Serum from Older Adults Increases Apoptosis and Molecular Aging Markers in Human Hippocampal Progenitor Cells.

Age-related alteration in neural stem cell function is linked to neurodegenerative conditions and cognitive decline. In rodents, this can be reversed by exposure to a young systemic milieu and conversely, the old milieu can inhibit stem cell function in young rodents. In this study, we investigated the effect of the human systemic milieu on human hippocampal progenitor cells (HPCs) using human serum from early adulthood, mid-life and older age.

Distinct Effects of Heparin and Interleukin-4 Functionalization on Macrophage Polarization and In Situ Arterial Tissue Regeneration Using Resorbable Supramolecular Vascular Grafts in Rats.

Two of the greatest challenges for successful application of small-diameter in situ tissue-engineered vascular grafts are 1) preventing thrombus formation and 2) harnessing the inflammatory response to the graft to guide functional tissue regeneration. This study evaluates the in vivo performance of electrospun resorbable elastomeric vascular grafts, dual-functionalized with anti-thrombogenic heparin (hep) and anti-inflammatory interleukin 4 (IL-4) using a supramolecular approach. The regenerative capacity of IL-4/hep, hep-only, and bare grafts is investigated as interposition graft in the rat abdominal aorta, with follow-up at key timepoints in the healing cascade (1, 3, 7 days, and 3 months).

Aging biological markers in a cohort of antipsychotic-naïve first-episode psychosis patients.

Schizophrenia is a severe and multifactorial disorder with an unknown causative pathophysiology. Abnormalities in neurodevelopmental and aging processes have been reported. Relative telomere length (RTL) and DNA methylation age (DMA), well-known biomarkers for estimating biological age, are both commonly altered in patients with schizophrenia compared to healthy controls.

A Supramolecular Platform for the Introduction of Fc-Fusion Bioactive Proteins on Biomaterial Surfaces.

Bioorthogonal chemistry is an excellent method for functionalization of biomaterials with bioactive molecules, as it allows for decoupling of material processing and bioactivation. Here, we report on a modular system created by means of tetrazine/-cyclooctene (Tz/TCO) click chemistry undergoing an inverse electron demand Diels-Alder cycloaddition. A reactive supramolecular surface based on ureido-pyrimidinones (UPy) is generated via a UPy-Tz additive, in order to introduce a versatile TCO-protein G conjugate for immobilization of Fc-fusion proteins.

Transcriptomic abnormalities in peripheral blood in bipolar disorder, and discrimination of the major psychoses.

We performed a transcriptome-wide meta-analysis and gene co-expression network analysis to identify genes and gene networks dysregulated in the peripheral blood of bipolar disorder (BD) cases relative to unaffected comparison subjects, and determined the specificity of the transcriptomic signatures of BD and schizophrenia (SZ). Nineteen genes and 4 gene modules were significantly differentially expressed in BD cases. Thirteen gene modules were shown to be differentially expressed in a combined case-group of BD and SZ subjects called "major psychosis", including genes biologically linked to apoptosis, reactive oxygen, chromatin remodeling, and immune signaling.

Genome-wide Burden of Rare Short Deletions Is Enriched in Major Depressive Disorder in Four Cohorts.

Background: Major depressive disorder (MDD) is moderately heritable, with a high prevalence and a presumed high heterogeneity. Copy number variants (CNVs) could contribute to the heritable component of risk, but the two previous genome-wide association studies of rare CNVs did not report significant findings.

Methods: In this meta-analysis of four cohorts (5780 patients and 6626 control subjects), we analyzed the association of MDD to 1) genome-wide burden of rare deletions and duplications, partitioned by length (<100 kb or >100 kb) and other characteristics, and 2) individual rare exonic CNVs and CNV regions.

Gene expression over the course of schizophrenia: from clinical high-risk for psychosis to chronic stages.

The study of patients with schizophrenia (SZ) at different clinical stages may help clarify what effects could be due to the disease itself, to the pharmacological treatment, or to the disease progression. We compared expression levels of targeted genes in blood from individuals in different stages of SZ: clinical high risk for psychosis (CHR), first episode of psychosis (FEP), and chronic SZ (CSZ). Then, we further verified whether single-nucleotide polymorphisms (SNPs) could be related to gene expression differences.

Liprin alfa 2 gene expression is increased by cannabis use and associated with neuropsychological function.

The relation of heavy cannabis use with decreased neuropsychological function has frequently been described but the underlying biological mechanisms are still largely unknown. This study investigates the relation of cannabis use with genome wide gene expression and subsequently examines the relations with neuropsychological function. Genome-wide gene expression in whole blood was compared between heavy cannabis users (N = 90) and cannabis naïve participants (N = 100) that were matched for psychotic like experiences.

The Alkaline Phosphatase (ALPL) Locus Is Associated with B6 Vitamer Levels in CSF and Plasma.

The active form of vitamin B6, pyridoxal phosphate (PLP), is essential for human metabolism. The brain is dependent on vitamin B6 for its neurotransmitter balance. To obtain insight into the genetic determinants of vitamin B6 homeostasis, we conducted a genome-wide association study (GWAS) of the B6 vitamers pyridoxal (PL), PLP and the degradation product of vitamin B6, pyridoxic acid (PA).

