Toward a better understanding of how a gyrified brain develops.

The size and shape of the cerebral cortex have changed dramatically across evolution. For some species, the cortex remains smooth (lissencephalic) throughout their lifetime, while for other species, including humans and other primates, the cortex increases substantially in size and becomes folded (gyrencephalic). A folded cortex boasts substantially increased surface area, cortical thickness, and neuronal density, and it is therefore associated with higher-order cognitive abilities. The mechanisms that drive gyrification in some species, while others remain lissencephalic despite many shared neurodevelopmental features, have been a topic of investigation for many decades, giving rise to multiple perspectives of how the gyrified cerebral cortex acquires its unique shape. Recently, a structurally unique germinal layer, known as the outer subventricular zone, and the specialized cell type that populates it, called basal radial glial cells, were identified, and these have been shown to be indispensable for cortical expansion and folding. Transcriptional analyses and gene manipulation models have provided an invaluable insight into many of the key cellular and genetic drivers of gyrification. However, the degree to which certain biomechanical, genetic, and cellular processes drive gyrification remains under investigation. This review considers the key aspects of cerebral expansion and folding that have been identified to date and how theories of gyrification have evolved to incorporate this new knowledge.

Effect of Sodium Benzoate vs Placebo Among Individuals With Early Psychosis: A Randomized Clinical Trial.

Importance: There is evidence that sodium benzoate (BZ) may be an effective adjunctive treatment for schizophrenia. The clinical efficacy of BZ has been investigated in chronic schizophrenia; however, the efficacy of this agent has not been studied in individuals with early psychosis. Objective: To examine the clinical efficacy of the adjunctive use of BZ for symptoms in people with early psychosis. Design, Setting, and Participants: Using a placebo-controlled double-masked parallel-group design, this randomized clinical trial was conducted from August 2015 to July 2018. Participants aged between 15 and 45 years experiencing early psychosis were enrolled from 5 major clinical sites in Queensland, Australia. Data analysis was conducted from October 2018 to February 2020. Interventions: Participants were randomized 1:1 (50 participants in each group) to receive 500 mg of sodium benzoate twice daily or placebo for 12 weeks. Main Outcomes and Measures: The primary efficacy outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 12 weeks. The key secondary efficacy measures were (1) the Clinical Global Impression score, (2) the Hamilton Depression Rating Scale for depression, (3) functioning as assessed by the clinician-rated Global Assessment of Function, and (4) the Assessment of Quality of Life Scale. The PANSS subscale scores and impact on selected amino acid concentrations were also assessed. Results: The study comprised 100 participants with a mean (SD) age of 21.4 (4.1) years, of whom 73 (73%) were male individuals. The mean (SD) baseline PANSS score was 75.3 (15.4). We found no improvement in total PANSS score in the BZ group compared with the placebo group. The end result of least-squares mean difference (SE) for total PANSS was -1.2 (2.4) (P = .63). There were no differences in any subscales of the PANSS, any secondary measures, nor any amino acid concentrations. The dose of BZ was well tolerated without any clinically significant treatment-emergent adverse event differences between BZ and placebo groups. Conclusions and Relevance: In this randomized clinical trial, there was no evidence that adjunctive use of 500 mg of BZ twice daily is an effective treatment for individuals with early psychosis. Trial Registration: anzctr.org.au Identifier: ACTRN12615000187549.

Gene expression variation in the brains of harvester ant foragers is associated with collective behavior.

Natural selection on collective behavior acts on variation among colonies in behavior that is associated with reproductive success. In the red harvester ant (Pogonomyrmex barbatus), variation among colonies in the collective regulation of foraging in response to humidity is associated with colony reproductive success. We used RNA-seq to examine gene expression in the brains of foragers in a natural setting. We find that colonies differ in the expression of neurophysiologically-relevant genes in forager brains, and a fraction of these gene expression differences are associated with two colony traits: sensitivity of foraging activity to humidity, and forager brain dopamine to serotonin ratio. Loci that were correlated with colony behavioral differences were enriched in neurotransmitter receptor signaling & metabolic functions, tended to be more central to coexpression networks, and are evolving under higher protein-coding sequence constraint. Natural selection may shape colony foraging behavior through variation in gene expression.

