Clinical, pathological and genetic characteristics of 17 unrelated children with Alagille Syndrome.

BACKGROUND: Alagille syndrome (ALGS) is a multisystem genetic disorder frequently characterized by hepatic manifestations. This study analyzed the clinical, pathological, and molecular genetic features of ALGS to improve the efficiency of clinical diagnosis. METHODS: We retrospectively analyzed the clinical manifestations, pathological examination findings, and genetic testing results of 17 children diagnosed with ALGS based on the revised criteria and hospitalized at our center from January 2012 to January 2022. RESULTS: The clinical manifestations are as follows: Cholestasis (16/17, 94%), characteristic facies (15/17, 88%), heart disease (12/16, 75%), butterfly vertebrae (12/17, 71%) and posterior embryotoxon (7/12, 58%). Among the 15 patients who underwent liver pathology examination, 13 (87%) were found to have varying degrees of bile duct paucity. Genetic testing was performed on 15 children, and pathogenic variants of the jagged canonical Notch ligand 1 (JAG1) gene were identified in 13 individuals, including 4 novel variants. No pathogenic variant in the notch homolog 2 (NOTCH2) gene were identified, and 2 children exhibited none of the aforementioned gene pathogenic variants. The median follow-up duration was 7 years. Of the remaining 15 patients (excluding 2 lost to follow-up), 11 remained stable, 4 deteriorated, and no patient died during the follow-up period. CONCLUSIONS: Among children diagnosed with ALGS, cholestasis stands as the most common feature. To minimize the risk of misdiagnosis, genetic testing should be performed on children exhibiting cholestasis, followed by the application of the revised diagnostic criteria for ALGS. While pharmacological therapy has shown effectiveness for ALGS patients, liver transplantation may be considered in instances of severe pruritus.

Research Progress of Collapse Response Mediator Proteins in Neurodegenerative Diseases.

Collapse response mediator proteins (CRMPs) are a family of cytoplasmic phosphorylated proteins, and the mechanism of action has always been the research focus of neurological diseases. Previous studies on the CRMPs family have revealed that CRMPs mediate the growth and development of neuronal cytoskeleton through different signaling pathways in the body. It plays an important role in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and spinocerebellar ataxia, which has attracted the attention of researchers. This article reviews the recent literature on the biological characteristics and mechanisms of CRMPs in different neurodegenerative diseases.

The utility of hierarchical genetic testing in paediatric liver disease.

BACKGROUND & AIMS: Genetic factors underlie a substantial proportion of paediatric liver diseases. Hereditary liver diseases have considerable genetic heterogeneity and variable clinical manifestations, which bring great challenges to clinical and molecular diagnoses. In this study, we investigated a group of paediatric patients with varying degrees of liver dysfunction using a hierarchical genetic testing strategy. METHODS: We first applied a panel encompassing 166 known causal genes of liver disease. We then used exome sequencing (ES) in those patients whose cases remained undiagnosed to identify the genetic aetiology of their symptoms. RESULTS: In total, we enrolled 131 unrelated paediatric patients with liver disease of Chinese Han ethnicity. We first applied targeted gene sequencing of 166 genes to all patients and yielded a diagnostic rate of 35.9% (47 of 131). Eighty-four patients who remained undiagnosed after target gene sequencing were subjected to ES. As a result, eight (8/84, 9.5%) of them obtained molecular diagnoses, including four patients suspected of abnormal bilirubin metabolism and four idiopathic cases. Non-typical genetic findings, including digenic inheritance and dual molecular diagnosis, were also identified. Through a comprehensive assessment of novel candidate variants of uncertain disease association, 11 patients of the remaining undiagnosed patients were able to obtain likely molecular diagnoses. CONCLUSIONS: Our study presents evidence for the diagnostic utility of sequential genetic testing in a cohort of patients with paediatric liver disease. Our findings expand the understanding of the phenotypic and mutational spectrum underlying this heterogeneous group of diseases.

Correlation between C9ORF72 mutation and neurodegenerative diseases: A comprehensive review of the literature.

Chromosome 9 open reading frame 72 (C9ORF72) encodes a 54-kDa protein with unknown function that is expressed at high levels in the central nervous system. The C9ORF72 hexanucleotide amplification is one of the most recently discovered repetitive amplification diseases related to neurodegeneration. Its association with amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) spectrum diseases has been fully established, although a causative role for C9ORF72 in Alzheimer's disease (AD) and Parkinson's disease (PD) remains to be established. Therefore, in this article, we will review the evidence for C9ORF72 as a causative factor in neurodegenerative diseases, the underlying mechanisms, and the potential for targeting C9ORF72 as a strategy to alleviate neurodegenerative disease progression.

Precise Orbit Determination of MEX Flyby Phobos Using Simulated Radiometric and Image Data.

