Settling velocity of atmospheric particles in seawater: Based on hydrostatic sedimentation method using video imaging techniques.

When atmospheric particles deposit to the ocean, their settling velocities and residence times associated are critical for their effects on oceanic ecosystems. We developed a hydrostatic sedimentation method using video imaging techniques to track particles of 5-20 µm in diameter falling into seawater and determine the particle settling velocities in relation to their diameter, shape, organic matter contained, and seawater salinity. The measured settling velocities varied from 0.025 to 0.41 mm/s. Irregular particle shape and organic matter contained in particles also, however, reduced the values. The settling velocities were decelerated by the dissolution process of particle in seawater. Combined with the experimental results, a formula for calculating the settling velocity formulae for atmospheric particles was estimated. Using this equation, the residence time of particles is estimated to be less than one month in continental shelf sea and more than 100 days in the oceans.

Heterozygous variants of NOD2, IL10RA, PLA2G6 and COL7A1 correlate with Crohn's disease.

To identify candidate pathogenic genes of early-stage Crohn's disease (CD) and predict potential roles of genetic factors in CD, we performed whole exome sequencing on a child with early-stage Crohn's disease (CD) and her parents (core family), found that the patient carried heterozygous variants of 4 genes: NOD2 c. 2257 C > T, IL10RA c. 301 C > T, PLA2G6 c. 2029 C > T, COL7A1 c. 3190 G > A. Heterozygous variants of NOD2, IL10RA, PLA2G6 and COL7A1, intestinal inflammatory response is triggered, normal intestinal wall tissue damage, leading to CD phenotype.

SLAMF7 Promotes Foam Cell Formation of Macrophage by Suppressing NR4A1 Expression During Carotid Atherosclerosis.

Macrophage-derived lipid-laden foam cells from the subendothelium play a crucial role in the initiation and progression of atherosclerosis. However, the molecule mechanism that regulates the formation of foam cells is not completely understood. Here, we found that SLAMF7 was upregulated in mice bone marrow-derived macrophages and RAW264.7 cells stimulated with oxidized low-density lipoprotein (ox-LDL). SLAMF7 promoted ox-LDL-mediated macrophage lipid accumulation and M1-type polarization. SLAMF7 deficiency reduced serum lipid levels and improved the lesions area of carotid plaque and aortic arch in high-fat diet-fed ApoE-/- mice. In response to ox-LDL, SLAMF7 downregulated NR4A1 and upregulated RUNX3 through transcriptome sequencing analysis. Overexpression NR4A1 reversed SLAMF7-induced lipid uptake and M1 polarization via inhibiting RUNX3 expression. Furthermore, RUNX3 enhanced foam cell formation and M1-type polarization. Taken together, the study suggested that SLAMF7 play contributing roles in the pro-atherogenic effects by regulating NR4A1-RUNX3.

Germline VWF/MPRIP and somatoplasm FGA variants synergically confer susceptibility to non-traumatic osteonecrosis of the femoral head.

Non-traumatic osteonecrosis of the femoral head (ONFH) relies on multiple pathogenic factors, including intravascular coagulation, osteoporosis and lipid metabolism disorders. Despite extensively explored from various aspects, genetic mechanism underlying non-traumatic ONFH has not been fully elucidated. We randomly collected blood and necrotic tissue samples from 32 patients with non-traumatic ONFH as well as blood samples from 30 healthy individuals for whole exome sequencing (WES). Germline mutation and somatic mutation were analyzed to identify new potential pathogenic genes responsible for non-traumatic ONFH. Three genes might correlate with non-traumatic ONFH: VWF, MPRIP (germline mutations) and FGA (somatic mutations). Germline or somatic mutations in VWF, MPRIP and FGA correlate with intravascular coagulation, thrombosis, and consequently, ischemic necrosis of the femoral head.

Identification of THSD7B and PRMT9 mutations as risk factors for familial lung adenocarcinoma: A case report.

