Abstract
Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disorder that is predicted to increase across the globe by ~70% in the following decades. Understanding the ...disease causal mechanism underlying ALS and identifying modifiable risks factors for ALS hold the key for the development of effective preventative and treatment strategies. Here, we investigate the causal effects of four blood lipid traits that include high-density lipoprotein, low-density lipoprotein (LDL), total cholesterol and triglycerides on the risk of ALS. By leveraging instrument variables from multiple large-scale genome-wide association studies in both European and East Asian populations, we carry out one of the largest and most comprehensive Mendelian randomization analyses performed to date on the causal relationship between lipids and ALS. Among the four lipids, we found that only LDL is causally associated with ALS and that higher LDL level increases the risk of ALS in both the European and East Asian populations. Specifically, the odds ratio of ALS per 1 standard deviation (i.e. 39.0 mg/dL) increase of LDL is estimated to be 1.14 95% confidence interval (CI), 1.05-1.24; P = 1.38E-3 in the European population and 1.06 (95% CI, 1.00-1.12; P = 0.044) in the East Asian population. The identified causal relationship between LDL and ALS is robust with respect to the choice of statistical methods and is validated through extensive sensitivity analyses that guard against various model assumption violations. Our study provides important evidence supporting the causal role of higher LDL on increasing the risk of ALS, paving ways for the development of preventative strategies for reducing the disease burden of ALS across multiple nations.
•Three kinds of nano-particles/polymer systems were proposed to modify SK-70 asphalt.•Influences of nano-particles/polymer on the properties of SK-70 asphalt were tested with TFOT, DSR and BBR ...tests.•Morphologies of modified asphalts and SK-70 asphalt were measured with SEM.•The chemical bondings of modified asphalts and SK-70 asphalt were analyzed through FTIR.
At present, most asphalts and modified asphalts cannot meet requirements of both high temperature stability and low temperature cracking resistance simultaneously. Hence, the objective of this paper is to find new modification system to improve the high and low temperature properties of SK-70 base asphalt. In this paper, nano-zinc oxide (nano-ZnO) particles, nano-titanium dioxide (nano-TiO2) particles, nano-calcium carbonate (nano-CaCO3) particles, styrene-butadiene-styrene (SBS) and styrene-butadiene-rubber (SBR) were selected as modifiers. The modified asphalt samples with three or two kinds of modifiers were prepared, and the softening point, ductility and penetration of modified asphalt samples were measured and compared. Eventually, three optimal nano-particles/polymer modification systems for SK-70 base asphalt including 3%nano-ZnO/0.5%nano-TiO2/3.7%SBS, 5%nano-ZnO/4.2%SBS, 5%nano-CaCO3/4%SBR were proposed. To study the effects of these three optimal modification formulations on high and low temperature properties of base asphalt, dynamic shear rheometer (DSR), thin film oven test (TFOT), and beam bending rheometer (BBR) tests were conducted on the asphalt of SK-70 and the nano-particles/polymer modified asphalts. The micro-morphology of SK-70 and the modified asphalts was examined using scanning electron microscope (SEM) and the reactions between modifiers and SK-70 base asphalt were studied by infrared spectrum instrument. From the test results, it was observed that the nano-materials were well dispersed in base asphalt, and could increase the dispersibility of polymer in base asphalt and improve the compatibility between polymer and base asphalt. Furthermore, the nano-materials could improve the high and low temperature properties of SK-70 base asphalt. Additionally, the results also revealed that for polymer modified asphalts the physical reaction between polymers and asphalt played the dominant role in the modification process, while for nano-particles/polymer modified asphalts, both physical and chemical reaction occurred in the modification process.
Using genotype data to perform accurate genetic prediction of complex traits can facilitate genomic selection in animal and plant breeding programs, and can aid in the development of personalized ...medicine in humans. Because most complex traits have a polygenic architecture, accurate genetic prediction often requires modeling all genetic variants together via polygenic methods. Here, we develop such a polygenic method, which we refer to as the latent Dirichlet process regression model. Dirichlet process regression is non-parametric in nature, relies on the Dirichlet process to flexibly and adaptively model the effect size distribution, and thus enjoys robust prediction performance across a broad spectrum of genetic architectures. We compare Dirichlet process regression with several commonly used prediction methods with simulations. We further apply Dirichlet process regression to predict gene expressions, to conduct PrediXcan based gene set test, to perform genomic selection of four traits in two species, and to predict eight complex traits in a human cohort.Genetic prediction of complex traits with polygenic architecture has wide application from animal breeding to disease prevention. Here, Zeng and Zhou develop a non-parametric genetic prediction method based on latent Dirichlet Process regression models.
