The sign problem across the QCD phase transition

The average phase factor of the QCD fermion determinant signals the strength of the QCD sign problem. We compute the average phase factor as a function of temperature and baryon chemical potential using a two-flavor NJL model. This allows us to study the strength of the sign problem at and above the chiral transition. It is discussed how the $U_A(1)$ anomaly affects the sign problem. Finally, we study the interplay between the sign problem and the endpoint of the chiral transition.Comment: 9 pages and 9 fig

A database of microRNA expression patterns in Xenopus laevis

MicroRNAs (miRNAs) are short, non-coding RNAs around 22 nucleotides long. They inhibit gene expression either by translational repression or by causing the degradation of the mRNAs they bind to. Many are highly conserved amongst diverse organisms and have restricted spatio-temporal expression patterns during embryonic development where they are thought to be involved in generating accuracy of developmental timing and in supporting cell fate decisions and tissue identity. We determined the expression patterns of 180 miRNAs in Xenopus laevis embryos using LNA oligonucleotides. In addition we carried out small RNA-seq on different stages of early Xenopus development, identified 44 miRNAs belonging to 29 new families and characterized the expression of 5 of these. Our analyses identified miRNA expression in many organs of the developing embryo. In particular a large number were expressed in neural tissue and in the somites. Surprisingly none of the miRNAs we have looked at show expression in the heart. Our results have been made freely available as a resource in both XenMARK and Xenbase

Morphological characteristics of motor neurons do not determine their relative susceptibility to degeneration in a mouse model of severe spinal muscular atrophy

Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality, resulting primarily from the degeneration and loss of lower motor neurons. Studies using mouse models of SMA have revealed widespread heterogeneity in the susceptibility of individual motor neurons to neurodegeneration, but the underlying reasons remain unclear. Data from related motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), suggest that morphological properties of motor neurons may regulate susceptibility: in ALS larger motor units innervating fast-twitch muscles degenerate first. We therefore set out to determine whether intrinsic morphological characteristics of motor neurons influenced their relative vulnerability to SMA. Motor neuron vulnerability was mapped across 10 muscle groups in SMA mice. Neither the position of the muscle in the body, nor the fibre type of the muscle innervated, influenced susceptibility. Morphological properties of vulnerable and disease-resistant motor neurons were then determined from single motor units reconstructed in Thy.1-YFP-H mice. None of the parameters we investigated in healthy young adult mice - including motor unit size, motor unit arbor length, branching patterns, motor endplate size, developmental pruning and numbers of terminal Schwann cells at neuromuscular junctions - correlated with vulnerability. We conclude that morphological characteristics of motor neurons are not a major determinant of disease-susceptibility in SMA, in stark contrast to related forms of motor neuron disease such as ALS. This suggests that subtle molecular differences between motor neurons, or extrinsic factors arising from other cell types, are more likely to determine relative susceptibility in SMA

Theory of Star Formation

We review current understanding of star formation, outlining an overall theoretical framework and the observations that motivate it. A conception of star formation has emerged in which turbulence plays a dual role, both creating overdensities to initiate gravitational contraction or collapse, and countering the effects of gravity in these overdense regions. The key dynamical processes involved in star formation -- turbulence, magnetic fields, and self-gravity -- are highly nonlinear and multidimensional. Physical arguments are used to identify and explain the features and scalings involved in star formation, and results from numerical simulations are used to quantify these effects. We divide star formation into large-scale and small-scale regimes and review each in turn. Large scales range from galaxies to giant molecular clouds (GMCs) and their substructures. Important problems include how GMCs form and evolve, what determines the star formation rate (SFR), and what determines the initial mass function (IMF). Small scales range from dense cores to the protostellar systems they beget. We discuss formation of both low- and high-mass stars, including ongoing accretion. The development of winds and outflows is increasingly well understood, as are the mechanisms governing angular momentum transport in disks. Although outstanding questions remain, the framework is now in place to build a comprehensive theory of star formation that will be tested by the next generation of telescopes.Comment: 120 pages, to appear in ARAA. No changes from v1 text; permission statement adde

Dienogest 2 mg Daily in the Treatment of Adolescents with Clinically Suspected Endometriosis: The VISanne Study to Assess Safety in ADOlescents