Correction: Increased proliferation and altered cell cycle regulation in pancreatic stem cells derived from patients with congenital hyperinsulinism.

[This corrects the article DOI: 10.1371/journal.pone.0222350.].

Increased proliferation and altered cell cycle regulation in pancreatic stem cells derived from patients with congenital hyperinsulinism.

Congenital hyperinsulinism (CHI) is characterised by inappropriate insulin secretion causing profound hypoglycaemia and brain damage if inadequately controlled. Pancreatic tissue isolated from patients with diffuse CHI shows abnormal proliferation rates, the mechanisms of which are not fully resolved. Understanding cell proliferation in CHI may lead to new therapeutic options, alongside opportunities to manipulate ß-cell mass in patients with diabetes. We aimed to generate cell-lines from CHI pancreatic tissue to provide in vitro model systems for research. Three pancreatic mesenchymal stem cell-lines (CHIpMSC1-3) were derived from patients with CHI disease variants: focal, atypical and diffuse. All CHIpMSC lines demonstrated increased proliferation compared with control adult-derived pMSCs. Cell cycle alterations including increased CDK1 levels and decreased p27Kip1 nuclear localisation were observed in CHIpMSCs when compared to control pMSCs. In conclusion, CHIpMSCs are a useful in vitro model to further understand the cell cycle alterations leading to increased islet cell proliferation in CHI.

Is there a role for antibodies targeting muscarinic acetylcholine receptors in the pathogenesis of schizophrenia?

OBJECTIVE: Muscarinic receptor dysfunction has been suggested to play an important role in the pathophysiology of schizophrenia. Recently, it has also become clear that immune reactivity directed against neurotransmitter receptors may play a pathogenic role in some cases of schizophrenia. The aim of this review is to summarize the case for muscarinic receptor dysfunction in schizophrenia and the evidence supporting the hypothesis that this dysfunction is related to the development of muscarinic receptor-targeting antibodies. METHOD: The article reviews studies of muscarinic receptors and the presence and potential role(s) of anti-muscarinic acetylcholine receptor antibodies in people with schizophrenia. RESULTS: There is accumulating evidence that altered or deficient muscarinic signalling underlies some of the key clinical features of schizophrenia. Although the number of studies investigating anti-muscarinic acetylcholine receptor antibodies in schizophrenia is relatively small, they consistently demonstrate that such antibodies are present in a proportion of patients. This evidence suggests that these antibodies could have pathogenic effects or exist as a biomarker to an unknown pathophysiological process in schizophrenia. CONCLUSION: The presence of elevated levels of anti-muscarinic acetylcholine receptor antibodies may identify a subgroup of people with schizophrenia, potentially informing aetiopathogenesis, clinical presentation and treatment. To date, all studies have examined antibodies in participants with chronic schizophrenia, who have likely received antipsychotic medication for many years. As these medications modulate immune functions and regulate receptor densities, it is recommended that future studies screen for the presence of anti-muscarinic antibodies in people experiencing their first episode of psychosis.

Myokine Regulation of Insulin Secretion: Impact of Inflammation and Type 2 Diabetes.