RATIONALE: Lung tumors arise from the unrestrained malignant growth of pulmonary epithelial cells. Lung cancer cases include both small and non-small cell lung cancers, with lung adenocarcinoma (LUAD) accounting for roughly half of all non-small cell lung cancer cases. Research focused on familial cancers suggests that approximately 8% of lung cancer cases are linked to genetic susceptibility or heritability. The precise genetic factors that underlie the onset of lung cancer, however, remain to be firmly established. PATIENT CONCERNS: A 43-year-old presented with nodules in the lower left lung lobe. Following initial antibiotic treatment in a local hospital, these nodules remained present and the patient subsequently underwent the resection of the left lower lobe of the lung. The patient also had 4 family members with a history of LUAD. DIAGNOSIS: Immunohistochemical staining results including cytokeratin 7 (+), TTF-1 (+), new aspartic proteinase A (+), CK5/6 (-), P63 (-), and Ki-67 (5%+) were consistent with a diagnosis of LUAD. INTERVENTION: Whole exome sequencing analyses of 5 patients and 6 healthy family members were performed to explore potential mutations associated with familial LUAD. OUTCOMES: Whole exome sequencing was conducted, confirming that the proband and their 4 other family members with LUAD harbored heterozygous THSD7B (c.A4000G:p.S1334G) mutations and homozygous PRMT9 (c.G40T:p.G14C) mutations, as further confirmed via Sanger sequencing. These mutations were predicted to be deleterious using the SIFT, PolyPhen2, and MutationTaster algorithms. Protein structure analyses indicated that the mutation of the serine at amino acid position 1334 in THSD7B to a glycine would reduce the minimum free energy from 8.08 kcal/mol to 68.57 kcal/mol. The identified mutation in the PRMT9 mutation was not present in the predicted protein structure. I-Mutant2.0 predictions indicated that both of these mutations (THSD7B:p.S1334G and PRMT9: p.G14C) were predicted to reduce protein stability. LESSONS: Heterozygous THSD7B (c.A4000G:p.S1334G) and the homozygous PRMT9 (c.G40T:p.G14C) mutations were found to be linked to LUAD incidence in the analyzed family. Early analyses of these genetic loci and timely genetic counseling may provide benefits and aid in the early diagnosis of familial LUAD.

Progressive hemifacial atrophy in a Chinese patient: A case report.

BACKGROUND: Progressive hemifacial atrophy (PHA) is a rare and progressive condition of unknown etiology that is characterized by chronic progressive atrophy of the skin, subcutaneous tissue, muscle, and bone on 1 side of the face. However, its precise pathogenesis remains poorly understood. CASE PRESENTATION: Here, we report a case of PHA, which manifested as left-sided facial atrophy. Whole-exome sequencing of peripheral blood samples from the patient and his parents, together with bioinformatics analyses, led to the identification of mutations in ARHGAP4 and CFAP47. CONCLUSION: This report is the first to describe ARHGAP4 and CFAP47 mutations in a patient with PHA. These mutations may be related to the occurrence of hemifacial atrophy, although further studies are needed to clarify the role of ARHGAP4 and CFAP47 in the context of PHA pathogenesis.

NTN4 as a prognostic marker and a hallmark for immune infiltration in breast cancer.

Netrin-4 (NTN4), a member of neurite guidance factor family, can promote neurite growth and elongation. This study aims to investigate if NTN4 correlates with prognosis and immune infiltration in breast cancer. The prognostic landscape of NTN4 and its relationship with immune infiltration in breast cancer were deciphered with public databases and immunohistochemistry (IHC) in tissue samples. The expression profiling and prognostic value of NTN4 were explored using UALCAN, TIMER, Kaplan-Meier Plotter and Prognoscan databases. Based on TIMER, relationships of NTN4 expression with tumor immune invasion and immune cell surface markers were evaluated. Transcription and survival analyses of NTN4 in breast cancer were investigated with cBioPortal database. The STRING database was explored to identify molecular functions and signaling pathways downstream of NTN4. NTN4 expression was significantly lower in invasive breast carcinoma compared with adjacent non-malignant tissues. Promoter methylation of NTN4 exhibited different patterns in breast cancer. Low expression of NTN4 was associated with poorer survival. NTN4 was significantly positively related to infiltration of CD8+ T cells, macrophages and neutrophils, whereas significantly negatively related to B cells and tumor purity. Association patterns varied with different subtypes. Various associations between NTN4 levels and immune cell surface markers were revealed. Different subtypes of breast cancer carried different genetic alterations. Mechanistically, NTN4 was involved in mediating multiple biological processes including morphogenesis and migration.

