Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide ...association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.
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Dense fine-grained pure W, W–1.0wt.%Zr (WZ), W–1.0wt.%ZrC (WZC) and W–1.0wt.%Zr–1.0wt.%ZrC (WZZC) alloys were fabricated by spark plasma sintering. The grains in WZ and WZZC alloys are stable at ...annealing temperatures below 1400°C (1h), while the grains in pure W grow significantly above 1100°C annealing. The tensile tests indicate that WZ is ductile already at 400°C, which is about 200°C lower than that for pure W. WZC exhibits higher hardness at room temperature than pure W. The ultimate tensile strength of WZC at 600°C is 798MPa, about 2.6 times that of pure W. Based on microstructural analysis, the good thermal stability of tungsten grains in WZ and WZZC samples is suggested to be originated from the W–Zr–O and/or Zr–C–O particles which are dispersed on or near the grain boundaries of tungsten and inhibit their migration. The improved tensile properties of the WZ, WZC and WZZC alloys originate (i) from the enhanced GB cohesion by Zr micro-alloying and (ii) from dispersion strengthening by nano-sized ZrC particles.
•W alloys were fabricated from Zr and ZrC addition.•Grain growth in WZ and WZZC starts after 1400°C (1h) annealing.•WZ alloys become ductile at 400°C, 200°C lower than pure W.•The elongation of WZ at 700°C is 20%, 2 times that of pure W.•The UTS of WZC is up to 798MPa at 600°C, 2.6 times that of pure W.
Oxidative stress and the formation of plaques which contain amyloid-β (Aβ) peptides are two key hallmarks of Alzheimer's disease (AD). Dityrosine is found in the plaques of AD patients and Aβ dimers ...have been linked to neurotoxicity. Here we investigate the formation of Aβ dityrosine dimers promoted by Cu
Fenton reactions. Using fluorescence measurements and UV absorbance, we show that dityrosine can be formed aerobically when Aβ is incubated with Cu
and hydrogen-peroxide
or in a Cu
and ascorbate redox mixture. The dityrosine cross-linking can occur for both monomeric and fibrillar forms of Aβ. We show that oxidative modification of Aβ impedes the ability for Aβ monomer to form fibres, as indicated by the amyloid specific dye Thioflavin T (ThT). Transmission electron microscopy (TEM) indicates the limited amyloid assemblies that form have a marked reduction in fibre length for Aβ(1-40). Importantly, the addition of Cu
and a reductant to preformed Aβ(1-40) fibers causes their widespread fragmentation, reducing median fibre lengths from 800 nm to 150 nm upon oxidation. The processes of covalent cross-linking of Aβ fibres, dimer formation, and fibre fragmentation within plaques are likely to have a significant impact on Aβ clearance and neurotoxicity.
The effective control of moisture and microbes is necessary for the success of restoration procedures. The rubber dam, as an isolation method, has been widely used in dental restorative treatments. ...The effects of rubber dam usage on the longevity and quality of dental restorations still require evidence-based discussion. This review compares the effects of rubber dam with other isolation methods in dental restorative treatments. This is an update of the Cochrane Review first published in 2016.
To assess the effects of rubber dam isolation compared with other types of isolation used for direct and indirect restorative treatments in dental patients.
Cochrane Oral Health's Information specialist searched the following electronic databases: Cochrane Oral Health's Trials Register (searched 13 January 2021), Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 12) in the Cochrane Library (searched 13 January 2021), MEDLINE Ovid (1946 to 13 January 2021), Embase Ovid (1980 to 13 January 2021), LILACS BIREME Virtual Health Library (Latin American and Caribbean Health Science Information database; 1982 to 13 January 2021), and SciELO BIREME Virtual Health Library (1998 to 13 January 2021). We also searched Chinese BioMedical Literature Database (CBM, in Chinese) (1978 to 13 January 2021), VIP database (in Chinese) (1989 to 13 January 2021), and China National Knowledge Infrastructure (CNKI, in Chinese) (1994 to 13 January 2021). We searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform, OpenGrey, and Sciencepaper Online (in Chinese) for ongoing trials. There were no restrictions on the language or date of publication when searching the electronic databases.