Skeletal muscle (SkM) secretes protein factors (myokines) that can exert multiple actions. To study the control of myokine regulation of ß-cell function, SkM biopsies were taken from non-diabetic (ND) and Type 2 diabetic (T2D) subjects and satellite cells cultured to myotubes (MT). MT were also treated with lipopolysaccharide (infectious inflammation - II) or a combination of glucose (10 mM), insulin (120 pM), and palmitate (0.4 mM) (metabolic inflammation - MI) to model the inflammatory and metabolic conditions seen in vivo with T2D. Conditioned media (CM) was collected from MT after 24 h and used to treat INS-1 cells for 24 h. Cell viability, total insulin content, glucose-stimulated insulin secretion (GSIS) and maximal (IBMX-stimulated) IS (ISmax) were monitored. Under baseline conditions, CM from ND and T2D MT had no effects on INS-1 cell viability, insulin content, GSIS, or ISmax. After exposure to II, CM from ND-MT augmented GSIS in INS-1 cells by 100 ± 25% over control (p < 0.05); T2D-CM had no effect. After exposure to MI, T2D-CM suppressed GSIS by 35 ± 5% (p < 0.05); ND-CM was without effect. Under either of these conditions cell viability, total insulin content and ISmax were unaffected. Effects of CM on GSIS were lost after CM was boiled. Both augmentation of GSIS by ND-CM from II-treated MT, and suppression by T2D-CM from MI-treated MT, were inhibited by wortmannin, Ro 31-8220, and SB203580. In summary: (1) ND-MT are able to augment GSIS when stressed, (2) T2D-MT responding to a diabetic-like environment secrete myokines that suppress GSIS, (3) Unknown protein factors exert effects specifically on GSIS, possibly through PI-3K, PKC, and/or p38 MAPK. In T2D, both insulin resistance and a suppression of adaptive increased insulin secretion are intrinsic properties of SkM that can contribute to the full T2D phenotype.

Correction to: Mitochondrial H+-ATP synthase in human skeletal muscle: contribution to dyslipidaemia and insulin resistance.

Owing to an oversight, the authors omitted to note that Dr Taub is a co-founder of and equity holder in Cardero Therapeutics.

Cognitive outcomes following anti-N-methyl-D-aspartate receptor encephalitis: A systematic review.

INTRODUCTION: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an immune-mediated neurological disorder that (among other severe neuropsychiatric symptoms) affects cognition. This study aimed to summarize current knowledge regarding the rates, nature, and predictors of neuropsychological dysfunction in patients recovering from anti-NMDAR encephalitis. METHOD: A systematic review of studies describing neuropsychological outcomes following anti-NMDAR encephalitis was conducted. Electronic databases Medline, PsycINFO, EMBASE, and CINAHL were searched from inception to September 2016. Results were summarized using descriptive statistics and a series of chi-square analyses. RESULTS: Of 4030 identified studies, 44 were included. These reported neuropsychological outcomes for 109 treated patients (83.5% female, Mage = 22.5 years, range = 2-67) recovering from anti-NMDAR encephalitis. High rates of neuropsychological dysfunction were identified, with diverse impairments of variable severity documented in >75% of patients at assessments conducted during acute, subacute, and longer term recovery periods. Despite this, cognitive outcomes were ultimately considered favorable in most cases (74.3%). This estimate does not account for the potential impact of relapses. The frequency of impairments in overall intellectual functioning, language, attention, working memory, and visuospatial functions were significantly higher within the acute recovery period than in later phases of convalescence. However, rates of impaired processing speed, episodic memory, and aspects of executive functioning were consistent across time points. Adverse neuropsychological outcomes occurred at significantly higher frequency in patients where immunotherapy was delayed, χ2(1, N = 66) = 10.84, p < .003. CONCLUSIONS: Neuropsychological deficits are prevalent at all points of recovery from anti-NMDAR encephalitis, although improvement in cognitive outcomes can be expected as patients recover. Some cognitive deficits may be less likely than others to resolve. Close neuropsychological monitoring is warranted in this population. Longitudinal studies of neuropsychological functioning of patients with anti-NMDAR encephalitis are needed to accurately inform prognosis.

Mitochondrial H+-ATP synthase in human skeletal muscle: contribution to dyslipidaemia and insulin resistance.

