Sphingosine 1-phosphate-regulated transcriptomes in heterogenous arterial and lymphatic endothelium of the aorta.

Despite the medical importance of G protein-coupled receptors (GPCRs), in vivo cellular heterogeneity of GPCR signaling and downstream transcriptional responses are not understood. We report the comprehensive characterization of transcriptomes (bulk and single-cell) and chromatin domains regulated by sphingosine 1-phosphate receptor-1 (S1PR1) in adult mouse aortic endothelial cells. First, S1PR1 regulates NFκB and nuclear glucocorticoid receptor pathways to suppress inflammation-related mRNAs.

Opposite Control of Excitatory and Inhibitory Synapse Formation by Slitrk2 and Slitrk5 on Dopamine Neurons Modulates Hyperactivity Behavior.

The neurodevelopmental origin of hyperactivity disorder has been suggested to involve the dopaminergic system, but the underlying mechanisms are still unknown. Here, transcription factors Lmx1a and Lmx1b are shown to be essential for midbrain dopaminergic (mDA) neuron excitatory synaptic inputs and dendritic development. Strikingly, conditional knockout (cKO) of Lmx1a/b in postmitotic mDA neurons results in marked hyperactivity.

Hydration free energies and solvation structures with molecular density functional theory in the hypernetted chain approximation.

The capability of molecular density functional theory in its lowest, second-order approximation, equivalent to the hypernetted chain approximation in integral equations, to predict accurately the hydration free-energies and microscopic structure of molecular solutes is explored for a variety of systems: spherical hydrophobic solutes, ions, water as a solute, and the Mobley's dataset of organic molecules. The successes and the caveats of the approach are carefully pinpointed. Compared to molecular simulations with the same force field and the same fixed solute geometries, the theory describes accurately the solvation of cations, less so that of anions or generally H-bond acceptors.

Sphingosine 1-Phosphate Receptor Signaling Establishes AP-1 Gradients to Allow for Retinal Endothelial Cell Specialization.

Transcriptional mechanisms that drive angiogenesis and organotypic vascular endothelial cell specialization are poorly understood. Here, we show that retinal endothelial sphingosine 1-phosphate receptors (S1PRs), which restrain vascular endothelial growth factor (VEGF)-induced angiogenesis, spatially restrict expression of JunB, a member of the activator protein 1 (AP-1) family of transcription factors (TFs). Mechanistically, VEGF induces JunB expression at the sprouting vascular front while S1PR-dependent vascular endothelial (VE)-cadherin assembly suppresses JunB expression in the nascent vascular network, thus creating a gradient of this TF.

Lipoconstruct surface topography grating size influences vascularization onset in the dorsal skinfold chamber model.

After skin tissue injury or pathological removal, vascularization timing is paramount in graft survival. As full thickness skin grafts often fail to become perfused over larger surfaces, split-thickness grafts are preferred and can be used together with biomaterials, which themselves are non-angiogenic. One way of promoting vascular ingrowth is to "pre-vascularize" an engineered substitute by introducing endothelial cells (ECs).

Structure Factor of EuCl Aqueous Solutions via Coupled Molecular Dynamics Simulations and Integral Equations.

Identifying the structure of an aqueous solution is essential to rationalize various phenomena such as crystallization in solution, chemical reactivity, extraction of rare earth elements, and so forth. Despite this, the efforts to describe the structure of an aqueous solution have been hindered by the difficulty to retrieve structural data both from experiments and simulations. To overcome this, first, undersaturated EuCl aqueous solutions of concentrations varying from 0.

KCC2 antagonism and gabaergic synchronization in the entorhinal cortex in the absence of ionotropic glutamatergic receptor signalling.

γ-Aminobutyric acid (GABA), which is released by interneurons, plays an active role in generating interictal epileptiform spikes during blockade of ionotropic glutamatergic signalling, but it remains unclear whether and how the K-Cl cotransporter 2 (KCC2) influences these paroxysmal events. Therefore, we employed tetrode recordings in the in vitro rat entorhinal cortex (EC) to analyze the effects of the KCC2 antagonist VU0463271 on 4-aminopyridine (4AP)-induced interictal spikes that were pharmacologically isolated by applying ionotropic glutamatergic receptor antagonists. After the addition of VU0463271, these interictal spikes continued to occur at similar rates as in control (i.

