MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume.

Background/Objective. Enlarged lateral ventricle (LV) volume and decreased volume in the corpus callosum (CC) are hallmarks of schizophrenia (SZ). We previously showed an inverse correlation between LV and CC volumes in SZ, with global functioning decreasing with increased LV volume. This study investigates the relationship between LV volume, CC abnormalities, and the microRNA MIR137 and its regulated genes in SZ, because of MIR137's essential role in neurodevelopment. Methods. Participants were 1224 SZ probands and 1466 unaffected controls from the GENUS Consortium. Brain MRI scans, genotype, and clinical data were harmonized across cohorts and employed in the analyses. Results. Increased LV volumes and decreased CC central, mid-anterior, and mid-posterior volumes were observed in SZ probands. The MIR137-regulated ephrin pathway was significantly associated with CC:LV ratio, explaining a significant proportion (3.42 %) of CC:LV variance, and more than for LV and CC separately. Other pathways explained variance in either CC or LV, but not both. CC:LV ratio was also positively correlated with Global Assessment of Functioning, supporting previous subsample findings. SNP-based heritability estimates were higher for CC central:LV ratio (0.79) compared to CC or LV separately. Discussion. Our results indicate that the CC:LV ratio is highly heritable, influenced in part by variation in the MIR137-regulated ephrin pathway. Findings suggest that the CC:LV ratio may be a risk indicator in SZ that correlates with global functioning.

Mapping neurodevelopment with sleep macro- and micro-architecture across multiple pediatric populations.

Profiles of sleep duration and timing and corresponding electroencephalographic activity reflect brain changes that support cognitive and behavioral maturation and may provide practical markers for tracking typical and atypical neurodevelopment. To build and evaluate a sleep-based, quantitative metric of brain maturation, we used whole-night polysomnography data, initially from two large National Sleep Research Resource samples, spanning childhood and adolescence (total N = 4,013, aged 2.5 to 17.5 years): the Childhood Adenotonsillectomy Trial (CHAT), a research study of children with snoring without neurodevelopmental delay, and Nationwide Children's Hospital (NCH) Sleep Databank, a pediatric sleep clinic cohort. Among children without neurodevelopmental disorders (NDD), sleep metrics derived from the electroencephalogram (EEG) displayed robust age-related changes consistently across datasets. During non-rapid eye movement (NREM) sleep, spindles and slow oscillations further exhibited characteristic developmental patterns, with respect to their rate of occurrence, temporal coupling and morphology. Based on these metrics in NCH, we constructed a model to predict an individual's chronological age. The model performed with high accuracy (r = 0.93 in the held-out NCH sample and r = 0.85 in a second independent replication sample - the Pediatric Adenotonsillectomy Trial for Snoring (PATS)). EEG-based age predictions reflected clinically meaningful neurodevelopmental differences; for example, children with NDD showed greater variability in predicted age, and children with Down syndrome or intellectual disability had significantly younger brain age predictions (respectively, 2.1 and 0.8 years less than their chronological age) compared to age-matched non-NDD children. Overall, our results indicate that sleep architectureoffers a sensitive window for characterizing brain maturation, suggesting the potential for scalable, objective sleep-based biomarkers to measure neurodevelopment.

Spindle Chirp and other Sleep Oscillatory Features in Young Children with Autism.

Objectives: To determine whether spindle chirp and other sleep oscillatory features differ in young children with and without autism. Methods: Automated processing software was used to re-assess an extant set of polysomnograms representing 121 children (91 with autism [ASD], 30 typically-developing [TD]), with an age range of 1.35-8.23 years. Spindle metrics, including chirp, and slow oscillation (SO) characteristics were compared between groups. SO and fast and slow spindle (FS, SS) interactions were also investigated. Secondary analyses were performed assessing behavioural data associations, as well as exploratory cohort comparisons to children with non-autism developmental delay (DD). Results: Posterior FS and SS chirp was significantly more negative in ASD than TD. Both groups had comparable intra-spindle frequency range and variance. Frontal and central SO amplitude were decreased in ASD. In contrast to previous manual findings, no differences were detected in other spindle or SO metrics. The ASD group displayed a higher parietal coupling angle. No differences were observed in phase-frequency coupling. The DD group demonstrated lower FS chirp and higher coupling angle than TD. Parietal SS chirp was positively associated with full developmental quotient. Conclusions: For the first time spindle chirp was investigated in autism and was found to be significantly more negative than in TD in this large cohort of young children. This finding strengthens previous reports of spindle and SO abnormalities in ASD. Further investigation of spindle chirp in healthy and clinical populations across development will help elucidate the significance of this difference and better understand this novel metric.

