Schizophrenia.

Schizophrenia, characterised by psychotic symptoms and in many cases social and occupational decline, remains an aetiological and therapeutic challenge. Contrary to popular belief, the disorder is modestly more common in men than in women. Nor is the outcome uniformly poor. A division of symptoms into positive, negative, and disorganisation syndromes is supported by factor analysis. Catatonic symptoms are not specific to schizophrenia and so-called first rank symptoms are no longer considered diagnostically important. Cognitive impairment is now recognised as a further clinical feature of the disorder. Lateral ventricular enlargement and brain volume reductions of around 2% are established findings. Brain functional changes occur in different subregions of the frontal cortex and might ultimately be understandable in terms of disturbed interaction among large-scale brain networks. Neurochemical disturbance, involving dopamine function and glutamatergic N-methyl-D-aspartate receptor function, is supported by indirect and direct evidence. The genetic contribution to schizophrenia is now recognised to be largely polygenic. Birth and early life factors also have an important aetiological role. The mainstay of treatment remains dopamine receptor-blocking drugs; a psychological intervention, cognitive behavioural therapy, has relatively small effects on symptoms. The idea that schizophrenia is better regarded as the extreme end of a continuum of psychotic symptoms is currently influential. Other areas of debate include cannabis and childhood adversity as causative factors, whether there is progressive brain change after onset, and the long-term success of early intervention initiatives.

Understanding the clinical manifestations of 16p11.2 deletion syndrome: a series of developmental case reports in children.

BACKGROUND: Copy number variants (CNVs) are genetic rearrangements, such as deletions and duplications, which result in a deviation from the normal number of copies of a given gene segment. CNVs are implicated in many neuropsychiatric disorders. Deletions of the human chromosomal region 16p11.2 are one of the most common genetic linkages to autism spectrum disorders (ASD). However, ASD is not the only presenting feature, and many patients with 16p11.2 deletions present with a variable clinical spectrum. METHODS: To better understand the nature and presentation of the syndrome throughout development, we present three different, unrelated clinical cases of children with 16p11.2 deletion and provide a detailed description of their clinical manifestations. RESULTS: Cognitive and motor impairments were characteristic of all three patients with 16p11.2 deletion, despite the differences in the extent and clinical presentation of impairment. Two patients had a clinical diagnosis of ASD and one showed several ASD traits. In addition, two patients also had severe speech and language impairments, which is in line with previous reports on 16p11.2 phenotypes. Although epilepsy and obesity have been frequently associated with 16p11.2 deletion, only one patient had a diagnosis of epilepsy and none of the three cases were obese. CONCLUSION: This variation in clinical phenotype renders correct clinical interpretation and diagnosis challenging. Therefore, it is critical to elucidate the variable clinical phenotypes of rare CNVs, including 16p11.2 deletions, to help guide clinical monitoring and counselling of patients and families.

Addition of volatile sulfur compounds to yeast at the early stages of fermentation reveals distinct biological and chemical pathways for aroma formation.

Volatile sulfur compounds (VSCs) greatly influence the sensory properties and quality of wine and arise via both biological and chemical mechanisms. VSCs formed can also act as precursors for further downstream VSCs, thus elucidating the pathways leading to their formation is paramount. Short-term additions of exogenous hydrogen sulfide (H2S), ethanethiol (EtSH), S-ethylthio acetate (ETA), methanethiol (MeSH) and S-methylthio acetate (MTA) were made to exponentially growing fermentations of synthetic grape medium. The VSC profiles produced from live yeast cells were compared with those from dead cells and no cells. Interestingly, this experiment allowed the identification of specific biochemical and/or chemical pathways; e.g. most of the conversion of H2S to EtSH, and the further step from EtSH to ETA, required the presence of live yeast cells, as did the conversion of MeSH to MTA. In contrast, the reaction from MTA to MeSH and ETA to EtSH was due primarily to chemical degradation. Ultimately, this research unravelled some of the complex interactions and interconversions between VSCs, pinpointing the key biochemical and chemical nodes. These pathways are highly interconnected and showcase the complexity of both the sulfur pathways in yeast and the reactive chemistry of sulfur-containing compounds.

Familial t(1;11) translocation is associated with disruption of white matter structural integrity and oligodendrocyte-myelin dysfunction.

