An expectation-maximization algorithm for probabilistic reconstructions of full-length isoforms from splice graphs.

Reconstructing full-length transcript isoforms from sequence fragments (such as ESTs) is a major interest and challenge for bioinformatic analysis of pre-mRNA alternative splicing. This problem has been formulated as finding traversals across the splice graph, which is a directed acyclic graph (DAG) representation of gene structure and alternative splicing. In this manuscript we introduce a probabilistic formulation of the isoform reconstruction problem, and provide an expectation-maximization (EM) algorithm for its maximum likelihood solution. Using a series of simulated data and expressed sequences from real human genes, we demonstrate that our EM algorithm can correctly handle various situations of fragmentation and coupling in the input data. Our work establishes a general probabilistic framework for splice graph-based reconstructions of full-length isoforms

Neuron-Specific HuR-Deficient Mice Spontaneously Develop Motor Neuron Disease

Human Ag R (HuR) is an RNA binding protein in the ELAVL protein family. To study the neuron-specific function of HuR, we generated inducible, neuron-specific HuR-deficient mice of both sexes. After tamoxifen-induced deletion of HuR, these mice developed a phenotype consisting of poor balance, decreased movement, and decreased strength. They performed significantly worse on the rotarod test compared with littermate control mice, indicating coordination deficiency. Using the grip-strength test, it was also determined that the forelimbs of neuron-specific HuR-deficient mice were much weaker than littermate control mice. Immunostaining of the brain and cervical spinal cord showed that HuR-deficient neurons had increased levels of cleaved caspase-3, a hallmark of cell apoptosis. Caspase-3 cleavage was especially strong in pyramidal neurons and α motor neurons of HuR-deficient mice. Genome-wide microarray and real-time PCR analysis further indicated that HuR deficiency in neurons resulted in altered expression of genes in the brain involved in cell growth, including trichoplein keratin filament-binding protein, Cdkn2c, G-protein signaling modulator 2, immediate early response 2, superoxide dismutase 1, and Bcl2. The additional enriched Gene Ontology terms in the brain tissues of neuron-specific HuR-deficient mice were largely related to inflammation, including IFN-induced genes and complement components. Importantly, some of these HuR-regulated genes were also significantly altered in the brain and spinal cord of patients with amyotrophic lateral sclerosis. Additionally, neuronal HuR deficiency resulted in the redistribution of TDP43 to cytosolic granules, which has been linked to motor neuron disease. Taken together, we propose that this neuron-specific HuR-deficient mouse strain can potentially be used as a motor neuron disease model

Mild Traumatic Brain Injury in Elderly Patients Receiving Direct Oral Anticoagulants:A Systematic Review and Meta-Analysis

The aim of this work was to conduct a systematic review and meta-analysis of studies reporting on the risk of traumatic intracerebral hemorrhage (tICH), the course of tICH, and its treatment and mortality rates in elderly mild traumatic brain injury (mTBI) patients using direct oral anticoagulants (DOACs). We consulted PubMed and Embase for relevant cohort and case-control studies with a control group. Two authors independently selected studies, assessed methodological quality, and extracted outcome data. Estimates were pooled with the Mantel-Haenszel random-effects method. We identified 16 articles comprising 3671 elderly mTBI patients using DOACs. Use of DOACs was associated with a reduced risk of tICH compared to the use of vitamin K antagonists (VKAs; odds ratio [OR], 0.44; 95% confidence interval [CI], 0.29-0.65; I2 = 22%) and a similar risk compared to the use of antiplatelet therapy (APT; OR, 0.98; 95% CI, 0.39-2.44; I2 = 0%). Reversal agent use and neurosurgical intervention rate were lower in patients using DOACs compared to patients using VKAs (OR, 0.10; 95% CI, 0.06-0.16; I2 = 0% and OR, 0.37; 95% CI, 0.21-0.67; I2 = 0%, respectively). There was no significant difference in neurosurgical intervention rate between patients who used DOACs versus patients who used APT (OR, 0.58; 95% CI, 0.15-2.21; I2 = 41%) or no antithrombotic therapy (OR, 0.76; 95% CI, 0.20-2.86; I2 = 23%). ICH progression, risk of delayed ICH, and TBI-related in-hospital mortality were comparable among treatment groups. The present study indicates that elderly patients using DOACs have a lower risk of adverse outcome compared to patients using VKAs and a similar risk compared to patients using APT after mTBI

