A novel ZRS variant causes preaxial polydactyly type I by increased sonic hedgehog expression in the developing limb bud.

PurposePreaxial polydactyly (PPD) is a common congenital hand malformation classified into four subtypes (PPD I-IV). Variants in the zone of polarizing activity regulatory sequence (ZRS) within intron 5 of the LMBR1 gene are linked to most PPD types. However, the genes responsible for PPD I and the underlying mechanisms are unknown.MethodsA rare large four-generation family with isolated PPD I was subjected to genome-wide genotyping and sequence analysis. In vitro and in vivo functional studies were performed in Caco-2 cells, 293T cells, and a knockin transgenic mouse model.ResultsA novel g.101779T>A (reference sequence: NG_009240.2; position 446 of the ZRS) variant segregates with all PPD I-affected individuals. The knockin mouse with this ZRS variant exhibited PPD I phenotype accompanying ectopic and excess expression of Shh. We confirmed that HnRNP K can bind the ZRS and SHH promoters. The ZRS mutant enhanced the binding affinity for HnRNP K and upregulated SHH expression.ConclusionOur results identify the first PPD I disease-causing variant. The variant leading to PPD I may be associated with enhancing SHH expression mediated by HnRNP K. This study adds to the ZRS-associated syndromes classification system for PPD and clarifies the underlying molecular mechanisms

Microbial traits determine soil C emission in response to fresh carbon inputs in forests across biomes

Soil priming is a microbial-driven process, which determines key soil–climate feedbacks in response to fresh carbon inputs. Despite its importance, the microbial traits behind this process are largely undetermined. Knowledge of the role of these traits is integral to advance our understanding of how soil microbes regulate carbon (C) emissions in forests, which support the largest soil carbon stocks globally. Using metagenomic sequencing and C-glucose, we provide unprecedented evidence that microbial traits explain a unique portion of the variation in soil priming across forest biomes from tropical to cold temperature regions. We show that microbial functional profiles associated with the degradation of labile C, especially rapid simple sugar metabolism, drive soil priming in different forests. Genes involved in the degradation of lignin and aromatic compounds were negatively associated with priming effects in temperate forests, whereas the highest level of soil priming was associated with β-glucosidase genes in tropical/subtropical forests. Moreover, we reconstructed, for the first time, 42 whole bacterial genomes associated with the soil priming effect and found that these organisms support important gene machinery involved in priming effect. Collectively, our work demonstrates the importance of microbial traits to explain soil priming across forest biomes and suggests that rapid carbon metabolism is responsible for priming effects in forests. This knowledge is important because it advances our understanding on the microbial mechanisms mediating soil–climate feedbacks at a continental scale.This work were financially supported by the National Natural Science Foundation of China (41907031), the Chinese Academy of Sciences “Light of West China” Program for Introduced Talent in the West, the National Natural Science Foundation of China (31570440, 31270484), the Key International Scientific and Technological Cooperation and Exchange Project of Shaanxi Province, China (2020KWZ-010), the 2021 First Funds for Central Government to Guide Local Science and Technology Development in Qinghai Province (2021ZY002), the i-LINK +2018 (LINKA20069) from CSIC, and a Ramón y Cajal grant from the Spanish Ministry of Science and Innovation (RYC2018-025483-I

Active removal of waste dye pollutants using Ta[sub]3N[sub]5/W[sub]18O[sub]49 nanocomposite fibres

A scalable solvothermal technique is reported for the synthesis of a photocatalytic composite material consisting of orthorhombic Ta3N5 nanoparticles and WOx≤3 nanowires. Through X-ray diffraction and X-ray photoelectron spectroscopy, the as-grown tungsten(VI) sub-oxide was identified as monoclinic W18O49. The composite material catalysed the degradation of Rhodamine B at over double the rate of the Ta3N5 nanoparticles alone under illumination by white light, and continued to exhibit superior catalytic properties following recycling of the catalysts. Moreover, strong molecular adsorption of the dye to the W18O49 component of the composite resulted in near-complete decolourisation of the solution prior to light exposure. The radical species involved within the photocatalytic mechanisms were also explored through use of scavenger reagents. Our research demonstrates the exciting potential of this novel photocatalyst for the degradation of organic contaminants, and to the authors’ knowledge the material has not been investigated previously. In addition, the simplicity of the synthesis process indicates that the material is a viable candidate for the scale-up and removal of dye pollutants on a wider scale

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Economical Optimum Gas Allocation Model Considering Different Types of Gas-Lift Performance Curves

The traditional optimum modes of gas-lift production are usually established by taking the injected gas rate as a decision variable and maximum oil production as the objective function. After solving the model, the injected gas rates of single wells are obtained, and then the oil productions of single wells, the total oil productions of well groups and economic profit can be obtained. However, the models do not take both different types of gas-lift performance curves (GLPCs) and the cost factors of gas-lift production technique into account. On the basis of GLPCs, this paper introduces the factors of a gas-lift production technique, which includes the water cut of crude oil, cost of gas injection and water treatment, and oil and gas prices. The concept of a gas-lift economic performance curve (GLEPC) is proposed, and an optimum gas allocation model is established, considering different types of GLPCs and taking economic benefits as the objective, and the model is solved by the method of mixed penalty function. Taking gas-lift well group JD as an example, four gas-lift gas allocation schemes are obtained, and the proposed economical optimum model is applied to optimize gas allocation and analyze profit. What is more, the oil production rate and the result of optimum gas allocation taking maximum oil production rate as the objective in the model are calculated and compared. Then the gas allocation scheme with maximum economical profit is selected, and the significance of considering different types of GLPCs and taking economic benefits as the objective to gas allocation is confirmed

