Identification of <em>CHIP</em> as a novel causative gene for autosomal recessive cerebellar ataxia

Autosomal recessive cerebellar ataxias are a group of neurodegenerative disorders that are characterized by complex clinical and genetic heterogeneity. Although more than 20 disease-causing genes have been identified, many patients are still currently without a molecular diagnosis. In a two-generation autosomal recessive cerebellar ataxia family, we mapped a linkage to a minimal candidate region on chromosome 16p13.3 flanked by single-nucleotide polymorphism markers rs11248850 and rs1218762. By combining the defined linkage region with the whole-exome sequencing results, we identified a homozygous mutation (c.493CT) in CHIP (NM_005861) in this family. Using Sanger sequencing, we also identified two compound heterozygous mutations (c.389AT/c.441GT; c.621C>G/c.707GC) in CHIP gene in two additional kindreds. These mutations co-segregated exactly with the disease in these families and were not observed in 500 control subjects with matched ancestry. CHIP colocalized with NR2A, a subunit of the N-methyl-D-aspartate receptor, in the cerebellum, pons, medulla oblongata, hippocampus and cerebral cortex. Wild-type, but not disease-associated mutant CHIPs promoted the degradation of NR2A, which may underlie the pathogenesis of ataxia. In conclusion, using a combination of whole-exome sequencing and linkage analysis, we identified CHIP, encoding a U-box containing ubiquitin E3 ligase, as a novel causative gene for autosomal recessive cerebellar ataxia

Fuzzy Multicriteria Decision-Making Analysis of Agricultural Product Logistics in Agricultural Economic Management

The purpose is to establish a logistics supplier evaluation and selection model for green supply chain, which can effectively take into account the environmental problems, while the enterprise economy is developing. The logistics supplier evaluation index system is established under the background of green logistics based on fuzzy theory and multicriteria decision-making theory. The green competitiveness index is innovatively introduced into the system. Moreover, a fuzzy hybrid multicriteria decision-making method model is established based on the deficiency of the current supplier evaluation and selection methods, so as to select logistics suppliers; finally, the established logistics supplier evaluation and selection method is applied to real enterprises for example verification. The results are as follows. The direct relationship matrix is obtained according to the opinions of the expert group, and the relationship matrix is defuzzified and standardized to obtain the clear value of the secondary index. Finally, the fit between the evaluation results of the five logistics companies and the positive and negative ideal values is calculated. According to the principle of maximum fit, the evaluation priority of the five companies is 4 &gt; 3 &gt; 2 &gt; 5 &gt; 1. Thereby, taking the fuzzy multicriteria decision-making analysis method as the evaluation model has high reference value for the evaluation of green logistics companies, solves the problem of how production and sales enterprises choose green logistics suppliers, fully meets the needs of enterprises and governments that focus on the green degree of suppliers in the supply chain, and can effectively promote the efficient operation of green supply chain management.</jats:p

Comparison of five single-file systems in the preparation of severely curved root canals: an ex vivo study

Abstract Background The ex vivo study is to compare the root canal preparation outcomes achieved by five nickel–titanium single-file instrumentation systems (M3-L, Reciproc Blue, V-Taper 2H, WaveOne Gold, XP-endo Shaper) in severely curved molar root canals. Methods A total of 60 root canals were selected from extracted human molar teeth with curvatures ranging from 25° to 50° and divided into five groups based on the instrumentation system employed (n = 12). Before and after root canal preparation, a Micro-CT scan was taken, and pre- and post-operative data were analyzed to evaluate the following parameters: volume increment of root canals (VI), untouched root canal areas (UTA), and canal transportation (CT). Apically extruded debris (AD) was collected during preparation. After that, all samples were separated into two parts and examined respectively by scanning electron microscope (SEM) to assess cleaning ability. Data were statistically analyzed with ANOVA (UTA, AD, VI) or Kruskal–Wallis test (CT, SEM-score), the level of significance was set at α = 0.05. Results There were no significant differences between the five systems regarding the AD, VI, and UTA parameters (P &gt; 0.05). In terms of CT, no significant difference was noted at the straight section of canal and apical levels, while XP-endo Shaper showed less canal transportation than M3-L at the level of curved vertex (P &lt; 0.05), and the centering ability of V-Taper 2H was significantly better than WaveOne Gold at the initial point of bending (P &lt; 0.05). Debris and smear layers were present on the canal walls of all specimens, the apical thirds of the canal presented higher SEM scores than the coronal thirds in all groups (P &lt; 0.05). Reciproc Blue and XP-endo Shaper showed fewer smear scores than WaveOne Gold in the apical thirds (P &lt; 0.01 and P &lt; 0.05, respectively), and no statistical difference was found between other groups in the middle and coronal thirds. Conclusion The five single-file systems evaluated performed equally in apically debris extrusion, dentin removal, and untouched root canal areas, while XP-endo Shaper and V-Taper 2H resulted in less canal transportation compared to M3-L and WaveOne Gold. Regarding cleaning ability, Reciproc Blue and XP-endo Shaper were associated with less smear layer than WaveOne Gold in the apical thirds. </jats:sec

Comparison of five single-file systems in the preparation of severely curved root canals: an ex vivo study

