Polygenic risk for schizophrenia converges on alternative polyadenylation as molecular mechanism underlying synaptic impairment.

Schizophrenia (SCZ) is a genetically heterogenous psychiatric disorder of highly polygenic nature. Correlative evidence from genetic studies indicate that the aggregated effects of distinct genetic risk factor combinations found in each patient converge onto common molecular mechanisms. To prove this on a functional level, we employed a reductionistic cellular model system for polygenic risk by differentiating induced pluripotent stem cells (iPSCs) from 104 individuals with high polygenic risk load and controls into cortical glutamatergic neurons (iNs). Multi-omics profiling identified widespread differences in alternative polyadenylation (APA) in the 3' untranslated region of many synaptic transcripts between iNs from SCZ patients and healthy donors. On the cellular level, 3'APA was associated with a reduction in synaptic density of iNs. Importantly, differential APA was largely conserved between postmortem human prefrontal cortex from SCZ patients and healthy donors, and strongly enriched for transcripts related to synapse biology. 3'APA was highly correlated with SCZ polygenic risk and affected genes were significantly enriched for SCZ associated common genetic variation. Integrative functional genomic analysis identified the RNA binding protein and SCZ GWAS risk gene PTBP2 as a critical trans-acting factor mediating 3'APA of synaptic genes in SCZ subjects. Functional characterization of PTBP2 in iNs confirmed its key role in 3'APA of synaptic transcripts and regulation of synapse density. Jointly, our findings show that the aggregated effects of polygenic risk converge on 3'APA as one common molecular mechanism that underlies synaptic impairments in SCZ.

Single-Cell Transcriptomics Supports a Role of CHD8 in Autism.

Chromodomain helicase domain 8 (CHD8) is one of the most frequently mutated and most penetrant genes in the autism spectrum disorder (ASD). Individuals with CHD8 mutations show leading symptoms of autism, macrocephaly, and facial dysmorphisms. The molecular and cellular mechanisms underpinning the early onset and development of these symptoms are still poorly understood and prevent timely and more efficient therapies of patients. Progress in this area will require an understanding of "when, why and how cells deviate from their normal trajectories". High-throughput single-cell RNA sequencing (sc-RNAseq) directly quantifies information-bearing RNA molecules that enact each cell's biological identity. Here, we discuss recent insights from sc-RNAseq of CRISPR/Cas9-editing of Chd8/CHD8 during mouse neocorticogenesis and human cerebral organoids. Given that the deregulation of the balance between excitation and inhibition (E/I balance) in cortical and subcortical circuits is thought to represent a major etiopathogenetic mechanism in ASD, we focus on the question of whether, and to what degree, results from current sc-RNAseq studies support this hypothesis. Beyond that, we discuss the pros and cons of these approaches and further steps to be taken to harvest the full potential of these transformative techniques.

Chromatin Remodeler CHD8 in Autism and Brain Development.

Chromodomain Helicase DNA-binding 8 (CHD8) is a high confidence risk factor for autism spectrum disorders (ASDs) and the genetic cause of a distinct neurodevelopmental syndrome with the core symptoms of autism, macrocephaly, and facial dysmorphism. The role of CHD8 is well-characterized at the structural, biochemical, and transcriptional level. By contrast, much less is understood regarding how mutations in CHD8 underpin altered brain function and mental disease. Studies on various model organisms have been proven critical to tackle this challenge. Here, we scrutinize recent advances in this field with a focus on phenotypes in transgenic animal models and highlight key findings on neurodevelopment, neuronal connectivity, neurotransmission, synaptic and homeostatic plasticity, and habituation. Against this backdrop, we further discuss how to improve future animal studies, both in terms of technical issues and with respect to the sex-specific effects of Chd8 mutations for neuronal and higher-systems level function. We also consider outstanding questions in the field including 'humanized' mice models, therapeutic interventions, and how the use of pluripotent stem cell-derived cerebral organoids might help to address differences in neurodevelopment trajectories between model organisms and humans.

