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This year, Cell Stem Cell and the International Society for Stem Cell Research (ISSCR) are celebrating their 15

Polymer nanocomposite samples were prepared by mechanical mixing of novolac epoxy polymer (EEW 180 g/eq) and varying concentrations of nano CaCO3 (0-5 wt%) for 30 min. using an electrical stirrer of 4000 rpm followed by uniform mixing of curing agent triethylenetetramine (TETA). The prepared mixtures were poured into a Teflon mold, designed as per ASTM standard. Thereafter subjected to cure at 110 °C for 1hr and post-cure at 70 °C for 5 hrs. The prepared nanocomposite samples were investigated for flexural strength, flexural modulus, impact strength, toughness, elongation at break, elastic modulus and hardness Shore D. It was observed that the sample containing 4 wt% nano CaCO3 showed the maximum value of flexural strength, flexural modulus, impact strength, toughness, elongation at break, elastic modulus and hardness Shore D, compared to the neat epoxy matrix. The curing reaction of nanocomposite samples was confirmed by FTIR spectroscopy and the morphological properties were investigated by SEM.

The modification of epoxy/fly ash composites by nano CaCO3 is an impressive way to enhance its prevailed properties. After modification of nano CaCO3, to understand mechanical behavior is meaningful in various fields, and enhancement in mechanical properties can advantageous to the convention in the various structural applications. The fly ash reinforced epoxy nanocomposite was prepared by mixing DGEBA epoxy resin and polyamine as a curing agent in which fly ash with 10 wt% and nano rCaCO3 with different (0, 1, 3 and 5) wt% were ultra-sonically dispersed for 30 min. The mechanical behavior of the prepared sample has been evaluated whereas the SEM technique was carried out to examine the morphological properties of epoxy/fly ash nanocomposite. Based on the morphological study, crack binding, crack transformation and strong interfacial bonding of CaCO3 nanoparticles were the prime reasons resulting in the enhancement of mechanical strength. The result indicates that the tensile strength of epoxy/fly ash composites increased by about 52.41% with the inclusion of 5 wt% CaCO3 nano reinforcement, whereas the impact strength and flexural strength were improved by 43.24% and 42.36% for the composition of 3 wt% nano CaCO3 reinforced epoxy/fly ash cast as compared to unmodified epoxy/fly ash cast. The thermal stability of epoxy/fly ash nanocomposites were analyzed by TGA and DSC technique. The degradation kinetics and water absorption behavior were also examined for above.

BackgroundAutism is a heterogenous collection of disorders with a complex molecular underpinning. Evidence from post-mortem brain studies using adult brains have indicated that early prenatal development may be altered in autism. Induced pluripotent stem cells (iPSCs) generated from autistic individuals with macrocephaly also indicate prenatal development as a critical period for this condition. But little is known about early altered cellular events during prenatal stages in autism.MethodsIPSCs were generated from 9 unrelated autistic individuals without macrocephaly and with heterogeneous genetic backgrounds, and 6 typically developing, control, individuals. IPSCs were differentiated towards either cortical or midbrain fates. Gene expression and high throughput cellular phenotyping was used to characterise iPSCs at different stage of differentiation.ResultsA subset of autism-iPSC cortical neurons were RNA-sequenced to reveal autism-specific signatures similar to post-mortem brain studies, indicating a potential common biological mechanism. Autism-iPSCs differentiated towards a cortical fate displayed impairments in the ability to self-form into neural rosettes. In addition, autism-iPSCs demonstrated significant differences in rate of cell type assignment of cortical precursors, and dorsal and ventral forebrain precursors. These cellular phenotypes occurred in the absence of alterations in cell proliferation during cortical differentiation, differing from previous studies. Acquisition of cell fate during midbrain differentiation was not different between control- and autism-iPSCs.ConclusionsTaken together, our data indicate that autism-iPSCs diverge from control-iPSCs at a cellular level during early stage of neurodevelopment. This suggests that unique developmental differences associated with autism may be established at early prenatal stages.

Congenital heart disease (CHD) is present in 1% of live births, yet identification of causal mutations remains a challenge despite large-scale genomic sequencing efforts. We hypothesized that genetic determinants for CHDs may lie in protein interactomes of GATA4 and TBX5, two transcription factors that cause CHDs. Defining their interactomes in human cardiac progenitors via affinity purification-mass spectrometry and integrating results with genetic data from the Pediatric Cardiac Genomic Consortium revealed an enrichment of de novo variants among proteins that interact with GATA4 or TBX5. A consolidative score that prioritized interactome members based on variant, gene, and proband features identified likely CHD-causing genes, including the epigenetic reader GLYR1. GLYR1 and GATA4 widely co-occupied cardiac developmental genes, resulting in co-activation, and the GLYR1 missense variant associated with CHD disrupted interaction with GATA4. This integrative proteomic and genetic approach provides a framework for prioritizing and interrogating the contribution of genetic variants in disease.