Non-synonymous alterations in AKR7A3 and ABCA6 correlate with bleeding in aged patients treated with rivaroxaban.

Rivaroxaban is an oral anticoagulant that inhibits thrombin and blocks coagulation cascade through directly inactivating factors Xa. Despite rivaroxaban is widely used for prevention and treatment of venous thrombosis, and its common adverse reactions have been reported, including abnormal coagulation, mucosal hemorrhage, hematuria, and intracranial hemorrhage. To explore potential drivers of individual differences in adverse reactions induced by rivaroxaban, we performed whole-exome sequencing and found that AKR7A3 rs1738023/rs1738025 and ABCA6 rs7212506 are susceptible sites for rivaroxaban-related bleeding in aged patients treated with rivaroxaban. Gene functional annotation and signaling pathway enrichment indicated that homozygous mutations in AKR7A3 and ABCA6 might alter normal rivaroxaban transport and metabolism, and lead to continuous accumulation of activated drugs and toxic substances in vivo. Our results suggested that interindividual differences in bleeding events induced by rivaroxaban may be potentially driven by genetic alterations related to abnormal metabolism and transport of rivaroxaban.

A Meta-Analysis and Systematic Review of Listeria monocytogenes Response to Sanitizer Treatments.

Listeria monocytogenes is a ubiquitous organism that can be found in food-related environments, and sanitizers commonly prevent and control it. The aim of this study is to perform a meta-analysis of L. monocytogenes response to sanitizer treatments. According to the principle of systematic review, we extracted 896 records on the mean log-reduction of L. monocytogenes from 84 publications as the dataset for this study. We applied a mixed-effects model to describe L. monocytogenes response to sanitizer treatment by considering sanitizer type, matrix type, biofilm status, sanitizer concentration, treatment time, and temperature. Based on the established model, we compared the response of L. monocytogenes under different hypothetical conditions using forest plots. The results showed that environmental factors (i.e., sanitizer concentration, temperature, and treatment time) affected the average log-reduction of L. monocytogenes (p < 0.05). L. monocytogenes generally exhibited strong resistance to citric acid and sodium hypochlorite but had low resistance to electrolyzed water. The planktonic cells of L. monocytogenes were less resistant to peracetic acid and sodium hypochlorite than the adherent and biofilm cells. Additionally, the physical and chemical properties of the contaminated or inoculated matrix or surface also influenced the sanitizer effectiveness. This review may contribute to increasing our knowledge of L. monocytogenes resistance to sanitizers and raising awareness of appropriate safety precautions.

Targeted capture sequencing identifies genetic variations of GRK4 and RDH8 in Han Chinese with essential hypertension in Xinjiang.

Essential hypertension is a common cardiovascular disease with complex etiology, closely related to genetic and environmental factors. The pathogenesis of hypertension involves alteration in vascular resistance caused by sympathetic nervous system (SNS) and renin angiotensin system (RAS). Susceptibility factors of hypertension vary with regions and ethnicities. In this study, we conducted target capture sequencing on 54 genes related to SNS and RAS derived from a collection of Han nationality, consisting of 151 hypertension patients and 65 normal subjects in Xinjiang, China. Six non-synonymous mutations related to hypertension were identified, including GRK4 rs1644731 and RDH8 rs1801058, Mutations are predicted to affect 3D conformation, force field, transmembrane domain and RNA secondary structure of corresponding genes. Based on protein interaction network and pathway enrichment, GRK4 is predicted to participate in hypertension by acting on dopaminergic synapse, together with interacting components. RDH8 is involved in vitamin A (retinol) metabolism and consequent biological processes related to hypertension. Thus, GRK4 and RDH8 may serve as susceptibility genes for hypertension. This finding provides new genetic evidence for elucidating risk factors of hypertension in Han nationality in Xinjiang, which in turn, enriches genetic resource bank of hypertension susceptibility genes.