Economical Optimum Gas Allocation Model Considering Different Types of Gas-Lift Performance Curves

The traditional optimum modes of gas-lift production are usually established by taking the injected gas rate as a decision variable and maximum oil production as the objective function. After solving the model, the injected gas rates of single wells are obtained, and then the oil productions of single wells, the total oil productions of well groups and economic profit can be obtained. However, the models do not take both different types of gas-lift performance curves (GLPCs) and the cost factors of gas-lift production technique into account. On the basis of GLPCs, this paper introduces the factors of a gas-lift production technique, which includes the water cut of crude oil, cost of gas injection and water treatment, and oil and gas prices. The concept of a gas-lift economic performance curve (GLEPC) is proposed, and an optimum gas allocation model is established, considering different types of GLPCs and taking economic benefits as the objective, and the model is solved by the method of mixed penalty function. Taking gas-lift well group JD as an example, four gas-lift gas allocation schemes are obtained, and the proposed economical optimum model is applied to optimize gas allocation and analyze profit. What is more, the oil production rate and the result of optimum gas allocation taking maximum oil production rate as the objective in the model are calculated and compared. Then the gas allocation scheme with maximum economical profit is selected, and the significance of considering different types of GLPCs and taking economic benefits as the objective to gas allocation is confirmed

PERK Pathway Activation Promotes Intracerebral Hemorrhage Induced Secondary Brain Injury by Inducing Neuronal Apoptosis Both in Vivo and in Vitro

The protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) signaling pathway was reported to exert an important role in neuronal apoptosis. The present study was designed to investigate the roles of the PERK signaling pathway in the secondary brain injury (SBI) induced by intracerebral hemorrhage (ICH) and its potential mechanisms. Sprague–Dawley rats were used to establish ICH models by injecting autologous blood (100 μl), and cultured primary rat cortical neurons were exposed to oxyhemoglobin (10 μM) to mimic ICH in vitro. The PERK antagonist, GSK2606414, and inhibitor of eukaryotic translation initiation factor 2 subunit α (eIF2α) dephosphorylation, salubrinal, were used to study the roles of PERK signaling pathway in ICH-induced SBI. Our results showed that the protein levels of p-eIF2α and ATF4 were upregulated following ICH, peaking at 48 h. Application of GSK2606414 reversed this increase in vivo and in vitro, thereby preventing ICH-induced neuronal apoptosis. On the contrary, salubrinal inhibited the dephosphorylation of eIF2α, resulting in the elevation of p-eIF2α, which could activate downstream of PERK signaling and induce neuronal apoptosis and necrosis following ICH in vitro and in vivo. Thus, PERK signaling pathway plays an important role in ICH-induced apoptosis and blocking its activation has neuroprotective effects that alleviates SBI, suggesting that targeting this pathway could be a promising therapeutic strategy for improving patient outcome after ICH

Osteochondroma: Review of 431 patients from one medical institution in South China

Background: The geographic distribution of osteochondroma (OC) varies greatly around the world. There has been no recent report on OC in a large Chinese population. The aim of this study was to characterize OC by an epidemiological analysis of the clinical data from one medical institution in South China. Methods: We searched medical electronic records from January 2001 to January 2016 in one large hospital in South China to identify patients with a definite diagnosis of OC. Their epidemiological data were collected and analyzed statistically, including gender, tumor site, age at first diagnosis and symptoms, local recurrence and malignant transformation. Differences between genders and between solitary osteochondroma (SO) and multiple osteochondroma (MO) were particularly analyzed. Results: A total of 431 OC patients (291 males and 140 females; 329 SOs and 102 MOs) were identified. The gender ratio was 2.08 with a male predominance. OCs were mostly located around the knee (250 cases). 280 patients were in their 0s to 20s upon first diagnosis. The average age at the time of first diagnosis was 20.63 years for all, 18.47 years for males and 25.11 years for females (P=0.000). OC recurred locally in 35 patients (15 SOs and 20 MOs), with a significant difference between SO/MO (P=0.000) but not between genders (P=0.100). The average interval from the primary surgery to local or malignant recurrence was 37.41 months. Malignant transformation was found in 5 patients (4 males and 1 female), showing no gender difference (P=0.549). Conclusions: OC may have a male predominance in Chinese population. It mostly occurred at 0–20 years of age and around the knee. Upon the first diagnosis of OC, the males tended to be younger than the females, and so did the MO patients than the SO ones. In addition, MO had a higher incidence of local recurrence. Intervals from primary surgery to local recurrence or malignant transformation in MO patients were longer than in SO patients

Ground Settlement of High-Permeability Sand Layer Induced by Shield Tunneling: A Case Study under the Guidance of DBN

During the shield construction of Harbin Subway Line No. 3 Project, the average ground settlement exceeds the warning value. In order to find the cause of settlement and improve it, this paper establishes a settlement prediction model to analyse the potential influencing factors based on the Deep Belief Network (DBN) and calculated the correlation degree between influencing factors and settlement through sensitivity analysis. It was found that the permeability coefficients of layer and cutter head torque are the main factors affecting settlement. Then, corresponding muck improvement measures were made according to the analysis of the layer conditions, which successfully reduced the permeability and shear strength of the muck, thereby controlling the surface settlement value within the warning range. The research results in this paper illustrate the applicability and robustness of DBN in tunnel engineering, and the related research ideas can be applied to other projects