Abstract Background The ex vivo study is to compare the root canal preparation outcomes achieved by five nickel–titanium single-file instrumentation systems (M3-L, Reciproc Blue, V-Taper 2H, WaveOne Gold, XP-endo Shaper) in severely curved molar root canals. Methods A total of 60 root canals were selected from extracted human molar teeth with curvatures ranging from 25° to 50° and divided into five groups based on the instrumentation system employed (n = 12). Before and after root canal preparation, a Micro-CT scan was taken, and pre- and post-operative data were analyzed to evaluate the following parameters: volume increment of root canals (VI), untouched root canal areas (UTA), and canal transportation (CT). Apically extruded debris (AD) was collected during preparation. After that, all samples were separated into two parts and examined respectively by scanning electron microscope (SEM) to assess cleaning ability. Data were statistically analyzed with ANOVA (UTA, AD, VI) or Kruskal–Wallis test (CT, SEM-score), the level of significance was set at α = 0.05. Results There were no significant differences between the five systems regarding the AD, VI, and UTA parameters (P > 0.05). In terms of CT, no significant difference was noted at the straight section of canal and apical levels, while XP-endo Shaper showed less canal transportation than M3-L at the level of curved vertex (P < 0.05), and the centering ability of V-Taper 2H was significantly better than WaveOne Gold at the initial point of bending (P < 0.05). Debris and smear layers were present on the canal walls of all specimens, the apical thirds of the canal presented higher SEM scores than the coronal thirds in all groups (P < 0.05). Reciproc Blue and XP-endo Shaper showed fewer smear scores than WaveOne Gold in the apical thirds (P < 0.01 and P < 0.05, respectively), and no statistical difference was found between other groups in the middle and coronal thirds. Conclusion The five single-file systems evaluated performed equally in apically debris extrusion, dentin removal, and untouched root canal areas, while XP-endo Shaper and V-Taper 2H resulted in less canal transportation compared to M3-L and WaveOne Gold. Regarding cleaning ability, Reciproc Blue and XP-endo Shaper were associated with less smear layer than WaveOne Gold in the apical thirds

Elevated Risk of Venous Thromboembolism in People Living with HIV

Human immunodeficiency virus (HIV) has been generally considered as a highly adaptive and rapidly evolving virus. It still constitutes a major public health problem all over the world despite an effective outcome in the prevention and reversal of the development and prognosis by using antiretroviral therapy. The salient question lies in the more frequent emergence of a series of comorbidities along with the prolongation of the life, which deeply affects the survival in such group. Venous thromboembolism (VTE) has been recognized to be the third most common cardiovascular condition within people living with HIV (PWH). In terms of its mechanism of action, the occurrence of VTE is quite multifactorial and complex in HIV. Prior exploration concerning the etiology of VTE in PWH identifies general, disease-specific, and miscellaneous factors for explaining its occurrence and development. VTE has constituted an important role in PWH and may increase its all-cause mortality. Therefore, it is quite necessary to understand VTE from the following aspects of epidemiology, pathophysiology, molecular mechanisms, and therapeutic interventions so as to balance the risks and benefits of anticoagulation and optimize corresponding treatment.</jats:p

Elevated Risk of Venous Thromboembolism in People Living with HIV

Human immunodeficiency virus (HIV) has been generally considered as a highly adaptive and rapidly evolving virus. It still constitutes a major public health problem all over the world despite an effective outcome in the prevention and reversal of the development and prognosis by using antiretroviral therapy. The salient question lies in the more frequent emergence of a series of comorbidities along with the prolongation of the life, which deeply affects the survival in such group. Venous thromboembolism (VTE) has been recognized to be the third most common cardiovascular condition within people living with HIV (PWH). In terms of its mechanism of action, the occurrence of VTE is quite multifactorial and complex in HIV. Prior exploration concerning the etiology of VTE in PWH identifies general, disease-specific, and miscellaneous factors for explaining its occurrence and development. VTE has constituted an important role in PWH and may increase its all-cause mortality. Therefore, it is quite necessary to understand VTE from the following aspects of epidemiology, pathophysiology, molecular mechanisms, and therapeutic interventions so as to balance the risks and benefits of anticoagulation and optimize corresponding treatment

Oxidatively stressed extracellular microenvironment drives fibroblast activation and kidney fibrosis

Kidney fibrosis is associated with tubular injury, oxidative stress and activation of interstitial fibroblasts. However, whether these events are somehow connected is poorly understood. In this study, we show that glutathione peroxidase-3 (GPX3) depletion in renal tubular epithelium after kidney injury plays a central role in orchestrating an oxidatively stressed extracellular microenvironment, which drives interstitial fibroblast activation and proliferation. Through transcriptional profiling by RNA-sequencing, we found that the expression of GPX3 was down-regulated in various models of chronic kidney disease (CKD), which was correlated with induction of nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase-4 (NOX4). By using decellularized extracellular matrix (ECM) scaffold, we demonstrated that GPX3-depleted extracellular microenvironment spontaneously induced NOX4 expression and reactive oxygen species (ROS) production in renal fibroblasts and triggered their activation and proliferation. Activation of NOX4 by advanced oxidation protein products (AOPPs) mimicked the loss of GPX3, increased the production of ROS, stimulated fibroblast activation and proliferation, and activated protein kinase C-α (PKCα)/mitogen-activated protein kinase (MAPK)/signal transducer and activator of transcription 3 (STAT3) signaling. Silencing NOX4 or inhibition of MAPK with small molecule inhibitors hampered fibroblast activation and proliferation. In mouse model of CKD, knockdown of NOX4 repressed renal fibroblast activation and proliferation and alleviated kidney fibrosis. These results indicate that loss of GPX3 orchestrates an oxidatively stressed extracellular microenvironment, which promotes fibroblast activation and proliferation through a cascade of signal transduction. Our studies underscore the crucial role of extracellular microenvironment in driving fibroblast activation and kidney fibrosis