NAPG mutation in family members with hereditary hemorrhagic telangiectasia in China.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a disease characterized by arteriovenous malformations in the skin and mucous membranes. We enrolled a large pedigree comprising 32 living members, and screened for mutations responsible for HHT. METHODS: We performed whole-exome sequencing to identify novel mutations in the pedigree after excluding three previously reported HHT-related genes using Sanger sequencing. We then performed in silico functional analysis of candidate mutations that were obtained using a variant filtering strategy to identify mutations responsible for HHT. RESULTS: After screening the HHT-related genes, activin A receptor-like type 1 (ACVRL1), endoglin (ENG), and SMAD family member 4 (SMAD4), we did not detect any co-segregated mutations in this pedigree. Whole-exome sequencing analysis of 7 members and Sanger sequencing analysis of 16 additional members identified a mutation (c.784A > G) in the NSF attachment protein gamma (NAPG) gene that co-segregated with the disease. Functional prediction showed that the mutation was deleterious and might change the conformational stability of the NAPG protein. CONCLUSIONS: NAPG c.784A > G may potentially lead to HHT. These results expand the current understanding of the genetic contributions to HHT pathogenesis.

Long non-coding RNA PCAT-1 regulates apoptosis of chondrocytes in osteoarthritis by sponging miR-27b-3p.

BACKGROUND: Osteoarthritis (OA) is a non-inflammatory degenerative disease, with progressive damages on the articular cartilages. In recent years, researchers have paid many efforts in the diagnostics and treatments of OA. However, no effective therapeutic method has been revealed to help inhibit the development of OA. Herein, we studied the roles and associations of PCAT-1 and miR-27-3p in the pathogenesis OA. METHODS: OA articular cartilages and healthy articular cartilages were isolated for investigation. The chondrocytes were isolated from articular cartilage samples. QRT-PCR and western blotting were used for the detection of expression of genes and proteins. cell Titer 96® AQueous one proliferation kit was applied for detect cell viability of Chondrocytes transfected with negative control vector, pcDNA3.1 PCAT-1 plasmid or siRNA against PCAT-1. RNA pull-down assays and Luciferase reporter assay were used to confirm the connection. SPSS 17.0 was employed for statistical analysis. RESULTS: We found that the expressions of PCAT-1 were up-regulated in OA chondrocytes compared with normal chondrocytes. si-PCAT-1 suppressed apoptotic OA chondrocytes. Over-expression of PCAT-1 enhanced the apoptosis of normal chondrocytes. In addition, the online database and luciferase assay confirmed that PCAT-1 could directly target miR-27b-3p. PCAT-1 could promote the apoptosis of OA and normal chondrocytes through binding with miR-27b-3p. CONCLUSIONS: Based on the comparisons and analysis, we could conclude that lncRNA PCAT-1 regulated the apoptosis of chondrocytes through sponging miR-27b-3p in OA. PCAT-1 has potential values to act as a new therapeutic target for OA patients.

GAA compound heterozygous mutations associated with autophagic impairment cause cerebral infarction in Pompe disease.

Clinical manifestations of the late-onset adult Pompe disease (glycogen storage disease type II) are heterogeneous. To identify genetic defects of a special patient population with cerebrovascular involvement as the main symptom, we performed whole-genome sequencing (WGS) analysis on a consanguineous Chinese family of total eight members including two Pompe siblings both had cerebral infarction. Two novel compound heterozygous variants were found in GAA gene: c.2238G>C in exon 16 and c.1388_1406del19 in exon 9 in the two patients. We verified the function of the two mutations in leading to defects in GAA protein expression and enzyme activity that are associated with autophagic impairment. We further performed a gut microbiome metagenomics analysis, found that the child's gut microbiome metagenome is very similar to his mother. Our finding enriches the gene mutation spectrum of Pompe disease, and identified the association of the two new mutations with autophagy impairment. Our data also indicates that gut microbiome could be shared within Pompe patient and cohabiting family members, and the abnormal microbiome may affect the blood biochemical index. Our study also highlights the importance of deep DNA sequencing in potential clinical applications.

