Blockade of myeloid differentiation 2 attenuates diabetic nephropathy by reducing activation of the renin-angiotensin system in mouse kidneys

Background and Purpose: Both innate immunity and the renin-angiotensin system (RAS) play important roles in the pathogenesis of diabetic nephropathy (DN). Myeloid differentiation factor 2 (MD2) is a co-receptor of toll-like receptor 4 (TLR4) in innate immunity. While TLR4 is involved in the development of DN, the role of MD2 in DN has not been characterized. It also remains unclear whether the MD2/TLR4 signalling pathway is associated with RAS activation in diabetes. Experimental Approach: MD2 was blocked using siRNA or the low MW inhibitor, L6H9, in renal proximal tubular cells (NRK-52E cells) exposed to high concentrations of glucose (HG). In vivo, C57BL/6 and MD2−/− mice were injected with streptozotocin to induce Type 1 diabetes and nephropathy. Key Results: Inhibition of MD2 by genetic knockdown or the inhibitor L6H9 suppressed HG-induced expression of ACE and angiotensin receptors and production of angiotensin II in NRK-52E cells, along with decreased fibrosis markers (TGF-β and collagen IV). Inhibition of the MD2/TLR4-MAPKs pathway did not affect HG-induced renin overproduction. In vivo, using the streptozotocin-induced diabetic mice, MD2 was overexpressed in diabetic kidney. MD2 gene knockout or L6H9 attenuated renal fibrosis and dysfunction by suppressing local RAS activation and inflammation. Conclusions and Implications: Hyperglycaemia activated the MD2/TLR4-MAPKs signalling cascade to induce renal RAS activation, leading to renal fibrosis and dysfunction. Pharmacological inhibition of MD2 may be considered as a therapeutic approach to mitigate DN and the low MW inhibitor L6H9 could be a candidate for such therapy

MD2 activation by direct AGE interaction drives inflammatory diabetic cardiomyopathy

Hyperglycemia activates toll-like receptor 4 (TLR4) to induce inflammation in diabetic cardiomyopathy (DCM). However, the mechanisms of TLR4 activation remain unclear. Here we examine the role of myeloid differentiation 2 (MD2), a co-receptor of TLR4, in high glucose (HG)- and diabetes-induced inflammatory cardiomyopathy. We show increased MD2 in heart tissues of diabetic mice and serum of human diabetic subjects. MD2 deficiency in mice inhibits TLR4 pathway activation, which correlates with reduced myocardial remodeling and improved cardiac function. Mechanistically, we show that HG induces extracellular advanced glycation end products (AGEs), which bind directly to MD2, leading to formation of AGEs-MD2-TLR4 complex and initiation of pro-inflammatory pathways. We further detect elevated AGE-MD2 complexes in heart tissues and serum of diabetic mice and human subjects with DCM. In summary, we uncover a new mechanism of HG-induced inflammatory responses and myocardial injury, in which AGE products directly bind MD2 to drive inflammatory DCM

Reduction of cardiac motion artifact in step-and-shoot coronary CT angiography with third-generation as compared with second-generation dual-source CT scanners

PURPOSEWe aimed to compare the effects of misregistration (stair-step artifact) occurrence during coronary computed tomography angiography (CCTA) using third- and second-generation dual-source computed tomography (DSCT) scanners.METHODSCCTA was performed in consecutive patients with suspected coronary heart disease. Patients were randomly assigned to two groups and imaged using a third-generation (n=68; group A) or second-generation (n=63; group B) DSCT scanner. Heart rate (HR), heart rate variability (HRV), the number of acquisition steps required, and the anatomical cardiac length of each patient were recorded and compared between the two groups. Qualitative interpretation and analyses were scored with respect to subjective image quality and misregistration (stair-step artifact) by two interpreters. Cohen’s kappa was used to evaluate the consistency between the observers.RESULTSAll CCTA images (100%) on both DSCT scanners yielded satisfactory image quality, with a subjective image quality score of 4.21±0.17. The consistency between the two observers with respect to misregistration and subjective scores were good (κ= 0.91 and 0.92, respectively). Both the number of acquisition steps required and the scan length of each patient in group A differed significantly (p 0.20).CONCLUSIONAs compared with second-generation DSCT, the reduced number of acquisition steps required and the shorter scan length in third-generation DSCT reduced the occurrence of misregistration artifacts in CCTA images

