A Mendelian Randomization Study: Roles of Gut Microbiota in Sepsis - Who is the Angle?

Gut microbiota (GM) is a crucial underlying player during sepsis pathogenesis. However, the causal relationship is unclear and remains to be determined. A two-sample Mendelian randomization study was implemented. The statistical data about sepsis together with GM summarized from genome-wide association studies were evaluated. Instrumental variables were defined as single-nucleotide polymorphisms with prominent correlations with exposure. The inverse-variance-weighted test was employed as a major approach of Mendelian randomization analysis to estimate of causal relationships. The inverse-variance-weighted analysis results demonstrated that at different taxa levels, Actinobacteria and Bifidobacteriaceae influence sepsis. Actinobacteria had negative relationships to sepsis risk at the phylum (ß = -0.34, SE = 0.10, p = 0.0008) and class (ß = -0.23, SE = 0.07, p = 0.0011) levels in outcome coded ieu-b-69. Actinobacteria at the phylum level (ß = -0.22, SE = 0.10, p = 0.027) was also negatively associated with sepsis in outcome coded ieu-b-4980. Bifidobacteriaceae at the order (ß = -0.20, SE = 0.06, p = 0.0021), family (ß = -0.20, SE = 0.06, p = 0.0021), and genus (ß = -0.20, SE = 0.06, p = 0.0007) levels were all negatively correlated with the risk of sepsis in outcome coded ieu-b-69. The results of the Wald ratio model showed that Tyzzerella genus (OR (95%CI) = 0.6902[0.4907,0.9708], p = 0.0331) and Gastranaerophilales order (OR (95%CI) = 0.5907[0.3516,0.9926], p = 0.0468) were negatively connected with sepsis. This study implied at different taxa levels Actinobacteria and Bifidobacteriaceae, Tyzzerella genus, and Gastranaerophilales order have a causal relationship with sepsis, indicating that they are protective factors for the incidence of sepsis.

Composition and sources of suspended particles in the Pacific Arctic region.

During the 6th (2014) and 7th (2016) Chinese Arctic Expedition (CHINARE), samples of suspended particulate matter (SPM) were collected from both surface (depth: <1.0 m) and subsurface (depth: approximately between 10 and 150 m) waters over the northern shelf of the Bering Sea and in the western Arctic Ocean. To investigate the distribution and sources of organic matter in both the surface water and the vertical profile, the concentration and stable carbon isotopic composition of SPM, particulate organic carbon (POC), and particulate nitrogen (only in surface water samples) were determined, and some particle samples were selected for examination using scanning electron microscopy. Results showed apparent geographical partitioning and temporal variation in both the concentration and the composition of SPM. Higher SPM concentrations were observed in nearshore, shelf break, and sea ice edge areas; the distribution of POC concentration displayed a similar pattern, with higher values found from the northern part of the Bering Shelf to southern parts of the Chukchi Shelf. In surface water, SPM mainly comprised clay and detrital minerals with higher POC contents, lighter δ13C values, and higher POC/PN ratios, indicating organic matter predominantly derived from terrestrial sources in areas south of St. Lawrence Island and north of 73°N. The downward trend of heavier δ13C values, together with reduction in clay and detrital minerals, suggests that vertical transport of SPM is hindered by stratification, resulting in transport of terrestrial materials toward northern basin areas. In the Chukchi Slope and Canada Basin areas, extremely light δ13C values (as low as -33.41‰ PDB) were mainly observed at depths of 20-60 m, where the Polar Mixed Layer (PML) intersects with the Upper Halocline Layer (UHL). Under the condition of low sea ice extent in 2016, the POC-δ13C values were heavier in the PML than in the UHL in the Chukchi Slope and Canada Basin areas. These findings provide insights into the sources, transport, and fate of organic matter in the Pacific Arctic region, which have important implications for understanding the biogeochemical cycles and ecosystem dynamics in this remote and rapidly changing environment.

Classification regularized dimensionality reduction improves ultrasound thyroid nodule diagnostic accuracy and inter-observer consistency.

