Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Hydrogen Sulfide Promotes Cardiomyocyte Proliferation and Heart Regeneration via ROS Scavenging

Neonatal mouse hearts can regenerate completely in 21 days after cardiac injury, providing an ideal model to exploring heart regenerative therapeutic targets. The oxidative damage by Reactive Oxygen Species (ROS) is one of the critical reasons for the cell cycle arrest of cardiomyocytes (CMs), which cause mouse hearts losing the capacity to regenerate in 7 days or shorter after birth. As an antioxidant, hydrogen sulfide (H2S) plays a protective role in a variety of diseases by scavenging ROS produced during the pathological processes. In this study, we found that blocking H2S synthesis by PAG (H2S synthase inhibitor) suspended heart regeneration and CM proliferation with ROS deposition increase after cardiac injury (myocardial infarction or apex resection) in 2-day-old mice. NaHS (a H2S donor) administration improved heart regeneration with CM proliferation and ROS elimination after myocardial infarction in 7-day-old mice. NaHS protected primary neonatal mouse CMs from H2O2-induced apoptosis and promoted CM proliferation via SOD2-dependent ROS scavenging. The oxidative DNA damage in CMs was reduced with the elimination of ROS by H2S. Our results demonstrated for the first time that H2S promotes heart regeneration and identified NaHS as a potent modulator for cardiac repair

Experimental study on TIG full welding and single pass welding quality of 6061-T6 aluminum alloy sheet

6061-T6 aluminum alloy plate (3 × 150 × 300 mm3) was welded by tungsten inert gas (TIG) welding. The welding process methods are single-pass welding process and full welding process respectively. The effects of different welding processes on the performance of TIG welding 6061-T6 aluminum alloy were compared and studied. The effects of microstructure and precipitation on the microhardness and tensile strength were analyzed by optical microscope, scanning electron microscopy (SEM), Energy Dispersive Spectroscopy (EDS) characterization, electron backscattering diffraction (EBSD) characterization, microhardness and tensile test. The microstructure of the weld zone is mainly composed of aluminum solid solution (α-Al) dendritic structure and Al–Si eutectic structure. Through EBSD characterization analysis, the average grain size of the weld zone of the full welding process and the single-pass welding process is about 45 μm and 55 μm, and the grain size of the heat-affected zone and the weld zone of the two welded joints does not change significantly. The hardness curves of the two welded joints have the same distribution trend, which is roughly 'W' type distribution. In the tensile test, the tensile strength of the single pass welding process is lower than that of the full welding process, and the fracture of the tensile parts is dimple structure, which is ductile fracture. Through analysis and comparative study, the full welding process is better than the single-pass welding process when welding 6061-T6 aluminum alloy sheet

Sex-related differences in the association between plasma fibrinogen and non-calcified or mixed coronary atherosclerotic plaques

Abstract Background Plasma fibrinogen (FIB) has been demonstrated to be a risk factor for cardiovascular disease. Patients with non-calcified plaque (NCP) or mix plaque (MP) have a higher risk of poor outcomes. However, the association between FIB and the presence of NCP or MP (NCP/MP) remains unclear, and if present, whether sex has any impact on this association remains unknown. The aim of this study was to investigate the role of FIB in predicting the presence of NCP/MP and evaluate whether sex has any impact on this association. Methods A total of 329 subjects were recruited, and the clinical and laboratory data were collected. Plasma FIB was detected by enzyme-linked immunosorbent assay. According to whether they had coronary atherosclerotic plaques and the characteristics of the most stenotic plaque, we divided them into three groups: no plaque (NP), calcified plaque (CP), and NCP/MP. Results Patients with NCP/MP had significantly higher FIB level in females, but not in males. Multiple logistic regression analysis showed that FIB was an independent risk factor for the presence of NCP/MP (odds ratio [OR] = 3.677, 95% CI 1.539–8.785, P = 0.003) in females. Receiver operating characteristic (ROC) curve analysis showed that the optimal cut-off value FIB for predicting the presence of NCP/MP was 3.41 g/L (area under curve [AUC] = 0.73, 95% CI 0.63–0.82, P <  0.001) in females. Conclusions FIB is independently associated with the presence of NCP/MP in females, but not in males. These results suggest that the potential significance of FIB-lowering regimens in females with NCP/MP

Early Devonian Arc-Related Volcanic Rocks in the Haerdaban, North Margin of the Yili Block: Constraint on the Southward Subduction of the Junggar Ocean

The origin and tectonic implication of Early–Middle Devonian magmatism in the northern margin of YB (Yili Block) remain enigmatic and are important for understanding Late Paleozoic evolution of the Junggar Ocean and southern Kazakhstan Orocline. Here, we present the systematic study of whole-rock geochemical and Sr–Nd isotope features as well as U–Pb–Hf isotope characteristics of zircon crystals for newly identified Early Devonian volcanic rocks from the northern margin of YB. The volcanic rocks are composed of rhyolite, rhyolite porphyry, and rhyolitic tuff. Zircon U-Pb age dating indicates they were formed at ca. 407~418 Ma. They have high SiO2 (70.16–77.52 wt.%) and alkali (5.10–9.56 wt.%) contents, and high Zr + Nb + Ce + Y content (~456 ppm), indicative of A-type magma. Their relative depletion of Nb, Ta, and Ti, and enrichment of LILEs show arc affinity. Their low initial 87Sr/86Sr ratios (0.699708–0.709822) and negative εNd(t) values (−1.8 to −4.0) indicate a mainly continental magma source and their positive εHf(t)values (+6.13 to +14.81) are possibly due to the garnet effect. All these above reveal that volcanic rocks were generated by re-melting of lower crust under a high temperature condition, which was induced by long-lived heat accumulation with no or minimal basalt flux. Combined with active continental margin inference evidenced by contemporaneous sedimentary rocks, we attribute the generation of the volcanic rocks to a continental arc setting related to the southward subduction of Junggar oceanic crust. Thus, we infer the Early–Middle Devonian arc-related magmatic rocks in the northern margin of YB are eastward counterparts of the southern limb of the Devonian Volcanic Belt, which resulted from a relatively steady-state southward subduction

