4-(2-Chloro­ethoxy)phthalonitrile

In the title compound, C10H7ClN2O, the O and both C atoms of the chloroethoxy group are disordered over two positions, the occupancy factor of the major disorder component refining to 0.54 (2)

Selective Generation of Dopaminergic Precursors from Mouse Fibroblasts by Direct Lineage Conversion.

Degeneration of midbrain dopaminergic (DA) neurons is a key pathological event of Parkinson\u27s disease (PD). Limited adult dopaminergic neurogenesis has led to novel therapeutic strategies such as transplantation of dopaminergic precursors (DPs). However, this strategy is currently restrained by a lack of cell source, the tendency for the DPs to become a glial-restricted state, and the tumor formation after transplantation. Here, we demonstrate the direct conversion of mouse fibroblasts into induced DPs (iDPs) by ectopic expression of Brn2, Sox2 and Foxa2. Besides expression with neural progenitor markers and midbrain genes including Corin, Otx2 and Lmx1a, the iDPs were restricted to dopaminergic neuronal lineage upon differentiation. After transplantation into MPTP-lesioned mice, iDPs differentiated into DA neurons, functionally alleviated the motor deficits, and reduced the loss of striatal DA neuronal axonal termini. Importantly, no iDPs-derived astrocytes and neoplasia were detected in mouse brains after transplantation. We propose that the iDPs from direct reprogramming provides a safe and efficient cell source for PD treatment

Validity and applicability of the global leadership initiative on malnutrition criteria in non-dialysis patients with chronic kidney disease

IntroductionThere are no standardized assessment criteria for selecting nutritional risk screening tools or indicators to assess reduced muscle mass (RMM) in the Global Leadership Initiative on Malnutrition (GLIM) criteria. We aimed to compare the consistency of different GLIM criteria with Subjective Global Assessment (SGA) and protein-energy wasting (PEW).MethodsIn this study, nutritional risk screening 2002 first four questions (NRS-2002-4Q), Nutritional Risk Screening 2002 (NRS-2002), Malnutrition Universal Screening Tool (MUST), and Mini-Nutritional Assessment Short-Form (MNA-SF) tools were used as the first step of nutritional risk screening for the GLIM. The RMM is expressed using different metrics. The SGA and PEW were used to diagnose patients and classify them as malnourished and non-malnourished. Kappa (κ) tests were used to compare the concordance between the SGA, PEW, and GLIM of each combination of screening tools.ResultsA total of 157 patients were included. Patients with Chronic kidney disease (CKD) stage 1–3 accounted for a large proportion (79.0%). The prevalence rates of malnutrition diagnosed using the SGA and PEW were 18.5% and 19.7%, respectively. The prevalence of GLIM-diagnosed malnutrition ranges from 5.1% to 37.6%, depending on the different screening methods for nutritional risk and the different indicators denoting RMM. The SGA was moderately consistent with the PEW (κ = 0.423, p < 0.001). The consistency among the GLIM, SGA, and PEW was generally low. Using the NRS-2002-4Q to screen for nutritional risk, GLIM had the best agreement with SGA and PEW when skeletal muscle index (SMI), fat-free mass index (FFMI), and hand grip strength (HGS) indicated a reduction in muscle mass (SGA: κ = 0.464, 95% CI 0.28–0.65; PEW: κ = 0.306, 95% CI 0.12–0.49).ConclusionThe concordance between the GLIM criteria and the SGA and PEW depended on the screening tool used in the GLIM process. The inclusion of RMM in the GLIM framework is important. The addition of HGS could further improve the performance of the GLIM standard compared to the use of body composition measurements

CD36 Participates in PrP106–126-Induced Activation of Microglia

Microglial activation is a characteristic feature of the pathogenesis of prion diseases. The molecular mechanisms that underlie prion-induced microglial activation are not very well understood. In the present study, we investigated the role of the class B scavenger receptor CD36 in microglial activation induced by neurotoxic prion protein (PrP) fragment 106–126 (PrP106–126). We first examined the time course of CD36 mRNA expression upon exposure to PrP106–126 in BV2 microglia. We then analyzed different parameters of microglial activation in PrP106–126-treated cells in the presence or not of anti-CD36 monoclonal antibody (mAb). The cells were first incubated for 1 h with CD36 monoclonal antibody to block the CD36 receptor, and were then treated with neurotoxic prion peptides PrP106–126. The results showed that PrP106–126 treatment led to a rapid yet transitory increase in the mRNA expression of CD36, upregulated mRNA and protein levels of proinflammatory cytokines (IL-1β, IL-6 and TNF-α), increased iNOS expression and nitric oxide (NO) production, stimulated the activation of NF-κB and caspase-1, and elevated Fyn activity. The blockade of CD36 had no effect on PrP106–126-stimulated NF-κB activation and TNF-α protein release, abrogated the PrP106–126-induced iNOS stimulation, downregulated IL-1β and IL-6 expression at both mRNA and protein levels as well as TNF-α mRNA expression, decreased NO production and Fyn phosphorylation, reduced caspase-1 cleavage induced by moderate PrP106–126 –treatment, but had no effect on caspase-1 activation after treatment with a high concentration of PrP106–126. Together, these results suggest that CD36 is involved in PrP106–126-induced microglial activation and that the participation of CD36 in the interaction between PrP106–126 and microglia may be mediated by Src tyrosine kinases. Our findings provide new insights into the mechanisms underlying the activation of microglia by neurotoxic prion peptides and open perspectives for new therapeutic strategies for prion diseases by modulation of CD36 signaling

