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Abstract Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.

Summary: Background: Consumption of fibre, fruits and vegetables have been linked with lower colorectal cancer (CRC) risk. A genome-wide gene-environment (G × E) analysis was performed to test whether genetic variants modify these associations. Methods: A pooled sample of 45 studies including up to 69,734 participants (cases: 29,896; controls: 39,838) of European ancestry were included. To identify G × E interactions, we used the traditional 1--degree-of-freedom (DF) G × E test and to improve power a 2-step procedure and a 3DF joint test that investigates the association between a genetic variant and dietary exposure, CRC risk and G × E interaction simultaneously. Findings: The 3-DF joint test revealed two significant loci with p-value

IntroductionOur study aimed to investigate the changes in hepatic endoplasmic reticulum (ER) stress, inflammation, insulin signaling, and lipid metabolism during the administration of a high-fat diet (HFD) in mice in order to identify correlations between obesity and metabolic disease development in the liver.MethodsWe used short-, medium-, and long-term HFD periods, corresponding to 4, 8, and 12 weeks, respectively, and isolated exosomes from adipose tissue. We confirmed the effect of adipose tissue-derived exosomes on metabolic disorders in obesity in alpha mouse liver 12 (AML12) hepatocytes.ResultsAdipose tissue-derived exosomes from HFD mice did not affect the AML12 cells after 4 weeks, but ER stress, inflammatory response, insulin resistance, and lipid synthesis were observed after 8 and 12 weeks. Furthermore, we confirmed that an HFD increases the amount of adipose tissue-derived exosomes in mice. Consequently, we can infer that adipose tissue-derived exosomes from HFD-fed mice significantly increase ER stress, inflammatory response, insulin resistance, and lipid synthesis in AML12 cells.DiscussionOur results demonstrate that obesity alters the effects of adipose tissue-derived exosomes in the liver, potentially becoming a risk factor in the development of obesity-induced liver diseases.

Abstract Purpose Angiogenesis is critical in various biological processes, such as blood vessel growth, fetal differentiation, wound healing, and organ regeneration. Various growth factors have been associated with vascular regeneration, including insulin-like growth factor 1 (IGF-1), transforming growth factor-β (TGF-β), and basic fibroblast growth factor (bFGF). One of the most important mediators of vascular regeneration is vascular endothelial growth factor (VEGF). VEGF is known to increase vascular permeability, induce the proliferation of endothelial cells, and stimulate capillary formation in vivo, which are core angiogenic functions. Methods The hydrolysates of lactic acid bacteria were produced by hydrolyzing Lactobacillus plantarum with proteases, treated with MG-63 osteoblasts, and screened to obtain samples with an excellent VEGF production effect. These samples were applied to human dermal papilla cells (hDPC) to examine the correlation between cell growth and VEGF secretion. Furthermore, the hair growth rate was measured in hair growth experiments using C57BL/6 male mice. Results The hydrolysates of the lactic acid bacteria produced in this study produced hair growth superior to the growth obtained with 5% minoxidil in hair growth experiments using C57BL/6 male mice. Conclusions This study aims to develop a material for application to the scalp that promotes angiogenesis in the scalp and facilitates the exchange of nutrients and wastes in the follicles to promote hair growth.

There is technology available for anti-thrombus with earthworms, but the procedure is complex and extracts protein with inferior purity. In order to develop a simplified process with a stronger purity of protease, we investigated the Lumbricus rubellus earthworm and Perinereis linea lugworm. We purified water extracts cut off at 10 kDa of molecular weight using ultrafiltration because proteins are large biomolecules, or macromolecules, consisting of one or more long chains of amino acid residues. We purified EW1 (raw earthworm extract), EW2 (molecular weight (m.w) > 10 kDa of earthworm extract), and EW3 (m.w 10 kDa), and LW3 (m.w EW1 > EW3 > LW2 > LW1 > LW3. In particular, EW2 and LW2 showed a potent fibrinolytic effect in two different worm specimens. The protein content of each sample was detected as 2.34 (EW1), 3.03 (EW2), 2.80 (LW1), 3.71 (LW2) mg/ml respectively, and their molecular weights were measured using SDS-PAGE. The samples contained the following amounts of total fatty acids: EW1, 3.61%; EW2, 0.48%; LW1, 4.96%; and LW2, 0.23%.We developed a process to increase the thrombolytic effect with a higher purity protein. The study results demonstrate this procedure and provide basic data for developing an anti-thrombolytic agent. Keywords: Lumbricus rubellus, Perinereis linea, Fibrinolytic effect, Fatty acid

