Establishing the accuracy of position-specific carbon isotope analysis of propane by GC-pyrolysis-GC-IRMS.

RATIONALE: Position-specific (PS) δ13 C values of propane have proven their ability to provide valuable information on the evolution history of natural gases. Two major approaches to measure PS δ13 C values of propane are isotopic 13 C nuclear magnetic resonance (NMR) and gas chromatography-pyrolysis-gas chromatography-isotope ratio mass spectrometry (GC-Py-GC-IRMS). Measurement accuracy of the isotopic 13 C NMR has been verified, but the requirements of large sample size and long experimental time limit its applications. GC-Py-GC-IRMS is a more versatile method with a small sample size, but its accuracy has not been demonstrated. METHODS: We measured the PS δ13 C values of propane from nine natural gases using both 13 C NMR and GC-Py-GC-IRMS, then evaluated the accuracy of the GC-Py-GC-IRMS method. RESULTS: The results show that large carbon isotope fractionations occurred for both terminal and central carbons within propane during pyrolysis. The isotope fractionations during the pyrolysis are reproducible at optimum conditions, but vary between the two GC-Py-GC-IRMS systems tested, affected by experimental conditions (e.g., pyrolysis temperature, flow rate, and reactor conditions). CONCLUSIONS: It is necessary to evaluate and calibrate each GC-Py-GC-IRMS system using propane gases with accurately determined PS δ13 C values. This study also highlights a need for PS isotope standards for propane and other molecules (e.g., butane and acetic acid).

Annexin A1 alleviates kidney injury by promoting the resolution of inflammation in diabetic nephropathy.

Since failed resolution of inflammation is a major contributor to the progression of diabetic nephropathy, identifying endogenously generated molecules that promote the physiological resolution of inflammation may be a promising therapeutic approach for this disease. Annexin A1 (ANXA1), as an endogenous mediator, plays an important role in resolving inflammation. Whether ANXA1 could affect established diabetic nephropathy through modulating inflammatory states remains largely unknown. In the current study, we found that in patients with diabetic nephropathy, the levels of ANXA1 were upregulated in kidneys, and correlated with kidney function as well as kidney outcomes. Therefore, the role of endogenous ANXA1 in mouse models of diabetic nephropathy was further evaluated. ANXA1 deficiency exacerbated kidney injuries, exhibiting more severe albuminuria, mesangial matrix expansion, tubulointerstitial lesions, kidney inflammation and fibrosis in high fat diet/streptozotocin-induced-diabetic mice. Consistently, ANXA1 overexpression ameliorated kidney injuries in mice with diabetic nephropathy. Additionally, we found Ac2-26 (an ANXA1 mimetic peptide) had therapeutic potential for alleviating kidney injuries in db/db mice and diabetic Anxa1 knockout mice. Mechanistic studies demonstrated that intracellular ANXA1 bound to the transcription factor NF-κB p65 subunit, inhibiting its activation thereby modulating the inflammatory state. Thus, our data indicate that ANXA1 may be a promising therapeutic approach to treating and reversing diabetic nephropathy.

Perturbation of amino acid metabolism mediates air pollution associated vascular dysfunction in healthy adults.

The molecular mechanisms of air pollution-associated adverse cardiovascular effects remain largely unknown. In the present study, we investigated the impacts of ambient air pollution on vascular function and the potential mediation effects of amino acids in a longitudinal follow-up of 73 healthy adults living in Beijing, China, between 2014 and 2016. We estimated associations between air pollutants and serum soluble intercellular adhesion molecule 1 (sICAM-1) and plasma levels of amino acids using linear mixed-effects models, and elucidated the biological pathways involved using mediation analyses. Higher air pollutant levels were significantly associated with increases in sICAM-1 levels. Metabolomics analysis showed that altered metabolites following short-term air pollution exposure were mainly involved in amino acid metabolism. Significant reductions in levels of plasma alanine, threonine and glutamic acid of 2.1 µM [95% confidence interval (CI): -3.8, -0.3] to 62.0 µM (95% CI: -76.1, -47.9) were associated with interquartile range increases in moving averages of PM2.5, BC, CO and SO2 in 1-7 days prior to clinical visits. Mediation analysis also showed that amino acids can mediate up to 48% of the changes in sICAM-1 associated with increased air pollution exposure. Our results indicated that air pollution may prompt vascular dysfunction through perturbing amino acid metabolism.