AIMS/HYPOTHESIS: Mitochondria are important regulators of the metabolic phenotype in type 2 diabetes. A key factor in mitochondrial physiology is the H+-ATP synthase. The expression and activity of its physiological inhibitor, ATPase inhibitory factor 1 (IF1), controls tissue homeostasis, metabolic reprogramming and signalling. We aimed to characterise the putative role of IF1 in mediating skeletal muscle metabolism in obesity and diabetes. METHODS: We examined the 'mitochondrial signature' of obesity and type 2 diabetes in a cohort of 100 metabolically characterised human skeletal muscle biopsy samples. The expression and activity of H+-ATP synthase, IF1 and key mitochondrial proteins were characterised, including their association with BMI, fasting plasma insulin, fasting plasma glucose and HOMA-IR. IF1 was also overexpressed in primary cultures of human myotubes derived from the same biopsies to unveil the possible role played by the pathological inhibition of the H+-ATP synthase in skeletal muscle. RESULTS: The results indicate that type 2 diabetes and obesity act via different mechanisms to impair H+-ATP synthase activity in human skeletal muscle (76% reduction in its catalytic subunit vs 280% increase in IF1 expression, respectively) and unveil a new pathway by which IF1 influences lipid metabolism. Mechanistically, IF1 altered cellular levels of α-ketoglutarate and L-carnitine metabolism in the myotubes of obese (84% of control) and diabetic (76% of control) individuals, leading to limited ß-oxidation of fatty acids (60% of control) and their cytosolic accumulation (164% of control). These events led to enhanced release of TNF-α (10 ± 2 pg/ml, 27 ± 5 pg/ml and 35 ± 4 pg/ml in control, obese and type 2 diabetic participants, respectively), which probably contributes to an insulin resistant phenotype. CONCLUSIONS/INTERPRETATION: Overall, our data highlight IF1 as a novel regulator of lipid metabolism and metabolic disorders, and a possible target for therapeutic intervention.

Cognitive and Social Functioning Deficits after Anti-N-Methyl-D-Aspartate Receptor Encephalitis: An Exploratory Case Series.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a recently described life-threatening autoimmune disorder associated with a characteristic multi-stage neuropsychiatric syndrome. Although it is known that the majority of patients experience neuropsychological disturbance post-treatment, some aspects of the cognitive profile remain unclear. METHODS: This study sought to investigate patterns of cognitive functioning in a sample of anti-NMDAR encephalitis patients. Seven (6F:1M; mean age, 26.4 years; range, 16-37 years) treated patients completed a comprehensive set of neurocognitive and social functioning measures. Performance was analyzed using normative data (where available), and comparison with matched controls (10F:4M; mean age, 25.8 years; range, 16-38 years). RESULTS: Individual cognitive profiles ranged from within normal limits to extensive dysfunction. Relative to controls, the patient group's performance was affected in the domains of verbal/ visual memory, working memory, attention, processing speed, executive functioning, and social cognition. The patient group also reported significantly higher levels of anxiety compared to controls. CONCLUSIONS: These results add to the accumulating evidence that neurocognitive deficits, consistent with the distribution and functions of the NMDAR system can persist during recovery from anti-NMDAR encephalitis. This is the first study to provide evidence of performance decrements on measures of social cognition, including some involving theory of mind. (JINS, 2016, 22, 828-838).

Altered Myokine Secretion Is an Intrinsic Property of Skeletal Muscle in Type 2 Diabetes.

Skeletal muscle secretes factors, termed myokines. We employed differentiated human skeletal muscle cells (hSMC) cultured from Type 2 diabetic (T2D) and non-diabetic (ND) subjects to investigate the impact of T2D on myokine secretion. Following 24 hours of culture concentrations of selected myokines were determined to range over 4 orders of magnitude. T2D hSMC released increased amounts of IL6, IL8, IL15, TNFa, Growth Related Oncogene (GRO)a, monocyte chemotactic protein (MCP)-1, and follistatin compared to ND myotubes. T2D and ND hSMC secreted similar levels of IL1ß and vascular endothelial growth factor (VEGF). Treatment with the inflammatory agents lipopolysaccharide (LPS) or palmitate augmented the secretion of many myokines including: GROa, IL6, IL8, IL15, and TNFa, but did not consistently alter the protein content and/or phosphorylation of IkBa, p44/42 MAPK, p38 MAPK, c-Jun N-terminal kinase (JNK) and NF-kB, nor lead to consistent changes in basal and insulin-stimulated glucose uptake or free fatty acid oxidation. Conversely, treatment with pioglitazone or oleate resulted in modest reductions in the secretion of several myokines. Our results demonstrate that altered secretion of a number of myokines is an intrinsic property of skeletal muscle in T2D, suggesting a putative role of myokines in the response of skeletal muscle to T2D.