The Quebec Parkinson Network: A Researcher-Patient Matching Platform and Multimodal Biorepository.

Background: Genetic, biologic and clinical data suggest that Parkinson's disease (PD) is an umbrella for multiple disorders with clinical and pathological overlap, yet with different underlying mechanisms. To better understand these and to move towards neuroprotective treatment, we have established the Quebec Parkinson Network (QPN), an open-access patient registry, and data and bio-samples repository.

Objective: To present the QPN and to perform preliminary analysis of the QPN data.

Asthma Medication Use in Congenital Diaphragmatic Hernia Survivors: A Retrospective Population Level Data Analysis.

Introduction:  The purpose of this study was to determine if congenital diaphragmatic hernia (CDH) survivors had worse long-term respiratory outcomes compared with age-matched controls, as measured by inhaled bronchodilator use, inhaled steroid use, and asthma-related physician visits.

Materials And Methods:  We performed a retrospective case-control study of infants with isolated CDH from 1991 to 2013. The primary outcome measures were inhaled bronchodilator prescriptions, inhaled steroid prescriptions, and asthma-related physician visits between 0 and 5 years of age and between 5 and 10 years of age.

Effects of Diazepam and Ketamine on Pilocarpine-Induced Status Epilepticus in Mice.

Status epilepticus (SE) is a life-threatening condition needing immediate care to prevent brain damage. SE with electrographic and behavioral features similar to those seen in humans is reproduced in rodents by i.p.

Inhibition of p38/MK2 Signaling Prevents Vascular Invasion of Melanoma.

Melanoma cells can switch between distinct gene expression profiles, resulting in proliferative or invasive phenotypes. Signaling pathways involved in this switch were analyzed by gene expression profiling of a cohort of 22 patient-derived melanoma cell lines. CDH1 negativity was identified as a surrogate marker for the invasive phenotype.

Nonepileptic, Stereotypical, and Intermittent Symptoms (NESIS) in Patients With Subdural Hematoma: Proposal for a New Clinical Entity With Therapeutic and Prognostic Implications.

Background: Transient neurological symptoms (TNS) are frequent in patients with subdural hematomas (SDH) and many will receive a diagnosis of epilepsy despite a negative workup.

Objective: To explore if patients with TNS and a negative epilepsy workup (cases) evolved differently than those with a positive EEG (controls), which would suggest the existence of alternative etiologies for TNS.

Methods: We performed a single-center, retrospective, case-control study of patients with TNS post-SDH.

A genome-wide CRISPR screen identifies FBXO42 involvement in resistance toward MEK inhibition in NRAS-mutant melanoma.

NRAS mutations are the most common alterations among RAS isoforms in cutaneous melanoma, with patients harboring these aggressive tumors having a poor prognosis and low survival rate. The main line of treatment for these patients is MAPK pathway-targeted therapies, such as MEK inhibitors, but, unfortunately, the response to these inhibitors is variable due to tumor resistance. Identifying genetic modifiers involved in resistance toward MEK-targeted therapy may assist in the development of new therapeutic strategies, enhancing treatment response and patient survival.

Lattice Boltzmann electrokinetics simulation of nanocapacitors.

We propose a method to model metallic surfaces in Lattice Boltzmann Electrokinetics (LBE) simulations, a lattice-based algorithm rooted in kinetic theory which captures the coupled solvent and ion dynamics in electrolyte solutions. This is achieved by a simple rule to impose electrostatic boundary conditions in a consistent way with the location of the hydrodynamic interface for stick boundary conditions. The proposed method also provides the local charge induced on the electrode by the instantaneous distribution of ions under voltage.

Morpho-Molecular Assessment Indicates New Prognostic Aspects and Personalized Therapeutic Options in Sinonasal Melanoma.