Multi-Sensor Registration in High-Precision CMM Based on a Composite Standard.

Registration is a critical step in multi-sensor dimensional measurement. As the accuracy of registration directly impacts the quality of final results, a reference sphere as a common standard is problematic in high-precision registration. In this paper, a novel method based on a composite standard is proposed to fuse the multiple heterogeneous sensors in high-precision coordinate measuring machines (CMMs), which will void the drawbacks of a reference sphere. The composite standard consists of a cone and cylinder, which share a same central axis. To ensure high precision in the submicron range, or better, the standard is manufactured by an ultra-precision machine. Three features of the composite standard are inspected by three sensors: a video camera (VC), a tactile probe (TP), and a chromatic confocal displacement sensor (CC). All features will concentrate on a common point through which the relation between the three sensors will be obtained. The errors of each measurement were analyzed theoretically, and simulations and real experiments were carried out to verify the composite standard. This study demonstrates that the proposed registration method is stable and that the standard has potential use for the registration of multiple sensors in high-precision dimensional measurement.

Oxidized low-density lipoprotein-induced microparticles promote endothelial monocyte adhesion via intercellular adhesion molecule 1.

Oxidized low-density lipoprotein (oxLDL) accumulates early in atherosclerotic lesions and plays an important role in the progressive formation of atherosclerotic plaques. Endothelial derived microparticles (EMPs) form a heterogeneous population of <1-µm particles that shed from endothelial membranes upon activation. While EMPs are shown to be involved in atherosclerotic pathophysiology and progression, there is no report regarding the relationship between oxLDL and EMPs. In this study, we aim to determine the influence of oxLDL on endothelial microparticle release and the subsequent regulation of the endothelial activation. EMPs were collected from the medium of human umbilical vein endothelial cells (HUVECs) treated with oxLDL or PBS as control. We find that oxLDL increases the release of EMPs containing intercellular adhesion molecule 1 (ICAM-1) but not vascular cell adhesion molecule 1 (VCAM-1). Confocal microscopy analysis further demonstrates that these EMPs interact with endothelial cells and increase the expression of ICAM-1 in HUVECs. The fact that injecting oxLDL-induced EMPs via the tail vein of ICR mice augments ICAM-1 expression on aortic endothelial cells confirms our results in vivo. Finally, oxLDL-induced EMPs from HUVECs increase the adhesion of monocytes to endothelial cells as determined by the adhesion assay. Our study suggests that oxLDL may augment the release of EMPs harboring increased levels of ICAM-1 that can be transferred to endothelial cells elsewhere. This leads to increased monocyte recruitment in other regions where oxLDL accumulation was initially more limited. EMPs may therefore serve as the mediator that propagates oxLDL-induced endothelial inflammation.

A Fast Measuring Method for the Inner Diameter of Coaxial Holes.

A new method for fast diameter measurement of coaxial holes is studied. The paper describes a multi-layer measuring rod that installs a single laser displacement sensor (LDS) on each layer. This method is easy to implement by rotating the measuring rod, and immune from detecting the measuring rod's rotation angles, so all diameters of coaxial holes can be calculated by sensors' values. While revolving, the changing angles of each sensor's laser beams are approximately equal in the rod's radial direction so that the over-determined nonlinear equations of multi-layer holes for fitting circles can be established. The mathematical model of the measuring rod is established, all parameters that affect the accuracy of measurement are analyzed and simulated. In the experiment, the validity of the method is verified, the inner diameter measuring precision of 28 µm is achieved by 20 µm linearity LDS. The measuring rod has advantages of convenient operation and easy manufacture, according to the actual diameters of coaxial holes, and also the varying number of holes, LDS's mounting location can be adjusted for different parts. It is convenient for rapid diameter measurement in industrial use.

Calibration of Laser Beam Direction for Inner Diameter Measuring Device.