The polygenic nature of telomere length and the anti-ageing properties of lithium.

Telomere length is a promising biomarker for age-related disease and a potential anti-ageing drug target. Here, we study the genetic architecture of telomere length and the repositioning potential of lithium as an anti-ageing medication. LD score regression applied to the largest telomere length genome-wide association study to-date, revealed SNP-chip heritability estimates of 7.

Telomere length as a predictor of emotional processing in the brain.

Shorter telomere length (TL) has been associated with the development of mood disorders as well as abnormalities in brain morphology. However, so far, no studies have considered the role TL may have on brain function during tasks relevant to mood disorders. In this study, we examine the relationship between TL and functional brain activation and connectivity, while participants (n = 112) perform a functional magnetic resonance imaging (fMRI) facial affect recognition task.

Associations between polygenic risk scores for four psychiatric illnesses and brain structure using multivariate pattern recognition.

Psychiatric illnesses are complex and polygenic. They are associated with widespread alterations in the brain, which are partly influenced by genetic factors. There have been some attempts to relate polygenic risk scores (PRS) - a measure of the overall genetic risk an individual carries for a disorder - to brain structure using univariate methods.

Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder.

Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree ( ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder.

Polygenic risk score analyses of symptoms and treatment response in an antipsychotic-naive first episode of psychosis cohort.

In this study, we aimed to test if the schizophrenia (SCZ) polygenic risk score (PRS) was associated with clinical symptoms in (a) the first episode of psychosis pre-treatment (FEP), (b) at nine weeks after initiation of risperidone treatment (FEP-9W) and (c) with the response to risperidone. We performed a detailed clinical assessment of 60 FEP patients who were antipsychotic-naive and, again, after nine weeks of standardized treatment with risperidone. After blood collection and DNA isolation, the samples were genotyped using the Illumina PsychArrayChip and then imputed.

Development of multivariable models to predict change in Body Mass Index within a clinical trial population of psychotic individuals.

Many antipsychotics promote weight gain, which can lead to non-compliance and relapse of psychosis. By developing models that accurately identify individuals at greater risk of weight gain, clinicians can make informed treatment decisions and target intervention measures. We examined clinical, genetic and expression data for 284 individuals with psychosis derived from a previously published randomised controlled trial (IMPACT).

The genome-wide expression effects of escitalopram and its relationship to neurogenesis, hippocampal volume, and antidepressant response.

Antidepressant-induced hippocampal neurogenesis (AHN) is hypothesized to contribute to increases in hippocampal volume among major depressive disorder patients after long-term treatment. Furthermore, rodent studies suggest AHN may be the cellular mechanism mediating the therapeutic benefits of antidepressants. Here, we perform the first investigation of genome-wide expression changes associated with AHN in human cells.

The polygenic risk for bipolar disorder influences brain regional function relating to visual and default state processing of emotional information.

Genome-wise association studies have identified a number of common single-nucleotide polymorphisms (SNPs), each of small effect, associated with risk to bipolar disorder (BD). Several risk-conferring SNPs have been individually shown to influence regional brain activation thus linking genetic risk for BD to altered brain function. The current study examined whether the polygenic risk score method, which models the cumulative load of all known risk-conferring SNPs, may be useful in the identification of brain regions whose function may be related to the polygenic architecture of BD.

Transcriptome-wide mega-analyses reveal joint dysregulation of immunologic genes and transcription regulators in brain and blood in schizophrenia.

The application of microarray technology in schizophrenia research was heralded as paradigm-shifting, as it allowed for high-throughput assessment of cell and tissue function. This technology was widely adopted, initially in studies of postmortem brain tissue, and later in studies of peripheral blood. The collective body of schizophrenia microarray literature contains apparent inconsistencies between studies, with failures to replicate top hits, in part due to small sample sizes, cohort-specific effects, differences in array types, and other confounders.

Separate and combined effects of genetic variants and pre-treatment whole blood gene expression on response to exposure-based cognitive behavioural therapy for anxiety disorders.

Objectives: Exposure-based cognitive behavioural therapy (eCBT) is an effective treatment for anxiety disorders. Response varies between individuals. Gene expression integrates genetic and environmental influences.

Gene-expression analysis of clozapine treatment in whole blood of patients with psychosis.

Objectives: Clozapine is an atypical antipsychotic primarily prescribed for treatment-resistant schizophrenia. We tested the specific effect of clozapine versus other drug treatments on whole-blood gene expression in a sample of patients with psychosis from the UK.

Methods: A total of 186 baseline whole-blood samples from individuals receiving treatment for established psychosis were analysed for gene expression on Illumina HumanHT-12.

Gene-set analysis based on the pharmacological profiles of drugs to identify repurposing opportunities in schizophrenia.

Genome-wide association studies (GWAS) have identified thousands of novel genetic associations for complex genetic disorders, leading to the identification of potential pharmacological targets for novel drug development. In schizophrenia, 108 conservatively defined loci that meet genome-wide significance have been identified and hundreds of additional sub-threshold associations harbour information on the genetic aetiology of the disorder. In the present study, we used gene-set analysis based on the known binding targets of chemical compounds to identify the 'drug pathways' most strongly associated with schizophrenia-associated genes, with the aim of identifying potential drug repositioning opportunities and clues for novel treatment paradigms, especially in multi-target drug development.