Visual spatial attention has opposite effects on bidirectional plasticity in the human motor cortex.

Long-term potentiation (LTP) and long-term depression (LTD) are key mechanisms of synaptic plasticity that are thought to act in concert to shape neural connections. Here we investigated the influence of visual spatial attention on LTP-like and LTD-like plasticity in the human motor cortex. Plasticity was induced using paired associative stimulation (PAS), which involves repeated pairing of peripheral nerve stimulation and transcranial magnetic stimulation to alter functional responses in the thumb area of the primary motor cortex. PAS-induced changes in cortical excitability were assessed using motor-evoked potentials. During plasticity induction, participants directed their attention to one of two visual stimulus streams located adjacent to each hand. When participants attended to visual stimuli located near the left thumb, which was targeted by PAS, LTP-like increases in excitability were significantly enhanced, and LTD-like decreases in excitability reduced, relative to when they attended instead to stimuli located near the right thumb. These differential effects on (bidirectional) LTP-like and LTD-like plasticity suggest that voluntary visual attention can exert an important influence on the functional organization of the motor cortex. Specifically, attention acts to both enhance the strengthening and suppress the weakening of neural connections representing events that fall within the focus of attention.

Isotretinoin and mental health in adolescents: Australian consensus.

Acne is a common condition among adolescents and has the potential to negatively impact on the psychological well-being of those who suffer from it. In particular, depression and suicidal ideation are more common in adolescents with acne. Successful treatment of acne can improve the quality of life and reduce levels of anxiety and depression in these individuals. The current treatment of choice for severe or refractive acne is isotretinoin, a retinoid. While the possible causal association between isotretinoin and mental illness remains a controversial topic, a recent systematic review has presented evidence to support this relationship. In light of this evidence, a group of dermatologists and psychiatrists have collaborated to develop these recommendations to aid the safe prescribing of isotretinoin in adolescents. These clinical suggestions are aimed at practitioners in both disciplines to increase awareness of the current evidence in support of the association between isotretinoin and adolescent depression.

The emerging role of PtdIns5P: another signalling phosphoinositide takes its place.

Of the seven phosphoinositides, PtdIns5P remains the most enigmatic. However, recent research has begun to elucidate its physiological functions. It is now clear that PtdIns5P is found in several distinct subcellular locations, and the identification of a number of PtdIns5P-binding proteins points to its involvement in a variety of key processes, including signal transduction, membrane trafficking and regulation of gene expression. Although the mechanisms that control its turnover are not yet fully understood, the existence of multiple pathways for PtdIns5P regulation is consistent with this emerging versatility.

Involvement of phosphatidylinositol 5-phosphate in insulin-stimulated glucose uptake in the L6 myotube model of skeletal muscle.

The phosphoinositide phospholipid PtdIns5P has previously been implicated in insulin-stimulated translocation of the glucose transporter GLUT4 into the plasma membrane of adipocytes, but its potential role in glucose transport in muscle has not been explored. The involvement of PtdIns5P in insulin-stimulated glucose uptake was therefore investigated in myotubes of the skeletal muscle cell line L6. Stimulation with insulin produced a transient increase in PtdIns5P, which was abolished by the over-expression of the highly active PtdIns5P 4-kinase PIP4Kα. PIP4Kα over-expression also abolished both the enhanced glucose uptake and the robust peak of PtdIns(3,4,5)P (3) production stimulated by insulin in myotubes. Delivery of exogenous PtdIns5P into unstimulated myotubes increased Akt phosphorylation, promoted GLUT4 relocalisation from internal membrane to plasma membrane fractions and its association with plasma membrane lawns and also stimulated glucose uptake in a tyrosine kinase and phosphoinositide 3-kinase (PI 3-kinase)-dependent fashion. Our results are consistent with a role for insulin-stimulated PtdIns5P production in regulating glucose transport by promoting PI 3-kinase signalling.