Although the underlying neurobiology of major mental illness (MMI) remains unknown, emerging evidence implicates a role for oligodendrocyte-myelin abnormalities. Here, we took advantage of a large family carrying a balanced t(1;11) translocation, which substantially increases risk of MMI, to undertake both diffusion tensor imaging and cellular studies to evaluate the consequences of the t(1;11) translocation on white matter structural integrity and oligodendrocyte-myelin biology. This translocation disrupts among others the DISC1 gene which plays a crucial role in brain development. We show that translocation-carrying patients display significant disruption of  white matter integrity compared with familial controls. At a cellular level, we observe dysregulation of key pathways controlling oligodendrocyte development and morphogenesis in induced pluripotent stem cell (iPSC) derived case oligodendrocytes. This is associated with reduced proliferation and a stunted morphology in vitro. Further, myelin internodes in a humanized mouse model that recapitulates the human translocation as well as after transplantation of t(1;11) oligodendrocyte progenitors were significantly reduced when  compared with controls. Thus we provide evidence that the t(1;11) translocation has biological effects at both the systems and cellular level that together suggest oligodendrocyte-myelin dysfunction.

A new analytical method to measure S-methyl-l-methionine in grape juice reveals the influence of yeast on dimethyl sulfide production during fermentation.

BACKGROUND: Dimethyl sulfide (DMS) is a small sulfur-containing impact odorant, imparting distinctive positive and / or negative characters to food and beverages. In white wine, the presence of DMS at perception threshold is considered to be a fault, contributing strong odors reminiscent of asparagus, cooked cabbage, and creamed corn. The source of DMS in wine has long been associated with S-methyl-l-methionine (SMM), a derivative of the amino acid methionine, which is thought to break down into DMS through chemical degradation, particularly during wine ageing. RESULTS: We developed and validated a new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a stable isotope dilution assay (SIDA) to measure SMM in grape juice and wine. The application of this new method for quantitating SMM, followed by the quantitation of DMS using headspace-solid phase micro-extraction coupled with gas chromatography-mass spectrometry (HS-SPME/GC-MS), confirmed that DMS can be produced in wine via the chemical breakdown of SMM to DMS, with greater degradation observed at 28 °C than at 14 °C. Further investigation into the role of grape juice and yeast strain on DMS formation revealed that the DMS produced from three different Sauvignon blanc grape juices, either from the SMM naturally present or SMM spiked at 50 mmol L-1 , was modulated depending on each of the four strains of Saccharomyces cerevisiae wine yeast used for fermentation. CONCLUSION: This study confirms the existence of a chemical pathway to the formation of DMS and reveals a yeast-mediated mechanism towards the formation of DMS from SMM during alcoholic fermentation. © 2019 Society of Chemical Industry.

Association of Whole-Genome and NETRIN1 Signaling Pathway-Derived Polygenic Risk Scores for Major Depressive Disorder and White Matter Microstructure in the UK Biobank.

BACKGROUND: Major depressive disorder is a clinically heterogeneous psychiatric disorder with a polygenic architecture. Genome-wide association studies have identified a number of risk-associated variants across the genome and have reported growing evidence of NETRIN1 pathway involvement. Stratifying disease risk by genetic variation within the NETRIN1 pathway may provide important routes for identification of disease mechanisms by focusing on a specific process, excluding heterogeneous risk-associated variation in other pathways. Here, we sought to investigate whether major depressive disorder polygenic risk scores derived from the NETRIN1 signaling pathway (NETRIN1-PRSs) and the whole genome, excluding NETRIN1 pathway genes (genomic-PRSs), were associated with white matter microstructure. METHODS: We used two diffusion tensor imaging measures, fractional anisotropy (FA) and mean diffusivity (MD), in the most up-to-date UK Biobank neuroimaging data release (FA: n = 6401; MD: n = 6390). RESULTS: We found significantly lower FA in the superior longitudinal fasciculus (ß = -.035, pcorrected = .029) and significantly higher MD in a global measure of thalamic radiations (ß = .029, pcorrected = .021), as well as higher MD in the superior (ß = .034, pcorrected = .039) and inferior (ß = .029, pcorrected = .043) longitudinal fasciculus and in the anterior (ß = .025, pcorrected = .046) and superior (ß = .027, pcorrected = .043) thalamic radiation associated with NETRIN1-PRS. Genomic-PRS was also associated with lower FA and higher MD in several tracts. CONCLUSIONS: Our findings indicate that variation in the NETRIN1 signaling pathway may confer risk for major depressive disorder through effects on a number of white matter tracts.

Reversal of proliferation deficits caused by chromosome 16p13.11 microduplication through targeting NFκB signaling: an integrated study of patient-derived neuronal precursor cells, cerebral organoids and in vivo brain imaging.

