Involvement of Rare Mutations of SCN9A, DPP4, ABCA13, and SYT14 in Schizophrenia and Bipolar Disorder

Rare mutations associated with schizophrenia (SZ) and bipolar disorder (BD) usually have high clinical penetrance; however, they are highly heterogeneous and personalized. Identifying rare mutations is instrumental in making the molecular diagnosis, understanding the pathogenesis, and providing genetic counseling for the affected individuals and families. We conducted whole-genome sequencing analysis in two multiplex families with the dominant inheritance of SZ and BD. We detected a G327E mutation of SCN9A and an A654V mutation of DPP4 cosegregating with SZ and BD in one three-generation multiplex family. We also identified three mutations cosegregating with SZ and BD in another two-generation multiplex family, including L711S of SCN9A, M4554I of ABCA13, and P159L of SYT14. These five missense mutations were rare and deleterious. Mutations of SCN9A have initially been reported to cause congenital insensitivity to pain and neuropathic pain syndromes. Further studies showed that rare mutations of SCN9A were associated with seizure and autism spectrum disorders. Our findings suggest that SZ and BD might also be part of the clinical phenotype spectra of SCN9A mutations. Our study also indicates the oligogenic involvement in SZ and BD and supports the multiple-hit model of SZ and BD.

Best Practices for Analysis of Carbon Fibers by Atom Probe Tomography

Carbon fiber technology drives significant development in lightweight and multifunctional applications. However, the microstructure of carbon fibers is not completely understood. A big challenge is to obtain the distribution of heteroatoms, for instance nitrogen, with high spatial resolution in three dimensions. Atom probe tomography (APT) has the potential to meet this challenge, but APT of carbon fibers is still relatively unexplored. We performed APT on three types of carbon fibers, including one high modulus type and two intermediate modulus types. Here, we present the methods to interpret the complex mass spectra of carbon fibers, enhance the mass resolution, and increase the obtained analysis volume. Finally, the origin of multiple hit events and possible methods to mitigate multiple hit events are also discussed. This paper provides guidance for future APT studies on carbon fibers, and thus leads the way to a deeper understanding of the microstructure, and consequently advancements in wide applications of carbon fibers.

Role of Carnitine in Non-alcoholic Fatty Liver Disease and Other Related Diseases: An Update

Carnitine is an amino acid-derived substance that coordinates a wide range of biological processes. Such functions include transport of long-chain fatty acids from the cytoplasm to the mitochondrial matrix, regulation of acetyl-CoA/CoA, control of inter-organellar acyl traffic, and protection against oxidative stress. Recent studies have found that carnitine plays an important role in several diseases, including non-alcoholic fatty liver disease (NAFLD). However, its effect is still controversial, and its mechanism is not clear. Herein, this review provides current knowledge on the biological functions of carnitine, the “multiple hit” impact of carnitine on the NAFLD progression, and the downstream mechanisms. Based on the “multiple hit” hypothesis, carnitine inhibits β-oxidation, improves mitochondrial dysfunction, and reduces insulin resistance to ameliorate NAFLD. L-carnitine may have therapeutic role in liver diseases including non-alcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma, alcoholic fatty liver disease, and viral hepatitis. We also discuss the prospects of L-carnitine supplementation as a therapeutic strategy in NAFLD and related diseases, and the factors limiting its widespread use.

Determination of Non-Recrystallization Temperature for Niobium Microalloyed Steel

In the present investigation, the non-recrystallization temperature (TNR) of niobium-microalloyed steel is determined to plan rolling schedules for obtaining the desired properties of steel. The value of TNR is based on both alloying elements and deformation parameters. In the literature, TNR equations have been developed and utilized. However, each equation has certain limitations which constrain its applicability. This study was completed using laboratory-grade low-carbon Nb-microalloyed steels designed to meet the API X-70 specification. Nb- microalloyed steel is processed by the melting and casting process, and the composition is found by optical emission spectroscopy (OES). Multiple-hit deformation tests were carried out on a Gleeble® 3500 system in the standard pocket-jaw configuration to determine TNR. Cuboidal specimens (10 (L) × 20 (W) × 20 (T) mm3) were taken for compression test (multiple-hit deformation tests) in gleeble. Microstructure evolutions were carried out by using OM (optical microscopy) and SEM (scanning electron microscopy). The value of TNR determined for 0.1 wt.% niobium bearing microalloyed steel is ~ 951 °C. Nb- microalloyed steel rolled at TNR produce partially recrystallized grain with ferrite nucleation. Hence, to verify the TNR value, a rolling process is applied with the finishing rolling temperature near TNR (~951 °C). The microstructure is also revealed in the pancake shape, which confirms TNR.

CHIP-mediated hyperubiquitylation of tau promotes its self-assembly into the insoluble tau filaments

Multiple-hit model for tau aggregation, where sequential events of tau phosphorylation and hyperubiquitylation function as a key driver of the fibrillization process.

Sterility of gamma-irradiated pathogens: a new mathematical formula to calculate sterilizing doses

In recent years there has been increasing advocacy for highly immunogenic gamma-irradiated vaccines, several of which are currently in clinical or pre-clinical trials. Importantly, various methods of mathematical modelling and sterility testing are employed to ensure sterility. However, these methods are designed for materials with a low bioburden, such as food and pharmaceuticals. Consequently, current methods may not be reliable or applicable to estimate the irradiation dose required to sterilize microbiological preparations for vaccine purposes, where bioburden is deliberately high. In this study we investigated the applicability of current methods to calculate the sterilizing doses for different microbes. We generated inactivation curves that demonstrate single-hit and multiple-hit kinetics under different irradiation temperatures for high-titre preparations of pathogens with different genomic structures. Our data demonstrate that inactivation of viruses such as Influenza A virus, Zika virus, Semliki Forest virus and Newcastle Disease virus show single-hit kinetics following exposure to gamma-irradiation. In contrast, rotavirus inactivation shows multiple-hit kinetics and the sterilizing dose could not be calculated using current mathematical methods. Similarly, Streptococcus pneumoniae demonstrates multiple-hit kinetics. These variations in killing curves reveal an important gap in current mathematical formulae to determine sterility assurance levels. Here we propose a simple method to calculate the irradiation dose required for a single log10 reduction in bioburden (D10) value and sterilizing doses, incorporating both single- and multiple-hit kinetics, and taking into account the possible existence of a resistance shoulder for some pathogens following exposure to gamma-irradiation.

C9orf72 loss-of-function: a trivial, stand-alone or additive mechanism in C9 ALS/FTD?

A repeat expansion in C9orf72 is responsible for the characteristic neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in a still unresolved manner. Proposed mechanisms involve gain-of-functions, comprising RNA and protein toxicity, and loss-of-function of the C9orf72 gene. Their exact contribution is still inconclusive and reports regarding loss-of-function are rather inconsistent. Here, we review the function of the C9orf72 protein and its relevance in disease. We explore the potential link between reduced C9orf72 levels and disease phenotypes in postmortem, in vitro, and in vivo models. Moreover, the significance of loss-of-function in other non-coding repeat expansion diseases is used to clarify its contribution in C9orf72 ALS/FTD. In conclusion, with evidence pointing to a multiple-hit model, loss-of-function on itself seems to be insufficient to cause neurodegeneration in C9orf72 ALS/FTD.