Dietary protein restriction has long been thought to play an important role in the progression of chronic kidney disease (CKD); however, the effect of dietary protein on the rate of decline in kidney ...function remains controversial.
We undertook a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the influence of protein restriction on chronic kidney disease.
Ovid MEDLINE (from 1946 to March 5, 2016), EMBASE (from 1966 to March 5, 2016), and the Cochrane Library (Inception to March 5, 2016) were searched to identify RCTs comparing different levels of protein intake for at least 24 weeks in adult patients with CKD. The outcomes included kidney failure events, the rate of change in estimated glomerular filtration rate (eGFR) per year, all cause death events, and changes in proteinuria, serum phosphorus concentration, serum albumin, and body mass index (BMI).
Nineteen trials with 2492 subjects were analyzed. A low protein diet reduced the risk of kidney failure (odds ratio (OR) = 0.59, 95% CI: 0.41 to 0.85) and end-stage renal disease (ESRD) (OR = 0.64, 95% CI: 0.43 to 0.96), but did not produce a clear beneficial effect for all cause death events (OR = 1.17, 95% CI: 0.67 to 2.06). The change in the mean difference (MD) for the rate of decline in the eGFR was significant (MD: -1.85, P = 0.001), and for proteinuria (MD: -0.44, P = 0.02). A low protein diet also reduced the serum phosphorus concentration (MD: -0.37, 95% CI: -0.5 to -0.24) and BMI (MD: -0.61, 95% CI: -1.05 to -0.17). However the change in albumin presented no significant difference between two groups (MD: 0.23, 95% CI: -0.51 to 0.97).
Based on the findings of our meta-analysis, protein-restricted diet may reduce the rate of decline in renal function and the risk of kidney failure for CKD populations, but did not produce a clear beneficial effect for all cause death events. Besides However, the optimal level of protein intake in different participants is left unanswered, and the nutritional status should be regarded with caution.
DNA‐based machines have attracted rapidly growing interest owing to their potential in drug delivery, biocomputing, and diagnostic applications. Herein, we report a type of exonuclease III (Exo ...III)‐powered stochastic DNA walker that can autonomously move on a spherical nucleic acid (SNA)‐based 3D track. The motion is propelled by unidirectional Exo III digestion of hybridized DNA tracks in a burnt‐bridge mechanism. The operation of this Exo III‐propelled DNA walker was monitored in real time and at the single‐particle resolution using total internal reflection fluorescence microscopy (TIRF). We further interrogated the morphological effect of the 3D track on the nuclease activity, which suggested that the performance of the DNA walker was critically dependent upon the DNA density and the track conformation. Finally, we demonstrated potential bioanalytical applications of this SNA‐based stochastic DNA walker by exploiting movement‐triggered cascade signal amplification.
An Exo III‐powered stochastic DNA walker is demonstrated that moves on the surface of spherical nucleic acids. The device is shown to be exquisitely sensitive to nucleic acid density, and this sensitivity can be coupled to amplification reactions for potential bioanalytical applications.
Cytosolic double‐stranded DNA (dsDNA) is a danger signal that is tightly monitored and sensed by nucleic acid‐sensing pattern recognition receptors. We study the inflammatory cascade on dsDNA ...recognition and investigate the neuroprotective effect of cyclic GMP‐AMP (cGAMP) synthase (cGAS) antagonist A151 and its mechanisms of neuroprotection in a mouse model of experimental stroke. Here, we found that cerebral ischemia promoted the release of dsDNA into the cytosol, where it initiated inflammatory responses by activating the cGAS. A151 effectively reduced the expression of cGAS, absent in melanoma 2 (AIM2) inflammasome, and pyroptosis‐related molecules, including caspase‐1, gasdermin D, IL‐1β, and IL‐18. Furthermore, mice treated with A151 showed a dampened immune response to stroke, with reduced counts of neutrophils, microglia, and microglial production of IL‐6 and TNF‐α after MCAO. Moreover, A151 administration significantly reduced infarct volume, attenuated neurodeficits, and diminished cell death. Notably, the protective effect of A151 was blocked in a microglia‐specific cGAS knockout mouse. These findings offer unique perspectives on stroke pathogenesis and indicate that inhibition of cGAS could attenuate brain inflammatory burden, representing a potential therapeutic opportunity for stroke.
Synopsis
Inflammation is involved in the progression of ischemic brain injury. This study focuses on the inflammatory cascade on double‐strand DNA (dsDNA) recognition and highlights the possibility of inhibiting dsDNA‐sensing cyclic GMP‐AMP synthase (cGAS) for treatment of ischemic stroke.
The release of dsDNA from necrotic tissue during brain infarction triggers an innate inflammatory cascade.
A synthetic oligonucleotide A151 that antagonizes cGAS regulates the microglial immune response and pyroptosis after ischemic stroke.