The laser triangulation method is one of the most advanced methods for large inner diameter measurement. Our research group proposed a kind of inner diameter measuring device that is principally composed of three laser displacement sensors known to be fixed in the same plane measurement position. It is necessary to calibrate the direction of the laser beams that are emitted by laser displacement sensors because they do not meet the theoretical model accurately. For the purpose of calibrating the direction of laser beams, a calibration method and mathematical model were proposed. The inner diameter measuring device is equipped with the spindle of the machine tool. The laser beams rotate and translate in the plane and constitute the rotary rays which are driven to scan the inner surface of the ring gauge. The direction calibration of the laser beams can be completed by the sensors' distance information and corresponding data processing method. The corresponding error sources are analyzed and the validity of the method is verified. After the calibration, the measurement error of the inner diameter measuring device reduced from ± 25 µ m to ± 15 µ m and the relative error was not more than 0.011%.

Serum Metabolomic Profiling Identifies Characterization of Non-Obstructive Azoospermic Men.

Male infertility is considered a common health problem, and non-obstructive azoospermia with unclear pathogenesis is one of the most challenging tasks for clinicians. The objective of this study was to investigate the differential serum metabolic pattern in non-obstructive azoospermic men and to determine potential biomarkers related to spermatogenic dysfunction. Serum samples from patients with non-obstructive azoospermia (n = 22) and healthy controls (n = 31) were examined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Serum metabolomic profiling could differentiate non-obstructive azoospermic patients from healthy control subjects. A total of 24 metabolites were screened and identified as potential markers, many of which are involved in energy production, oxidative stress and cell apoptosis in spermatogenesis. Moreover, the results showed that various metabolic pathways, including d-glutamine and d-glutamate metabolism, taurine and hypotaurine metabolism, pyruvate metabolism, the citrate cycle and alanine, aspartate and glutamate metabolism, were disrupted in patients with non-obstructive azoospermia. Our results indicated that the serum metabolic disorders may contribute to the etiology of non-obstructive azoospermia. This study suggested that serum metabolomics could identify unique metabolic patterns of non-obstructive azoospermia and provide novel insights into the pathogenesis underlying male infertility.

Flying spot laser triangulation scanner using lateral synchronization for surface profile precision measurement.

High-speed surface profile measurement with high precision is crucial for target inspection and quality control. In this study, a laser scanner based on a single point laser triangulation displacement sensor and a high-speed rotating polygon mirror is proposed. The autosynchronized scanning scheme is introduced to alleviate the trade-off between the field of view and the range precision, which is the inherent deficiency of the conventional triangulation. The lateral synchronized flying spot technology has excellent characteristics, such as programmable and larger field of view, high immunity to ambient light or secondary reflections, high optical signal-to-noise ratio, and minimum shadow effect. Owing to automatic point-to-point laser power control, high accuracy and superior data quality are possible when measuring objects featuring varying surface characteristics even in demanding applications. The proposed laser triangulation scanner is validated using a laboratory-built prototype and practical considerations for design and implementation of the system are described, including speckle noise reduction method and real-time signal processing. A method for rapid and accurate calibration of the laser triangulation scanner using lookup tables is also devised, and the system calibration accuracy is generally smaller than ±0.025 mm. Experimental results are presented and show a broad application prospect for fast surface profile precision measurement.

Effects of immediate blood pressure reduction on death and major disability in patients with acute ischemic stroke: the CATIS randomized clinical trial.