Sinonasal melanoma is a rare subtype of melanoma and little is known about its molecular fingerprint. Systemic treatment options are limited, as targetable mutations are rare compared to cutaneous melanoma. Currently, metastatic sinonasal melanoma is being treated according to the guidelines of cutaneous melanoma.

Contrasting resistance and resilience to extreme drought and late spring frost in five major European tree species.

Extreme climate events (ECEs) such as severe droughts, heat waves, and late spring frosts are rare but exert a paramount role in shaping tree species distributions. The frequency of such ECEs is expected to increase with climate warming, threatening the sustainability of temperate forests. Here, we analyzed 2,844 tree-ring width series of five dominant European tree species from 104 Swiss sites ranging from 400 to 2,200 m a.

Paradoxical effects of optogenetic stimulation in mesial temporal lobe epilepsy.

Objective: To establish the effects induced by long-term, unilateral stimulation of parvalbumin (PV)-positive interneurons on seizures, interictal spikes, and high-frequency oscillations (80-500Hz) occurring after pilocarpine-induced status epilepticus (SE)-a proven model of mesial temporal lobe epilepsy (MTLE)-in transgenic mice expressing or not expressing ChR2.

Methods: PV-ChR2 (n = 6) and PV-Cre (n = 6) mice were treated with pilocarpine to induce SE. Three hours after SE onset, unilateral optogenetic stimulation (450nm, 25mW, 20-millisecond pulses delivered at 8Hz for 30 seconds every 2 minutes) of CA3 PV-positive interneurons was implemented for 14 continuous days in both groups.

A Fatty Acid Oxidation-dependent Metabolic Shift Regulates the Adaptation of -mutated Melanoma to MAPK Inhibitors.

Purpose: Treatment of -mutant melanomas with MAPK inhibitors (MAPKi) results in significant tumor regression, but acquired resistance is pervasive. To understand nonmutational mechanisms underlying the adaptation to MAPKi and to identify novel vulnerabilities of melanomas treated with MAPKi, we focused on the initial response phase during treatment with MAPKi.

Experimental Design: By screening proteins expressed on the cell surface of melanoma cells, we identified the fatty acid transporter CD36 as the most consistently upregulated protein upon short-term treatment with MAPKi.

KCC2 antagonism increases neuronal network excitability but disrupts ictogenesis in vitro.

The potassium-chloride cotransporter 2 (KCC2) plays a role in epileptiform synchronization, but it remains unclear how it influences such a process. Here, we used tetrode recordings in the in vitro rat entorhinal cortex (EC) to analyze the effects of the KCC2 antagonist VU0463271 on 4-aminopyridine (4AP)-induced ictal and interictal activity. During 4AP application, ictal events were associated with significant increases in interneurons and principal cells activities.

Piriform cortex ictogenicity in vitro.

The piriform cortex is recognized to play critical roles in focal ictogenesis, both in animal models and in humans. We review here the contribution of in vitro studies performed on rodent brain tissue that were aimed at understanding the ictogenic properties of the piriform cortex and the contiguous olfactory areas. During in vitro experiments, epileptiform events can be easily generated in the piriform area by diverse pro-convulsive drugs (4-aminopyridine, bicuculline, picrotoxin) or by electrical stimulation.

Osteoblasts contribute to a protective niche that supports melanoma cell proliferation and survival.

Melanoma is the deadliest form of skin cancer; a primary driver of this high level of morbidity is the propensity of melanoma cells to metastasize. When malignant tumours develop distant metastatic lesions the new local tissue niche is known to impact on the biology of the cancer cells. However, little is known about how different metastatic tissue sites impact on frontline targeted therapies.

Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets.

Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2.

Proteomic identification of a marker signature for MAPKi resistance in melanoma.

MAPK inhibitors (MAPKi) show outstanding clinical response rates in melanoma patients harbouring BRAF mutations, but resistance is common. The ability of melanoma cells to switch from melanocytic to mesenchymal phenotypes appears to be associated with therapeutic resistance. High-throughput, subcellular proteome analyses and RNAseq on two panels of primary melanoma cells that were either sensitive or resistant to MAPKi revealed that only 15 proteins were sufficient to distinguish between these phenotypes.