Secretory carrier membrane proteins (SCAMPs) are widely distributed integral membrane proteins implicated in membrane trafficking. Secretory carrier membrane protein 5 (SCAMP5) is expected to be involved in regulation of the immune response because it is expressed in a variety of immune tissues and promotes the secretion of cytokines in monocytes and macrophages. In this study, we performed an analysis of the molecular characteristics and phylogenetic of the SCAMP5 gene identified in Pagrus major (PmSCAMP5). In addition, we analysed PmSCAMP5 gene expression levels in the tissues of red sea bream infected with various pathogens [Edwardsiella piscicida (E. piscicida), Streptococcus iniae (S. iniae) and Red sea bream iridovirus (RSIV)], and we analysed PmSCAMP5 gene expression levels in the tissues of healthy red sea bream. This study was carried out to provide basic data on the non-specific immune system of the red sea bream. Keywords: Secretory carrier membrane protein 5, Red sea bream, Edwardsiella piscicida, Streptococcus iniae, Red sea bream iridovirus

Streptococcus parauberis is a known etiologic agent that causes damage leading to death in flatfish (paralichthys olivaceus). Liposomes were used to deliver streptococcal oral vaccines to the intestinal mucous membranes of paralichthys olivaceus. The liposomes were coated for stabilization, and stability was measured with high performance liquid chromatography (HPLC). The liposomes were stable until day nine and were orally administered to flatfish as a vaccine. The resultant antibody titers were analyzed. The titers resulting from the uncoated liposomes were highest two weeks after the oral administration, and those resulting from the coated liposomes were highest one week after boosting. In addition, the bacteria were subcutaneously injected to artificially infect flatfish and the survival rates and relative survival rates were analyzed. The coated liposomes were found to yield the highest survival rate.

The interferon-related developmental regulator 1 (IFRD1) protein is expected to play a role in the regulation of inflammatory responses in adult mice, since it is known to repress transcription of NF-κB in myoblasts that regenerate skeletal muscle after traumatic injury Micheli et al., 2011. The IFRD2 gene is expressed in many tissues including skeletal muscle, kidney, heart, brain, lung, placenta and liver in adult humans and is highly expressed in adult human skeletal muscle and heart. In mice, interferon-related developmental regulator 2 (IFRD2) may be associated with early haematopoiesis after gastrulation and in the hepatic primordium Buanne et al., 1998. In this study, we analysed the molecular characteristics of the IFRD2 gene identified from Pagrus major (PmIFRD2) and performed multiple alignments and phylogenetic analyses of the protein sequence. In addition, we examined the expression pattern of IFRD2 in healthy red sea bream tissues and the temporal expression pattern after challenging with various pathogens [Edwardsiella piscicida (E. piscicida), Streptococcus iniae (S. iniae) and red sea bream iridovirus (RSIV)]. This study characterises the non-specific immune response of the red sea bream after viral and microbial infections. Keywords: Interferon-related developmental regulator 2 (IFRD2), Red sea bream, Edwardsiella piscicida, Streptococcus iniae, Red sea bream iridovirus (RSIV)

This study investigated the anti-inflammatory effects of mixed extracts of Achyranthes japonica Nakai (AJ) and Aralia continentalis Kitagawa (AC) (ratios of 1:2, 1:3, 1:5, 2:1, 3:1 and 5:1) on RAW264.7 macrophages and evaluated the anti-inflammatory effects of the mixed extracts of AJ and AC by measuring IL-1β, IL-6, and TNFα using the ELISA kit assay. In particular, the formation of nitric oxide (NO) was found to decrease in the group treated with the combined extracts of AJ and AC at all ratios. In particular, extracts of ratio of 2:1 (AJ:AC) deceased the formation of NO level that is approximately 60% of the group treated with only lipopolysaccharide (LPS). Also, extracts of ratio of 2:1 (AJ:AC) reduced the production of IL-1β, IL-6, TNFα and PGE2 with statistical significance. Volunteers over the age of 50 who complain of discomfort in knee joints were selected as the experimental subjects. The subjects took daily administration of 2000 mg of the combined extracts of ratio of 2:1 (AJ:AC) for 12 weeks. A survey (VAS (Visual Analog Scale), WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index)) was conducted after the 12 weeks of oral administration. The experimental group showed the change between each visit and baseline time compared with the control group. In the intention-to-treat (ITT) analysis, VAS score and WOMAC stiffness score decreased significantly. And the WOMAC total score and function score tended to decrease. In the per-protocol (PP) analysis, the WOMAC stiffness score was significantly decreased and the VAS and WOMAC total and function scores were decreased. There was no significant difference in all parameters of ITT and PP in radiological examinations.

To verify the prevalence of pneumonia associated with mechanical ventilation through the collection and analysis of tracheobronchial secretions. Methods: an observational study with 13 male patients. The scale of Acute Physiology and Chronic Health Evaluation and the Clinical Pulmonary Infection Score were applied after 72 hours of orotracheal hospitalization. Results: an average score of 33 points was observed, that is, these patients presented on average a 75% chance of death. Staphylococcus aureus (23.07%) and Klebsiella pneumoniae (15.38%) were found as the most prevalent microorganisms. Conclusion: the prevalence of ventilator-associated pneumonia was 25% of the cases and the most prevalent microorganisms were Klebsiella pneumoniae and Staphylococcus aureus.