IMPORTANCE: Although the benefit of reducing blood pressure for primary and secondary prevention of stroke has been established, the effect of antihypertensive treatment in patients with acute ischemic stroke is uncertain. OBJECTIVE: To evaluate whether immediate blood pressure reduction in patients with acute ischemic stroke would reduce death and major disability at 14 days or hospital discharge. DESIGN, SETTING, AND PARTICIPANTS: The China Antihypertensive Trial in Acute Ischemic Stroke, a single-blind, blinded end-points randomized clinical trial, conducted among 4071 patients with nonthrombolysed ischemic stroke within 48 hours of onset and elevated systolic blood pressure. Patients were recruited from 26 hospitals across China between August 2009 and May 2013. INTERVENTIONS: Patients (n = 2038) were randomly assigned to receive antihypertensive treatment (aimed at lowering systolic blood pressure by 10% to 25% within the first 24 hours after randomization, achieving blood pressure less than 140/90 mm Hg within 7 days, and maintaining this level during hospitalization) or to discontinue all antihypertensive medications (control) during hospitalization (n = 2033). MAIN OUTCOMES AND MEASURES: Primary outcome was a combination of death and major disability (modified Rankin Scale score ≥3) at 14 days or hospital discharge. RESULTS: Mean systolic blood pressure was reduced from 166.7 mm Hg to 144.7 mm Hg (-12.7%) within 24 hours in the antihypertensive treatment group and from 165.6 mm Hg to 152.9 mm Hg (-7.2%) in the control group within 24 hours after randomization (difference, -5.5% [95% CI, -4.9 to -6.1%]; absolute difference, -9.1 mm Hg [95% CI, -10.2 to -8.1]; P < .001). Mean systolic blood pressure was 137.3 mm Hg in the antihypertensive treatment group and 146.5 mm Hg in the control group at day 7 after randomization (difference, -9.3 mm Hg [95% CI, -10.1 to -8.4]; P < .001). The primary outcome did not differ between treatment groups (683 events [antihypertensive treatment] vs 681 events [control]; odds ratio, 1.00 [95% CI, 0.88 to 1.14]; P = .98) at 14 days or hospital discharge. The secondary composite outcome of death and major disability at 3-month posttreatment follow-up did not differ between treatment groups (500 events [antihypertensive treatment] vs 502 events [control]; odds ratio, 0.99 [95% CI, 0.86 to 1.15]; P = .93). CONCLUSION AND RELEVANCE: Among patients with acute ischemic stroke, blood pressure reduction with antihypertensive medications, compared with the absence of hypertensive medication, did not reduce the likelihood of death and major disability at 14 days or hospital discharge. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01840072.

The stratum corneum barrier: impaired function in relation to associated lipids and proteins.

The skin is the largest organ of the human body and is widely considered to be the first-line defense of the body, providing essential protection against mechanical, physical, and chemical damage. Keratinocytes are the primary cells of the outer layer of the epidermis, which acts as a mechanical and permeability barrier. The epidermis is a permanently renewed tissue where undifferentiated keratinocytes located at the basal layer proliferate and migrate to the overlying layers. Here we report that some components of keratinocytes affect the formation and differentiation of the stratum corneum, which is the most specialized layer of the epidermis.

Online water vapor removal membrane inlet mass spectrometer for high-sensitivity detection of dissolved methane.

Underwater mass spectrometry is characterized by excellent consistency, strong specificity, and the ability to simultaneously detect multiple substances, making it a valuable tool in research fields such as aquatic ecosystems, hydrothermal vents, and the global carbon cycle. Nevertheless, current underwater mass spectrometry encounters challenges stemming from the high-water vapor content, constituting proportions of nearly 90%. This results in issues such as peak overlap, interference with peak height, decreased ionization efficiency and, consequently, make it difficult to achieve low detection limits for extremely low concentrations of gases, such as methane, and impede the detection of background CH4 levels. In this study, we optimized the design of the sampling gas path and developed a high gas-tightness, high pressure-resistant membrane inlet system, coupled with a small-volume, low-power online water vapor removal system. This innovation efficiently eliminates water vapor while maintaining a high permeation flux of the target gases. By elevating the vacuum level to the order of 1E-6 Torr, the ionization efficiency and detection performance were improved. Based on this, we created an online water vapor removal membrane inlet mass spectrometer and conducted experimental research. Results indicated that the water removal efficiency approached 100%, and the vacuum level was elevated by more than 2 orders of magnitude. The detection limit for CH4 increased from over 600 nmol/L to 0.03 nmol/L, representing an improvement of over 4 orders of magnitude, and reaching the level of detecting background CH4 signals in deep-sea and lakes. Furthermore, the instrument exhibited excellent responsiveness and tracking capability to concentration changes on the second scale, enabling in situ analysis of rapidly changing concentration scenarios.

The "blownknee" patient's stress fracture of distal tibial component after unilateral TKA: A case report.