A navigation camera or topography camera is a standard payload for deep space missions and the image data are normally used for auto-navigation. In this work, we study the potential contribution of image data in precise orbit determination for deep space spacecraft. The Mars Express (MEX) spacecraft has generated extensive Phobos image data during flybys of Phobos, but these data have not been used in precise orbit determination because of the difficulty in employing these image data. Therefore, we did an experiment using simulated image data as the first step for exploring how to use real image data in precise orbit determination of spacecraft. Our results demonstrate that image data can provide stronger constraints on orbit in the tangential and normal directions than Doppler data. When the image data were used in the MEX orbit determination during the MEX Phobos flyby, the orbit determination accuracies in the tangential and normal directions were significantly improved. This work will provide a reference for real image data processing during MEX Phobos flyby to improve MEX orbit accuracy as well as Phobos ephemeris accuracy.

The BRCC3 regulated by Cdk5 promotes the activation of neuronal NLRP3 inflammasome in Parkinson's disease models.

BRCA1-BRCA2-containing complex subunit 3 (BRCC3), a Lys-63-specific deubiquitinase, is a member of the JAMM/MPN family of zinc metalloproteases. BRCC3 have been shown to promote the inflammasome activation by deubiquitinating NOD-like receptor containing pyrin domain 3 (NLRP3). We reported the involvement of neuronal inflammasome in Parkinson's Disease (PD), but the molecular mechanism remains unknown. In this study, we showed that BRCC3 expression was increased in PD models. Knock-down of BRCC3 with shRNA lentivirus decreased NLRP3 neuronal inflammasome. Interestingly, upregulating cyclin-dependent kinase 5 (Cdk5) increased the expression of BRCC3 in HEK293 cell, while inhibition of Cdk5 decreased the upregulated BRCC3 level in MPP+-induced PD cell model. The interaction between Cdk5 and BRCC3 was further confirmed by immunoprecipitation. Moreover, inhibition of Cdk5 suppressed the expression of NLRP3, pro-caspase-1, the adaptor molecule apoptosis-associated speck-like protein containing a CARD (ASC) and interleukin-1 beta (IL-1ß). Besides, inhibition of BRCC3 blocked the increased secretion of IL-1ß. Together, these results suggest that Cdk5-mediated BRCC3 expression may play a critical role in neuronal inflammation by regulating the NLRP3 inflammasome in PD.

Density Structure of the Von Kármán Crater in the Northwestern South Pole-Aitken Basin: Initial Subsurface Interpretation of the Chang'E-4 Landing Site Region.

The Von Kármán Crater, within the South Pole-Aitken (SPA) Basin, is the landing site of China's Chang'E-4 mission. To complement the in situ exploration mission and provide initial subsurface interpretation, we applied a 3D density inversion using the Gravity Recovery and Interior Laboratory (GRAIL) gravity data. We constrain our inversion method using known geological and geophysical lunar parameters to reduce the non-uniqueness associated with gravity inversion. The 3D density models reveal vertical and lateral density variations, 2600-3200 kg/m3, assigned to the changing porosity beneath the Von Kármán Crater. We also identify two mass excess anomalies in the crust with a steep density contrast of 150 kg/m3, which were suggested to have been caused by multiple impact cratering. The anomalies from recovered near surface density models, together with the gravity derivative maps extending to the lower crust, are consistent with surface geological manifestation of excavated mantle materials from remote sensing studies. Therefore, we suggest that the density distribution of the Von Kármán Crater indicates multiple episodes of impact cratering that resulted in formation and destruction of ancient craters, with crustal reworking and excavation of mantle materials.

CDK5-mediated phosphorylation of Sirt2 contributes to depressive-like behavior induced by social defeat stress.

Major depressive disorder (MDD) is a common, severe and recurrent psychiatric disorder worldwide; however, the underlying neuropathological mechanisms remain elusive. Histone deacetylases (HDACs) appear to play an essential role in depression. As the class III HDACs, Sirt1 and Sirt2 have attracted the most interest in the nervous system. Indeed, chronic stress decreased Sirt1 activity and down-regulated Sirt1 gene expression in MDD. Nevertheless, there is a paucity of literature on the role of Sirt2. To study the role of Sirt2 we established a MDD mouse model in wild type and Sirt2 knockout C57BL/6 mice using social defeat stress (SDS). We found that a lack of Sirt2 blocked the development of SDS-induced depressive-like behavior. Moreover, SDS led to Sirt2 phosphorylation in the amygdala without changing total Sirt2 levels, and blocking the phosphorylation of Sirt2 by CDK5 at serine residues 368 and 372 prevented SDS-induced depressive-like behavior and Sirt2 nuclear import. We also discovered that SDS-induced Sirt2 phosphorylation was involved in VTA-amygdala modulation using TetTag-pharmacogenetic method. These results suggest that CDK5 mediates phosphorylation of Sirt2 in the amygdala and contributes to the depressive-like behavior induced by SDS. This study highlights that inhibiting CDK5-dependent phosphorylation of Sirt2 at serine residues 368 and 372 by myristoylated membrane-permeabilising peptide (Sirt2-p), rather than using non-specific sirtuin inhibitors, may be a novel strategy for treating depression.

