Loss of Activity-Induced Mitochondrial ATP Production Underlies the Synaptic Defects in a Drosophila model of ALS

Mutations in the gene encoding VAPB (vesicle-associated membrane protein B) cause a familial form of Amyotrophic Lateral Sclerosis (ALS). Expression of an ALS-related variant of vapb (vapbP58S) in Drosophila motor neurons results in morphological changes at the larval neuromuscular junction (NMJ) characterized by the appearance of fewer, but larger, presynaptic boutons. Although diminished microtubule stability is known to underlie these morphological changes, a mechanism for the loss of presynaptic microtubules has been lacking. Here, we demonstrate the suppression of vapbP58S-induced changes in NMJ morphology by either the loss of ER Ca2+ release channels or the inhibition Ca2+/calmodulin (CaM)-activated kinase II (CaMKII). These data suggest a model in which decreased stability of presynaptic microtubules at vapbP58S NMJs result from hyperactivation of CaMKII due to elevated cytosolic [Ca2+]. We attribute the Ca2+ dyshomeostasis to delayed extrusion of cytosolic Ca2+ stemming from a paucity of activity-induced mitochondrial ATP production coupled with elevated rates of ATP consumption. Taken together, our data point to bioenergetic dysfunction as the root cause for the synaptic defects in vapbP58S-expressing Drosophila motor neurons.

A Novel Terrestrial Rabies Virus Lineage Occurring in South America: Origin, Diversification, and Evidence of Contact between Wild and Domestic Cycles

The rabies virus (RABV) is characterized by a history dominated by host shifts within and among bats and carnivores. One of the main outcomes of long-term RABV maintenance in dogs was the establishment of variants in a wide variety of mesocarnivores. In this study, we present the most comprehensive phylogenetic and phylogeographic analysis, contributing to a better understanding of the origins, diversification, and the role of different host species in the evolution and diffusion of a dog-related variant endemic of South America. A total of 237 complete Nucleoprotein gene sequences were studied, corresponding to wild and domestic species, performing selection analyses, ancestral states reconstructions, and recombination analyses. This variant originated in Brazil and disseminated through Argentina and Paraguay, where a previously unknown lineage was found. A single host shift was identified in the phylogeny, from dog to the crab-eating fox (Cerdocyon thous) in the Northeast of Brazil. Although this process occurred in a background of purifying selection, there is evidence of adaptive evolution -or selection of sub-consensus sequences- in internal branches after the host shift. The interaction of domestic and wild cycles persisted after host switching, as revealed by spillover and putative recombination events.

The Incidence of Atlanto-Occipitalization and Additional Foramina Present in The Dry Skulls of Nepalese Population

Introduction: Atlanto-occipitalization(AOZ) is one of the congenital anomalies related to craniovertebral synostosis. The clear understanding of its anatomical features and cranial foraminal variants plays a critical role in finding the possible coping mechanism with its pathogenesis such as segmental instability or neurologic deficits. Objective: This study aimed to investigate the incidence of occipitalization of Atlas and related variant foramina, as the baseline awareness of these conditions among the Nepalese population is yet to be documented. Methodology: A retrospective study was performed for the total 86 dry skulls available in the department of Anatomy in Katmandu University of Medical Sciences, Institute of Medical Science, and B.P. Koirala Institute of Health Sciences. The skulls were examined thoroughly to evidence the occurrence of cranio-vertebral variations. Result: Out of 86 human adult skulls, 2 cases (2.32 %) were found with partial AOZ presenting posterior spina bifida close to the midline. Sphenoidal emissary foramen (SEF) was also observed in 17 skulls (19.76 %), an additional foramen lying anteromedial to the foramen ovale. Moreover, one of the skulls (1.16 %) was found with the presence of pterygospinous bar creating an additional foramen ‘foramen of Civinini’ in the lateral pterygoid plate of the sphenoid bone. Conclusion: The incidence of AOZ and pterygospinous bar seems to be quite low as compared to the cases of SEF. However, the knowledge of such variations and the presence of additional foramina carry great significance for orthopedists and neurosurgeons to have prognostic implications and an accurate surgical approach.

TBE in Bosnia and Herzegovina

Very limited information is available for Bosnia showing the occurrence of TBE Even though there have been some elder case reports in the northern parts of the country, including alimentary infections, details have not been published. In early 1996 United States military forces were deployed to Bosnia as part of Operation Joint Endeavor. Only 4 (0.42%) unvaccinated individuals, all males, demonstrated a 4-fold seroconversion. All 4 seemingly were infected with TBE virus (or a closely-related variant) during their 6–9-month deployment period in Bosnia, but did not report with symptoms to any health care provider.