The molecular basis of how chromosome 16p13.11 microduplication leads to major psychiatric disorders is unknown. Here we have undertaken brain imaging of patients carrying microduplications in chromosome 16p13.11 and unaffected family controls, in parallel with iPS cell-derived cerebral organoid studies of the same patients. Patient MRI revealed reduced cortical volume, and corresponding iPSC studies showed neural precursor cell (NPC) proliferation abnormalities and reduced organoid size, with the NPCs therein displaying altered planes of cell division. Transcriptomic analyses of NPCs uncovered a deficit in the NFκB p65 pathway, confirmed by proteomics. Moreover, both pharmacological and genetic correction of this deficit rescued the proliferation abnormality. Thus, chromosome 16p13.11 microduplication disturbs the normal programme of NPC proliferation to reduce cortical thickness due to a correctable deficit in the NFκB signalling pathway. This is the first study demonstrating a biologically relevant, potentially ameliorable, signalling pathway underlying chromosome 16p13.11 microduplication syndrome in patient-derived neuronal precursor cells.

The impact of postharvest ultra-violet light irradiation on the thiol content of Sauvignon blanc grapes.

Sauvignon blanc grapes were exposed to an ultra-violet (UV) light source post-hand harvest (whole bunches) or post-machine harvest. The thiol precursors S-3-(hexan-1-ol)-l-cysteine (Cys-3MH) and S-3-(hexan-1-ol)-l-glutathione (GSH-3MH) were quantified in the juices before and after UV treatment. Results showed that irradiation of the grapes with UV light had little to no effect on the thiol precursors. Wines were fermented from the corresponding juices and 18 aroma compounds were quantified. Differences were found between UV treatments of the wines for 3-mercaptohexanol, hexan-1-ol, ethyl butanoate, ethyl hexanoate, ethyl octanoate and phenylethyl alcohol. However, these changes were not significant (p < 0.05) for both grape media trialled. Future studies involving larger sample sizes and replicate numbers should be completed in order to ascertain any changes in aroma chemistry as a result of UV light application to grapes postharvest.

Effect of Cluster Thinning Vitis vinifera cv. Pinot Noir on Wine Volatile and Phenolic Composition.

The effects of two cluster thinning regimes (low and moderate) with Vitis vinifera cv. Pinot noir, in vineyards located in Central Otago, New Zealand, on wine composition, were studied across three consecutive seasons. There were strong correlations between the extent of cluster thinning and pH and bunch weights, and the concentrations of the C13-norisoprenoids, monoterpenes, fatty acids, cinnamic esters, ß-phenylethyl alcohol, and all polyphenols. The sensory terms herbaceous and acidic consistently received the highest ranking in the control wines without cluster thinning. The thinning treatments produced wines with higher marks in the descriptors fruity, spice, sweet, and body. Cluster thinning also had a measurable effect on timing of harvest, in addition to effects on chemical composition and wine sensory, which demonstrate benefits to wine quality that can be expected with cluster thinning of Pinot noir.

DISC1 regulates N-methyl-D-aspartate receptor dynamics: abnormalities induced by a Disc1 mutation modelling a translocation linked to major mental illness.

The neuromodulatory gene DISC1 is disrupted by a t(1;11) translocation that is highly penetrant for schizophrenia and affective disorders, but how this translocation affects DISC1 function is incompletely understood. N-methyl-D-aspartate receptors (NMDAR) play a central role in synaptic plasticity and cognition, and are implicated in the pathophysiology of schizophrenia through genetic and functional studies. We show that the NMDAR subunit GluN2B complexes with DISC1-associated trafficking factor TRAK1, while DISC1 interacts with the GluN1 subunit and regulates dendritic NMDAR motility in cultured mouse neurons. Moreover, in the first mutant mouse that models DISC1 disruption by the translocation, the pool of NMDAR transport vesicles and surface/synaptic NMDAR expression are increased. Since NMDAR cell surface/synaptic expression is tightly regulated to ensure correct function, these changes in the mutant mouse are likely to affect NMDAR signalling and synaptic plasticity. Consistent with these observations, RNASeq analysis of the translocation carrier-derived human neurons indicates abnormalities of excitatory synapses and vesicle dynamics. RNASeq analysis of the human neurons also identifies many differentially expressed genes previously highlighted as putative schizophrenia and/or depression risk factors through large-scale genome-wide association and copy number variant studies, indicating that the translocation triggers common disease pathways that are shared with unrelated psychiatric patients. Altogether, our findings suggest that translocation-induced disease mechanisms are likely to be relevant to mental illness in general, and that such disease mechanisms include altered NMDAR dynamics and excitatory synapse function. This could contribute to the cognitive disorders displayed by translocation carriers.

Stem Cells to Inform the Neurobiology of Mental Illness.