Inhibition of cGAS leads to a decline in neutrophil infiltration into the brain.
Suppression of the dsDNA‐sensing cGAS pathway reduces ischemic brain injury via mitigating neuroinflammation.
Inflammation is involved in the progression of ischemic brain injury. This study focuses on the inflammatory cascade on double‐strand DNA (dsDNA) recognition and highlights the possibility of inhibiting dsDNA‐sensing cyclic GMP‐AMP synthase (cGAS) for treatment of ischemic stroke.
The effects of uric acid-lowering therapy in patients with chronic kidney disease (CKD) remain uncertain. Therefore, we undertook a systematic review and meta-analysis to investigate the effects of ...uric acid-lowering agents on major clinical outcomes of CKD.
According to the pre-specified protocol that was registered with PROSPERO (No. CRD42016038030), we searched systematically in MEDLINE, EMBASE, and the Cochrane Library for trials up to February 2016. Prospective, randomized, controlled trials assessing the effects of uric acid-lowering agents on cardiovascular and kidney outcomes in patients with CKD were included. Random-effects analytical methods were used.
Sixteen eligible trials were identified, providing data for 1,211 patients with CKD, including 146 kidney failure events and 69 cardiovascular events. Uric acid-lowering therapy produced a 55% relative risk (RR) reduction (95% confidence interval 95% CI, 31-64) for kidney failure events (P < 0.001), and a 60% RR reduction (95% CI, 17-62) for cardiovascular events (P < 0.001), but had no significant effect on the risk of all-cause death (RR, 0.86; 95% CI, 0.50-1.46). The mean differences in rate of decline in the estimated glomerular filtration rate (4.10 mL/min/1.73 m2 per year slower in uric acid-lowering therapy recipients, 95% CI, 1.86-6.35) and the standardized mean differences in the change in proteinuria or albuminuria (-0.23 units of standard deviation greater in uric acid-lowering therapy recipients; 95% CI, -0.43 to -0.04) were also statistically significant.
Uric acid-lowering therapy seemed to improve kidney outcomes and reduce the risk of cardiovascular events in adults with CKD.
Objective. To investigate the awareness of dysphagia-related complications and risks and the importance of early intervention in patients with Parkinson’s disease (PD). Methods. Using the ...phenomenological approach of the qualitative study, 18 patients with PD in a Grade A tertiary hospital in Nantong were selected, and semistructured personal in-depth interviews were conducted. The interview content was analyzed using Colaizzi’s seven-step method, and the topics and subtopics were further refined. Results. Awareness of dysphagia-related complications and risks and the importance of early intervention in patients with PD can be summarized into three topics: lack of knowledge about PD and dysphagia, changes in emotional cognition, and low need for early intervention for dysphagia. Conclusions. Patients with PD have a low awareness of dysphagia, do not follow any preventative measures, and have difficulty in recognizing the disease symptoms; hence, there is a vital need for early intervention. Medical staff need to create awareness among patients and their families, provide health education through multiple channels, popularize the knowledge of PD complications such as dysphagia, improve patient compliance with respect to medication, regular consultation, and medical treatment, guide the transformation of negative emotions in patients to positive emotions, and help patients with PD to actively prevent dysphagia and other complications and improve their quality of life.
This article looks at the central and local governments’ policymaking and implementation of compulsory education for migrant children in China. Three distinct models of policy implementation were ...identified through a case study approach. They indicated a selective adaptation of central policy objective and principles by the local governments and revealed diverse conditions of compulsory education for migrant children across the nation. In spite of substantial improvement over the years, migrant children still could not receive equitable compulsory education as urban children, due to three system barriers in general and local policy differences in particular.
A new bis-Schiff base (L) Ca(II) complex, CaL, was synthesized by the reaction of calcium perchlorate tetrahydrate, 1,3-diamino-2-hydroxypropane, and 2-formyl phenoxyacetic acid in an ethanol–water ...(v:v = 2:1) solution and characterized by IR, UV-vis, TG-DTA, and X-ray single crystal diffraction analysis. The structural analysis indicates that the Ca(II) complex crystallizes in the monoclinic system, space group P121/n1, and the Ca(II) ions are six-coordinated with four O atoms (O8, O9, O11, O12, or O1, O2, O4, O6) and two N atoms (N1, N2, or N3, N4) of one bis-Schiff base ligand. The Ca(II) complex forms a tetramer by intermolecular O-H…O hydrogen bonds. The tetramer units further form a three-dimensional network structure by π–π stacking interactions of benzene rings. The Hirschfeld surface of the Ca(II) complex shows that the H…H contacts represent the largest contribution (41.6%) to the Hirschfeld surface, followed by O…H/H…O and C…H/H…C contacts with contributions of 35.1% and 18.1%, respectively. To understand the electronic structure of the Ca(II) complex, the DFT calculations were carried out. The photocatalytic CO2 reduction test of the Ca(II) complex exhibited a yield of 47.9 μmol/g (CO) and a CO selectivity of 99.3% after six hours.