RATIONALE: Periprosthetic fractures (PPF) are rare complications of total knee arthroplasty (TKA). The most common PPF after TKA is supracondylar femoral fracture, which is a relatively rare complication that is usually associated with high-energy trauma, with a reported incidence ranging from 0.4 to 1.7% according to the AOANJRR. However, in TKA patients, it is rarer that the stress fracture around the tibial prosthesis occurs due to changes in the lower limb force line, increasing weight-bearing, and changes in walking gait. PATIENT CONCERNS: A 68-year-old woman visited our hospital with "both knees had aggravated pain and deformity for 8 years." TKA was performed first on the left knee and the patient was discharged within 1 week. Three months later, the patient complained of pain in the upper middle 1/3 part of the medial tibia for 2 weeks, which gradually worsened and affected weight-bearing. DIAGNOSES: Physical examination showed that the left knee joint presented varus deformity, and the right valgus deformity, which diagnosed as osteoarthritis of both knees and was so-called "blownknee". The disease was initially diagnosed as osteoarthritis of both knees on first admission and PPF of the tibia in second. INTERVENTIONS: Three operations were performed on this patient. The first was TKA of the left knee, the second was open reduction and internal fixation of the PPF of the tibia 3 months after the first operation, and the third was TKA of the right knee. OUTCOMES: Until now, the patient has had no recurrent PPF, and the fracture is healing from the last X-ray. LESSONS: Clinicians should be aware of the possibility of PPF after TKA, especially in such patients, the most preferred surgical treatment method was open reduction and internal fixation of fractures using locking plates, and if the PPF with loosened implants, Revision TKA, or megaprosthesis was the better choice.

Short-Term Effects of Primary and Secondary Particulate Matter on Ceramide Metabolism, Pro-Inflammatory Response, and Blood Coagulation.

Evidence of the precise biological pathway responsible for acute cardiovascular events triggered by particulate matter (PM) exposure from anthropogenic emissions is sparse. We investigated the associations of biomarkers relevant to the pathophysiology of atherothrombosis (ceramide metabolism, pro-inflammatory response, and blood coagulation) with primary and secondary components in particulate matter with aerodynamic diameters less than 2.5 µm (PM2.5). A total of 152 healthy participants were followed with four repeated clinical visits between September 2019 and January 2020 in Beijing. Exposure to ambient inorganic aerosols (sulfate, nitrate, ammonium, and chloride), as well as organic aerosols (OA) in PM2.5, was measured by a real-time aerosol chemical speciation monitor, and sources of OA were performed by positive matrix factorization. We found significant increases of 101.9-397.9% in ceramide indicators associated with interquartile-range increases in inorganic aerosols and OA prior to 72 h of exposure. Higher levels of organic and inorganic aerosols in PM2.5 were associated with increases of 3.1-6.0% in normal T cells regulated upon activation and expressed and secreted relevant to the pro-inflammatory response; increases of 276.9-541.5% were observed in D-dimers relevant to coagulation. Detrimental effects were further observed following OA exposure from fossil fuel combustion. Mediation analyses indicated that ceramide metabolism could mediate the associations of PM2.5 components with pro-inflammatory responses. Our findings expand upon the current understanding of potential pathophysiological pathways of cardiovascular events posed by ambient particulates and highlight the importance of reducing primary and secondary PM from anthropogenic combustions.

Annexin A1 binds PDZ and LIM domain 7 to inhibit adipogenesis and prevent obesity.

Obesity is a global issue that warrants the identification of more effective therapeutic targets and a better understanding of the pivotal molecular pathogenesis. Annexin A1 (ANXA1) is known to inhibit phospholipase A2, exhibiting anti-inflammatory activity. However, the specific effects of ANXA1 in obesity and the underlying mechanisms of action remain unclear. Our study reveals that ANXA1 levels are elevated in the adipose tissue of individuals with obesity. Whole-body or adipocyte-specific ANXA1 deletion aggravates obesity and metabolic disorders. ANXA1 levels are higher in stromal vascular fractions (SVFs) than in mature adipocytes. Further investigation into the role of ANXA1 in SVFs reveals that ANXA1 overexpression induces lower numbers of mature adipocytes, while ANXA1-knockout SVFs exhibit the opposite effect. This suggests that ANXA1 plays an important role in adipogenesis. Mechanistically, ANXA1 competes with MYC binding protein 2 (MYCBP2) for interaction with PDZ and LIM domain 7 (PDLIM7). This exposes the MYCBP2-binding site, allowing it to bind more readily to the SMAD family member 4 (SMAD4) and promoting its ubiquitination and degradation. SMAD4 degradation downregulates peroxisome proliferator-activated receptor gamma (PPARγ) transcription and reduces adipogenesis. Treatment with Ac2-26, an active peptide derived from ANXA1, inhibits both adipogenesis and obesity through the mechanism. In conclusion, the molecular mechanism of ANXA1 inhibiting adipogenesis was first uncovered in our study, which is a potential target for obesity prevention and treatment.