Mismatch negativity (MMN) is a differential electrophysiological response measuring cortical adaptability to unpredictable stimuli. MMN is consistently attenuated in patients with psychosis. However, the genetics of MMN are uncharted, limiting the validation of MMN as a psychosis endophenotype. We therefore performed a transcriptome-wide association study of 728 individuals, which revealed two genes (FAM89A and ENGASE) whose expression in cortical tissues is associated with MMN. Enrichment analyses of neurodevelopmental expression signatures showed that genes associated with MMN tend to be overexpressed in frontal cortex during prenatal development but significantly downregulated in adulthood. In our Endophenotype Ranking Value calculation comparing MMN and three other candidate psychosis endophenotypes (lateral ventricular volume and two auditory-verbal learning measures), MMN was considerably superior. These results yield promising insights into sensory processing in the cortex and endorse the notion of MMN as a psychosis endophenotype.

Butyric acid is a monocarboxylic acid which can be produced economically by fermentation from green feedstock. As the recovery of butyric acid from dilute fermentation broth is a challenge and hence it needs to develop a competitive downstream recovery process. Butyric acid finds a wide range of applications in pharmaceutical, food, cosmetics and power industries. Reactive extraction is one of the most promising and accessible methods which can be used as first separation step for recovery of butyric acid from dilute wastewater stream or fermentation broth. In present study, the physical and reactive extraction of butyric acid using tri-n-octylamine (TOA) in biodiesel made from sesame oil, rice bran oil, karanja oil and sunflower oil were studied at 298K and comparatively found the reactive extraction as more efficient. The Partition coefficient P, dimerization constant D and the distribution coefficient KD were obtained in the physical extraction study. In reactive extraction, the results were obtained in terms of distribution coefficient KD, loading ratio O and the degree of extraction E%.

The Amritpur Granite, sandwiched between the two intensely deformed rock packages, occurs adjacent to the Main Boundary Thrust (MBT) in the outer part of the Kumaun Lesser Himalaya. Characteristically, the granite lacks any penetrative tectonic fabric at the microscopic or mesoscopic scales. Using high-resolution mapping, litholog, and outcrop-scale overprinting relationships, we first revisit the tectonic setting of the Amritpur Granite and then attempt to detect the magnetic fabric, if any, in it. For this, we investigate the anisotropy of magnetic susceptibility in the Amritpur Granite and the adjacent lithounits deformed presumably during the Himalayan orogeny. High-resolution mapping demonstrates that the MBT traces the boundary between the Neogene Siwalik sediments and the Proterozoic amphibolite of the Nagthat Formation in the study area. Field relationships and structural setting imply that the granite occurs either as a probable klippe or a basement sliver. The orientations of the mesoscopic scale foliations and lineations are similar to the respective magnetic fabric orientations in the deformed lithounits occurring adjacent to the Amritpur Granite. The tectonically induced magnetic fabric orientations in the deformed lithounits also correlate well with the magnetic fabric orientations in the Amritpur Granite. Several lines of evidence suggest that the magnetic fabrics in the Amritpur Granite and those in the adjacent deformed lithounits were induced during a common deformation phase.

Thermogravimetric Analysis (TGA) is concluding expanding applicability in determination of the thermal stability and degradation nature of materials. The present study investigates the thermal degradation behavior and the kinetics of degradation of epoxy mixed with varying percentages of 0, 2.5, 5, and 7.5 ​wt% fly ash. Thermal stability and degradation behavior of fly ash modified epoxy cast were determined by thermogravimetric analysis. The kinetic parameters of the EF composites were calculated by using Coats–Redfern, Broido and Horowitz–Metzger models under best-fit analysis and further proved by linear regression analysis. The kinetics of thermal degradation was calculated from data scanned at a heating rate of 10 ​°C/min. The obtained results reveal that kinetic parameters and thermal behavior of EF composites were improved with the reinforcement of fly ash. The cure kinetics of the varying content of fly ash reinforced epoxy cast were also studied by using a nonisothermal differential scanning calorimetric (DSC) technique at four different heating rates 5 ​°C/min, 10 ​°C/min, 15 ​°C/min and 20 ​°C/min. The curing kinetics of the EF composite was derived from the nonisothermal differential scanning calorimetry (DSC) data with the three Kissinger, Ozawa, and Flynn–Wall–Ozawa models, respectively.