•An analytical study of the failure behavior of coal–rock model is proposed.•A compression–shear strength criterion considering interface effect is established.•Laboratory tests are carried out on ...the mudstone-coal combination sample.•The theoretical results agree well with the laboratory experiment ones.
Surrounding rocks around coal tunnel in western mining area of China are typical composite structures composed of weakly cemented soft rock and hard coal, and the tunnel stability is closely related to the overall mechanical behavior of the combination body. The equivalent homogeneous model of coal–rock combination body and its stress state expressions were firstly established based on the strain energy equivalency principle. Then, the general compression–shear failure criterion of the equivalent model which takes into account the cohesive strength of the interface between coal and soft rock was derived by assuming that the yielded mediums all met Mohr–Coulomb criterion. Furthermore, accuracy of the proposed analytical model was verified by carrying out laboratory test for coal-mudstone specimen, and it found that the theoretical results were in good agreement with the test values. Strength of the combination body lies between the strong body and weak body. Finally, the effects of interface cohesion strength, rock thickness and stress level on the failure behavior of combination model were analyzed based on the analytical model. Results show that the proposed model not only contains the classical sliding failure theory for two-dimensional weak plane presented by Jaeger, but also reflect strength behavior of a more complex composite model composed of different rock mediums and structural plane. Thus, the analytical model provides theoretical basis for further studying the mechanical behavior of coal–rock combination model.
Cross-talk between competitive endogenous RNAs (ceRNAs) through shared miRNAs represents a novel layer of gene regulation that plays important roles in the physiology and development of cancers. ...However, a global view of their system-level properties across various types of cancers is still unknown. Here, we constructed the mRNA related ceRNA-ceRNA interaction landscape across 20 cancer types by systematically analyzing molecular profiles of 5203 tumors and miRNA regulations. Our study highlights the conserved features shared by pan-cancer and higher similarity within similar origin cell type. Moreover, a core ceRNA network was identified. Function analysis identified a common theme of cancer hallmarks, however they exhibit phenotype-specific connectivity patterns. Besides, we found a marked rewiring in the ceRNA program between various cancers, and further revealed conserved and rewired network ceRNA hubs in each cancer, which were tensely competitive interactions to constitute conserved and cancer-specific modules. By providing mechanistic linkage between known cancer miRNAs, their mediated ceRNA-ceRNA interactions, and the associations with known cancer hallmarks, the inferred cancer ceRNA-ceRNA interaction landscape will serve as a powerful public resource for further biological discoveries of tumorigenesis.
N‐acetylaspartylglutamate (NAAG) is an abundant neuropeptide in the mammalian nervous system, synthesized by two related NAAG synthetases I and II (NAAGS‐I and ‐II) encoded by the genes Rimklb and ...Rimkla, respectively. NAAG plays a role in cognition and memory, according to studies using inhibitors of the NAAG hydrolase glutamate carboxypeptidase II that increase NAAG concentration. To examine consequences of reduced NAAG concentration, Rimkla‐deficient (Rimkla−/−) mice were generated. These mice exhibit normal NAAG level at birth, likely because of the intact Rimklb gene, but have significantly reduced NAAG levels in all brain regions in adulthood. In wild type mice NAAGS‐II was most abundant in brainstem and spinal cord, as demonstrated using a new NAAGS‐II antiserum. In the hippocampus, NAAGS‐II was only detectable in neurons expressing parvalbumin, a marker of GABAergic interneurons. Apart from reduced open field activity, general behavior of adult (6 months old) Rimkla−/− mice examined in different tests (dark‐light transition, optokinetic behavior, rotarod, and alternating T‐maze) was not significantly altered. However, Rimkla−/− mice were impaired in a short‐term novel object recognition test. This was also the case for mice lacking NAA synthase Nat8l, which are devoid of NAAG. Together with results from previous studies showing that inhibition of the NAAG degrading enzyme glutamate carboxypeptidase II is associated with a significant improvement in object recognition, these results suggest a direct involvement of NAAG synthesized by NAAGS‐II in the memory consolidation underlying the novel object recognition task.
NAA synthase NAT8L and NAAG synthetase II (NAAGS‐II, encoded by the gene Rimkla) act together to synthesize the neuropeptide N‐acetylaspartylglutamate (NAAG), a cotransmitter at various synapses, a ligand of metabotropic glutamate receptor mGluR3 and a substrate of glutamate carboxypeptidase II (GCPII). Adult mice deficient in the gene Rimkla have strongly reduced brain NAAG levels (residual NAAG present is synthesized by a related enzyme encoded by the gene Rimklb) and are impaired in a short term (one hour delay) novel object recognition test. This suggests that NAAG plays an important role in at least some types of memory and cognition.
PDF
