TGF-β and RAS jointly unmask primed enhancers to drive metastasis.

Epithelial-to-mesenchymal transitions (EMTs) and extracellular matrix (ECM) remodeling are distinct yet important processes during carcinoma invasion and metastasis. Transforming growth factor β (TGF-β) and RAS, signaling through SMAD and RAS-responsive element-binding protein 1 (RREB1), jointly trigger expression of EMT and fibrogenic factors as two discrete arms of a common transcriptional response in carcinoma cells. Here, we demonstrate that both arms come together to form a program for lung adenocarcinoma metastasis and identify chromatin determinants tying the expression of the constituent genes to TGF-β and RAS inputs.

TPPU_DSF: A Web Application to Calculate Thermodynamic Parameters Using DSF Data.

Here we present TPPU_DSF (https://maciasnmr.net/tppu_dsf/). This is a free and open-source web application that opens, converts, fits, and calculates the thermodynamic parameters of protein unfolding from standard differential scanning fluorimetry (DSF) data in an automated manner.

HTSDSF Explorer, A Novel Tool to Analyze High-throughput DSF Screenings.

The identification of new drugs for novel therapeutic targets requires the screening of libraries containing tens of thousands of compounds. While experimental screenings are assisted by high-throughput technologies, in target-based biophysical assays, such as differential scanning fluorimetry (DSF), the analysis steps must be calculated manually, often combining several software packages. To simplify the determination of the melting temperature (T) of the target and the change induced by ligand binding (ΔT), we developed the HTSDSF explorer, a versatile, all-in-one, user-friendly application suite.

Preparing Graduate Students for Community Engagement in Health Services Research.

The purpose of this paper is to shed light on the importance of didactic and experiential training in community engagement for students conducting Health Services Research (HSR) in pharmacy. The incorporation of community-based learning (CBL) courses can be beneficial for graduate students because they provide an opportunity to gain important skills in stakeholder engagement and developing sustainable research partnerships. Early exposure and mentorship of graduate students through CBL courses could minimize the risk of students entering communities in their future careers with harmful tactics such as stereotypes and implicit biases.

Unveiling the dimer/monomer propensities of Smad MH1-DNA complexes.

Smad transcription factors are the main downstream effectors of the Transforming growth factor β superfamily (TGFβ) signalling network. The DNA complexes determined here by X-ray crystallography for the Bone Morphogenetic Proteins (BMP) activated Smad5 and Smad8 proteins reveal that all MH1 domains bind [GGC(GC)|(CG)] motifs similarly, although TGFβ-activated Smad2/3 and Smad4 MH1 domains bind as monomers whereas Smad1/5/8 form helix-swapped dimers. Dimers and monomers are also present in solution, as revealed by NMR.

Clozapine and desmethylclozapine: correlation with neutrophils and leucocytes counting in Mexican patients with schizophrenia.

Purpose: The aim of present study is to measure plasma clozapine (CLZ) and N-desmethyl clozapine (DMC) as biomarkers to correlate drug concentrations with the appearance of preclinical adverse hematic effects.

Methods: A high-performance liquid chromatographic method, using a diode-array (ultraviolet) detector, was validated to obtain reliable concentrations of CLZ and DMC, its main metabolite, in plasma of 41 schizophrenic patients taking CLZ. Blood neutrophils and leucocytes counting were concurrently assessed as a proxy to subclinical adverse reactions.

Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-β signaling.

TGF-β receptors phosphorylate SMAD2 and SMAD3 transcription factors, which then form heterotrimeric complexes with SMAD4 and cooperate with context-specific transcription factors to activate target genes. Here we provide biochemical and structural evidence showing that binding of SMAD2 to DNA depends on the conformation of the E3 insert, a structural element unique to SMAD2 and previously thought to render SMAD2 unable to bind DNA. Based on this finding, we further delineate TGF-β signal transduction by defining distinct roles for SMAD2 and SMAD3 with the forkhead pioneer factor FOXH1 as a partner in the regulation of differentiation genes in mouse mesendoderm precursors.

TGIF1 homeodomain interacts with Smad MH1 domain and represses TGF-β signaling.

TGIF1 is a multifunctional protein that represses TGF-β-activated transcription by interacting with Smad2-Smad4 complexes. We found that the complex structure of TGIF1-HD bound to the TGACA motif revealed a combined binding mode that involves the HD core and the major groove, on the one hand, and the amino-terminal (N-term) arm and the minor groove of the DNA, on the other. We also show that TGIF1-HD interacts with the MH1 domain of Smad proteins, thereby indicating that TGIF1-HD is also a protein-binding domain.

Ultrastructural changes and immunolocalization of P-selectin in platelets from patients with major depression.

Depression is considered an important risk factor in patients with cardiovascular disease (CVD). Although the biological mechanism is unknown, it has been suggested that hyperactivity of platelets may have an important role in the onset and evolution of cardiovascular damage. The goals of this study were to evaluate by transmission electron microscopy and immunohistochemistry the presence of ultra-structural variations in platelets from individuals with recent diagnosis of major depression disease (MDD, patients without previous anti-depressant treatment and from healthy control subjects.

Auditory brainstem responses as a clinical evaluation tool in children after perinatal encephalopathy.

Unlabelled: Auditory brainstem responses (ABR) reveals the neurophysiological status of the neural axis. In this study we compared the ABR of healthy children, under 1-year-old, with children who suffered from perinatal encephalopathy (PE).

Objective: The purpose of this study was to characterize the ABR differences between children with PE and healthy children in order to identify groups with specific neurophysiological profiles, associated with their neurological condition.

Methodologic pitfalls in measurement of 5-hydroxytriptamine uptake transporters in human platelets by [3H]-paroxetine binding assay.

Background: Studies in platelet of 5-HT uptake transporters have been performed using binding assay methodology designed for ligand-receptor interactions; however, uptake transporters present requirements that may question the validity of these particular binding assays.

Methods: To explore methodologic aspects that may be crucial to the validity of these assays, we studied the binding of [3H]-paroxetine to platelet membranes of healthy subjects under different conditions of time, temperature, and protein concentrations.

Results: A correlation between protein concentration in incubation media and percentage of specific binding of [3H]-paroxetine was found: the lower the protein concentrations (10 and 20 microg/mL) in incubation media, the lower the percentage of specific [3H]-paroxetine binding.

[Proposal of a model of a mental system based on mental functions].

Based on the mental functions according to classical physiological criteria, the authors propose an information management system with heuristical value for Psychiatry. This system assumes that information will be received by the sensoperceptual area, being analyzed within both the cognitive and affective areas later on, the analysis output thus taking place through the psychomotor area. Such a system allows a theoretical structure -correlating some aspects of Neurosciences with psychiatric clinical events, to be elaborated.

High affinity uptake and Ca2+-dependent release of glutamic acid in the developing cerebellum.

This study was undertaken in order to evaluate the postulated role of glutamic acid as the neurotransmitter for the parallel fibers of the cerebellar cortex. We studied the Ca2+-dependent release and the high affinity uptake of glutamic acid in the developing cerebellum. The Ca2+-dependent release of glutamic acid from cerebellar molecular layer during development closely follows the time course of parallel fibers synaptogenesis.