Positron emission tomography studies using the synaptic vesicle glycoprotein 2A (SV2A) radioligand [11C]-UCB-J provide in vivo evidence for synaptic dysfunction and/or loss in the cingulate and frontal cortex of patients with schizophrenia. In exploring potential confounding effects of antipsychotic medication, we previously demonstrated that chronic (28-day) exposure to clinically relevant doses of haloperidol does not affect [3H]-UCB-J radioligand binding in the cingulate and frontal cortex of male rats. Furthermore, neither chronic haloperidol nor olanzapine exposure had any effect on SV2A protein levels in these brain regions. These data do not exclude the possibility, however, that more subtle changes in SV2A may occur at pre-synaptic terminals, or the post-synaptic density, following chronic antipsychotic drug exposure. Moreover, relatively little is known about the potential effects of psychotropic drugs other than antipsychotics on SV2A. To address these questions directly, we herein used immunostaining and confocal microscopy to explore the effect of chronic (28-day) exposure to clinically relevant doses of haloperidol, olanzapine or the mood stabilizer lithium on presynaptic SV2A, postsynaptic Neuroligin (NLGN) puncta and their overlap as a measure of total synaptic density in the rat prefrontal and anterior cingulate cortex. We found that, under the conditions tested here, exposure to antipsychotics had no effect on SV2A, NLGN, or overall synaptic puncta count. In contrast, chronic lithium exposure significantly increased NLGN puncta density relative to vehicle, with no effect on either SV2A or total synaptic puncta. Future studies are required to understand the functional consequences of these changes.

The stress inversion of geological or geophysical observations is a nonlinear problem. In most existing methods, it is solved by linearization, under certain assumptions. These linear algorithms not only oversimplify the problem but also are vulnerable to entrapment of the solution in a local optimum. We propose the use of a nonlinear heuristic technique, the genetic algorithm, which searches the global optimum without making any linearizing assumption or simplification. The algorithm mimics the natural evolutionary processes of selection, crossover and mutation and, minimizes a composite misfit function for searching the global optimum, the fittest stress tensor. The validity and efficacy of the algorithm are demonstrated by a series of tests on synthetic and natural fault-slip observations in different tectonic settings and also in situations where the observations are noisy. It is shown that the genetic algorithm is superior to other commonly practised methods, in particular, in those tectonic settings where none of the principal stresses is directed vertically and/or the given data set is noisy.

SUMMARY Determining genes that orchestrate cell differentiation in development and disease remains a fundamental goal of cell biology. This study establishes a genome-wide metric based on the gene-repressive trimethylation of histone H3 at lysine 27 (H3K27me3) across hundreds of diverse cell types to identify genetic regulators of cell differentiation. We introduce a computational method, TRIAGE, which uses discordance between gene-repressive tendency and expression to identify genetic drivers of cell identity. We apply TRIAGE to millions of genome-wide single-cell transcriptomes, diverse omics platforms, and eukaryotic cells and tissue types. Using a wide range of data, we validate the performance of TRIAGE in identifying cell-type-specific regulatory factors across diverse species including human, mouse, boar, bird, fish, and tunicate. Using CRISPR gene editing, we use TRIAGE to experimentally validate RNF220 as a regulator of Ciona cardiopharyngeal development and SIX3 as required for differentiation of endoderm in human pluripotent stem cells. A record of this paper’s transparent peer review process is included in the Supplemental Information., In Brief Perturbing genes controlling cell decisions have major implications in development or disease. However, identifying key regulatory genes from the thousands expressed in a cell is challenging. TRIAGE is a computational method that distills patterns of epigenetic repression across diverse cell types to infer regulatory genes using input gene expression data from any cell type. Demonstrating its utility, we combine single-cell RNA-seq and TRIAGE to identify and experimentally confirm novel regulators of heart development in evolutionarily distant species., Graphical Abstract

Genetic mutations in the cardiomyocyte contractile apparatus cause aberrant cardiac growth categorized morphologically as hypertrophic or dilated. A recent study leverages an array of mutant mouse models to extrapolate a new integrated parameter: the myofilament ‘tension index', which predicts patterns of cardiac growth resulting from individual sarcomeric mutations. These findings may inform genotype-specific therapies.

Field data on fault-slip observations is commonly heterogeneous. Paleostress estimation from such data sets is, in general, carried out in two steps: (i) the classification of the heterogeneous data set into homogeneous subsets and (ii) an inversion of each homogeneous subset. This study gives a new approach, the HGA, that combines the two issues in a single step process and gives the stress tensors directly. The given heterogeneous data are directly operated upon by the genetic algorithm operators, initialization, elitism, selection, encoding, crossover and mutation. These operations simulate such a guided search that finds successively fitter solutions, the stress tensors, until the globally fittest solution is obtained. We first explain the basic steps of the algorithm on a working example and then demonstrate its veracity using several synthetic and two natural examples. The proposed genetic algorithm method obviates the necessity of having first to classify the heterogeneous data into homogeneous sets. It directly estimates different stress states by inversion of the given heterogeneous fault-slip data. In contrast to the existing linear methods, the method is not vulnerable to entrapment of the solution in a local optimum. Although the method requires an a priori estimate of the maximum number of expected homogeneous sets in a given population, this estimate does not control the final results. Like any other method, the genetic algorithm method too has its merits and limitations and these are discussed.

