Copy number variations (CNVs) are implicated across many neurodevelopmental disorders (NDDs) and contribute to their shared genetic etiology. Multiple studies have attempted to identify shared etiology among NDDs, but this is the first genome-wide CNV analysis across autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) at once. Using microarray (Affymetrix CytoScan HD), we genotyped 2,691 subjects diagnosed with an NDD (204 SCZ, 1,838 ASD, 427 ADHD and 222 OCD) and 1,769 family members, mainly parents. We identified rare CNVs, defined as those found in <0.1% of 10,851 population control samples. We found clinically relevant CNVs (broadly defined) in 284 (10.5%) of total subjects, including 22 (10.8%) among subjects with SCZ, 209 (11.4%) with ASD, 40 (9.4%) with ADHD, and 13 (5.6%) with OCD. Among all NDD subjects, we identified 17 (0.63%) with aneuploidies and 115 (4.3%) with known genomic disorder variants. We searched further for genes impacted by different CNVs in multiple disorders. Examples of NDD-associated genes linked across more than one disorder (listed in order of occurrence frequency) are NRXN1, SEH1L, LDLRAD4, GNAL, GNG13, MKRN1, DCTN2, KNDC1, PCMTD2, KIF5A, SYNM, and long non-coding RNAs: AK127244 and PTCHD1-AS. We demonstrated that CNVs impacting the same genes could potentially contribute to the etiology of multiple NDDs. The CNVs identified will serve as a useful resource for both research and diagnostic laboratories for prioritization of variants.

Clozapine is an important antipsychotic drug. However, its use is often accompanied by metabolic adverse effects and, in rare instances, agranulocytosis. The molecular mechanisms underlying these adverse events are unclear. To gain more insights into the response to clozapine at the molecular level, we exposed lymphoblastoid cell lines (LCLs) to increasing concentrations of clozapine and measured genome-wide gene expression and DNA methylation profiles. We observed robust and significant changes in gene expression levels due to clozapine (n = 463 genes at FDR < 0.05) affecting cholesterol and cell cycle pathways. At the level of DNA methylation, we find significant changes upstream of the LDL receptor, in addition to global enrichments of regulatory, immune and developmental pathways. By integrating these data with human tissue gene expression levels obtained from the Genotype-Tissue Expression project (GTEx), we identified specific tissues, including liver and several tissues involved in immune, endocrine and metabolic functions, that clozapine treatment may disproportionately affect. Notably, differentially expressed genes were not enriched for genome-wide disease risk of schizophrenia or for known psychotropic drug targets. However, we did observe a nominally significant association of genetic signals related to total cholesterol and low-density lipoprotein levels. Together, these results shed light on the biological mechanisms through which clozapine functions. The observed associations with cholesterol pathways, its genetic architecture and specific tissue effects may be indicative of the metabolic adverse effects observed in clozapine users. LCLs may thus serve as a useful tool to study these molecular mechanisms further.

Gun, projectile and propellant are three fundamental components of a launching system. Generally, a barrel has to be condemned after a number of rounds have been fired. During the total useful life of gun barrel, it bears severe damage induced from erosion by high pressure and high temperature propellant combustion gas, and wear due to high speed friction between projectile and gun bore. Meanwhile, the gun barrel undergoes a dynamic loading of gas pressure, mechanical stress and thermal stress when firing a round. Thousands of firing cycles lead to gun barrel fatigue. Interaction of wear, including erosion, and fatigue damages the gun barrel and eventually the gun will become inaccurate because of wearing away gun bore materials. However, a gun barrel will fracture in a sudden manner because of fatigue. It is found that microcracks form on the bore surface after only a few rounds have been fired, which lays the foundation for growth and propagation of cracks under fatigue loading. In this paper, laboratory hydraulic fatigue tests were carried out on a tube with pre-machined crack on its inner surface by using an MTS 809. Strain gauges were adhered to the outer surface of the tube to monitor strain during testing process. The hydraulic oil pressure was measured by a pressure sensor. The experimental results show that there are three stages of outer surface strain variation, namely stable increase, fast increase and abrupt increase, which corresponds to the history of crack evolution. Crack grew stably in the initial stage under cycle of loading and a major crack is gradually formed. When the major crack size reaches a certain value, the propagation velocity of crack is accelerated fast and the critical size is reached in a short time. Eventually the tube fractured suddenly. The experimental findings will help us to gain new insight into the physical mechanism of fatigue and fracture of gun barrel and provide a possible method to evaluate health of gun barrel in service.