Cystatin B is essential for proliferation and interneuron migration in individuals with EPM1 epilepsy.

Progressive myoclonus epilepsy (PME) of Unverricht-Lundborg type (EPM1) is an autosomal recessive neurodegenerative disorder with the highest incidence of PME worldwide. Mutations in the gene encoding cystatin B (CSTB) are the primary genetic cause of EPM1. Here, we investigate the role of CSTB during neurogenesis in vivo in the developing mouse brain and in vitro in human cerebral organoids (hCOs) derived from EPM1 patients. We find that CSTB (but not one of its pathological variants) is secreted into the mouse cerebral spinal fluid and the conditioned media from hCOs. In embryonic mouse brain, we find that functional CSTB influences progenitors' proliferation and modulates neuronal distribution by attracting interneurons to the site of secretion via cell-non-autonomous mechanisms. Similarly, in patient-derived hCOs, low levels of functional CSTB result in an alteration of progenitor's proliferation, premature differentiation, and changes in interneurons migration. Secretion and extracellular matrix organization are the biological processes particularly affected as suggested by a proteomic analysis in patients' hCOs. Overall, our study sheds new light on the cellular mechanisms underlying the development of EPM1.

Isolation and characterization of a lithiated pyridine - aggregation in the solid state and in solution.

Pyridyllithiums are ubiquitous intermediates used for the electrophilic functionalization of pyridines. In this work, the isolation of a pyridyllithium is reported. Single crystal XRD revealed a dimer in the solid state. In THF solution it was identified as a monomer using DOSY NMR spectroscopy. Calculations showed that the pyridyllithium is a very electron rich pyridine superbase, which may account for its high reactivity.

Focus on Causality in ESC/iPSC-Based Modeling of Psychiatric Disorders.

Genome-wide association studies (GWAS) have identified an increasing number of genetic variants that significantly associate with psychiatric disorders. Despite this wealth of information, our knowledge of which variants causally contribute to disease, how they interact, and even more so of the functions they regulate, is still poor. The availability of embryonic stem cells (ESCs) and the advent of patient-specific induced pluripotent stem cells (iPSCs) has opened new opportunities to investigate genetic risk variants in living disease-relevant cells. Here, we analyze how this progress has contributed to the analysis of causal relationships between genetic risk variants and neuronal phenotypes, especially in schizophrenia (SCZ) and bipolar disorder (BD). Studies on rare, highly penetrant risk variants have originally led the field, until more recently when the development of (epi-) genetic editing techniques spurred studies on cause-effect relationships between common low risk variants and their associated neuronal phenotypes. This reorientation not only offers new insights, but also raises issues on interpretability. Concluding, we consider potential caveats and upcoming developments in the field of ESC/iPSC-based modeling of causality in psychiatric disorders.

Progress in iPSC-Based Modeling of Psychiatric Disorders.

Progress in iPSC-based cellular systems provides new insights into human brain development and early neurodevelopmental deviations in psychiatric disorders. Among these, studies on schizophrenia (SCZ) take a prominent role owing to its high heritability and multifarious evidence that it evolves from a genetically induced vulnerability in brain development. Recent iPSC studies on patients with SCZ indicate that functional impairments of neural progenitor cells (NPCs) in monolayer culture extend to brain organoids by disrupting neocorticogenesis in an in vitro model. In addition, the formation of hippocampal circuit-like structures in vitro is impaired in patients with SCZ as is the case for glia development. Intriguingly, chimeric-mice experiments show altered oligodendrocyte and astrocyte development in vivo that highlights the importance of cell-cell interactions in the pathogenesis of early-onset SCZ. Likewise, cortical imbalances in excitatory-inhibitory signaling may result from a cell-autonomous defect in cortical interneuron (cIN) development. Overall, these findings indicate that genetic risk in SCZ impacts neocorticogenesis, hippocampal circuit formation, and the development of distinct glial and neuronal subtypes. In light of this remarkable progress, we discuss current limitations and further steps necessary to harvest the full potential of iPSC-based investigations on psychiatric disorders.