Background The human neural progenitor cell line CTX0E16 is a robust source of forebrain-like glutamatergic cortical neurons that display intrinsic functional properties (Anderson et al., 2015, Stem Cell Res). This cell line was obtained from the embryonic cortex of a 12-week gestation XY fetus, and conditionally immortalised by ectopic expression of the c-MycER TAM transgene. This construct allows the stem cells to be maintained in a proliferative state under the presence of hydroxytamoxifen (4-OHT), while removal of 4-OHT and growth factors stimulates progenitor differentiation. The cortex is generally smaller in schizophrenia patients, and understanding the global gene expression changes occurring during cortical development, and its relationship to genetic risk for schizophrenia, might reveal clues as to which genetic mechanisms are responsible for mediating the differences observed in patients. Our hypothesis is that neurodevelopmental diseases such as schizophrenia might share a genetic component with processes driving early cortical maturation, which can be modelled in vitro. Methods The CTX0E16 cell line was provided by ReNeuron and total RNA was extracted from proliferating neural progenitor cells (NPCs, n=3) and from cells that underwent a 28-day differentiation protocol (n=3). RNA samples were then processed on Illumina HT12 v4 chips. Raw fluorescence probe intensity values were extracted using GenomeStudio, and were subsequently background-corrected and log-transformed in R using the lumi package. Differentially expressed probes were determined using t-tests and the false-discovery rate of multiple testing correction was applied (q Results We expect to identify and annotate sets of genes involved in cortical maturation that are additionally involved in the aetiology of schizophrenia. Discussion The discussion will focus on the role of cortical maturation as a process that may be involved in schizophrenia aetiology.

Human adult cardiomyocytes have limited regenerative capacity resulting in permanent loss of cardiomyocytes in the setting of many forms of heart disease. In an effort to replace lost cells, several groups have reported successful reprogramming of fibroblasts into induced cardiomyocyte-like cells (iCMs) without going through an intermediate progenitor or stem cell stage in murine and human models. This direct cardiac reprogramming approach holds promise as a potential method for regenerative medicine in the future and for dissecting the regulatory control of cell fate determination. Here we review the recent advances in the direct cardiac reprogramming field and the challenges that must be overcome to move this strategy closer to clinical application.

© 2015 Elsevier Inc. The mechanisms by which transcription factor haploinsufficiency alters the epigenetic and transcriptional landscape in human cells to cause disease are unknown. Here, we utilized human induced pluripotent stem cell (iPSC)-derived endothelial cells (ECs) to show that heterozygous nonsense mutations in NOTCH1 that cause aortic valve calcification disrupt the epigenetic architecture, resulting in derepression of latent pro-osteogenic and -inflammatory gene networks. Hemodynamic shear stress, which protects valves from calcification in vivo, activated anti-osteogenic and anti-inflammatory networks in NOTCH1+/+, but not NOTCH1+/-, iPSC-derived ECs. NOTCH1 haploinsufficiency altered H3K27ac at NOTCH1-bound enhancers, dysregulating downstream transcription of more than 1,000 genes involved in osteogenesis, inflammation, and oxidative stress. Computational predictions of the disrupted NOTCH1-dependent gene network revealed regulatory nodes that, when modulated, restored the network toward the NOTCH1+/+state. Our results highlight how alterations in transcription factor dosage affect gene networks leading to human disease and reveal nodes for potential therapeutic intervention.

Cardanol-based vinyl ester resin ( CVER ) was blended with varying concentrations of Carboxyl terminated butadiene acrylonitrile (CTBN) ranging between 0 and 15 wt% with an interval increment of 5 wt%, by two different approaches, viz., physical and chemical blending. The formation of various products during the curing of blend samples has been studied by FTIR spectroscopic analysis. The dynamic DSC scans showed that the blend samples of CVERs cured in the temperature range of 100–150 °C. It was observed that the blend sample containing 5 wt% and 10 wt% liquid rubber, for physical and chemical blending, respectively, showed least cure time, at 120 °C, amongst all other blend samples. On evaluation, it was found that in toughened samples thermal and mechanical properties were marginally affected with the increase of CTBN concentration. The blend morphology, studied by scanning electron microscopy analysis, showed the presence of precipitated discrete rubber particles which dispersed throughout the vinyl ester matrix, i.e., they revealed the presence of two phase morphology.