New findings in preventing recurrence and improving renal function in AHUS patients after renal transplantation treated with eculizumab: a systemic review and meta-analyses

AbstractBackground The long-term mortality of kidney transplantation patients with atypical hemolytic uremic syndrome remains high, and the efficacy of the main treatment eculizumab is still controversial.Objective A comprehensive systematic review and meta-analysis of clinical trials using eculizumab in renal transplant patients with atypical hemolytic uremic syndrome was conducted to evaluate the efficacy of this therapy and its impact on renal function.Methods A comprehensive systematic search was conducted across multiple reputable databases, including Ovid (MEDLINE, EMBASE), PubMed, and the Cochrane Library (since database inception), to identify relevant studies exploring the use of eculizumab in patients with atypical hemolytic uremic kidney transplantation. Various renal function parameters, such as dialysis, rejection, glomerular filtration rate, serum creatinine, lactate dehydrogenase, and platelet count, along with patient relapse rates, were extracted and summarized using a combination of robust statistical methods, including fixed effects, random effects, and general inverse variance methods.Result Eighteen trials with 618 subjects were analyzed. Our analysis suggests that the use of eculizumab is associated with a reduced likelihood of AHUS recurrence (odds ratio (OR) = 0.05, 95% CI: 0.00–0.13), as well as a significant reduction in the need for dialysis (odds ratio (OR) = 0.13, 95% CI: 0.01–0.32). Additionally, eculizumab treatment led to lower serum creatinine levels (mean differences (MD) = 126.931μmoI/L, 95% CI: 115.572μmoI/L–138.290μmoI/L) and an improved glomerular filtration rate (mean differences (MD) = 59.571 ml/min, 95% CI: 57.876 ml/min–61.266 mL/min). Our results also indicate that the use of eculizumab reduces the likelihood of rejection (odds ratio (OR) = 0.09, 95% CI: 0.01–0.22). Furthermore, the drug was effective in improving platelet counts (×10∧9/L) (mean differences (MD) = 163.421, 95% CI: 46.998–279.844) and lactate dehydrogenase levels (mean differences (MD) = 336.608 U/L, 95% CI: 164.816 U/L–508.399 U/L).Conclusions Based on the meta-analysis, treatment with eculizumab can reduce dialysis rates and improve patients’ quality of life by enhancing renal function

Impact of Rapid Urbanization on Vulnerability of Land System from Complex Networks View: A Methodological Approach

Rapid urbanization is responsible for the increased vulnerability of land systems and the loss of many crucial ecosystem services. Land systems are typical complex systems comprised of different land use types which interact with each other and respond to external environment processes (such as urbanization), resulting in dynamics in land systems. This work develops a methodology approach by integrating complex networks and disruptive scenarios and applies it to a case study area (Wuhan City in China) to explore the effects of urbanization on land system structural vulnerability. The land system network topologies of Wuhan City during five time periods from 1990 to 2015 are extracted. Our results reveal that (1) the urban land expands at a higher speed than the urban population in Wuhan City; (2) the period of 2005–2010 has witnessed more land area conversions from ecological lands to urban land than other periods; (3) the land system is more vulnerable to intentional attacks on nodes with higher integrated node centrality and larger land area, such as paddy, dryland, and lake; and (4) the network efficiency of the land system would decline sharply if the area shrinkage of paddy, dryland, and lake is larger than 30%, 50%, and 20%, respectively. The results provide some insights into building a resilient urban land system, such as increasing the efficiency of existing urban land and controlling the shrinkage rate of important land use types. This study contributes to existing literature on complex networks by expanding its application in land systems, which highlight the potential of complex networks to capture the complexity, dynamics, heterogeneity, and emergent phenomena in land systems