Association Between Polymorphisms in Gastric Cancer Related Genes and Risk of Gastric Cancer: A Case-Control Study

Gastric cancer has the second highest incidence among all the malignancies in China, just below lung cancer. Gastric cancer is likewise one of the main sources of cancer related passings. Gastric cancer therefore remains a huge threat to human health. The primary reason is absence of high sensitivity and specificity for early detection while the pathogenesis of GC is stayed muddled. During the last few decades, a lot of GC related genes have been identified. To find candidate GC related variant in these GC related genes, we conducted this case-control study. 29 tagSNPs located in 7 GC related genes were included. 228 gastric cancer patients and 299 healthy controls were enrolled. Significant differences were found between the genotype frequencies of EFNA1 rs4971066 polymorphism between gastric cancer patients and healthy controls. The result indicated that ephrin-A1 tagSNP rs4971066 GT/TT genotypes was significantly associated with reduced susceptibility of gastric cancer development.

Specifications of the variant curation guidelines for ITGA2B/ITGB3: ClinGen Platelet Disorder Variant Curation Panel

Accurate and consistent sequence variant interpretation is critical to the correct diagnosis and appropriate clinical management and counseling of patients with inherited genetic disorders. To minimize discrepancies in variant curation and classification among different clinical laboratories, the American College of Medical Genetics and Genomics (ACMG), along with the Association for Molecular Pathology (AMP), published standards and guidelines for the interpretation of sequence variants in 2015. Because the rules are not universally applicable to different genes or disorders, the Clinical Genome Resource (ClinGen) Platelet Disorder Expert Panel (PD-EP) has been tasked to make ACMG/AMP rule specifications for inherited platelet disorders. ITGA2B and ITGB3, the genes underlying autosomal recessive Glanzmann thrombasthenia (GT), were selected as the pilot genes for specification. Eight types of evidence covering clinical phenotype, functional data, and computational/population data were evaluated in the context of GT by the ClinGen PD-EP. The preliminary specifications were validated with 70 pilot ITGA2B/ITGB3 variants and further refined. In the final adapted criteria, gene- or disease-based specifications were made to 16 rules, including 7 with adjustable strength; no modification was made to 5 rules; and 7 rules were deemed not applicable to GT. Employing the GT-specific ACMG/AMP criteria to the pilot variants resulted in a reduction of variants classified with unknown significance from 29% to 20%. The overall concordance with the initial expert assertions was 71%. These adapted criteria will serve as guidelines for GT-related variant interpretation to increase specificity and consistency across laboratories and allow for better clinical integration of genetic knowledge into patient care.

Review of SBR process in effluent treatment

SBR process evolved from activated sludge process. Because the long cultivation period of activated sludge process and the treatment effect can not meet the needs of production and life, SBR process and related variant improved process came into being. Since the 21st century, with the development of automatic control technology, SBR process has become a widely used technology. This paper introduces the SBR technology and the related improvement process, and puts forward suggestions for the development of SBR Technology in the field of sewage treatment.

Analysis of microRNA-34a expression profile and rs2666433 variant in colorectal cancer: a pilot study

MicroRNAs (miRNAs) are implicated in every stage of carcinogenesis and play an essential role as genetic biomarkers of cancer. We aimed to evaluate microRNA-34a gene (MIR34A) expression in colorectal cancer (CRC) tissues compared with non-cancer one and to preliminarily explore the association of one related variant to CRC risk. A total of 116 paraffin-embedded colon specimens were enrolled. MiR-34a was quantified by qPCR, and rs2666433 (A/G) genotyping was performed by TaqMan Real-Time PCR. Also, the somatic mutation burden was assessed. MIR34A expression in the CRC specimens was significantly upregulated (median = 21.50, IQR: 7.0–209.2; P = 0.001) relative to the non-cancer tissues. Allele (A) was highly prevalent in CRC tissues represented 0.56 (P < 0.001). AA/AG genotype carriers were 5.7 and 2.8 more likely to develop cancer than GG carriers. Tumor-normal tissue paired analysis revealed genotype concordance in 33 out of 58 tissue samples. Approximately 43% of the specimens showed a tendency for G to A shift. Additionally, a higher frequency of somatic mutation (92%) was observed in adenocarcinoma (P = 0.006). MIR34A expression and gene variant did not show associations with the clinicopathological data. However, G > A somatic mutation carriers had more prolonged DFS and OS. Bioinformatics analysis revealed miR-34a could target 30 genes that are implied in all steps of CRC tumorigenesis. In conclusion, this study confirms MIR34A upregulation in CRC tissues, and its rs2666433 (A/G) variant showed association with CRC and a high somatic mutation rate in cancer tissues. MiR-34a could provide a novel targeted therapy after validation in large-scale studies.