Cardanol-based vinyl ester resin (CVER) was prepared by reacting indigenously synthesized cardanol-based epoxidized novolac resin (CENR) with methacrylic acid (MA) in the presence of triphenylphosphine as catalyst. Five samples of cardanol-based vinyl ester resin containing styrene and glycidyl methacrylate (GMA), as diluents, in the weight ratios 40:0, 30:10, 20:20, 10:30 and 0:40 were prepared at room temperature. Sharp exotherms were observed in DSC scans in the temperature range of 60–170 °C. The onset temperature ( T onset ), peak exothermic temperature ( T p ) and completion temperature ( T stop ) decreased with increase in GMA content in the ternary blend systems of CVER/styrene/GMA. A broad exotherm was observed after the initial sharp exotherm that was attributed to the etherification reaction. Cured samples were found to be stable up to 205–235 °C and started loosing weight above this temperature. Rapid decomposition was observed in the temperature range of 400–550 °C as evidenced by TGA analysis. Increase of GMA content in ternary blend systems of CVER/styrene/GMA lowered the tensile strength progressively and enhanced the impact strength and elongation-at-break. The cured films of VER containing mixture of styrene and GMA exhibited good gloss and impact resistance. The chemical resistance of cured films of VER containing mixture of styrene and GMA showed good resistance to acids, deionized water, synthetic sea water and mineral turpentine oil.

Fry method is a graphical technique that displays the strain ellipse in the form of central vacancy on a point distribution, the Fry plot. For objective strain estimation from the Fry plot, the central vacancy must appear as a sharply focused ellipse. In practice, however, a diffused appearance of the central vacancy in the Fry plots induces considerable subjectivity in direct strain estimation. Several alternative computer-based methods have recently been proposed for objective strain estimation from the Fry plots. Relative merits and limitations of these methods are, however, not yet well understood. This study compares the accuracy and efficacy of the six recent methods proposed for objective strain estimation from the Fry plot. The six methods are based on four different approaches, the point density contrast, the image analysis, the Delaunay triangulation and the point distribution analysis. We test and compare these methods by: (i) generating variously sorted object sets through computer simulations, (ii) distorting the object sets, with the help of computer graphics software, by pure shear, simple shear and simultaneous pure-and-simple shear and, (iii) estimating the errors. Results from more than 2900 tests imply that the continuous function method and the Delaunay triangulation method yield most accurate strain estimates. The image analysis method gives very accurate principal strain orientations but overestimates the strain ratio, specially, in strongly distorted object sets. The point distribution analysis methods are successful mostly on those point distributions that are obtained by pure shear distortion of well-sorted objects with specific boundary conditions. With respect to the time-efficiency, the image analysis method and the Delaunay triangulation method are found to be most rapid.

The method and the advantages of an evolutionary computing based approach using a steady state genetic algorithm (GA) for the parameterization of interatomic potentials for metal oxides within the shell model framework are developed and described. We show that the GA based methodology for the parameterization of interatomic force field functions is capable of (a) simultaneous optimization of the multiple phases or properties of a material in a single run, (b) facilitates the incremental re-optimization of the whole system as more data is made available for either additional phases or material properties not included in previous runs, and (c) successful global optimization in the presence of multiple local minima in the parameter space. As an example, we apply the method towards simultaneous optimization of four distinct crystalline phases of Barium Titanate (BaTiO3 or BTO) using an ab initio density functional theory (DFT) based reference dataset. We find that the optimized force field function is capable of the prediction of the two phases not used in the optimization procedure, and that many derived physical properties such as the equilibrium lattice constants, unit cell volume, elastic properties, coefficient of thermal expansion, and average electronic polarization are in good agreement with the experimental results available from the literature.

A combination of two groups of boudins, exposed in orthogonal sections, is observed as chocolate tablet structures in the South Almora Thrust (SAT) zone, Kumaun Lesser Himalaya. Evidence from boudin associated veins, fractures, folds and microstructures suggest that the chocolate-tablet boudins were developed as a consequence of layer-parallel stretching in two orthogonal directions during two successive phases of ductile shearing in the SAT zone. The early phase of top-to-NW shearing is speculated as a pre-Himalayan deformation during which the early boudins were developed. This deformation was superposed by a late phase of top-to-SW Himalayan shearing and development of the attendant late boudins. It is concluded that the interference of two phases of successively developed boudins has resulted into development of the chocolate tablet structures in the SAT. Fluid inclusion and microstructures indicate a low temperature, about 300 °C, growth of the chocolate-tablet boudins. The finite strain analysis reveals that a maximum strain ratio (Rs) of 1.7 was accumulated during the pre-Himalayan phase of deformation whereas Rs was of the order of 2.1 in the Himalayan phase of deformation.