The inception of human-induced pluripotent stem cell (hiPSCs) technology has provided an exciting platform upon which the modelling and treatment of human neurodevelopmental and neuropsychiatric disorders may be expedited. Although the genetic architecture of these disorders is far more complex than previously imagined, many key loci have at last been identified. This has allowed in vivo and in vitro technologies to be refined to model specific high-penetrant genetic loci involved in both disorders. Animal models of neurodevelopmental disorders, such as schizophrenia and autism spectrum disorders, show limitations in recapitulating the full complexity and heterogeneity of human neurodevelopmental disease states. Indeed, patient-derived hiPSCs offer distinct advantages over classical animal models in the study of human neuropathologies. Here we have discussed the current, relative translational merit of hiPSCs in investigating human neurodevelopmental and neuropsychiatric disorders with a specific emphasis on the utility of such systems to aid in the identification of biomarkers. We have highlighted the promises and pitfalls of reprogramming cell fate for the study of these disorders and provide recommendations for future directions in this field in order to overcome current limitations. Ultimately, this will aid in the development of effective clinical strategies for diverse patient populations affected by these disorders with the aim of also leading to biomarker identification.

HippoCA3mpal Stem Cell Models Expose Dysfunctional Circuits in Schizophrenia.

In this issue of Cell Stem Cell, Sarkar et al. (2018) describe an efficient method for the generation of human hippocampal pyramidal neurons from stem cells. They developed a compelling in vitro model that recapitulates synaptic connectivity within the hippocampus and showed that cells derived from patients with schizophrenia exhibit abnormal electrical activity.

Using mouse transgenic and human stem cell technologies to model genetic mutations associated with schizophrenia and autism.

Solid progress has occurred over the last decade in our understanding of the molecular genetic basis of neurodevelopmental disorders, and of schizophrenia and autism in particular. Although the genetic architecture of both disorders is far more complex than previously imagined, many key loci have at last been identified. This has allowed in vivo and in vitro technologies to be refined to model specific high-penetrant genetic loci involved in both disorders. Using the DISC1/NDE1 and CYFIP1/EIF4E loci as exemplars, we explore the opportunities and challenges of using animal models and human-induced pluripotent stem cell technologies to further understand/treat and potentially reverse the worst consequences of these debilitating disorders.This article is part of a discussion meeting issue 'Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists'.

Facile gas chromatography-tandem mass spectrometry stable isotope dilution method for the quantification of sesquiterpenes in grape.

Sesquiterpenes are a widespread class of compounds of increasing interest found in grapes and wines, amongst many other natural sources. Due to a lack of standards and the complexity of the mass spectra fragmentation, accurate quantification of these low concentration compounds had not previously been accomplished. The current paper presents a new method for the concurrent quantification of several sesquiterpenes. The multivariate method optimisation is presented. Synthesised isotopic standards were utilised in conjunction with solid phase microextraction (SPME) and gas chromatography-tandem mass spectrometry (GC-MS/MS) to perform a standard isotope dilution assay (SIDA). The method was successfully applied to several grape must samples of four different cultivar. To the best of our knowledge this was the first time some of these sesquiterpenes were quantified in grape.

The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability.

By performing a meta-analysis of rare coding variants in whole-exome sequences from 4,133 schizophrenia cases and 9,274 controls, de novo mutations in 1,077 family trios, and copy number variants from 6,882 cases and 11,255 controls, we show that individuals with schizophrenia carry a significant burden of rare, damaging variants in 3,488 genes previously identified as having a near-complete depletion of loss-of-function variants. In patients with schizophrenia who also have intellectual disability, this burden is concentrated in risk genes associated with neurodevelopmental disorders. After excluding known risk genes for neurodevelopmental disorders, a significant rare variant burden persists in other genes intolerant of loss-of-function variants; although this effect is notably stronger in patients with both schizophrenia and intellectual disability, it is also seen in patients with schizophrenia who do not have intellectual disability. Together, our results show that rare, damaging variants contribute to the risk of schizophrenia both with and without intellectual disability and support an overlap of genetic risk between schizophrenia and other neurodevelopmental disorders.

Pre-fermentation fining effects on the aroma chemistry of Marlborough Sauvignon blanc press fractions.