Pre‐symptomatic transmission of novel coronavirus in community settings

We used contact tracing to document how COVID‐19 was transmitted across 5 generations involving 10 cases, starting with an individual who became ill on January 27. We calculated the incubation period of the cases as the interval between infection and development of symptoms. The median incubation period was 6.0 days (interquartile range, 3.5‐9.5 days). The last two generations were infected in public places, 3 and 4 days prior to the onset of illness in their infectors. Both had certain underlying conditions and comorbidity. Further identification of how individuals transmit prior to being symptomatic will have important consequences.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163478/2/irv12773.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163478/1/irv12773_am.pd

Implications of a high-definition multileaf collimator (HD-MLC) on treatment planning techniques for stereotactic body radiation therapy (SBRT): a planning study

<p>Abstract</p> <p>Purpose</p> <p>To assess the impact of two multileaf collimator (MLC) systems (2.5 and 5 mm leaf widths) on three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and dynamic conformal arc techniques for stereotactic body radiation therapy (SBRT) of liver and lung lesions.</p> <p>Methods</p> <p>Twenty-nine SBRT plans of primary liver (n = 11) and lung (n = 18) tumors were the basis of this study. Five-millimeter leaf width 120-leaf Varian Millennium (M120) MLC-based plans served as reference, and were designed using static conformal beams (3DCRT), sliding-window intensity-modulated beams (IMRT), or dynamic conformal arcs (DCA). Reference plans were either re-optimized or recomputed, with identical planning parameters, for a 2.5-mm width 120-leaf BrainLAB/Varian high-definition (HD120) MLC system. Dose computation was based on the anisotropic analytical algorithm (AAA, Varian Medical Systems) with tissue heterogeneity taken into account. Each plan was normalized such that 100% of the prescription dose covered 95% of the planning target volume (PTV). Isodose distributions and dose-volume histograms (DVHs) were computed and plans were evaluated with respect to target coverage criteria, normal tissue sparing criteria, as well as treatment efficiency.</p> <p>Results</p> <p>Dosimetric differences achieved using M120 and the HD120 MLC planning were generally small. Dose conformality improved in 51.7%, 62.1% and 55.2% of the IMRT, 3DCRT and DCA cases, respectively, with use of the HD120 MLC system. Dose heterogeneity increased in 75.9%, 51.7%, and 55.2% of the IMRT, 3DCRT and DCA cases, respectively, with use of the HD120 MLC system. DVH curves demonstrated a decreased volume of normal tissue irradiated to the lower (90%, 50% and 25%) isodose levels with the HD120 MLC.</p> <p>Conclusion</p> <p>Data derived from the present comparative assessment suggest dosimetric merit of the high definition MLC system over the millennium MLC system. However, the clinical significance of these results warrants further investigation in order to determine whether the observed dosimetric advantages translate into outcome improvements.</p

A tau fragment links depressive-like behaviors and cognitive declines in Alzheimer’s disease mouse models through attenuating mitochondrial function