Summary Direct reprogramming of adult somatic cells into alternative cell types has been shown for several lineages. We previously showed that GATA4, MEF2C, and TBX5 (GMT) directly reprogrammed nonmyocyte mouse heart cells into induced cardiomyocyte-like cells (iCMs) in vitro and in vivo. However, GMT alone appears insufficient in human fibroblasts, at least in vitro. Here, we show that GMT plus ESRRG and MESP1 induced global cardiac gene-expression and phenotypic shifts in human fibroblasts derived from embryonic stem cells, fetal heart, and neonatal skin. Adding Myocardin and ZFPM2 enhanced reprogramming, including sarcomere formation, calcium transients, and action potentials, although the efficiency remained low. Human iCM reprogramming was epigenetically stable. Furthermore, we found that transforming growth factor β signaling was important for, and improved the efficiency of, human iCM reprogramming. These findings demonstrate that human fibroblasts can be directly reprogrammed toward the cardiac lineage, and lay the foundation for future refinements in vitro and in vivo., Highlights • Human fibroblasts can be directly induced toward a CM-like state by defined factors • Reprogramming of fibroblasts toward a CM state is epigenetically stable • Human and mouse in vitro iCMs display a comparable gene-expression shift • TGF-β signaling is important for human iCM reprogramming

Tectonic history of the Himalaya is punctuated by successive development of the faults that run along the boundaries between different lithotectonic terrains. The Main Boundary Fault, defining the southern limit of the Lesser Himalayan terrain, is tectonically most active. A review of published literature reveals that the nature and age of reactivation events on the Main Boundary Fault is one of the poorly understood aspects of the Himalayan orogen. By systematic outcrop mapping of the seismites, this study identifies a Late Miocene-Early Pliocene reactivation on the Main Boundary Thrust in southeast Kumaun Himalaya. Relatively friable and cohesionless Neogene sedimentary sequences host abundant soft-sediment deformation structures in the vicinity of the Main Boundary Thrust. Among a large variety of structures, deformed cross-beds, liquefaction pockets, slump folds, convolute laminations, sand dykes, mushroom structures, fluid escape structures, flame and load structures and synsedimentary faults are common. The morphological attributes, the structural association and the distribution pattern of the soft-sediment deformation structures with respect to the Main Boundary Fault strongly suggest their development by seismically triggered liquefaction and fluidization. Available magnetostratigraphic age data imply that the seismites were developed during a Late Miocene-Early Pliocene slip on the Main Boundary Thrust. The hypocenter of the main seismic event may lie on the Main Boundary Thrust or to the north of the study area on an unknown fault or the Basal Detachment Thrust.

Regional differences in cardiomyocyte automaticity permit the sinoatrial node (SAN) to function as the leading cardiac pacemaker and the atrioventricular (AV) junction as a subsidiary pacemaker. The regulatory mechanisms controlling the distribution of automaticity within the heart are not understood. To understand regional variation in cardiac automaticity, we carried out an in vivo analysis of cis-regulatory elements that control expression of the hyperpolarization-activated cyclic-nucleotide gated ion channel 4 (Hcn4). Using transgenic mice, we found that spatial and temporal patterning of Hcn4 expression in the AV conduction system required cis-regulatory elements with multiple conserved fragments. One highly conserved region, which contained a myocyte enhancer factor 2C (Mef2C) binding site previously described in vitro, induced reporter expression specifically in the embryonic non-chamber myocardium and the postnatal AV bundle in a Mef2c-dependent manner in vivo. Inhibition of histone deacetylase (HDAC) activity in cultured transgenic embryos showed expansion of reporter activity to working myocardium. In adult animals, hypertrophy induced by transverse aortic constriction, which causes translocation of HDACs out of the nucleus, resulted in ectopic activation of the Hcn4 enhancer in working myocardium, recapitulating pathological electrical remodeling. These findings reveal mechanisms that control the distribution of automaticity among cardiomyocytes during development and in response to stress. © 2012 Elsevier Inc.

The 2012 annual meeting of the International Society for Stem Cell Research (ISSCR) marked the Tenth Anniversary of the ISSCR. Held in Japan, the meeting showcased recent discoveries and surveyed the remarkable progress that has been made in a decade of stem cell research.