In the wine industry, fining agents are commonly used with many choices now commercially available. Here the influence of pre-fermentation fining on wine aroma chemistry has been explored. Free run and press fraction Sauvignon blanc juices from two vineyards were fined using gelatin, activated carbon, polyvinylpolypyrrolidone (PVPP) and a combination agent which included bentonite, PVPP and isinglass. Over thirty aroma compounds were quantified in the experimental wines. Results showed that activated carbon fining led to a significant (p<0.05) concentration decrease of hexan-1-ol and linalool in the experimental wines when compared to a control, consistent across all vineyard and fraction combinations. Other aroma compounds were also influenced by fining agent, even if vineyards and press fractions played a crucial role. This study confirmed that fining agents used pre-fermentation can influence wine aroma profiles and therefore needs specific tailoring addressing style and origin of grape.

Hydrogen sulfide production during yeast fermentation causes the accumulation of ethanethiol, S-ethyl thioacetate and diethyl disulfide.

Hydrogen sulfide (H2S) is produced by yeast during winemaking and possesses off-flavors reminiscent of rotten eggs. The production of H2S during fermentation has also been associated in the finished wine with the rise of additional volatile sulfur compounds (VSCs) with strong aromas of cooked onions and vegetables. To characterize these more complex VSCs produced from H2S, we performed fermentations in synthetic grape juice. H2S production was manipulated experimentally by feeding increasing concentrations of sulfate to mutant strains that are unable to incorporate H2S efficiently as part of the sulfur assimilation pathway. In finished wines from these mutants, three VSCs - ethanethiol, S-ethyl thioacetate and diethyl disulfide - increased proportionally to H2S. (34)S-labeled sulfate fed to the MET17-deleted strain was incorporated into same three VSCs, demonstrating that they are formed directly from H2S.

Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders.

By analyzing the whole-exome sequences of 4,264 schizophrenia cases, 9,343 controls and 1,077 trios, we identified a genome-wide significant association between rare loss-of-function (LoF) variants in SETD1A and risk for schizophrenia (P = 3.3 × 10(-9)). We found only two heterozygous LoF variants in 45,376 exomes from individuals without a neuropsychiatric diagnosis, indicating that SETD1A is substantially depleted of LoF variants in the general population. Seven of the ten individuals with schizophrenia carrying SETD1A LoF variants also had learning difficulties. We further identified four SETD1A LoF carriers among 4,281 children with severe developmental disorders and two more carriers in an independent sample of 5,720 Finnish exomes, both with notable neuropsychiatric phenotypes. Together, our observations indicate that LoF variants in SETD1A cause a range of neurodevelopmental disorders, including schizophrenia. Combining these data with previous common variant evidence, we suggest that epigenetic dysregulation, specifically in the histone H3K4 methylation pathway, is an important mechanism in the pathogenesis of schizophrenia.

Evolution of Volatile Sulfur Compounds during Wine Fermentation.

Volatile sulfur compounds (VSCs) play a significant role in the aroma of foods and beverages. With very low sensory thresholds and strong unpleasant aromas, most VSCs are considered to have a negative impact on wine quality. In this study, headspace solid phase microextraction coupled with gas chromatography-mass spectrometry (HS-SPME/GC-MS) was used to analyze the time course of the biosynthesis of 12 VSCs formed during wine fermentation. Two different strains of Saccharomyces cerevisiae, the laboratory strain BY4743 and a commercial strain, F15, were assessed using two media: synthetic grape media and Sauvignon Blanc juice. Seven VSCs were detected above background, with three rising above their sensory thresholds. The data revealed remarkable differences in the timing and evolution of production during fermentation, with a transient spike in methanethiol production early during anaerobic growth. Heavier VSCs such as benzothiazole and S-ethyl thioacetate were produced at a steady rate throughout grape juice fermentation, whereas others, such as diethyl sulfide, appear toward the very end of the winemaking process. The results also demonstrate significant differences between yeast strains and fermentation media.

Copy Number Variations in DISC1 and DISC1-Interacting Partners in Major Mental Illness.

Robust statistical, genetic and functional evidence supports a role for DISC1 in the aetiology of major mental illness. Furthermore, many of its protein-binding partners show evidence for involvement in the pathophysiology of a range of neurodevelopmental and psychiatric disorders. Copy number variants (CNVs) are suspected to play an important causal role in these disorders. In this study, CNV analysis of DISC1 and its binding partners PAFAH1B1, NDE1, NDEL1, FEZ1, MAP1A, CIT and PDE4B in Scottish and Northern Swedish population-based samples was carried out using multiplex amplicon quantification. Here, we report the finding of rare CNVs in DISC1, NDE1 (together with adjacent genes within the 16p13.11 duplication), NDEL1 (including the overlapping MYH10 gene) and CIT. Our findings provide further evidence for involvement of DISC1 and its interaction partners in neuropsychiatric disorders and also for a role of structural variants in the aetiology of these devastating diseases.