PROBLEM: Convolutional Neural Networks (CNNs) for medical image analysis usually only output a probability value, providing no further information about the original image or inter-relationships between different images. Dimensionality Reduction Techniques (DRTs) are used for visualization of high dimensional medical image data, but they are not intended for discriminative classification analysis. AIM: We develop an interactive phenotype distribution field visualization system for medical images to accurately reflect the pathological characteristics of lesions and their similarity to assist radiologists in diagnosis and medical research. METHODS: We propose a novel method, Classification Regularized Uniform Manifold Approximation and Projection (UMAP) referred as CReUMAP, combining the advantages of CNN and DRT, to project the extracted feature vector fused with the malignant probability predicted by a CNN to a two-dimensional space, and then apply a spatial segmentation classifier trained on 2614 ultrasound images for prediction of thyroid nodule malignancy and guidance to radiologists. RESULTS: The CReUMAP embedding correlates well with the TI-RADS categories of thyroid nodules. The parametric version that embeds external test dataset of 303 images in presence of the training data with known pathological diagnosis improves the benign and malignant nodule diagnostic accuracy (p-value = 0.016) and confidence (p-value = 1.902 × 10-6) of eight radiologists of different experience levels significantly as well as their inter-observer agreements (kappa≥0.75). CReUMAP achieve 90.8% accuracy, 92.1% sensitivity and 88.6% specificity in test set. CONCLUSION: CReUMAP embedding is well correlated with the pathological diagnosis of thyroid nodules, and helps radiologists achieve more accurate, confident and consistent diagnosis. It allows a medical center to generate its locally adapted embedding using an already-trained classification model in an updateable manner on an ever-growing local database as long as the extracted feature vectors and predicted diagnostic probabilities of the correspondent classification model can be outputted.

Variability of the Indonesian Throughflow in the Makassar Strait over the Last 30 ka.

The hydrological characteristics, including temperatures and salinities, of the upper water over the last 30 ka from two sites connected by the Indonesian Throughflow (ITF) across the Makassar Strait are reconstructed and compared. The thermocline hydrological gradient in the strait was larger during 13.4~19 ka BP and 24.2~27 ka BP than that in the Holocene. The weakened ITF during those periods in the last glacial period, corresponding to the decreased trade wind stress under an El Niño-like climate mean state, likely accounts for the increased thermocline gradient. The thermocline water temperature variabilities of the two sites, in particular the highest peaks at ~7 ka BP, are different from the records of the open western Pacific. Reoccurrence of the South China Sea Throughflow and thus a decreased surface throughflow along the Makassar Strait perhaps led to a warmer peak of thermocline temperature at ~7 ka BP than at ~11 ka BP.

Chronic intermittent hypoxia induces cardiac inflammation and dysfunction in a rat obstructive sleep apnea model.

Chronic intermittent hypoxia is considered to play an important role in cardiovascular pathogenesis during the development of obstructive sleep apnea (OSA). We used a well-described OSA rat model induced with simultaneous intermittent hypoxia. Male Sprague Dawley rats were individually placed into plexiglass chambers with air pressure and components were electronically controlled. The rats were exposed to intermittent hypoxia 8 hours daily for 5 weeks. The changes of cardiac structure and function were examined by ultrasound. The cardiac pathology, apoptosis, and fibrosis were analyzed by H&E staining, TUNNEL assay, and picosirius staining, respectively. The expression of inflammation and fibrosis marker genes was analyzed by quantitative real-time PCR and Western blot. Chronic intermittent hypoxia/low pressure resulted in significant increase of left ventricular internal diameters (LVIDs), end-systolic volume (ESV), end-diastolic volume (EDV), and blood lactate level and marked reduction in ejection fraction and fractional shortening. Chronic intermittent hypoxia increased TUNNEL-positive myocytes, disrupted normal arrangement of cardiac fibers, and increased Sirius stained collagen fibers. The expression levels of hypoxia induced factor (HIF)-1α, NF-kB, IL-6, and matrix metallopeptidase 2 (MMP-2) were significantly increased in the heart of rats exposed to chronic intermittent hypoxia. In conclusion, the left ventricular function was adversely affected by chronic intermittent hypoxia, which is associated with increased expression of HIF-1α and NF-kB signaling molecules and development of cardiac inflammation, apoptosis and fibrosis.

Effect and mechanism of Qishen Yiqi Pills on adriamycin- induced cardiomyopathy in mice.