This Review summarizes the advances in the construction of all-carbon quaternary stereocenters via catalytic enantioselective desymmetrization of prochiral and meso-compounds, highlights the power ...and potential of this strategy in the total synthesis of natural products and biologically active compounds, and outlines the synthetic opportunities still available.
Highlights ► Microbial production of 1,3-propanediol from glucose is a major achievement of industrial biotechnology. ► Raw glycerol as a by-product of biofuel production is attractive for production ...of diol. ► The use of raw glycerol for the bioproduction of 1,3-propanediol is technically feasible and economically competitive. ► Unsterile or mixed culture fermentation of glycerol can significantly reduce the investment and operation costs for microbial 1,3-propanediol. ► The concentration and yield of 2,3-buatnediol from biomass have been significantly improved in the last years.
Bioconversion of natural microorganisms generally results in a mixture of various compounds. Downstream processing (DSP) which only targets a single product often lacks economic competitiveness due ...to incomplete use of raw material and high cost of waste treatment for by‐products. Here, we show with the efficient microbial conversion of crude glycerol by an artificially evolved strain and how a catalytic conversion strategy can improve the total products yield and process economy of the DSP. Specifically, Clostridium pasteurianum was first adapted to increased concentration of crude glycerol in a novel automatic laboratory evolution system. At m3 scale bioreactor the strain achieved a simultaneous production of 1,3‐propanediol (PDO), acetic and butyric acids at 81.21, 18.72, and 11.09 g/L within only 19 h, respectively, representing the most efficient fermentation of crude glycerol to targeted products. A heterogeneous catalytic step was developed and integrated into the DSP process to obtain high‐value methyl esters from acetic and butyric acids at high yields. The coproduction of the esters also greatly simplified the recovery of PDO. For example, a cosmetic grade PDO (96% PDO) was easily obtained by a simple single‐stage distillation process (with an overall yield more than 77%). This integrated approach provides an industrially attractive route for the simultaneous production of three appealing products from the crude glycerol fermentation broth, which greatly improve the process economy and ecology.
The crude glycerol tolerance and 1,3‐propanediol production of Clostridium pasteurianum were significantly enhanced by subjecting the strain to a novel automatic adaptive laboratory evolution system. A heterogeneous catalytic step was developed and integrated into the downstream process for coproducing high‐value ester of acetic and butyric acids with 1,3‐propanediol. This integrated approach provides an industrially attractive route for simultaneous production of three appealing products from crude glycerol, which greatly improves the process economy and ecology.
Diols encompass important bulk and fine chemicals for the chemical, pharmaceutical and cosmetic industries. During the past decades, biological production of C3-C5 diols from renewable feedstocks has ...received great interest. Here, we elaborate a general principle for effectively synthesizing structurally diverse diols by expanding amino acid metabolism. Specifically, we propose to combine oxidative and reductive formations of hydroxyl groups from amino acids in a thermodynamically favorable order of four reactions catalyzed by amino acid hydroxylase, L-amino acid deaminase, α-keto acid decarboxylase and aldehyde reductase consecutively. The oxidative formation of hydroxyl group from an alkyl group is energetically more attractive than the reductive pathway, which is exclusively used in the synthetic pathways of diols reported so far. We demonstrate this general route for microbial production of branched-chain diols in E. coli. Ten C3-C5 diols are synthesized. Six of them, namely isopentyldiol (IPDO), 2-methyl-1,3-butanediol (2-M-1,3-BDO), 2-methyl-1,4-butanediol (2-M-1,4-BDO), 2-methyl-1,3-propanediol (MPO), 2-ethyl-1,3-propanediol (2-E-1,3-PDO), 1,4-pentanediol (1,4-PTD), have not been biologically synthesized before. This work opens up opportunities for synthesizing structurally diverse diols and triols, especially by genome mining, rational design or directed evolution of proper enzymes.