Speciation of Zn and Cd in sierozem soil, northwest China: bulk EXAFS and micro synchrotron X-ray fluorescence.

Previous research studies have confirmed that Zn and Cd are the most predominant heavy metals in the Baiyin district, Gansu province, China. Furthermore, the speciation of Zn and Cd is a key factor in controlling the mobility, bioavailability, and toxicity of metals in Zn/Cd co-contaminated soil. In this study, the speciation of Zn and Cd in different types of agricultural soils including the Yellow River irrigated soil (s3) and sewage irrigated soil (s1 and s2) was investigated and compared by a combination of sequential extraction, bulk X-ray absorption fine structure (XAFS), and micro-X-ray fluorescence (µ-XRF) techniques. The results of the speciation quantified by XAFS were in general agreement with those obtained by sequential extraction, and the combination of both approaches allowed a reliable description of Zn/Cd speciation in soil. The speciation of Zn in the s1 soil exposed around the smelter was similar to speciation of Zn in the sewage irrigated s2 soil. In both soils, Zn was predominantly present as Zn-Al LDH (31-36%), Zn adsorbed on calcite (37-47%), and primary minerals (14-18% sphalerite and 9% franklinite). In contrast, the proportions of organic Zn (23%) and Zn-Al LDH (53%) were significantly higher in the Yellow River irrigated s3 soil, while that of Zn-calcite (24%) was lower. This indicated that Zn in s3 was less mobile and bioavailable than that in s1 and s2 soils. The content of bioavailable Zn in s3 was much lower than the background value and Zn did not pose a threat to the Yellow River irrigated soil. In addition, Cd was strongly correlated with Zn content and exhibited a simpler speciation. Cd adsorbed on illite and calcite was found as the major species in both soil types, posing higher migration and toxicity to the environment. Our study reported the speciation and correlation of Zn/Cd in sierozem soil for the first time and provided a significant theoretical basis for remediation actions to minimize Zn/Cd risks.

Pro-inflammation and pro-atherosclerotic responses to short-term air pollution exposure associated with alterations in sphingolipid ceramides and neutrophil extracellular traps.

Air pollution has been associated with the development of atherosclerosis; however, the pathophysiological mechanisms underlying pro-atherosclerotic effects of air pollution exposure remain unclear. We conducted a prospective panel study in Beijing and recruited 152 participants with four monthly visits from September 2019 to January 2020. Linear mixed-effect models were applied to estimate the associations linking short-term air pollution exposure to biomarkers relevant to ceramide metabolism, pro-inflammation (neutrophil extracellular traps formation and systemic inflammation) and pro-atherosclerotic responses (endothelial stimulation, plaque instability, coagulation activation, and elevated blood pressure). We further explored whether ceramides and inflammatory indicators could mediate the alterations in the profiles of pro-atherosclerotic responses. We found that significant increases in levels of circulating ceramides of 9.7% (95% CIs: 0.7, 19.5) to 96.9% (95% CIs: 23.1, 214.9) were associated with interquartile range increases in moving averages of ambient air pollutant metrics, including fine particulate matter (PM2.5), black carbon, particles in size fractions of 100-560 nm, nitrogen dioxide, carbon monoxide and sulfur dioxide at prior up to 7 days. Higher air pollution levels were also associated with activated neutrophils (increases in citrullinated histone H3, neutrophil elastase, double-stranded DNA, and myeloperoxidase) and exacerbation of pro-atherosclerotic responses (e.g., increases in vascular endothelial growth factor, lipoprotein-associated phospholipase A2, matrix metalloproteinase-8, P-selectin, and blood pressure). Mediation analyses further showed that dysregulated ceramide metabolism and potentiated inflammation could mediate PM2.5-associated pro-atherosclerotic responses. Our findings extend the understanding on potential mechanisms of air pollution-associated atherosclerosis, and suggest the significance of reducing air pollution as priority in urban environments.