Temperature impacts Atlantic salmon's (Salmo salar) immunological response to infectious salmon anemia virus (ISAv).

Ocean temperatures continue to rise annually due to the ever-growing consequences of global climate change. These temperature changes can have an impact on the immunological robustness of cultured fish, especially cold-water species such as Atlantic salmon. The salmon farming industry already loses hundreds of millions of dollars each year to infectious and non-infectious diseases. One particularly important and WOAH reportable disease is infectious salmon anemia caused by the orthomyxovirus ISAv. Considering the changing environment, it is necessary to find ways to mitigate the effect of diseases on the industry. For this study, 20 Atlantic salmon families were housed in each of 38 different tanks at the AVC, with half of the fish being kept at 10 °C and half being kept at 20 °C. Donor Atlantic salmon IP- injected with a highly virulent ISAv isolate (HPR4; TCID50 of 1 × 105/mL) were added to each tank as the source of co-habitation infection. Both temperatures were sampled at onset of mortality in co-habited fish and at resolution of mortality. Family background and temperature significantly impacted ISAv load, as assessed by qPCR, time to mortality and overall mortality. Mortality was more acute at 20 °C, but overall mortality was higher at 10 °C. Based on percent mortality calculated over the course of the study, different families demonstrated different levels of survival. The three families that demonstrated the highest percent mortality, and the three families with the lowest percent mortality were then assessed for their antiviral responses using relative gene expression. Genes significantly upregulated between the unexposed fish and ISAv exposed fish included mx1, il4/13a, il12rb2, and trim25, and these were further impacted by temperature. Understanding how ISAv resistance is impacted by temperature can help identify seasonal risks of ISAv outbreaks as well as ideal responses to be targeted through immunopotentiation.

Treatment of moderate grade dog bite wounds using amoxicillin-clavulanic acid with and without enrofloxacin: a randomised non-inferiority trial.

BACKGROUND: Dog-to-dog bite wounds are a common veterinary emergency presentation: despite this, there is insufficient information to guide veterinarians on appropriate empirical antimicrobial management. OBJECTIVES: Investigate the effectiveness of amoxicillin-clavulanic acid with and without enrofloxacin in the treatment of moderate grade dog bite wounds (DBW). To describe common pathogens and their antimicrobial susceptibility patterns. MATERIALS AND METHODS: In a single-centre parallel group pragmatic trial, 50 dogs presenting with moderate grade DBW were prospectively randomised to receive amoxicillin-clavulanic acid (group A) or amoxicillin-clavulanic acid and enrofloxacin (group B). Swabs were taken for culture and susceptibility testing at admission. Stabilisation, wound care and surgical debridement were performed at the discretion of admitting clinicians. The primary outcome was complication due to infection at 10 days, with Bayesian inference used to estimate the difference in proportions between treatment groups. RESULTS: Of the 24 dogs in treatment group A, 1 required the addition of enrofloxacin at re-examination. None of the 26 dogs in group B required alteration of antimicrobial coverage. The difference in complication rate due to infection between treatment groups was 4.2%. Twenty-one different organisms were identified: Staphylococcus pseudintermedius, Neisseria spp., Pasteurella multocida and P. canis were the most common. Over 90% of gram-negative and gram-positive isolates were susceptible to amoxicillin-clavulanic acid. Ninety-six percent of gram-negative and 86% of gram-positive isolates were susceptible to enrofloxacin. CONCLUSION AND CLINICAL SIGNIFICANCE: Amoxicillin-clavulanic acid is an appropriate empirical antimicrobial choice for moderate DBW in South East Queensland. Reduced empirical enrofloxacin use will promote antimicrobial stewardship and potentially antimicrobial resistance.

