Corticotropin releasing factor neurons in the visual cortex mediate long-term changes in visual function induced by early adversity.

Early adversity can cause malfunction of the visual system in adulthood. Adult female but not male mice undergoing early chronic mild stress (ECMS) maintain ocular dominance (OD) plasticity after the critical period. How early stressful experiences have a long-term impact on it is largely unknown. Here, we observed a wide distribution of corticotropin-releasing factor (CRF)-positive neurons, which mainly colocalized with a subpopulation of GABAergic interneurons in the mouse primary visual cortex (V1). Optogenetic activation of CRF-positive neurons transfected with AAV-ChR2 evoked inhibitory currents in nearby pyramidal cells. ECMS induced a reduction in the expression of CRF mRNA in adult mouse V1. Chemogenetic activation of V1 CRF neurons impaired OD plasticity in adult ECMS females. We further showed that local administration of the corticotropin releasing factor receptor 1 (CRFR1) antagonist via an osmotic minipump into the visual cortex mimicked OD plasticity in adult ECMS females. Whole-cell recording in layer 2/3 pyramidal neurons revealed that the CRFR1 antagonist reduced the short-term depression (STD) of evoked inhibitory postsynaptic current (IPSC) in females but not in males. Likewise, CRF agonists have the opposite effect. In summary, our findings indicate that the local CRF-CRFR1 system within V1 may mediate the long-term and sex-dependent effect of early stress experiences on visual plasticity and provide a target for the prevention of visual deficits in adults with a history of early-life adversity.

Identification of potential SLA-I-restricted CTL epitopes within the M protein of porcine reproductive and respiratory syndrome virus.

CD8+ cytotoxic T lymphocytes (CTLs), are essential for clearance of porcine reproductive and respiratory syndrome virus (PRRSV) infection and regulation of host immune responses. Identification of SLA I-restricted CD8+ CTL epitopes would facilitate PRRSV vaccine development. Here, cells isolated from peripheral blood mononuclear cells (PBMCs) of PRRSV-immunized Large White pigs (JXA1-R strain) were screened for immunodominant PRRSV-2 M protein T cell epitopes via ELISPOT assay. Of nine immunodominant epitopes detected, eight elicited significant IFN-γ secretion responses that varied among individual pigs and according to epitope. To predict which epitopes harbored potential CTL epitopes, swine leukocyte antigen (SLA) class I genes of Large White pigs were cloned and sequenced, yielding fourteen distinct SLA class I gene sequences. Based on ELISPOT and SLA genotyping results, SLA-restricted binding of the fourteen predicted class I proteins to peptides derived from the eight immunodominant epitopes were predicted in-silico. After evaluation of 42 pET-peptide-SLA-I-ß2m complexes containing predicted restricted peptides, extracellular SLA class I domains and ß2m, ELISA testing of 33 peptide-SLA-I-ß2m complexes detected four complexed peptides. These four peptides were evaluated using in vitro complex refolding assays that confirmed that M2-5 and M6-1 peptides each formed complexes with SLA-2*0502 and sß2m, while M9-1 formed a complex with SLA-2*1201 and sß2m. ELISPOT results confirmed these three 9-mer potential CTL epitopes efficiently stimulated IFN-γ secretion when presented by SLA class I molecules specified here. This study describes effective CTL epitope identification methods for use in future investigations of swine cellular immunity toward T cell-based vaccine development.

Factors related to lithium blood concentrations in Chinese Han patients with bipolar disorder.

Background: The goal of this study was to identify the physiological factors related to the blood concentration of lithium in Chinese Han patients with bipolar disorder (BD). Materials and methods: A total of 186 Chinese Han patients with BD were assessed. Patients were recruited from the Anhui Mental Health Center. The concentrations of serum lithium were measured by a Dimension RxL Max biochemistry analyzer. Physiological factors, including body weight, body mass index (BMI), and routine laboratory parameters, were collected. Relationships between the serum lithium concentration and relevant clinical data were analyzed by Pearson correlation tests, and the independent relationships were determined by multivariate linear regression analysis. Results: Pearson correlation analysis showed that serum lithium concentrations were positively correlated with creatinine concentrations (r=0.147, P=0.046), Mg2+ concentrations (r=0.151, P=0.04), and the percentage of neutrophils (r=0.178, P=0.015) and negatively correlated with high-density lipoprotein (HDL) concentrations (r=-0.142, P=0.05), apolipoprotein A1 concentrations (r=-0.169, P=0.02), and Na+ concentrations (r=-0.148, P=0.046) in 186 patients with BD. Furthermore, multivariate linear regression analysis showed that serum lithium concentrations were negatively associated with Na+ concentrations and positively associated with the percentage of neutrophils. Conclusion: These results suggest that physiological factors, including creatinine, HDL, apolipoprotein A1, Na+, and Mg2+ concentrations and percentage of neutrophils, might be related to serum lithium concentrations and provide a basis for parameter selection of lithium population pharmacokinetics in Chinese Han patients with BD.

MicroRNA-Based Biomarkers in the Diagnosis and Monitoring of Therapeutic Response in Patients with Depression.

Depression is a debilitating mental illness that affects up to 120 million people worldwide; it is currently determined based on subjective diagnostic schemes that are limited by high uncertainty. Hence, there is an urgent need to identify effective and reliable biomarkers to increase diagnostic accuracy. MicroRNAs (miRNAs) constitute a recently discovered class of non-coding RNAs that play a key role in the regulation of gene expression by modulating translation, messenger RNA (mRNA) degradation, or stability of mRNA targets. Dysregulated expression of miRNAs is being investigated as a clinical biomarker for a variety of diseases, including depression. Accumulating evidence has shown that miRNAs participate in many aspects of neural plasticity, neurogenesis, and the stress response. This is supported by more direct studies based on human postmortem brain tissue that strongly indicate that miRNAs not only play a key role in the pathogenesis of major depressive disorder, but also present potential for the development of therapeutic targets. miRNAs in the peripheral and central nervous system are being considered as potential biomarkers in the diagnosis of depression and in monitoring the therapeutic response to antidepressants, owing to their stability, tissue-specificity, and disease-specific expression. In this review, we focus on various miRNAs in tissues and fluids that could be employed as diagnostic and therapeutic biomarkers in patients with depression.

Stretchy and strong polyurethane-urea supramolecular (PUUS) hydrogels with various stimulus-responsive behaviours: the effect of chain-extenders.

The development of an easy synthetic strategy combined with straightforward tailoring of physical properties and functionalities, such that optimal performance can be targeted for various applications, still remains challenging. Previously, we reported the construction of thermo- and water-responsive strong and tough supramolecular hydrogels based on the cooperatively enhancing effect between H-bonding and hydrophobic forces. Recently, the strategy was greatly simplified to a one-pot two-step approach. In this work, by simply changing the chain extenders used in the second step, different kinds of functional units are easily introduced into the hard segments in the main chain of the copolymers to endow the resultant strong and tough supramolecular hydrogels with various stimulus-responsive properties. A dynamic covalent bond (disulphide or imine bond, e.g.-S-S- or -C[double bond, length as m-dash]N-) in the main chain provides the resulting hydrogels with reduction or pH responsive degradation (gel-to-sol transition) on demand behaviors, respectively; the azobenzene unit endows the yielding hydrogels with UV-Vis controlled stiffness; the pyridine group containing supramolecular hydrogel shows metal ion responsive mechanical and fluorescent behavior. These results provide progress toward addressing the challenges of achieving structural and synthetic simplicity married with sophisticated functionalities.