IntroductionAlzheimer’s disease (AD) is the most prevalent neurodegenerative disease characterized by extracellular senile plaques including amyloid-β peptides and intracellular neurofibrillary tangles consisting of abnormal Tau. Depression is one of the most common neuropsychiatric symptoms in AD, and clinical evidence demonstrates that depressive symptoms accelerate the cognitive deficit of AD patients. However, the underlying molecular mechanisms of depressive symptoms present in the process of AD remain unclear.MethodsDepressive-like behaviors and cognitive decline in hTau mice were induced by chronic restraint stress (CRS). Computational prediction and molecular experiments supported that an asparagine endopeptidase (AEP)-derived Tau fragment, Tau N368 interacts with peroxisome proliferator-activated receptor delta (PPAR-δ). Further behavioral studies investigated the role of Tau N368-PPAR-δ interaction in depressive-like behaviors and cognitive declines of AD models exposed to CRS.ResultsWe found that mitochondrial dysfunction was positively associated with depressive-like behaviors and cognitive deficits in hTau mice. Chronic stress increased Tau N368 and promoted the interaction of Tau N368 with PPAR-δ, repressing PPAR-δ–mediated transactivation in the hippocampus of mice. Then we predicted and identified the binding sites of PPAR-δ. Finally, inhibition of AEP, clearance of Tau N368 and pharmacological activation of PPAR-δ effectively alleviated CRS-induced depressive-like behaviors and cognitive decline in mice.ConclusionThese results demonstrate that Tau N368 in the hippocampus impairs mitochondrial function by suppressing PPAR-δ, facilitating the occurrence of depressive-like behaviors and cognitive decline. Therefore, our findings may provide new mechanistic insight in the pathophysiology of depression-like phenotype in mouse models of Alzheimer’s disease

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Thyroid function analysis after roxadustat or erythropoietin treatment in patients with renal anemia: a cohort study

AbstractPurpose This cohort study was designed to explore whether roxadustat or erythropoietin could affect thyroid function in patients with renal anemia.Methods The study involved 110 patients with renal anemia. Thyroid profile and baseline investigations were carried out for each patient. The patients were divided into two groups: 60 patients taking erythropoietin served as the control group (rHuEPO group) and 50 patients using roxadustat served as the experimental group (roxadustat group).Results The results indicated that there were no significant differences in serum total thyroxine (TT4), total triiodothyronine (TT3), free triiodothyronine (FT3), free thyroxine (FT4) or thyroid stimulating hormone (TSH) between the two groups at baseline. After treatment, TSH, FT3, and FT4 were significantly lower in the roxadustat group than in the rHuEPO group (p < 0.05). After adjusting for age, sex, dialysis modality, thyroid nodules and causes of kidney disease, Cox regression showed that roxadustat was an independent influencing factor on thyroid dysfunction (HR 3.37; 95% CI 1.94–5.87; p < 0.001). After 12 months of follow-up, the incidence of thyroid dysfunction was higher in the roxadustat group than in the rHuEPO group (log-rank p < 0.001).Conclusion Roxadustat may lead to a higher risk of thyroid dysfunction, including low TSH, FT3 and FT4, than rHuEPO in patients with renal anemia

Study on the Effect of Surface Properties of Non-Metallic Materials on the Growth Mechanism of Crystallization Fouling

In order to alleviate the serious problem of scaling in oilfield water injection pipelines, we developed a scale collection device and applied it in the field based on the idea to “change passive descaling to active descaling”, but the effect is not stable, so we need to improve the descaling effect. Firstly, this paper analyzed the effect of surface physical properties of eight non-metallic materials on CaCO3 scale growth and their mechanisms through shear experiments. Then, the influence of surface properties (roughness, contact angle, surface energy) on the scale growth characteristics was investigated. Finally, the influence of material surface properties on the friction coefficient was studied by a cyclic experiment. The results showed that except for PTFE (polytetrafluoroethylene), the fouling amount of the other seven materials changed abruptly at 18 h, and the maximum fouling amount of FRP was 2.05 g/m3. It was found by scanning electron microscopy that the fouling particles on the surface of FRP were interconnected and presented in the form of flakes, which was related to the larger surface wettability, surface energy, and roughness. At the same time, the surface properties of the material have a certain relationship with the friction coefficient, and the influence of the contact angle on the friction coefficient is greater than the surface energy and roughness