Sarcopenia Prevalence Using Different Definitions in Older Community-Dwelling Canadians.

OBJECTIVES: Sarcopenia is a debilitating condition affecting millions of individuals worldwide and is defined with different criteria. The objective of this study was to determine the prevalence of sarcopenia in older Canadians using three internationally accepted criteria. DESIGN: Observational cohort study. SETTINGS AND PARTICIPANTS: Data from 12,592 subjects [6,314 males (50.1%), 6,278 females (49.9%)] ≥65 years old in the Canadian Longitudinal Study on Aging were included. MEASUREMENTS: Appendicular lean mass (ALM; kg) and appendicular lean mass index (ALM kg/height in m2) were collected from dual X-ray absorptiometry measurements. Physical performance was assessed using the 4-m gait speed test, and muscle strength was measured by hand dynamometry. Sarcopenia was defined according to criteria put forth by the International Working Group on Sarcopenia (IWGS), Foundation for the National Institutes of Health (FNIH) Sarcopenia Project, and revised European Working Group on Sarcopenia in Older People (EWGSOP). Positive and negative percent agreements and Cohen's kappa (κ) described the agreement among sarcopenia definitions. RESULTS: Among the evaluated criteria, gait speed ≤ 1.0 m/s (IWGS definition of slowness) was the most frequently identified deficit (56.8% males, 57.2% females). The prevalence of sarcopenia ranged from 1.4 to 5.2% in males and 1.6 to 7.2 % in females among the different definitions. Positive percent agreement values among criteria were generally low (range: 1.5 - 55.3%) and corresponded to κ indicating none to minimal agreement (0.01 - 0.23). Negative percent agreement values were ≥ 95%. CONCLUSION: Sarcopenia prevalence was relatively low in older Canadian adults and current definitions had poor agreement in diagnosing individuals as sarcopenic.

Internal quantum efficiency of AlGaN/AlN quantum dot superlattices for electron-pumped ultraviolet sources.

In this paper, we describe the growth and characterization of ≈530 nm thick superlattices (100 periods) of AlxGa1-xN/AlN (0 ⩽ x ⩽ 0.1) Stranski-Krastanov quantum dots (QDs) for application as the active region of electron-beam pumped ultraviolet lamps. Highly dense (>1011 cm-2) QD layers are deposited by molecular beam epitaxy, and we explore the effect of the III/V ratio during the growth process on their optical performance. The study considers structures emitting in the 244-335 nm range at room temperature, with a relative linewidth in the 6%-11% range, mainly due to the QD diameter dispersion inherent in self-assembled growth. Under electron pumping, the emission efficiency remains constant for acceleration voltages below ≈9 kV. The correlation of this threshold with the total thickness of the SL and the penetration depth of the electron beam confirms the homogeneity of the nanostructures along the growth axis. Below the threshold, the emission intensity scales linearly with the injected current. The internal quantum efficiency (IQE) is characterized at low injection, which reveals the material properties in terms of non-radiative processes, and high injection, which emulates carrier injection in operation conditions. In QDs synthesized with III/V ratio <0.75, the IQE remains around 50% from low injection to pumping power densities as high as 200 kW cm-2, being the first kind of nanostructure that present such stable behaviour.

Assessment of AlGaN/AlN superlattices on GaN nanowires as active region of electron-pumped ultraviolet sources.

