Caspersenbuhl2869

Autism spectrum disorders (ASD) are highly heritable neurodevelopmental disorders with significant genetic heterogeneity. Noncoding microRNAs (miRNAs) are recognised as playing key roles in development of ASD albeit the function of these regulatory genes remains unclear. We previously conducted whole-exome sequencing of Australian families with ASD and identified four novel single nucleotide variations in mature miRNA sequences. A pull-down transcriptome analysis using transfected SH-SY5Y cells proposed a mechanistic model to examine changes in binding affinity associated with a unique mutation found in the conserved 'seed' region of miR-873-5p (rs777143952 T > A). Results suggested several ASD-risk genes were differentially targeted by wild-type and mutant miR-873 variants. In the current study, a dual-luciferase reporter assay confirmed miR-873 variants have a 20-30% inhibition/dysregulation effect on candidate autism risk genes ARID1B, SHANK3 and NRXN2 and also confirmed the affected expression with qPCR. In vitro mouse hippocampal neurons transfected with mutant miR-873 showed less morphological complexity and enhanced sodium currents and excitatory neurotransmission compared to cells transfected with wild-type miR-873. A second in vitro study showed CRISPR/Cas9 miR-873 disrupted SH-SY5Y neuroblastoma cells acquired a neuronal-like morphology and increased expression of ASD important genes ARID1B, SHANK3, ADNP2, ANK2 and CHD8. These results represent the first functional evidence that miR-873 regulates key neural genes involved in development and cell differentiation.We present comboFM, a machine learning framework for predicting the responses of drug combinations in pre-clinical studies, such as those based on cell lines or patient-derived cells. comboFM models the cell context-specific drug interactions through higher-order tensors, and efficiently learns latent factors of the tensor using powerful factorization machines. The approach enables comboFM to leverage information from previous experiments performed on similar drugs and cells when predicting responses of new combinations in so far untested cells; thereby, it achieves highly accurate predictions despite sparsely populated data tensors. We demonstrate high predictive performance of comboFM in various prediction scenarios using data from cancer cell line pharmacogenomic screens. Subsequent experimental validation of a set of previously untested drug combinations further supports the practical and robust applicability of comboFM. For instance, we confirm a novel synergy between anaplastic lymphoma kinase (ALK) inhibitor crizotinib and proteasome inhibitor bortezomib in lymphoma cells. Overall, our results demonstrate that comboFM provides an effective means for systematic pre-screening of drug combinations to support precision oncology applications.About a thousand genes in the human genome encode for membrane transporters. Among these, several solute carrier proteins (SLCs), representing the largest group of transporters, are still orphan and lack functional characterization. We reasoned that assessing genetic interactions among SLCs may be an efficient way to obtain functional information allowing their deorphanization. Here we describe a network of strong genetic interactions indicating a contribution to mitochondrial respiration and redox metabolism for SLC25A51/MCART1, an uncharacterized member of the SLC25 family of transporters. Through a combination of metabolomics, genomics and genetics approaches, we demonstrate a role for SLC25A51 as enabler of mitochondrial import of NAD, showcasing the potential of genetic interaction-driven functional gene deorphanization.Forests are critical for stabilizing our climate, but costs of mitigation over space, time, and stakeholder group remain uncertain. Using the Global Timber Model, we project mitigation potential and costs for four abatement activities across 16 regions for carbon price scenarios of $5-$100/tCO2. We project 0.6-6.0 GtCO2 yr-1 in global mitigation by 2055 at costs of 2-393 billion USD yr-1, with avoided tropical deforestation comprising 30-54% of total mitigation. Higher prices incentivize larger mitigation proportions via rotation and forest management activities in temperate and boreal biomes. Forest area increases 415-875 Mha relative to the baseline by 2055 at prices $35-$100/tCO2, with intensive plantations comprising less then 7% of this increase. Mitigation costs borne by private land managers comprise less than one-quarter of total costs. For forests to contribute ~10% of mitigation needed to limit global warming to 1.5 °C, carbon prices will need to reach $281/tCO2 in 2055.Lung cancer is the fastest growth rate of morbidity and mortality in nearly a decade, and remains difficult to treat. Furthermore, the molecular mechanisms underlying its development are still unclear. In this study, bioinformatics analysis showed that MELK was highly expressed in lung cancer and negatively correlated to the survival of lung adenocarcinoma (LUAD). WAY-309236-A cell line Immunohistochemistry analysis of LUAD patient tissues revealed there were a high level of MELK expression in LUAD. Knockdown of MELK expression inhibits the migration and invasion of LUAD cells, which may be mediated by Twist1, Slug, MMP7, and N-catenin. Overexpression of MELK promoted the growth of LUAD cells in medium, 3D Matrigel, and nude mice. Inhibition of MELK by OTSSP167 arrested cycle of LUAD cells at G2/M phase via PLK1-CDC25C-CDK1 pathway, and triggered apoptosis-mediated pyroptosis. Together, these data indicate that MELK is critical for metastasis, mitotic progression, and programmed death of LUAD and may be a promising therapeutic target for LUAD.BACKGROUND Radiofrequency ablation (RFA) is the criterion standard treatment for patients with atrioventricular nodal reentrant tachycardia (AVNRT). Knowledge about RFA in patients with dextrocardia and situs inversus is limited due to their rare incidence and complexity. The incidence of dextrocardia is reported to be 1 in 12 000 births, with situs inversus occurring in one-third of the cases. The incidence of congenital heart disease is about 5% in these patients. However, data on rhythm and conduction disorders in this group of patients are currently limited, making management more difficult owing to their individual anatomy. CASE REPORT We report the case of an obese 21-year-old man with complex congenital heart disease (CCHD) (situs inversus dextrocardia, pulmonary atresia, single ventricle, common atrium with single atrioventricular valve), asplenia, and multiple cardiac-corrective surgeries (Fontan repair, bidirectional Glenn anastomosis, and Blalock-Taussig shunt) who underwent successful RFA of recurrent supraventricular tachycardia.