Targeted capture sequencing identifies novel genetic variations in Chinese patients with idiopathic inflammatory myopathies.

OBJECTIVES: Previous association studies have identified genetic variants in the human leukocyte antigen (HLA) complex as substantial risk factors for idiopathic inflammatory myopathies (IIMs). However, a great number of genes are located in the HLA region, and thus fine mapping is quite necessary. METHODS: Targeted capture sequencing were performed on the whole HLA region in 42 IIM patients and 24 healthy controls. A microarray analysis was applied to analyze gene expression profiles in additional 20 newly diagnosed IIM and five healthy controls. RESULTS: The HLA region was confirmed to be associated with IIMs in Chinese patients. By gene expression profiling and pathway analysis, several genes were identified as candidates for IIM risk factors, including HLA-A, HLA-B, HLA-DRB5, HLA-DRB1, HLA-DQA1, HLA-DQB1 and HLA-DQB2. Interestingly, p.Y107V of the HLA-DRB1 was predicted to be a potential causal non-synonymous variation for IIMs that may affect the antigen-binding groove of the HLA-II molecule. CONCLUSIONS: Our data have revealed novel genetic variations in the HLA region of IIM patients and provide new insight into the pathogenesis and diagnosis of IIMs.

Integrated DNA methylation and gene expression analysis identifies SLAMF7 as a key regulator of atherosclerosis.

Atherosclerosis (AS) is a multifactorial disease. Exploration of DNA methylation in regulating gene transcription in a cell type- and stage-specific manner will shed light on understanding the biological processes associated with plaque stability. We identified 174 up-regulated genes with hypo-methylation in the promoter, and 86 down-regulated genes with hyper-methylation in the promoter, in AS vs. healthy controls. Among them, high expression of signaling lymphocytic activation molecule 7 (SLAM7) was examined in carotid plaque vs. intact tissue, in advanced plaque vs. early atherosclerotic tissue, and SLAMF7 protein expressed significantly higher in the unstable plaques than that in the stable plaques, especially in the CD68-positive macrophages. Depletion of SLAMF7 in plaque-derived macrophages induced a suppressed secretion of proinflammatory cytokines, and inhibited proliferation of vascular smooth muscle cells. These data provide emerging evidence that SLAMF7 could be a target of potential therapeutic intervention in carotid AS.

Mitochondrial DNA Mutations Associated with Type 2 Diabetes Mellitus in Chinese Uyghur Population.

A hospital-based case-control study was conducted to investigate potential association between mitochondrial DNA and Type 2 diabetes mellitus (T2DM) in Chinese Uyghur population. We sequenced mitochondrial DNA from 210 Uyghur individuals including 88 T2DM patients and 122 controls. Using haplogroup classification and association test, we found that haplogroup H (odds ratio [OR] = 1.40; 95% confidence interval [CI]: 1.20-1.64; P = 0.0005138) and D4 (odds ratio = 1.47; 95% CI: 1.22-1.77; P = 0.001064) were associated with an increased risk of T2DM in Chinese Uyghur population. Two markers of haplogroup D4 and H, MT-ATP8 m.8414 T > G (p.Leu17Phe) and m.2706 G > A encoding 16S rRNA in mitochondria, were predicted to affect the structure of MT-ATP8 and 16S RNA, respectively, and may be involved in the pathogenesis of T2DM. Our study provides a new clue for mitochondrial DNA in the etiology of T2DM in Chinese Uyghur population.

Discovery of susceptibility loci associated with tuberculosis in Han Chinese.