We included randomised controlled trials (including split-mouth trials) over one month in length assessing the effects of rubber dam compared with alternative isolation methods for dental restorative treatments.
Two review authors independently screened the results of the electronic searches, extracted data, and assessed the risk of bias of the included studies. Disagreement was resolved by discussion. We strictly followed Cochrane's statistical guidelines and assessed the certainty of the evidence using GRADE.
We included six studies conducted worldwide between 2010 and 2015 involving a total of 1342 participants (of which 233 participants were lost to follow-up). All the included studies were at high risk of bias. Five studies compared rubber dam with traditional cotton rolls isolation. One study was excluded from the analysis due to inconsistencies in the presented data. Of the four remaining trials, three reported survival rates of the restorations with a minimum follow-up of six months. Pooled results from two studies involving 192 participants indicated that the use of rubber dam isolation may increase the survival rates of direct composite restorations of non-carious cervical lesions (NCCLs) at six months (odds ratio (OR) 2.29, 95% confidence interval (CI) 1.05 to 4.99; low-certainty evidence). However, the use of rubber dam in NCCLs composite restorations may have little to no effect on the survival rates of the restorations compared to cotton rolls at 12 months (OR 1.38, 95% CI 0.45 to 4.28; 1 study, 30 participants; very low-certainty evidence) and at 18 months (OR 1.00, 95% CI 0.45 to 2.25; 1 study, 30 participants; very low-certainty evidence) but the evidence is very uncertain. At 24 months, the use of rubber dam may decrease the risk of failure of the restorations in children undergoing proximal atraumatic restorative treatment in primary molars but the evidence is very uncertain (hazard ratio (HR) 0.80, 95% CI 0.66 to 0.97; 1 study, 559 participants; very low-certainty evidence). None of the included studies mentioned adverse effects or reported the direct cost of the treatment.
This review found some low-certainty evidence that the use of rubber dam in dental direct restorative treatments may lead to a lower failure rate of the restorations compared with cotton roll usage after six months. At other time points, the evidence is very uncertain. Further high-quality research evaluating the effects of rubber dam usage on different types of restorative treatments is required.
It has been suspected that cell-cycle progression might be functionally coupled with RNA processing. However, little is known about the role of the precise splicing control in cell-cycle progression. ...Here, we report that SON, a large Ser/Arg (SR)-related protein, is a splicing cofactor contributing to efficient splicing of cell-cycle regulators. Downregulation of SON leads to severe impairment of spindle pole separation, microtubule dynamics, and genome integrity. These molecular defects result from inadequate RNA splicing of a specific set of cell-cycle-related genes that possess weak splice sites. Furthermore, we show that SON facilitates the interaction of SR proteins with RNA polymerase II and other key spliceosome components, suggesting its function in efficient cotranscriptional RNA processing. These results reveal a mechanism for controlling cell-cycle progression through SON-dependent constitutive splicing at suboptimal splice sites, with strong implications for its role in cancer and other human diseases.
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► A large RS-like factor, SON, is critical for mitotic progression and genome stability ► Knockdown of SON downregulates a large set of cell-cycle-related genes ► SON is required for removal of many constitutive introns with weak splice sites ► SON facilitates SR protein-RNAP II interaction for cotranscriptional splicing
Manipulating magnetic domains is essential for many technological applications. Recent breakthroughs in Antiferromagnetic Spintronics brought up novel concepts for electronic device development. ...Imaging antiferromagnetic domains is of key importance to this field. Unfortunately, some of the basic domain types, such as antiphase domains, cannot be imaged by conventional techniques. Herein, we present a new domain projection imaging technique based on the localization of domain boundaries by resonant magnetic diffraction of coherent X rays. Contrast arises from reduction of the scattered intensity at the domain boundaries due to destructive interference effects. We demonstrate this approach by imaging antiphase domains in a collinear antiferromagnet Fe
Mo
O
, and observe evidence of domain wall interaction with a structural defect. This technique does not involve any numerical algorithms. It is fast, sensitive, produces large-scale images in a single-exposure measurement, and is applicable to a variety of magnetic domain types.