In this paper, we describe the design and characterization of 400 nm long (88 periods) Al x Ga1-x N/AlN (0 ≤ x ≤ 0.1) quantum dot superlattices deposited on self-assembled GaN nanowires for application in electron-pumped ultraviolet sources. The optical performance of GaN/AlN superlattices on nanowires is compared with the emission of planar GaN/AlN superlattices with the same periodicity and thickness grown on bulk GaN substrates along the N-polar and metal-polar crystallographic axes. The nanowire samples are less sensitive to nonradiative recombination than planar layers, attaining internal quantum efficiencies (IQE) in excess of 60% at room temperature even under low injection conditions. The IQE remains stable for higher excitation power densities, up to 50 kW cm-2. We demonstrate that the nanowire superlattice is long enough to collect the electron-hole pairs generated by an electron beam with an acceleration voltage V A = 5 kV. At such V A, the light emitted from the nanowire ensemble does not show any sign of quenching under constant electron beam excitation (tested for an excitation power density around 8 kW cm-2 over the scale of minutes). Varying the dot/barrier thickness ratio and the Al content in the dots, the nanowire peak emission can be tuned in the range from 340 to 258 nm.

Anaphylaxis associated with intravenous administration of alphaxalone in a dog.

CASE REPORT: We describe the clinical signs and management of a case of anaphylaxis in a dog after intravenous administration of alphaxalone (Alfaxan®, Jurox, NSW, Aust), which has not been previously published. A female spayed cattle dog undergoing routine imaging for forelimb lameness was induced with Alfaxan after receiving sedation with acepromazine and methadone 70 min prior. Immediately after intravenous administration of Alfaxan, the dog exhibited vomiting and diarrhoea associated with acute hypotension. Gallbladder wall oedema was visualised consistent with anaphylaxis. The dog responded to rapid volume expansion. Adrenaline was not required. The dog made a full recovery within 6 h of the reaction and was re-anaesthetised 3 days later without incident, using propofol as the induction agent. CONCLUSION: To our knowledge, this is the first published case of anaphylaxis associated with intravenous Alfaxan in the dog. The APVMA reporting of reactions in small animals from 2003 to 2013 of Alfaxan is consistent with this case report's finding involving the respiratory, circulatory and gastrointestinal systems.

The Early Psychosis Screener for Internet (EPSI)-SR: Predicting 12 month psychotic conversion using machine learning.

INTRODUCTION: A faster and more accurate self-report screener for early psychosis is needed to promote early identification and intervention. METHODS: Self-report Likert-scale survey items were administered to individuals being screened with the Structured Interview for Psychosis-risk Syndromes (SIPS) and followed at eight early psychosis clinics. An a priori analytic plan included Spectral Clustering Analysis to reduce the item pool, followed by development of Support Vector Machine (SVM) classifiers. RESULTS: The cross-validated positive predictive value (PPV) of the EPSI at the default cut-off (76.5%) exceeded that of the clinician-administered SIPS (68.5%) at separating individuals who would not convert to psychosis within 12 months from those who either would convert within 12 months or who had already experienced a first episode psychosis (FEP). When used in tandem with the SIPS on clinical high risk participants, the EPSI increased the combined PPV to 86.6%. The SVM classified as FEP/converters only 1% of individuals in non-clinical and 4% of clinical low risk populations. Sensitivity of the EPSI, however, was 51% at the default cut-off. DISCUSSION: The EPSI identifies, comparably to the SIPS but in less time and with fewer resources, individuals who are either at very high risk to develop a psychotic disorder within 12 months or who are already psychotic. At its default cut-off, EPSI misses 49% of current or future psychotic cases. The cut-off can, however, be adjusted based on purpose. The EPSI is the first validated assessment to predict 12-month psychotic conversion. An online screening system, www.eps.telesage.org, is under development.

Giant, Voltage Tuned, Quality Factors of Single Wall Carbon Nanotubes and Graphene at Room Temperature.