Genome-wide association studies (GWASs) have revealed the worldwide heterogeneity of genetic factors in tuberculosis (TB) susceptibility. Despite having the third highest global TB burden, no TB-related GWAS has been performed in China. Here, we performed the first three-stage GWAS on TB in the Han Chinese population. In the stage 1 (discovery stage), after quality control, 691 388 SNPs present in 972 TB patients and 1537 controls were retained. After replication on an additional 3460 TB patients and 4862 controls (stages 2 and 3), we identified three significant loci associated with TB, the most significant of which was rs4240897 (logistic regression P = 1.41 × 10-11, odds ratio = 0.79). The aforementioned three SNPs were harbored by MFN2, RGS12 and human leukocyte antigen class II beta chain paralogue encoding genes, all of which are candidate immune genes associated with TB. Our findings provide new insight into the genetic background of TB in the Han Chinese population.

Propagation effects in the generation process of high-order vortex harmonics.

We numerically study the propagation of a Laguerre-Gaussian beam through polar molecular media via the exact solution of full-wave Maxwell-Bloch equations where the rotating-wave and slowly-varying-envelope approximations are not included. It is found that beyond the coexistence of odd-order and even-order vortex harmonics due to inversion asymmetry of the system, the light propagation effect results in the intensity enhancement of a high-order vortex harmonics. Moreover, the orbital momentum successfully transfers from the fundamental laser driver to the vortex harmonics which topological charger number is directly proportional to its order.

Large-Scale Analysis of Drug Side Effects via Complex Regulatory Modules Composed of microRNAs, Transcription Factors and Gene Sets.

Identifying the occurrence mechanism of drug-induced side effects (SEs) is critical for design of drug target and new drug development. The expression of genes in biological processes is regulated by transcription factors(TFs) and/or microRNAs. Most of previous studies were focused on a single level of gene or gene sets, while studies about regulatory relationships of TFs, miRNAs and biological processes are very rare. Discovering the complex regulating relations among TFs, gene sets and miRNAs will be helpful for researchers to get a more comprehensive understanding about the mechanism of side reaction. In this study, a framework was proposed to construct the relationship network of gene sets, miRNAs and TFs involved in side effects. Through the construction of this network, the potential complex regulatory relationship in the occurrence process of the side effects was reproduced. The SE-gene set network was employed to characterize the significant regulatory SE-gene set interaction and molecular basis of accompanied side effects. A total of 117 side effects complex modules including four types of regulating patterns were obtained from the SE-gene sets-miRNA/TF complex regulatory network. In addition, two cases were used to validate the complex regulatory modules which could more comprehensively interpret occurrence mechanism of side effects.

Circulating interleukin-10 levels and human papilloma virus and Epstein-Barr virus-associated cancers: evidence from a Mendelian randomization meta-analysis based on 11,170 subjects.

Recent studies have showed interleukin 10 (IL-10) is a critical cytokine that determines antiviral immune response and is related to virus-associated cancers. However, whether genetically elevated circulating IL-10 levels are associated with the risk of human papilloma virus and Epstein-Barr virus-associated cancers (HEACs) is still unclear. Mendelian randomization method was implemented to meta-analyze available observational studies by employing IL-10 three variants (-592C>A, -819C>T, and -1082A>G) as instruments. A total of 24 articles encompassing 11,170 subjects were ultimately eligible for the meta-analysis. Overall, there was a significant association between IL-10 promoter variant -1082A>G and HEACs under allelic and dominant models (both P<0.01). Subgroup analysis by cancer type indicated that the risk estimate of -1082A>G was significant for nasopharyngeal cancer under allelic, homozygous genotypic and dominant models (all P<0.001). Moreover by ethnicity, carriers of -1082G allele had a 74% increased risk for nasopharyngeal cancer in Asians under dominant model (odds ratio [OR] =1.737; 95% confidence interval [CI]: 1.280-2.358; P<0.001). In further Mendelian randomization analysis, the predicted OR for 10 pg/mL increment in IL-10 levels was 1.14 (95% CI: 1.01-16.99) in HEACs. Our findings provided strong evidence for a critical role of genetically elevated circulating IL-10 levels in the development of HEACs, especially in Asian population and for nasopharyngeal cancer.