Influence of copper telluride nanodomains on the transport properties of n-type bismuth telluride

The high processing cost, poor mechanical properties and moderate performance of BiTe–based alloys used in thermoelectric devices limit the cost-effectiveness of this energy conversion technology. Towards solving these current challenges, in the present work, we detail a low temperature solution-based approach to produce BiTe-CuTe nanocomposites with improved thermoelectric performance. Our approach consists in combining proper ratios of colloidal nanoparticles and to consolidate the resulting mixture into nanocomposites using a hot press. The transport properties of the nanocomposites are characterized and compared with those of pure BiTe nanomaterials obtained following the same procedure. In contrast with most previous works, the presence of CuTe nanodomains does not result in a significant reduction of the lattice thermal conductivity of the reference BiTe nanomaterial, which is already very low. However, the introduction of CuTe yields a nearly threefold increase of the power factor associated to a simultaneous increase of the Seebeck coefficient and electrical conductivity at temperatures above 400 K. Taking into account the band alignment of the two materials, we rationalize this increase by considering that CuTe nanostructures, with a relatively low electron affinity, are able to inject electrons into BiTe, enhancing in this way its electrical conductivity. The simultaneous increase of the Seebeck coefficient is related to the energy filtering of charge carriers at energy barriers within BiTe domains associated with the accumulation of electrons in regions nearby a CuTe/BiTe heterojunction. Overall, with the incorporation of a proper amount of CuTe nanoparticles, we demonstrate a 250% improvement of the thermoelectric figure of merit of BiTeThis work was supported by the European Regional Development Funds and by the Generalitat de Catalunya through the project 2017SGR1246. Y.Z, C.X, M.L, K.X and X.H thank the China Scholarship Council for the scholarship support. MI acknowledges financial support from IST Austria. YL acknowledges funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No. 754411. ICN2 acknowledges funding from Generalitat de Catalunya 2017 SGR 327 and the Spanish MINECO project ENE2017-85087-C3. ICN2 is supported by the Severo Ochoa program from the Spanish MINECO (grant no. SEV-2017-0706) and is funded by the CERCA Program/Generalitat de Catalunya. Part of the present work has been performed in the framework of Universitat Autònoma de Barcelona Materials Science PhD program

Dual Targeted Extracellular Vesicles Regulate Oncogenic Genes in Advanced Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) tumours carry multiple gene mutations and respond poorly to treatments. There is currently an unmet need for drug carriers that can deliver multiple gene cargoes to target high solid tumour burden like PDAC. Here, we report a dual targeted extracellular vesicle (dtEV) carrying high loads of therapeutic RNA that effectively suppresses large PDAC tumours in mice. The EV surface contains a CD64 protein that has a tissue targeting peptide and a humanized monoclonal antibody. Cells sequentially transfected with plasmid DNAs encoding for the RNA and protein of interest by Transwell®-based asymmetric cell electroporation release abundant targeted EVs with high RNA loading. Together with a low dose chemotherapy drug, Gemcitabine, dtEVs suppress large orthotopic PANC-1 and patient derived xenograft tumours and metastasis in mice and extended animal survival. Our work presents a clinically accessible and scalable way to produce abundant EVs for delivering multiple gene cargoes to large solid tumours

In Vitro Differentiation of Mouse Embryonic Stem Cells into Neurons of the Dorsal Forebrain

Pluripotent embryonic stem cells (ESCs) are able to differentiate into all cell types in the organism including cortical neurons. To follow the dynamic generation of progenitors of the dorsal forebrain in vitro, we generated ESCs from D6-GFP mice in which GFP marks neocortical progenitors and neurons after embryonic day (E) 10.5. We used several cell culture protocols for differentiation of ESCs into progenitors and neurons of the dorsal forebrain. In cell culture, GFP-positive cells were induced under differentiation conditions in quickly formed embryoid bodies (qEBs) after 10–12 day incubation. Activation of Wnt signaling during ESC differentiation further stimulated generation of D6-GFP-positive cortical cells. In contrast, differentiation protocols using normal embryoid bodies (nEBs) yielded only a few D6-GFP-positive cells. Gene expression analysis revealed that multiple components of the canonical Wnt signaling pathway were expressed during the development of embryoid bodies. As shown by immunohistochemistry and quantitative qRT-PCR, D6-GFP-positive cells from qEBs expressed genes that are characteristic for the dorsal forebrain such as Pax6, Dach1, Tbr1, Tbr2, or Sox5. qEBs culture allowed the formation of a D6-GFP positive pseudo-polarized neuroepithelium with the characteristic presence of N-cadherin at the apical pole resembling the structure of the developing neocortex