Chromatin Remodeling Complex NuRD in Neurodevelopment and Neurodevelopmental Disorders.

The nucleosome remodeling and deacetylase (NuRD) complex presents one of the major chromatin remodeling complexes in mammalian cells. Here, we discuss current evidence for NuRD's role as an important epigenetic regulator of gene expression in neural stem cell (NSC) and neural progenitor cell (NPC) fate decisions in brain development. With the formation of the cerebellar and cerebral cortex, NuRD facilitates experience-dependent cerebellar plasticity and regulates additionally cerebral subtype specification and connectivity in postmitotic neurons. Consistent with these properties, genetic variation in NuRD's subunits emerges as important risk factor in common polygenic forms of neurodevelopmental disorders (NDDs) and neurodevelopment-related psychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BD). Overall, these findings highlight the critical role of NuRD in chromatin regulation in brain development and in mental health and disease.

Oxidative Fluorination of Cu/ZnO Methanol Catalysts.

The influence of a mild difluorine treatment on Cu/ZnO precatalysts for methanol synthesis was investigated. It led to the incorporation of 1.2…1.3±0.1 wt % fluoride into the material. Fluorination considerably increased the amount of ZnOx related defect sites on the catalysts and significantly increased the space-time yields. Although the apparent activation energy EA,app for methanol formation from CO2 and H2 was almost unchanged, the EA,app for the reverse water-gas shift (rWGS) reaction increased considerably. Overall, fluorination led to a significant gain in methanol selectivity and productivity. Apparently, also the quantity of active sites increased.

The Mitochondrion as Potential Interface in Early-Life Stress Brain Programming.

Mitochondria play a central role in cellular energy-generating processes and are master regulators of cell life. They provide the energy necessary to reinstate and sustain homeostasis in response to stress, and to launch energy intensive adaptation programs to ensure an organism's survival and future well-being. By this means, mitochondria are particularly apt to mediate brain programming by early-life stress (ELS) and to serve at the same time as subcellular substrate in the programming process. With a focus on mitochondria's integrated role in metabolism, steroidogenesis and oxidative stress, we review current findings on altered mitochondrial function in the brain, the placenta and peripheral blood cells following ELS-dependent programming in rodents and recent insights from humans exposed to early life adversity (ELA). Concluding, we propose a role of the mitochondrion as subcellular intersection point connecting ELS, brain programming and mental well-being, and a role as a potential site for therapeutic interventions in individuals exposed to severe ELS.

Childhood-Onset Schizophrenia: Insights from Induced Pluripotent Stem Cells.

Childhood-onset schizophrenia (COS) is a rare psychiatric disorder characterized by earlier onset, more severe course, and poorer outcome relative to adult-onset schizophrenia (AOS). Even though, clinical, neuroimaging, and genetic studies support that COS is continuous to AOS. Early neurodevelopmental deviations in COS are thought to be significantly mediated through poorly understood genetic risk factors that may also predispose to long-term outcome. In this review, we discuss findings from induced pluripotent stem cells (iPSCs) that allow the generation of disease-relevant cell types from early brain development. Because iPSCs capture each donor's genotype, case/control studies can uncover molecular and cellular underpinnings of COS. Indeed, recent studies identified alterations in neural progenitor and neuronal cell function, comprising dendrites, synapses, electrical activity, glutamate signaling, and miRNA expression. Interestingly, transcriptional signatures of iPSC-derived cells from patients with COS showed concordance with postmortem brain samples from SCZ, indicating that changes in vitro may recapitulate changes from the diseased brain. Considering this progress, we discuss also current caveats from the field of iPSC-based disease modeling and how to proceed from basic studies to improved diagnosis and treatment of COS.

Tracing Early Neurodevelopment in Schizophrenia with Induced Pluripotent Stem Cells.