Mastering dissipation in graphene-based nanostructures is still the major challenge in most fundamental and technological exploitations of these ultimate mechanical nanoresonators. Although high quality factors have been measured for carbon nanotubes (>106) and graphene (>105) at cryogenic temperatures, room-temperature values are orders of magnitude lower (≃102). We present here a controlled quality factor increase of up to ×103 for these basic carbon nanostructures when externally stressed like a guitar string. Quantitative agreement is found with theory attributing this decrease in dissipation to the decrease in viscoelastic losses inside the material, an effect enhanced by tunable "soft clamping". Quality factors exceeding 25 000 for SWCNTs and 5000 for graphene were obtained on several samples, reaching the limits of the graphene material itself. The combination of ultralow size and mass with high quality factors opens new perspectives for atomically localized force sensing and quantum computing as the coherence time exceeds state-of-the-art cryogenic devices.

Determining the composition of the vacuum-liquid interface in ionic-liquid mixtures.

The vacuum-liquid interfaces of a number of ionic-liquid mixtures have been investigated using the combination of reactive-atom scattering with laser-induced fluorescence detection (RAS-LIF), selected surface tension measurements, and molecular dynamics (MD) simulations. The mixtures are based on the widespread 1-alkyl-3-methylimidazolium ([Cnmim]+) cation, including mixed cations which differ in chain length or chemical functionality with a common anion; and different anions for a common cation. RAS-LIF results imply that the surface compositions exhibit a general form of non-stoichiometric behaviour that mimics the well-known Henry's and Raoult's laws at low and high mole fraction, respectively. The extended Langmuir model provides a moderately good single-parameter fit, but higher-order terms are required for an accurate description. The quantitative relationship between RAS-LIF and surface tension, which probes the surface composition only indirectly, is explored for mixtures of [C2mim]+ and [C12mim]+ with a common bis(trifluoromethylsulfonyl)imide ([NTf2]-) anion. Extended Langmuir model fits to surface tension data are broadly consistent with those to RAS-LIF; however, several other common approaches to extracting surface compositions from measured surface tensions result in much larger discrepancies. MD simulations suggest that RAS-LIF faithfully reports on the alkyl-chain exposure at the surface, which is only subtly modified by composition-dependent structural reorganisation.

DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/ß-catenin signaling.

Mice lacking DIX domain containing-1 (DIXDC1), an intracellular Wnt/ß-catenin signal pathway protein, have abnormal measures of anxiety, depression and social behavior. Pyramidal neurons in these animals' brains have reduced dendritic spines and glutamatergic synapses. Treatment with lithium or a glycogen synthase kinase-3 (GSK3) inhibitor corrects behavioral and neurodevelopmental phenotypes in these animals. Analysis of DIXDC1 in over 9000 cases of autism, bipolar disorder and schizophrenia reveals higher rates of rare inherited sequence-disrupting single-nucleotide variants (SNVs) in these individuals compared with psychiatrically unaffected controls. Many of these SNVs alter Wnt/ß-catenin signaling activity of the neurally predominant DIXDC1 isoform; a subset that hyperactivate this pathway cause dominant neurodevelopmental effects. We propose that rare missense SNVs in DIXDC1 contribute to psychiatric pathogenesis by reducing spine and glutamatergic synapse density downstream of GSK3 in the Wnt/ß-catenin pathway.

Fat mass to fat-free mass ratio reference values from NHANES III using bioelectrical impedance analysis.

BACKGROUND & AIM: Low fat-free mass (FFM) or high fat mass (FM) are abnormal body composition phenotypes associated with morbidity. These conditions in combination lead to worse health outcomes, and can be identified by a high FM/FFM ratio. Here, we developed sex, age, and body mass index (BMI) stratified, population-based FM/FFM reference values using bioelectrical impedance analysis (BIA) measurements. METHODS: White, non-Hispanic individuals aged 18-90 years old with data for weight, stature and BIA resistance measures from the third National Health and Nutrition Examination Survey (NHANES) III were included. Previously validated and sex-specific BIA prediction equations were used to calculate FM and FFM. FM/FFM values were generated at 5th, 50th and 95th percentiles for each sex, age (18-39.9, 40-59.9, 60-69.9 and 70-90 years), and BMI category (underweight, normal weight, overweight, class I/II and class III obesity). RESULTS: A total of 6372 individuals who had estimated FM and FFM values were identified (3366 females, 3006 males). Median values of FM/FFM were 0.24 and 0.40 for young (≤39.9 years) males and females with normal BMI, and 0.34 for males and 0.59 for females who were overweight. For elderly individuals aged >70 years, median FM/FFM for males and females were respectively 0.28 and 0.45 for those with normal BMI, and 0.37 and 0.61 for those in the overweight category. CONCLUSIONS: These FM/FFM reference values provide information on body composition characteristics that account for age, sex and BMI, which can be useful to identify individuals at risk for body composition abnormalities.