A novel ZrSi2–MgO system was used as sintering additive for fabricating high thermal conductivity silicon nitride ceramics by gas pressure sintering at 1900°C for 12 hours. By keeping the total ...amount of additives at 7 mol% and adjusting the amount of ZrSi2 in the range of 0‐7 mol%, the effect of ZrSi2 addition on sintering behaviors and thermal conductivity of silicon nitride were investigated. It was found that binary additives ZrSi2–MgO were effective for the densification of Si3N4 ceramics. XRD observations demonstrated that ZrSi2 reacted with native silica on the Si3N4 surface to generate ZrO2 and β‐Si3N4 grains. TEM and in situ dilatometry confirmed that the as formed ZrO2 collaborated with MgO and Si3N4 to form Si–Zr–Mg–O–N liquid phase promoting the densification of Si3N4. Abnormal grain growth was promoted by in situ generated β‐Si3N4 grains. Consequently, compared to ZrO2‐doped materials, the addition of ZrSi2 led to enlarged grains, extremely thin grain boundary film and high contiguity of Si3N4–Si3N4 grains. Ultimately, the thermal conductivity increased by 34.6% from 84.58 to 113.91 W·(m·K)−1 when ZrO2 was substituted by ZrSi2.
The figure in the left shows the original state of the green compact including alpha‐silicon nitride with a thin SiO2 film and sintering additives (ZrSi2 and MgO). The figure in the middle shows the β‐Si3N4 grains were in situ generated by the reaction between ZrSi2 and native SiO2. Thus, abnormal grain growth was promoted by in‐situ generated β‐Si3N4 grains. The figure in the right shows a bimodal microstructure composed of a fraction of large elongated grains and a majority of fine matrix grains was achieved in densified samples.
Complex liquid–solid reactions occur during brazing. A deep understanding of brazing liquid evolution is therefore of important concern for the bonding between filler and substrates. The joining of ...gas‐pressure‐sintered silicon nitride (Si3N4) ceramic to oxygen‐free copper (OFC) foil was prepared using Ag–Cu–TiH2 filler at 875°C for 0.5 h. The effect of the Ag:Cu ratio on the interfacial microstructure and peeling strength of the joints was analyzed. The reaction of brazing liquid with Si3N4 ceramic includes reactions with both the β‐Si3N4 and the grain boundary phases (Y–Si–Mg–O–N). The resulting interfacial reaction products include TiN, Ti5Si3, and potential Cu3Ti3O. Based on the phase composition and three‐dimensional morphology of the interfacial reaction products in the Si3N4 ceramic/OFC foil joints, a model for the evolution of the brazing liquid as the reaction proceeds was proposed. Peeling test results indicated that the peeling strength of the joints rises unilaterally with the increase of the Ag:Cu ratio in the filler until reaching the peak value of 24.3 N/mm at the maximum Ag:Cu ratio of 90:10. The mechanisms of the joint peeling fracture were discussed in detail.
Bacteria that successfully adapt to different substrates and environmental niches within the lung and overcome the immune defence can cause serious lung infections. Such infections are generally ...complex, and recognized as polymicrobial in nature. Both Pseudomonas aeruginosa and Streptococcus pneumoniae can cause chronic lung infections and were both detected in cystic fibrosis (CF) lung at different stages. In this study, single and dual species cultures of Pseudomonas aeruginosa and Streptococcus pneumoniae were studied under well‐controlled planktonic growth conditions. Under pH‐controlled conditions, both species apparently benefited from the presence of the other. In co‐culture with P. aeruginosa, S. pneumoniae grew efficiently under aerobic conditions, whereas in pure S. pneumoniae culture, growth inhibition occurred in bioreactors with dissolved oxygen concentrations above the microaerobic range. Lactic acid and acetoin that are produced by S. pneumoniae were efficiently utilized by P. aeruginosa. In pH‐uncontrolled co‐cultures, the low pH triggered by S. pneumoniae assimilation of glucose and lactic acid production negatively affected the growth of both strains. Nevertheless, ammonia production improved significantly, and P. aeruginosa growth dominated at later growth stages. This study revealed unreported metabolic interactions of two important pathogenic microorganisms and shed new lights into pathophysiology of bacterial lung infection.
PDF
