had a very weak trend with or remained constant over vascular sizes. Average WSS for umbilical arteries and vein was 2.81 and 0.52 Pa, respectively. Umbilical vein WSS showed a significant negative correlation with the vessel diameter, but umbilical artery did not show any correlation. We hypothesize that this may be due to differential regulation of vascular sizes based on WSS sensing. Due to the helical geometry of umbilical arteries, bending of the umbilical cord did not significantly alter the vascular resistance or WSS, unlike that in the umbilical veins. We hypothesize that the helical shape of umbilical arteries may be an adaptation feature to render a higher constancy of WSS and flow in the arteries despite umbilical cord bending. [ABSTRACT FROM AUTHOR]

The current gold standard for the definitive diagnosis of fetal aneuploidy uses either chorionic villus sampling (CVS) or amniocentesis, both of which are which are invasive procedures carrying a procedure-related risk of miscarriage of up to 0.1–0.2%. Non-invasive prenatal diagnosis using fetal nucleated red blood cells (FNRBCs) isolated from maternal peripheral venous blood would remove this risk of miscarriage since these cells can be isolated from the mother's blood. We aimed to detect whole-chromosome aneuploidies from single nucleated fetal red blood cells using whole-genome amplification followed by massively parallel sequencing performed on a semiconductor sequencing platform. Twenty-six single cells were picked from the placental villi of twelve patients thought to have a normal fetal genotype and who were undergoing elective first-trimester surgical termination of pregnancy. Following karyotyping, it was subsequently found that two of these cases were also abnormal (one trisomy 15 and one mosaic genotype). One single cell from chorionic villus samples for two patients carrying a fetus with trisomy 21 and two single cells from women carrying fetuses with T18 were also picked. Pooled libraries were sequenced on the Ion Proton and data were analysed using Ion Reporter software. We correctly classified fetal genotype in all 24 normal cells, as well as the 2 T21 cells, the 2 T18 cells, and the two T15 cells. The two cells picked from the fetus with a mosaic result by CVS were classified as unaffected, suggesting that this was a case of confined placental mosaicism. Fetal sex was correctly assigned in all cases. We demonstrated that semiconductor sequencing using commercially available software for data analysis can be achieved for the non-invasive prenatal diagnosis of whole-chromosome aneuploidy with 100% accuracy. [ABSTRACT FROM AUTHOR]

Coagulation factor XIII (FXIII) circulates in plasma as a pro-transglutaminase heterotetrameric complex (FXIIIA2B2), which upon activation by thrombin and calcium covalently crosslinks preformed fibrin polymers. The heterotetrameric complex is composed of a catalytic FXIIIA2 subunit and a protective/regulatory FXIII-B2 subunit coded by F13A1 and F13B genes, respectively. The catalytic FXIIIA2 subunit is encoded by the F13A1 gene, expressed primarily in cells of mesenchymal origin, whereas the FXIIIB subunit encoded by the F13B gene is expressed and secreted from hepatocytes. The plasma FXIIIA2 subunit, which earlier was believed to be secreted from cells of megakaryocytic lineage, is now understood to result primarily from resident macrophages. The regulation of the FXIII subunits at the genetic level is still poorly understood. The current study adopts a purely bioinformatic approach to analyze the temporal, time-specific expression array-data corresponding to both the subunits in specific cell lineages, with respect to the gene promoters. We analyze the differentially expressed genes correlated with F13A1 and F13B expression levels in an array of cell types, utilizing publicly available microarray data. We attempt to understand the regulatory mechanism underlying the variable expression of FXIIIA2 subunit in macrophages (M0, M1, M2 and aortic resident macrophages). Similarly, the FXIIIB2 subunit expression data from adult, fetal hepatocytes and embryonic stem cells derived hepatoblasts (hESC-hepatoblast) was analyzed. The results suggest regulatory dependence between the two FXIII subunits at the transcript level. Our analysis also predicts the involvement of the FXIIIA2 subunit in macrophage polarization, plaque stability, and inflammation. [ABSTRACT FROM AUTHOR]