Characterizing sleep spindles in 11,630 individuals from the National Sleep Research Resource.

Sleep spindles are characteristic electroencephalogram (EEG) signatures of stage 2 non-rapid eye movement sleep. Implicated in sleep regulation and cognitive functioning, spindles may represent heritable biomarkers of neuropsychiatric disease. Here we characterize spindles in 11,630 individuals aged 4 to 97 years, as a prelude to future genetic studies. Spindle properties are highly reliable but exhibit distinct developmental trajectories. Across the night, we observe complex patterns of age- and frequency-dependent dynamics, including signatures of circadian modulation. We identify previously unappreciated correlates of spindle activity, including confounding by body mass index mediated by cardiac interference in the EEG. After taking account of these confounds, genetic factors significantly contribute to spindle and spectral sleep traits. Finally, we consider topographical differences and critical measurement issues. Taken together, our findings will lead to an increased understanding of the genetic architecture of sleep spindles and their relation to behavioural and health outcomes, including neuropsychiatric disorders.

Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder.

We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Disorder Working Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P=3.28 × 10-8) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP-h2=0.35; BD II SNP-h2=0.25; P=0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined.

Interleukin-8, interleukin-1ß and tumour necrosis factor-α in sequential units of packed red blood cells collected from retired racing Greyhounds.

BACKGROUND: We hypothesised that concentrations of interleukin-8 (IL-8), interleukin-1ß (IL-1ß) and tumour necrosis factor-α (TNF-α) would increase during storage in the third sequential unit (U3) of canine packed red blood cells (PRBC) collected from terminal donors in haemorrhagic shock. We further hypothesised that leucoreduction would prevent cytokine accumulation in U3 and that cytokine concentrations in U3 would be higher than in the first units (U1) collected from the same dogs. METHODS: U1 and U3 were each collected from 12 anaesthetised healthy Greyhounds. Removal of leucocytes from half of each PRBC unit produced one leucoreduced (LR) and one non-leucoreduced (NLR) unit. Canine IL-8, IL-1ß and TNF-α concentrations were measured in samples collected from the units during storage on days 0, 10, 20, 30 and 37. RESULTS: The IL-8 concentration in U3 NLR units was significantly higher on days 10, 20, 30 and 37 than on day 0 and was significantly higher than in the LR units at all time points. The IL-1ß concentration in U3 did not change over time, or between LR and NLR units. TNF-α was not detected in any unit. There were no significant differences in IL-8 or IL-1ß concentrations between U3 and U1 at any time point; however, some NLR U3 units had markedly elevated IL-8 concentrations at day 37 (2060-20,682 pg/mL) compared with NLR U1 units (3369-5280 pg/mL). CONCLUSION: NLR U3 units collected from dogs in haemorrhagic shock showed a significant increase in IL-8 concentrations during storage. Leucoreduction was effective at preventing the accumulation of IL-8. There was no difference detected between U3 and U1.

Functional analysis of rare variants found in schizophrenia implicates a critical role for GIT1-PAK3 signaling in neuroplasticity.