Vortex Line Fluctuations in Model High Temperature Superconductors

We carry out Monte Carlo simulations of the uniformly frustrated 3d XY model as a model for vortex line fluctuations in a high Tc superconductor. A density of vortex lines of f=1/25 is considered. We find two sharp phase transitions. The low T phase is an ordered vortex line lattice. The high T normal phase is a vortex line liquid with much entangling, cutting, and loop excitations. An intermediate phase is found which is characterized as a vortex line liquid of disentangled lines. In this phase, the system displays superconducting properties in the direction parallel to the magnetic field, but normal behavior in planes perpendicular to the magnetic field.Comment: 38 pages, LaTeX 15 figures (upon request to [email protected]

The glycolytic enzyme PFKFB3 determines bone marrow endothelial progenitor cell damage after chemotherapy and irradiation

Bone marrow (BM) endothelial progenitor cell (EPC) damage of unknown mechanism delays the repair of endothelial cells (EC) and recovery of hematopoiesis after chemo-radiotherapy. We found increased levels of the glycolytic enzyme PFKFB3 in the damaged BM EPC of patients with poor graft function, a clinical model of EPC damage-associated poor hematopoiesis after allogeneic hematopoietic stem cell transplantation. Moreover, in vitro the glycolysis inhibitor 3-(3-pyridinyl)- 1-(4-pyridinyl)-2-propen-1-one (3PO) alleviated the damaged BM EPC from patients with poor graft function. Consistently, PFKFB3 overexpression triggered BM EPC damage after 5-fluorouracil treatment and impaired hematopoiesis-supporting ability in vitro. Mechanistically, PFKFB3 facilitated pro-apoptotic transcription factor FOXO3A and expression of its downstream genes, including p21, p27, and FAS, after 5-fluorouracil treatment in vitro. Moreover, PFKFB3 induced activation of NF-κB and expression of its downstream adhesion molecule E-selectin, while it reduced hematopoietic factor SDF-1 expression, which could be rescued by FOXO3A silencing. High expression of PFKFB3 was found in damaged BM EC of murine models of chemo-radiotherapy-induced myelosuppression. Furthermore, a murine model of BM EC-specific PFKFB3 overexpression demonstrated that PFKFB3 aggravated BM EC damage, and impaired the recovery of hematopoiesis after chemotherapy in vivo, effects which could be mitigated by 3PO, indicating a critical role of PFKFB3 in regulating BM EC damage. Clinically, PFKFB3-induced FOXO3A expression and NF-κB activation were confirmed to contribute to the damaged BM EPC of patients with acute leukemia after chemotherapy. 3PO repaired the damaged BM EPC by reducing FOXO3A expression and phospho-NF-κB p65 in patients after chemotherapy. In summary, our results reveal a critical role of PFKFB3 in triggering BM EPC damage and indicate that endothelial-PFKFB3 may be a potential therapeutic target for myelosuppressive injury

Pairing symmetry and properties of iron-based high temperature superconductors

Pairing symmetry is important to indentify the pairing mechanism. The analysis becomes particularly timely and important for the newly discovered iron-based multi-orbital superconductors. From group theory point of view we classified all pairing matrices (in the orbital space) that carry irreducible representations of the system. The quasiparticle gap falls into three categories: full, nodal and gapless. The nodal-gap states show conventional Volovik effect even for on-site pairing. The gapless states are odd in orbital space, have a negative superfluid density and are therefore unstable. In connection to experiments we proposed possible pairing states and implications for the pairing mechanism.Comment: 4 pages, 1 table, 2 figures, polished versio