The Fry method, based on the relative movement of different material points, typically grain centers, with reference to each other graphically yields a point distribution that displays the finite strain ellipse as a central vacancy. The diffused nature of the central vacancy induces subjectivity in strain estimation, particularly, if the point population when undeformed lacked an isotropic anticlustered distribution. Most existing methods use analytical and/or iterative approaches for improving the sharpness of the central vacancy and positioning the best-fit strain ellipse in a Fry plot. We provide an image-analysis method that is independent of any iteration or analytical solution. It is also an efficient technique for extraction of the central vacancy without any subjectivity. The method is more direct, simple and easy-to-use than most existing techniques. The image-analysis method uses Gaussian blur filter for distinction between the areas of largest and smallest pixel intensities in a Fry plot image. It then applies the optimal threshold value and an inversion filter for extraction of the sharp central vacancy. The method also searches for the best-fit strain ellipse through the extracted central vacancy and displays axial ratio and orientation of the ellipse in a separate window. The validity of the method is tested using several computer-simulated and natural examples.

Outcrop mapping and structural analyses in a 100 m thick fault damage zone elucidate geometry and kinematics of the Main Boundary Thrust in the study area. The north-dipping fault damage zone is sandwiched between the Proterozoic Amritpur granite in the hangingwall and the Neogene Siwalik sediments in the footwall. The Amritpur granite is overlain by the volcanic-sedimentary sequence along a top-to-the-south thrust. The footwall sediments are deformed into gentle upright and steeply-plunging folds. By contrast, the hangingwall granite is generally massive. The km-scale folds in the Sub Himalayan sediments are geometrically discordant to the folds in the Lesser Himalayan volcanic-sedimentary sequence. The damage zone contains both the Sub Himalayan sediments and the Lesser Himalayan amphibolite. It consists of an imbricate structure, tectonic wedges and pressure solution bands. The imbricate structure is made up of seven fault-bounded lithotectonic domains that record the imprints of coaxial refolding and subsequent modification of the folds into sheath-like structures. The geometry and kinematics of mesoscopic structures and the results of paleostress analysis reveal a sinistral wrench accompanied N-S to NNE-SSW directed subhorizontal shortening in the damage zone. The aforesaid evidences also help distinguish between pure contractional, pure wrench, contraction-dominated and wrench-dominated deformation in the different domains and the tectonic wedges. The sinistral transpression in the damage zone is ascribed to the occurrence of an oblique/lateral ramp along the Main Boundary Thrust in the study area.

Cardiovascular disease encompasses a range of conditions extending from myocardial infarction to congenital heart disease, most of which are heritable. Enormous effort has been invested in understanding the genes and specific DNA sequence variants that are responsible for this heritability. Here, we review the lessons learned for monogenic and common, complex forms of cardiovascular disease. We also discuss key challenges that remain for gene discovery and for moving from genomic localization to mechanistic insights, with an emphasis on the impact of next-generation sequencing and the use of pluripotent human cells to understand the mechanism by which genetic variation contributes to disease.

The cure kinetics of vinyl ester–styrene system was studied by non-isothermal differential scanning calorimetric (DSC) technique at four different heating rates. The kinetic parameters of the curing process were determined by isoconversional method for the kinetic analysis of the data obtained by the thermal treatment. Activation energy (Ea = 56.63 kJ mol−1) was evaluated for the cure process and a two-parameter (m, n) autocatalytic model was found to be the most adequate to describe the cure kinetics of the studied cardanol-based vinyl ester resin. Non-isothermal DSC curves, as obtained by using the experimental data, show good agreement with the DSC curves obtained by theoretically calculated data.

Assignment of alleles to haplotypes for nearly all the variants on all chromosomes can be performed by genetic analysis of a nuclear family with three or more children. Whole-genome sequence data enable deterministic phasing of nearly all sequenced alleles by permitting assignment of recombinations to precise chromosomal positions and specific meioses. We demonstrate this process of genetic phasing on two families each with four children. We generate haplotypes for all of the children and their parents; these haplotypes span all genotyped positions, including rare variants. Misassignments of phase between variants (switch errors) are nearly absent. Our algorithm can also produce multimegabase haplotypes for nuclear families with just two children and can handle families with missing individuals. We implement our algorithm in a suite of software scripts (Haploscribe). Haplotypes and family genome sequences will become increasingly important for personalized medicine and for fundamental biology.

SummaryMany molecular pathways involved in heart disease have their roots in evolutionarily ancient developmental programs that depend critically on gene dosage and timing. MicroRNAs (miRNAs) modulate gene dosage posttranscriptionally, and among these, the muscle-specific miR-1 is particularly important for developing and maintaining somatic/skeletal and cardiac muscle. To identify pathways regulated by miR-1, we performed a forward genetic screen in Drosophila using wing-vein patterning as a biological assay. We identified several unexpected genes that genetically interacted with dmiR-1, one of which was kayak, encodes a developmentally regulated transcription factor. Additional studies directed at this genetic relationship revealed a previously unappreciated function of dmiR-1 in regulating the polarity of cardiac progenitor cells. The mammalian ortholog of kayak, c-Fos, was dysregulated in hearts of gain- or loss-of-function miR-1 mutant mice in a stress-dependent manner. These findings illustrate the power of Drosophila-based screens to find points of intersection between miRNAs and conserved pathways in mammals.