Although the pathogenesis of schizophrenia (SCZ) is proposed to involve alterations of neural circuits via synaptic dysfunction, the underlying molecular mechanisms remain poorly understood. Recent exome sequencing studies of SCZ have uncovered numerous single-nucleotide variants (SNVs); however, the majority of these SNVs have unknown functional consequences, leaving their disease relevance uncertain. Filling this knowledge gap requires systematic application of quantitative and scalable assays to assess known and novel biological functions of genes. Here we demonstrate loss-of-function effects of multiple rare coding SNVs found in SCZ subjects in the GIT1 (G protein-coupled receptor kinase interacting ArfGAP 1) gene using functional cell-based assays involving coexpression of GIT1 and PAK3 (p21 protein (Cdc42/Rac)-activated kinase 3). Most notably, a GIT1-R283W variant reported in four independent SCZ cases was defective in activating PAK3 as well as MAPK (mitogen-activated protein kinase). Similar functional deficits were found for a de novo SCZ variant GIT1-S601N. Additional assays revealed deficits in the capacity of GIT1-R283W to stimulate PAK phosphorylation in cultured hippocampal neurons. In addition, GIT1-R283W showed deficits in the induction of GAD1 (glutamate decarboxylase 1) protein expression. Extending these functional assays to 10 additional rare GIT1 variants revealed the existence of an allelic series with the majority of the SCZ case variants exhibiting loss of function toward MAPK activation in a manner correlated with loss of PAK3 activation. Taken together, we propose that rare variants in GIT1, along with other genetic and environmental factors, cause dysregulation of PAK3 leading to synaptic deficits in SCZ.

Key determinants of energy expenditure in cancer and implications for clinical practice.

Great discrepancies exist in the reported prevalence of altered energy metabolism (hypo- or hypermetabolism) in cancer patients, which is likely due to the vast array of phenomena that can affect energy expenditure in these patients. The purpose of this review was to critically evaluate key determinants of energy expenditure in cancer and the relevance for clinical practice. Resting energy expenditure (REE) is the largest and most commonly measured component of total energy expenditure. In addition to the energetic demand of the tumor itself, REE may be increased due to changes in inflammation, body composition and brown adipose tissue activation. Energy expenditure from physical activity is often lower in cancer compared with healthy populations, and there is evidence to suggest that the thermic effect of food might also be blunted and affected by cancer therapy. Although accurate assessment of energy metabolism is a cornerstone of adequate nutritional therapy, prediction methods often do not capture the true energy expenditure of most cancer patients. In fact, limits of agreement of prediction equations may range from 40% below to 30% above measured REE. Such variability highlights the need for a more comprehensive understanding of energy expenditure in cancer and the value of accurately assessing the energy needs of these patients.

Analysis of exome sequence in 604 trios for recessive genotypes in schizophrenia.

Genetic associations involving both rare and common alleles have been reported for schizophrenia but there have been no systematic scans for rare recessive genotypes using fully phased trio data. Here, we use exome sequencing in 604 schizophrenia proband-parent trios to investigate the role of recessive (homozygous or compound heterozygous) nonsynonymous genotypes in the disorder. The burden of recessive genotypes was not significantly increased in probands at either a genome-wide level or in any individual gene after adjustment for multiple testing. At a system level, probands had an excess of nonsynonymous compound heterozygous genotypes (minor allele frequency, MAF ⩽ 1%) in voltage-gated sodium channels (VGSCs; eight in probands and none in parents, P = 1.5 × 10(-)(4)). Previous findings of multiple de novo loss-of-function mutations in this gene family, particularly SCN2A, in autism and intellectual disability provide biological and genetic plausibility for this finding. Pointing further to the involvement of VGSCs in schizophrenia, we found that these genes were enriched for nonsynonymous mutations (MAF ⩽ 0.1%) in cases genotyped using an exome array, (5585 schizophrenia cases and 8103 controls), and that in the trios data, synaptic proteins interacting with VGSCs were also enriched for both compound heterozygosity (P = 0.018) and de novo mutations (P = 0.04). However, we were unable to replicate the specific association with compound heterozygosity at VGSCs in an independent sample of Taiwanese schizophrenia trios (N = 614). We conclude that recessive genotypes do not appear to make a substantial contribution to schizophrenia at a genome-wide level. Although multiple lines of evidence, including several from this study, suggest that rare mutations in VGSCs contribute to the disorder, in the absence of replication of the original findings regarding compound heterozygosity, this conclusion requires evaluation in a larger sample of trios.