Mixed lineage leukemia 5 (MLL5) protein is a trithorax family histone 3 lysine 4 (H3K4) methyltransferase that regulates diverse biological processes, including cell cycle progression, hematopoiesis ...and cancer. The mechanisms by which MLL5 protein stability is regulated have remained unclear to date. Here, we showed that MLL5 protein stability is cooperatively regulated by O-GlcNAc transferase (OGT) and ubiquitin-specific protease 7 (USP7). Depletion of OGT in cells led to a decrease in the MLL5 protein level through ubiquitin/proteasome-dependent proteolytic degradation, whereas ectopic expression of OGT protein suppressed MLL5 ubiquitylation. We further identified deubiquitinase USP7 as a novel MLL5-associated protein using mass spectrometry. USP7 stabilized the MLL5 protein through direct binding and deubiquitylation. Loss of USP7 induced degradation of MLL5 protein. Conversely, overexpression of USP7, but not a catalytically inactive USP7 mutant, led to decreased ubiquitylation and increased MLL5 stability. Co-immunoprecipitation and co-immunostaining assays revealed that MLL5, OGT and USP7 interact with each other to form a stable ternary complex that is predominantly located in the nucleus. In addition, upregulation of MLL5 expression was correlated with increased expression of OGT and USP7 in human primary cervical adenocarcinomas. Our results collectively reveal a novel molecular mechanism underlying regulation of MLL5 protein stability and provide new insights into the functional interplay among O-GlcNAc transferase, deubiquitinase and histone methyltransferase.
Serum vascular endothelial growth factor-C (VEGF-C), transforming growth factor-β (TGF-β), and interleukin (IL)-6 promote angiogenesis and metastases in colon cancer. We hypothesized that patients ...who received propofol–epidural anaesthesia (PEA) would exhibit decreases in VEGF-C, TGF-β, and IL-6 and an increase in IL-10 compared with patients who received general anaesthesia (GA).
Colon cancer surgery patients were randomly assigned to the PEA (n=20) or GA (n=20) group. Serum VEGF-C, TGF-β, IL-6, and IL-10 levels before surgery and 24 h after surgery were measured.
Patients who received PEA showed decreases in VEGF-C 526 (261) vs 834 (304) pg ml−1, P=0.001, TGF-β (P=0.027), and IL-6 (P=0.007) and an increase in IL-10 (P=0.001) 24 h after surgery compared with patients subjected to GA. The visual analogue scale scores at rest and during coughing at 2 and 24 h after operation were significantly lower in PEA patients (P<0.05).
PEA reduces serum concentrations of factors associated with angiogenesis during colon cancer surgery.
ChiCTR-TRC-13003146 (www.chictr.org).
Basal forebrain cholinergic neurons modulate how organisms process and respond to environmental stimuli through impacts on arousal, attention, and memory. It is unknown, however, whether basal ...forebrain cholinergic neurons are directly involved in conditioned behavior, independent of secondary roles in the processing of external stimuli. Using fluorescent imaging, we found that cholinergic neurons are active during behavioral responding for a reward - even prior to reward delivery and in the absence of discrete stimuli. Photostimulation of basal forebrain cholinergic neurons, or their terminals in the basolateral amygdala (BLA), selectively promoted conditioned responding (licking), but not unconditioned behavior nor innate motor outputs. In vivo electrophysiological recordings during cholinergic photostimulation revealed reward-contingency-dependent suppression of BLA neural activity, but not prefrontal cortex. Finally, ex vivo experiments demonstrated that photostimulation of cholinergic terminals suppressed BLA projection neuron activity via monosynaptic muscarinic receptor signaling, while also facilitating firing in BLA GABAergic interneurons. Taken together, we show that the neural and behavioral effects of basal forebrain cholinergic activation are modulated by reward contingency in a target-specific manner.
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