Cardiogenesis involves the contributions of multiple progenitor pools, including mesoderm-derived cardiac progenitors known as the first and second heart fields. Disruption of genetic pathways regulating individual subsets of cardiac progenitors likely underlies many forms of human cardiac malformations. Hand2 is a member of the basic helix loop helix (bHLH) family of transcription factors and is expressed in numerous cell lineages that contribute to the developing heart. However, the early embryonic lethality of Hand2-null mice has precluded lineage-specific study of its function in myocardial progenitors. Here, we generated and used a floxed allele of Hand2 to ablate its expression in specific cardiac cell populations at defined developmental points. We found that Hand2 expression within the mesoderm-derived second heart field progenitors was required for their survival and deletion in this domain recapitulated the complete Hand2-null phenotype. Loss of Hand2 at later stages of development and in restricted domains of the second heart field revealed a spectrum of cardiac anomalies resembling forms of human congenital heart disease. Molecular analyses of Hand2 mutant cells revealed several genes by which Hand2 may influence expansion of the cardiac progenitors. These findings demonstrate that Hand2 is essential for survival of second heart field progenitors and that the graded loss of Hand2 function in this cardiac progenitor pool can cause a spectrum of congenital heart malformation.

In the mammalian forebrain, most glutamatergic excitatory synapses occur on small dendritic protrusions called dendritic spines. Dendritic spines are highly plastic and can rapidly change morphology in response to numerous stimuli. This dynamic remodeling of dendritic spines is thought to be critical for information processing, memory and cognition. Conversely, multiple studies have revealed that neuropathologies such as autism spectrum disorders (ASDs) are linked with alterations in dendritic spine morphologies and miswiring of neural circuitry. One compelling hypothesis is that abnormal dendritic spine remodeling is a key contributing factor for this miswiring. Ongoing research has identified a number of mechanisms that are critical for the control of dendritic spine remodeling. Among these mechanisms, regulation of small GTPase signaling by guanine-nucleotide exchange factors (GEFs) is emerging as a critical mechanism for integrating physiological signals in the control of dendritic spine remodeling. Furthermore, multiple proteins associated with regulation of dendritic spine remodeling have also been implicated with multiple neuropathologies, including ASDs. Epac2, a GEF for the small GTPase Rap, has recently been described as a novel cAMP (yet PKA-independent) target localized to dendritic spines. Signaling via this protein in response to pharmacological stimulation or cAMP accumulation, via the dopamine D1/5 receptor, results in Rap activation, promotes structural destabilization, in the form of dendritic spine shrinkage, and functional depression due to removal of GluR2/3-containing AMPA receptors. In addition, Epac2 forms macromolecular complexes with ASD-associated proteins, which are sufficient to regulate Epac2 localization and function. Furthermore, rare non-synonymous variants of the EPAC2 gene associated with the ASD phenotype alter protein function, synaptic protein distribution, and spine morphology. We review here the role of Epac2 in the remodeling of dendritic spines under normal conditions, the mechanisms that underlie these effects, and the implications these disease-associated variants have on our understanding of the pathophysiology of ASD.

Cardanol-based epoxidized novolac vinyl ester resin (CNEVER) was synthesized by reacting cardanol-based epoxidized novolac (CNE) resin and methacrylic acid (MA) (CNE:MA molar ratio 1:0.9) in presence of triphenylphosphine as catalyst at 90 °C. The CNE resin was prepared by the reaction of cardanol-based novolac-type phenolic (CFN) resin and epichlorohydrin, in basic medium, at 120 °C. The CFN resin was synthesized by reacting cardanol (C) and formaldehyde (F) (C/F ratio = 1:0.7) with p -toluene sulphonic acid (PTSA) as catalyst (0.5 wt.%) at 120 °C for 7 h. The resin products were analyzed by Fourier-transform infra-red (FTIR) and nuclear magnetic resonance (NMR) spectroscopic analysis. The number-average molecular weight of the prepared CNEVER was found to be 859 gmol −1 as determined by gel permeation chromatographic (GPC) analysis. The resin was cured by using the mixture of resin, benzoyl peroxide, and styrene at 120 °C. The CNEVER resin was found to be cured in 60 min at 120 °C. Differential scanning calorimetric (DSC) technique was used to investigate the curing behaviour. Single step mass loss in dynamic thermogravimetric (TG) trace of CNEVER was observed. Thermal stability of the vinyl ester sample containing 40 wt.% styrene was the highest amongst all other prepared systems.