Schizophrenia (SCZ) is a devastating mental disorder that is characterized by distortions in thinking, perception, emotion, language, sense of self, and behavior. Epidemiological evidence suggests that subtle perturbations in early neurodevelopment increase later susceptibility for disease, which typically manifests in adolescence to early adulthood. Early perturbations are thought to be significantly mediated through incompletely understood genetic risk factors. The advent of induced pluripotent stem cell (iPSC) technology allows for the in vitro analysis of disease-relevant neuronal cell types from the early stages of human brain development. Since iPSCs capture each donor's genotype, comparison between neuronal cells derived from healthy and diseased individuals can provide important insights into the molecular and cellular basis of SCZ. In this review, we discuss results from an increasing number of iPSC-based SCZ/control studies that highlight alterations in neuronal differentiation, maturation, and neurotransmission in addition to perturbed mitochondrial function and micro-RNA expression. In light of this remarkable progress, we consider also ongoing challenges from the field of iPSC-based disease modeling that call for further improvements on the generation and design of patient-specific iPSC studies to ultimately progress from basic studies on SCZ to tailored treatments.

From the Psychiatrist's Couch to Induced Pluripotent Stem Cells: Bipolar Disease in a Dish.

Bipolar disease (BD) is one of the major public health burdens worldwide and more people are affected every year. Comprehensive genetic studies have associated thousands of single nucleotide polymorphisms (SNPs) with BD risk; yet, very little is known about their functional roles. Induced pluripotent stem cells (iPSCs) are powerful tools for investigating the relationship between genotype and phenotype in disease-relevant tissues and cell types. Neural cells generated from BD-specific iPSCs are thought to capture associated genetic risk factors, known and unknown, and to allow the analysis of their effects on cellular and molecular phenotypes. Interestingly, an increasing number of studies on BD-derived iPSCs report distinct alterations in neural patterning, postmitotic calcium signaling, and neuronal excitability. Importantly, these alterations are partly normalized by lithium, a first line treatment in BD. In light of these exciting findings, we discuss current challenges to the field of iPSC-based disease modelling and future steps to be taken in order to fully exploit the potential of this approach for the investigation of BD and the development of new therapies.

Synergetic effects of Fe3+ doped spinel Li4Ti5O12 nanoparticles on reduced graphene oxide for high surface electrode hybrid supercapacitors.

In this work, reduced graphene oxide (rGO) based electrode materials were developed to achieve a hybrid supercapacitor (SC) function. Therefore, several synthesis methods were developed to prepare a cost effective and environmentally friendly rGO. Additionally, to maintain the high surface area, spinel lithium titanate (sLTO) nanoparticles (NPs) were synthesized and deposited on the rGO surface to inhibit the restacking of the rGO layers on graphite. Furthermore, the adequate Fe-doping of sLTO increased the ionic conductivity and the intercalation capacity, which is necessary for a SC performance. The sLTO/rGO-composites were electrochemically analysed by chronopotentiometry and electrochemical impedance spectroscopy (EIS) to determine the stability during charge/discharge cycling and the capacity, respectively. To overcome the drawback of LTO's low conductivity values, its value has been drastically increased by Fe-doping. The results demonstrated the remarkable cycling performance of the Fe:LTO/rGO composite as well as a higher capacity compared to LTO/rGO and pure rGO-electrodes. The thermal stability, degradation and weight loss of the sLTO/rGO in the temperature range between 20 °C and 800 °C were investigated by thermogravimetry (TG)/DTA. As a conclusion, it can be stated that, increasing the ionic conductivity by Fe-doping drastically increases the hybrid capacity of the SC electrodes.

Epigenomics of Major Depressive Disorders and Schizophrenia: Early Life Decides.