Study Objective: To study the safety and efficacy of dienogest 2 mg in adolescents with suspected endometriosis.Design: A 52-week, open-label, single-arm study.Setting: In 21 study centers, in 6 European countries.Participants: Adolescents aged 12 to younger than 18 years with clinically suspected or laparoscopically confirmed endometriosis.Interventions: Dienogest 2 mg once daily.Main Outcome Measures: The primary end point was relative change in lumbar spine (L2-L4) bone mineral density (BMD) measured using dual-energy x-ray absorptiometry. A key secondary end point was change in endometriosis-associated pain assessed using a visual analogue scale.Results: Of 120 patients screened, 111 comprised the full-analysis set (ie, patients who took >= 1 dose of study drug and had >= 1 post-treatment observation) and 97 (87.4%) completed the study. Mean lumbar BMD at baseline was 1.1046 (SD, 0.1550) g/cm(2). At the end of dienogest treatment (EOT; defined as at 52 weeks or premature study discontinuation), mean relative change in BMD from baseline was -1.2% (SD, 2.3%; n 5 103). Follow-up measurement 6 months after EOT in the subgroup with decreased BMD at EOT (n 5 60) showed partial recovery in lumbar BMD (mean change from baseline: -2.3% at EOT, -0.6% 6 months after EOT). Mean endometriosis-associated pain score was 64.3 (SD, 19.1) mm at baseline and decreased to 9.0 (SD, 13.9) mm by week 48.Conclusion: In adolescents with suspected endometriosis, dienogest 2 mg for 52 weeks was associated with a decrease in lumbar BMD, followed by partial recovery after treatment discontinuation. Endometriosis-associated pain was substantially reduced during treatment. Because bone accretion is critical during adolescence, results of the VISanne study to assess safety in ADOlescents (VISADO) study highlights the need for tailored treatment in this population, taking into account the expected efficacy on endometriosis-associated pain and an individual's risk factors for osteoporosis

Kinetic modelling of competition and depletion of shared miRNAs by competing endogenous RNAs

Non-conding RNAs play a key role in the post-transcriptional regulation of mRNA translation and turnover in eukaryotes. miRNAs, in particular, interact with their target RNAs through protein-mediated, sequence-specific binding, giving rise to extended and highly heterogeneous miRNA-RNA interaction networks. Within such networks, competition to bind miRNAs can generate an effective positive coupling between their targets. Competing endogenous RNAs (ceRNAs) can in turn regulate each other through miRNA-mediated crosstalk. Albeit potentially weak, ceRNA interactions can occur both dynamically, affecting e.g. the regulatory clock, and at stationarity, in which case ceRNA networks as a whole can be implicated in the composition of the cell's proteome. Many features of ceRNA interactions, including the conditions under which they become significant, can be unraveled by mathematical and in silico models. We review the understanding of the ceRNA effect obtained within such frameworks, focusing on the methods employed to quantify it, its role in the processing of gene expression noise, and how network topology can determine its reach.Comment: review article, 29 pages, 7 figure

Inhibition of Apoptosis Blocks Human Motor Neuron Cell Death in a Stem Cell Model of Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is a genetic disorder caused by a deletion of the survival motor neuron 1 gene leading to motor neuron loss, muscle atrophy, paralysis, and death. We show here that induced pluripotent stem cell (iPSC) lines generated from two Type I SMA subjects–one produced with lentiviral constructs and the second using a virus-free plasmid–based approach–recapitulate the disease phenotype and generate significantly fewer motor neurons at later developmental time periods in culture compared to two separate control subject iPSC lines. During motor neuron development, both SMA lines showed an increase in Fas ligand-mediated apoptosis and increased caspase-8 and-3 activation. Importantly, this could be mitigated by addition of either a Fas blocking antibody or a caspase-3 inhibitor. Together, these data further validate this human stem cell model of SMA, suggesting that specific inhibitors of apoptotic pathways may be beneficial for patients

Chromosome 7 and 19 Trisomy in Cultured Human Neural Progenitor Cells

BACKGROUND:Stem cell expansion and differentiation is the foundation of emerging cell therapy technologies. The potential applications of human neural progenitor cells (hNPCs) are wide ranging, but a normal cytogenetic profile is important to avoid the risk of tumor formation in clinical trials. FDA approved clinical trials are being planned and conducted for hNPC transplantation into the brain or spinal cord for various neurodegenerative disorders. Although human embryonic stem cells (hESCs) are known to show recurrent chromosomal abnormalities involving 12 and 17, no studies have revealed chromosomal abnormalities in cultured hNPCs. Therefore, we investigated frequently occurring chromosomal abnormalities in 21 independent fetal-derived hNPC lines and the possible mechanisms triggering such aberrations. METHODS AND FINDINGS:While most hNPC lines were karyotypically normal, G-band karyotyping and fluorescent in situ hybridization (FISH) analyses revealed the emergence of trisomy 7 (hNPC(+7)) and trisomy 19 (hNPC(+19)), in 24% and 5% of the lines, respectively. Once detected, subsequent passaging revealed emerging dominance of trisomy hNPCs. DNA microarray and immunoblotting analyses demonstrate epidermal growth factor receptor (EGFR) overexpression in hNPC(+7) and hNPC(+19) cells. We observed greater levels of telomerase (hTERT), increased proliferation (Ki67), survival (TUNEL), and neurogenesis (beta(III)-tubulin) in hNPC(+7) and hNPC(+19), using respective immunocytochemical markers. However, the trisomy lines underwent replicative senescence after 50-60 population doublings and never showed neoplastic changes. Although hNPC(+7) and hNPC(+19) survived better after xenotransplantation into the rat striatum, they did not form malignant tumors. Finally, EGF deprivation triggered a selection of trisomy 7 cells in a diploid hNPC line. CONCLUSIONS:We report that hNPCs are susceptible to accumulation of chromosome 7 and 19 trisomy in long-term cell culture. These results suggest that micro-environmental cues are powerful factors in the selection of specific hNPC aneuploidies, with trisomy of chromosome 7 being the most common. Given that a number of stem cell based clinical trials are being conducted or planned in USA and a recent report in PLoS Medicine showing the dangers of grafting an inordinate number of cells, these data substantiate the need for careful cytogenetic evaluation of hNPCs (fetal or hESC-derived) before their use in clinical or basic science applications