Early Devonian Arc-Related Volcanic Rocks in the Haerdaban, North Margin of the Yili Block: Constraint on the Southward Subduction of the Junggar Ocean

The origin and tectonic implication of Early–Middle Devonian magmatism in the northern margin of YB (Yili Block) remain enigmatic and are important for understanding Late Paleozoic evolution of the Junggar Ocean and southern Kazakhstan Orocline. Here, we present the systematic study of whole-rock geochemical and Sr–Nd isotope features as well as U–Pb–Hf isotope characteristics of zircon crystals for newly identified Early Devonian volcanic rocks from the northern margin of YB. The volcanic rocks are composed of rhyolite, rhyolite porphyry, and rhyolitic tuff. Zircon U-Pb age dating indicates they were formed at ca. 407~418 Ma. They have high SiO2 (70.16–77.52 wt.%) and alkali (5.10–9.56 wt.%) contents, and high Zr + Nb + Ce + Y content (~456 ppm), indicative of A-type magma. Their relative depletion of Nb, Ta, and Ti, and enrichment of LILEs show arc affinity. Their low initial 87Sr/86Sr ratios (0.699708–0.709822) and negative εNd(t) values (−1.8 to −4.0) indicate a mainly continental magma source and their positive εHf(t)values (+6.13 to +14.81) are possibly due to the garnet effect. All these above reveal that volcanic rocks were generated by re-melting of lower crust under a high temperature condition, which was induced by long-lived heat accumulation with no or minimal basalt flux. Combined with active continental margin inference evidenced by contemporaneous sedimentary rocks, we attribute the generation of the volcanic rocks to a continental arc setting related to the southward subduction of Junggar oceanic crust. Thus, we infer the Early–Middle Devonian arc-related magmatic rocks in the northern margin of YB are eastward counterparts of the southern limb of the Devonian Volcanic Belt, which resulted from a relatively steady-state southward subduction

De novo Transcriptome Analysis of Miscanthus Iutarioriparius Indentifies Candidate Genes in Rhizome Development

Miscanthus lutarioriparius is a promising lignocellulosic feedstock for second-generation bioethanol production. However, the genomic resource for this species is relatively limited thus hampers our understanding of the molecular mechanisms underlying many important biological processes. In this study, we performed the first de novo transcriptome analysis of five tissues (leaf, stem, root, lateral bud and rhizome bud) of M. lutarioriparius with an emphasis to identify putative genes involved in rhizome development. Approximately 66 gigabase (GB) paired-end clean reads were obtained and assembled into 169,064 unigenes with an average length of 759 bp. Among these unigenes, 103,899 (61.5%) were annotated in seven public protein databases. Differential gene expression profiling analysis revealed that 4,609, 3,188, 1,679, 1,218, and 1,077 genes were predominantly expressed in root, leaf, stem, lateral bud, and rhizome bud, respectively. Their expression patterns were further classified into 12 distinct clusters. Pathway enrichment analysis revealed that genes predominantly expressed in rhizome bud were mainly involved in primary metabolism and hormone signaling and transduction pathways. Noteworthy, 19 transcription factors (TFs) and 16 hormone signaling pathway-related genes were identified to be predominantly expressed in rhizome bud compared with the other tissues, suggesting putative roles in rhizome formation and development. In addition, a predictive regulatory network was constructed between four TFs and six auxin and abscisic acid (ABA) -related genes. Furthermore, the expression of 24 rhizome-specific genes was further validated by quantitative real-time RT-PCR (qRT-PCR) analysis. Taken together, this study provide a global portrait of gene expression across five different tissues and reveal preliminary insights into rhizome growth and development. The data presented will contribute to our understanding of the molecular mechanisms underlying rhizome development in M. lutarioriparius and remarkably enrich the genomic resources of Miscanthus

A view of the pan‐genome of domesticated Cowpea (Vigna unguiculata [L.] Walp.)

Cowpea, Vigna unguiculata L. Walp., is a diploid warm-season legume of critical importance as both food and fodder in sub-Saharan Africa. This species is also grown in Northern Africa, Europe, Latin America, North America, and East to Southeast Asia. To capture the genomic diversity of domesticates of this important legume, de novo genome assemblies were produced for representatives of six subpopulations of cultivated cowpea identified previously from genotyping of several hundred diverse accessions. In the most complete assembly (IT97K-499-35), 26,026 core and 4963 noncore genes were identified, with 35,436 pan genes when considering all seven accessions. GO terms associated with response to stress and defense response were highly enriched among the noncore genes, while core genes were enriched in terms related to transcription factor activity, and transport and metabolic processes. Over 5 million single nucleotide polymorphisms (SNPs) relative to each assembly and over 40 structural variants &gt;1 Mb in size were identified by comparing genomes. Vu10 was the chromosome with the highest frequency of SNPs, and Vu04 had the most structural variants. Noncore genes harbor a larger proportion of potentially disruptive variants than core genes, including missense, stop gain, and frameshift mutations; this suggests that noncore genes substantially contribute to diversity within domesticated cowpea