Brain development is guided by the interactions between the genetic blueprint and the environment. Epigenetic mechanisms, especially DNA methylation, can mediate these interactions and may also trigger long-lasting adaptations in developmental programs that increase the risk of major depressive disorders (MDD) and schizophrenia (SCZ). Early life adversity is a major risk factor for MDD/SCZ and can trigger persistent genome-wide changes in DNA methylation at genes important to early, but also to mature, brain function, including neural proliferation, differentiation, and synaptic plasticity, among others. Moreover, genetic variations controlling dynamic DNA methylation in early life are thought to influence later epigenomic changes in SCZ. This finding corroborates the high genetic load and a neurodevelopmental origin of SCZ and shows that epigenetic responses to the environment are, at least in part, genetically controlled. Interestingly, genetic variants influencing DNA methylation are also enriched in risk variants from genome-wide association studies (GWAS) on SCZ supporting a role in neurodevelopment. Overall, epigenomic responses to early life adversity appear to be controlled to different degrees by genetics in MDD/SCZ, even though the potential reversibility of epigenomic processes may offer new hope for timely therapeutic interventions in MDD/SCZ.

Inhibiting Polysulfide Shuttle in Lithium-Sulfur Batteries through Low-Ion-Pairing Salts and a Triflamide Solvent.

The step-change in gravimetric energy density needed for electrochemical energy storage devices to power unmanned autonomous vehicles, electric vehicles, and enable low-cost clean grid storage is unlikely to be provided by conventional lithium ion batteries. Lithium-sulfur batteries comprising lightweight elements provide a promising alternative, but the associated polysulfide shuttle in typical ether-based electrolytes generates loss in capacity and low coulombic efficiency. The first new electrolyte based on a unique combination of a relatively hydrophobic sulfonamide solvent and a low ion-pairing salt, which inhibits the polysulfide shuttle, is presented. This system behaves as a sparingly solvating electrolyte at slightly elevated temperatures, where it sustains reversible capacities as high as 1200-1500 mAh g-1 over a wide range of current density (2C-C/5, respectively) when paired with a lithium metal anode, with a coulombic efficiency of >99.7 % in the absence of LiNO3 additive.

Synthesis, Crystal Structure, and Properties of Bi3 TeBO9 or Bi3 (TeO6 )(BO3 ): A Non-Centrosymmetric Borate-Tellurate(VI) of Bismuth.

Pale-yellow single crystals of the new borate tellurate(VI) Bi3 TeBO9 were obtained by reaction of stoichiometric amounts of Bi2 O3 , B2 O3 , and Te(OH)6 at 780 °C. The non-centrosymmetric crystal structure (P63 , Z=2, a=8.7454(16), c=5.8911(11) Å, 738 refl., 43 param, R1=0.037, wR2=0.093) contains isolated trigonal-planar BO3 units and nearly undistorted TeO6 octahedra. The Bi3+ cations are located in between in octahedral voids. The BiO6 octahedra are significantly distorted to a [3+3] pattern (2.25/2.50 Å) due to the ns2 configuration. According to the structural features, the formula can be written as Bi3 (TeO6 )(BO3 ). Alternatively, the structure can also be described as hcp of oxygen with TeVI and BiIII in octahedral voids and BIII in trigonal- planar voids. The vibrational spectra show the typical features of BO3 and TeO6 units with a significant 10 B/11 B isotopic splitting of the IR-active B-O valence mode (1248 and 1282 cm-1 ). The UV/Vis spectrum shows an optical band edge with an onset around 480 nm (2.6 eV). MAS-NMR spectra of 11 B show an anisotropic signal with a quadrupole coupling constant of CQ =2.55 MHz. and a very small deviation from rotational symmetry (η=0.2). The isotropic chemical shift is 20.1 ppm. The second harmonic generation (SHG) test was positive with an activity comparable to potassium dihydrogen phosphate (KDP). Bi3 TeBO9 decomposes in air at 825 °C to Bi2 TeO5 .

The Future is The Past: Methylation QTLs in Schizophrenia.