Search for cardiac calcium cycling gene mutations in familial ventricular arrhythmias resembling catecholaminergic polymorphic ventricular tachycardia

<p>Abstract</p> <p>Background</p> <p>Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inherited cardiac disorder caused by mutations predominantly in the ryanodine receptor (<it>RyR2</it>) gene. We sought to identify mutations in genes affecting cardiac calcium cycling in patients with CPVT and in less typical familial exercise-related ventricular arrhythmias.</p> <p>Methods and Results</p> <p>We recruited 33 consecutive patients with frequent ventricular premature complexes (VPCs) without structural heart disease and often history of syncope or sudden death in family. Sixteen of the patients featured a phenotype typical of CPVT. In 17 patients, VPCs emerged also at rest. Exercise stress test and echocardiography were performed to each patient and 232 family members. Familial background was evident in 42% of cases (n = 14). We sequenced all the coding exons of the <it>RyR2</it>, <it>FKBP1B</it>, <it>ATP2A2 </it>and <it>SLC8A1 </it>genes from the index patients. Single channel recordings of a mutant RyR2 were performed in planar lipid bilayers. Two novel <it>RyR2 </it>missense mutations (R1051P and S616L) and two <it>RyR2 </it>exon 3 deletions were identified, explaining 25% of the CPVT phenotypes. A rare variant (N3308S) with open probabilities similar to the wild type channels <it>in vitro</it>, was evident in a patient with resting VPCs. No disease-causing variants were detectable in the <it>FKBP1B</it>, <it>ATP2A2 </it>or <it>SLC8A1 </it>genes.</p> <p>Conclusion</p> <p>We report two novel CPVT-causing <it>RyR2 </it>mutations and a novel <it>RyR2 </it>variant of uncertain clinical significance in a patient with abundant resting VPCs. Our data also strengthen the previous assumption that exon 3 deletions of <it>RyR2 </it>should screened for in CPVT and related phenotypes.</p

The Relationship of Within-Host Multiplication and Virulence in a Plant-Virus System

Background. Virulence does not represent any obvious advantage to parasites. Most models of virulence evolution assume that virulence is an unavoidable consequence of within-host multiplication of parasites, resulting in trade-offs between within-host multiplication and between-host transmission fitness components. Experimental support for the central assumption of this hypothesis, i.e., for a positive correlation between within-host multiplication rates and virulence, is limited for plant-parasite systems. Methodology/Principal Findings. We have addressed this issue in the system Arabidopsis thaliana-Cucumber mosaic virus (CMV). Virus multiplication and the effect of infection on plant growth and on viable seed production were quantified for 21 Arabidopsis wild genotypes infected by 3 CMV isolates. The effect of infection on plant growth and seed production depended of plant architecture and length of postembryonic life cycle, two genetically-determined traits, as well as on the time of infection in the plant's life cycle. A relationship between virus multiplication and virulence was not a general feature of this host-parasite system. This could be explained by tolerance mechanisms determined by the host genotype and operating differently on two components of plant fitness, biomass production and resource allocation to seeds. However, a positive relationship between virus multiplication and virulence was detected for some accessions with short life cycle and high seed weight to biomass ratio, which show lower levels of tolerance to infection. Conclusions/Significance. These results show that genotype-specific tolerance mechanisms may lead to the absence of a clear relationship between parasite multiplication and virulence. Furthermore, a positive correlation between parasite multiplication and virulence may occur only in some genotypes and/or environmental conditions for a given host-parasite system. Thus, our results challenge the general validity of the trade-off hypothesis for virulence evolution, and stress the need of considering the effect of both the host and parasite genotypes in analyses of host-parasite interactions. © 2007 Pagán et al.Ministerio de Educación y Ciencia, Spain.Peer Reviewe