Integrating Choline and Specific Intestinal Microbiota to Classify Type 2 Diabetes in Adults: A Machine Learning Based Metagenomics Study.

Emerging evidence is examining the precise role of intestinal microbiota in the pathogenesis of type 2 diabetes. The aim of this study was to investigate the association of intestinal microbiota and microbiota-generated metabolites with glucose metabolism systematically in a large cross-sectional study in China. 1160 subjects were divided into three groups based on their glucose level: normal glucose group (n=504), prediabetes group (n=394), and diabetes group (n=262). Plasma concentrations of TMAO, choline, betaine, and carnitine were measured. Intestinal microbiota was measured in a subgroup of 161 controls, 144 prediabetes and 56 diabetes by using metagenomics sequencing. We identified that plasma choline [Per SD of log-transformed change: odds ratio 1.36 (95 confidence interval 1.16, 1.58)] was positively, while betaine [0.77 (0.66, 0.89)] was negatively associated with diabetes, independently of TMAO. Individuals with diabetes could be accurately distinguished from controls by integrating data on choline, and certain microbiota species, as well as traditional risk factors (AUC=0.971). KOs associated with the carbohydrate metabolism pathway were enhanced in individuals with high choline level. The functional shift in the carbohydrate metabolism pathway in high choline group was driven by species Ruminococcus lactaris, Coprococcus catus and Prevotella copri. We demonstrated the potential ability for classifying diabetic population by choline and specific species, and provided a novel insight of choline metabolism linking the microbiota to impaired glucose metabolism and diabetes.

Gut microbiota production of trimethyl-5-aminovaleric acid reduces fatty acid oxidation and accelerates cardiac hypertrophy.

Numerous studies found intestinal microbiota alterations which are thought to affect the development of various diseases through the production of gut-derived metabolites. However, the specific metabolites and their pathophysiological contribution to cardiac hypertrophy or heart failure progression still remain unclear. N,N,N-trimethyl-5-aminovaleric acid (TMAVA), derived from trimethyllysine through the gut microbiota, was elevated with gradually increased risk of cardiac mortality and transplantation in a prospective heart failure cohort (n = 1647). TMAVA treatment aggravated cardiac hypertrophy and dysfunction in high-fat diet-fed mice. Decreased fatty acid oxidation (FAO) is a hallmark of metabolic reprogramming in the diseased heart and contributes to impaired myocardial energetics and contractile dysfunction. Proteomics uncovered that TMAVA disturbed cardiac energy metabolism, leading to inhibition of FAO and myocardial lipid accumulation. TMAVA treatment altered mitochondrial ultrastructure, respiration and FAO and inhibited carnitine metabolism. Mice with γ-butyrobetaine hydroxylase (BBOX) deficiency displayed a similar cardiac hypertrophy phenotype, indicating that TMAVA functions through BBOX. Finally, exogenous carnitine supplementation reversed TMAVA induced cardiac hypertrophy. These data suggest that the gut microbiota-derived TMAVA is a key determinant for the development of cardiac hypertrophy through inhibition of carnitine synthesis and subsequent FAO.

Origin of pyrite nodules at the top of the nantuo diamictites, Southern China.

Pyrite nodules up to 20 cm in diameter are found at the top of the Marinoan (~ 635 Ma) Nantuo glacial diamictite as well as in the cap dolostones and shale/siltstones in the lower Doushantuo Formation in eastern Guizhou, southern China. Field occurrences, petrography, and stable sulfur isotopic compositions of pyrite nodules were studied from a section at Taoying, eastern Guizhou, China. Pyrite δ34S values from different nodules varied from 7.3 to 60.5‰ at different stratigraphic levels. No stratigraphic trend existed for the δ34S, supporting the scenario of pyrite formation in sediments before the precipitation of the cap dolostone. Pyrite δ34S values were also homogeneous within individual nodules at a 0.3 to 1 cm sampling scale, but were more heterogeneous at a 2 mm sampling scale. Homogeneity was not expected from the particular model for pyrite nodule formation in a largely closed or semi-closed environment. Thus, differential cementation and compaction of the pyrite-bearing sediments may have produced the nodular shape of the pyrite deposit.