Genome-wide association studies (GWAS) have remarkably advanced insight into the genetic basis of schizophrenia (SCZ). Still, most of the functional variance in disease risk remains unexplained. Hence, there is a growing need to map genetic variability-to-genes-to-functions for understanding the pathophysiology of SCZ and the development of better treatments. Genetic variation can regulate various cellular functions including DNA methylation, an epigenetic mark with important roles in transcription and the mediation of environmental influences. Methylation quantitative trait loci (meQTLs) are derived by mapping levels of DNA methylation in genetically different, genotyped individuals and define loci at which DNA methylation is influenced by genetic variation. Recent evidence points to an abundance of meQTLs in brain tissues whose functional contributions to development and mental diseases are still poorly understood. Interestingly, fetal meQTLs reside in regulatory domains affecting methylome reconfiguration during early brain development and are enriched in loci identified by GWAS for SCZ. Moreover, fetal meQTLs are preserved in the adult brain and could trace early epigenomic deregulation during vulnerable periods. Overall, these findings highlight the role of fetal meQTLs in the genetic risk for and in the possible neurodevelopmental origin of SCZ.

Role of ZAC1 in transient neonatal diabetes mellitus and glucose metabolism.

Transient neonatal diabetes mellitus 1 (TNDM1) is a rare genetic disorder representing with severe neonatal hyperglycaemia followed by remission within one and a half year and adolescent relapse with type 2 diabetes in half of the patients. Genetic defects in TNDM1 comprise uniparental isodisomy of chromosome 6, duplication of the minimal TNDM1 locus at 6q24, or relaxation of genomically imprinted ZAC1/HYMAI. Whereas the function of HYMAI, a non-coding mRNA, is still unidentified, biochemical and molecular studies show that zinc finger protein 1 regulating apoptosis and cell cycle arrest (ZAC1) behaves as a factor with versatile transcriptional functions dependent on binding to specific GC-rich DNA motives and interconnected regulation of recruited coactivator activities. Genome-wide expression profiling enabled the isolation of a number of Zac1 target genes known to regulate different aspects of ß-cell function and peripheral insulin sensitivity. Among these, upregulation of Pparγ and Tcf4 impairs insulin-secretion and ß-cell proliferation. Similarly, Zac1-mediated upregulation of Socs3 may attenuate ß-cell proliferation and survival by inhibition of growth factor signalling. Additionally, Zac1 directly represses Pac1 and Rasgrf1 with roles in insulin secretion and ß-cell proliferation. Collectively, concerted dysregulation of these target genes could contribute to the onset and course of TNDM1. Interestingly, Zac1 overexpression in ß-cells spares the effects of stimulatory G-protein signaling on insulin secretion and raises the prospect for tailored treatments in relapsed TNDM1 patients. Overall, these results suggest that progress on the molecular and cellular foundations of monogenetic forms of diabetes can advance personalized therapy in addition to deepening the understanding of insulin and glucose metabolism in general.

Molecular epigenetic switches in neurodevelopment in health and disease.

Epigenetic mechanisms encode information above and beyond DNA sequence and play a critical role in brain development and the long-lived effects of environmental cues on the pre- and postnatal brain. Switch-like, rather than graded changes, illustrate par excellence how epigenetic events perpetuate altered activity states in the absence of the initial cue. They occur from early neural development to maturation and can give rise to distinct diseases upon deregulation. Many neurodevelopmental genes harbor bivalently marked chromatin domains, states of balanced inhibition, which guide dynamic "ON or OFF" decisions once the balance is tilted in response to developmental or environmental cues. Examples discussed in this review include neuronal differentiation of embryonic stem cells (ESC) into progenitors and beyond, activation of Kiss1 at puberty onset, and early experience-dependent programming of Avp, a major stress gene. At the genome-scale, genomic imprinting can be epigenetically switched on or off at select genes in a tightly controlled temporospatial manner and provides a versatile mechanism for dosage regulation of genes with important roles in stem cell quiescence or differentiation. Moreover, retrotransposition in neural progenitors provides an intriguing example of an epigenetic-like switch, which is stimulated by bivalently marked neurodevelopmental genes and possibly results in increased genomic flexibility regarding unprecedented challenge. Overall, we propose that molecular epigenetic switches illuminate the catalyzing function of epigenetic mechanisms in guiding dynamic changes in gene expression underpinning robust transitions in cellular and organismal phenotypes as well as in the mediation between dynamically changing environments and the static genetic blueprint.