AIM: To study the effect and probable mechanism of Qishen Yiqi Pills on adriamycin (ADR)-induced cardiomyopathy in mice. METHODS: Sixty-four mice were randomly divided into (1) the ADR group: saline (1 mL/100 g) administered every day by intragavage, ADR (4 mg·kg(-1)) administered to each mouse by intraperitoneal injection twice a week for four weeks; (2) the ADR + Qishen Yiqi Pills I group: ADR (4 mg·kg(-1)) administered to each mouse by intraperitoneal injection twice a week for four weeks, and at the beginning of the third week Qishen Yiqi Pills (3.5 mg/100 g) administered by intragavage every day for four weeks; (3) the ADR + Qishen Yiqi Pills II group: ADR (4 mg·kg(-1)) administered to each mouse by intraperitoneal injection twice a week for four weeks, and at the same time Qishen Yiqi Pills (3.5 mg/100 g) administered by intragavage every day for four weeks; (4) the control group: saline (1 mL/100 g) administered every day by intragavage, saline (1 mL·kg(-1)) administered to each mouse by intraperitoneal injection twice a week for four weeks. Six weeks later, cardiac function, myocardial pathology, and expression of Bcl-2 and Bax were evaluated. RESULTS: 1. The left ventricular diastolic diameter and the left ventricular systolic diameter were significantly increased (P < 0.05) and the left ventricular ejection fraction was significantly decreased (P < 0.05) in the ADR group, and the cardiac function of both the ADR + Qishen Yiqi Pills I group and the ADR + Qishen Yiqi Pills II group improved. 2. Myocardial morphologic observation showed that the myocardial fibers were disordered, there was cell edema, and gap widening in the ADR group. The degree of myocardial cell injury was reduced in the ADR + Qishen Yiqi Pills I group and ADR + Qishen Yiqi Pills II group compared with the ADR group. 3. The expression of Bax in the ADR group was significantly up-regulated, and the expression of Bcl-2 was significantly downregulated in the ADR group compared with the ADR + Qishen Yiqi Pills I group, the ADR + Qishen Yiqi Pills II group, and the control group (P < 0.05). CONCLUSIONS: Qishen Yiqi Pills can effectively improve the cardiac function of ADR-induced cardiomyopathy, and the earlier it is used is better. The probable mechanism of action may be the inhibition of the apoptosis of myocardial cells.

Mesenchymal stem cell transplantation enhancement in myocardial infarction rat model under ultrasound combined with nitric oxide microbubbles.

OBJECTIVE: This study evaluated the effects of ultrasound combined with the homemade nitric oxide (NO) micro-bubble destruction on the in vitro proliferation, apoptosis, and migration of mesenchymal stem cells (MSCs). Furthermore, we studied whether or not irradiation of the NO micro-bubble combined with bone-marrow derived MSC infusion had a better effect on treating myocardial infarction. The possible mechanism of MSC delivery into the infarcted myocardium was also investigated. METHODS: The murine bone marrow-derived MSCs were isolated, cultured, irradiated, and combined with different concentrations of NO microbubbles. MTT proliferation assay, annexin V-FITC apoptosis detection, migration assay, and RT-PCR were performed 24 h after the irradiation. The NO micro-bubbles was a intravenously injected, followed by the infusion of MSCs, which were labeled by CM-Dil. Myocardium was harvested 48 h later and the distribution of MSCs was observed by laser scanning confocal microscope after frozen sectioning. Echocardiography, histological examination, RT-PCR, and western blotting were performed four weeks after the cell transplantation. RESULTS: Ultrasound combined with 1:70 NO micro-bubbles had no significant impact on the proliferation or apoptosis of MSCs. Transwell chamber findings demonstrated that MSCs migrated more efficiently in group that underwent ultrasound combined with 1:70 NO micro-bubbles. The Real-time PCR results indicated that the expression of CXCR4 was much higher in the group undergoing ultrasound combined with 1:70 NO micro-bubbles. The normalized fluorescence intensity greatly increased in the group of US+NO micro-bubbles and the cardiac function was also markedly improved. Immunohistochemical staining showed that the capillary density was much greater in the group of US+NO micro-bubbles as compared to that of the other groups. RT-PCR and western blotting also revealed a higher SDF-1 and VEGF expression in the group of US+NO micro-bubbles. CONCLUSIONS: NO micro-bubbles could be used in the cell transplantation, which efficiently promoted the MSC homing into the infarcted myocardium.