Induction of Tca8113 tumor cell apoptosis by icotinib is associated with reactive oxygen species mediated p38-MAPK activation.

Icotinib, a selective EGFR tyrosine kinase inhibitor (EGFR-TKI), has been shown to exhibit anti-tumor activity against several tumor cell lines. However, the exact molecular mechanism of icotinib's anti-tumor effect remains unknown. This study aims to examine the zytotoxic effect of icotinib on Tca8113 cells and its potential molecular mechanism. Icotinib significantly resulted in dose-dependent cell death as determined by MTT assay, accompanied by increased levels of Bax and DNA fragmentation. Icotinib could also induce Reactive Oxygen Species (ROS) generation. Further studies confirmed that scavenging of reactive oxygen species by N-acetyl-L-cysteine (NAC), and pharmacological inhibition of MAPK reversed icotinib-induced apoptosis in Tca8113 cells. Our data provide evidence that icotinib induces apoptosis, possibly via ROS-mediated MAPK pathway in Tca8113 cells.

Multiscale approach to the characterization of the interfacial properties of micellar casein and whey protein blends and their effects on recombined dairy creams.

In this study, whipped cream with blends of micellar casein (MCN) and whey protein (WPI) in different ratios were prepared to investigate the role of protein interfacial behavior in determining foam properties at multiple scales, using theoretical modeling, and microscopic and macroscopic analysis. Fluid force microscopy has been used for the first time as a more realistic and direct means of analyzing interfaces properties in multiphase systems. The adsorption kinetics showed that the interfacial permeability constant of WPI (4.24 × 10-4 s-1) was significantly higher than that of the MCN (2.97 × 10-4 s-1), and the WPI interfacial layer had a higher modulus of elasticity (71.38 mN/m) than that of the MCN (47.89 mN/m). This model was validated via the mechanical analysis of the fat globules in real emulsions. The WPI-stabilized fat globule was found to have a higher Young's modulus (219.67 Pa), which contributes to the integrity of its fat globule morphology. As the ratio of MCN was increased in the sample, however, both the interfacial modulus and Young's modulus decreased. Moreover, the rate of partial coalescence was found to increase, a phenomenon that decreased the stability of the emulsion and increased the rate of aeration. The mechanical analysis also revealed a higher level of adhesion between MCN-stabilized fat globule (25.16 nN), which increased fat globule aggregation and emulsion viscosity, while improving thixotropic recovery. The synergistic effect of the blended MCN and WPI provided the highest overrun, at 194.53 %. These studies elucidate the role of the interfacial behavior of proteins in determining the quality of whipped cream and provide ideas for the application of proteins in multiphase systems.

Oil-water interfacial behaviour of different caseins and stability of emulsions: Effect of micelle content and caseins concentrations.

This study aimed to investigate the interfacial behaviour of caseins in different micelle content and its effect on the stability of emulsions, including micellar casein concentrate (MCN), calcium caseinate (CaC) and sodium caseinate (NaC). Results revealed that at high protein concentrations (0.5 %-2.5 %), MCN, CaC and NaC exhibited similar interfacial behaviour as well as unfolding rate constants (k 1 ) of 3.11-3.41 × 10-4 (s-1), 2.96-3.35 × 10-4 (s-1) and 2.75-3.27 × 10-4 (s-1), respectively. The interfacial layer formed was dominated by non-micelles, and microscopic images revealed the thickness of the interfacial layer to be 10-20 nm. By contrast, at low concentrations, the differences in the slope of E-π curves and k 1 indicated that the micelle content of casein affects protein interfacial behaviour and properties and that micellar casein is involved in the formation of the interfacial layer. The formation of large numbers of droplets during emulsion preparation results in a similar low concentration environment. Cryo-TEM showed adsorption of micellar casein in all three casein-stabilised emulsions, and the amount of adsorption was proportional to the micelle content. NaC has faster adsorption and rearrangement rates due to fewer micelles and more non-micelles, so that NaC forms smaller droplets and more stable emulsions than those formed by MCN and CaC within the range of 0.5 % to 2.0 %.

Clinical and genetic study of ABCB4 gene-related cholestatic liver disease in China: children and adults.

BACKGROUND: ABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. The correlation between genotype and clinical phenotype still unclear. This study retrospectively analyzed the clinical and pathological characteristics of 23 patients with ABCB4 gene-related cholestatic liver diseases. Next-generation sequencing was used to identify the genetic causes. RESULTS: The 23 included patients (15 children and 8 adults) were diagnosed as progressive familial intrahepatic cholestasis type 3 (PFIC3), drug-induced liver injury (DILI), cirrhosis cholestasis, cirrhosis, and mild liver fibrosis. Nineteen patients underwent liver pathological examination of the liver, exhibiting fibrosis, small bile duct hyperplasia, CK7(+), Cu(+), bile duct deletion, and cirrhosis. Thirty ABCB4 variants were identified, including 18 novel variants. CONCLUSION: ABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. Biallelic ABCB4 mutation carriers tended to severe PFIC3, which mostly occurs in children; while ABCB4 non-biallelic variants can lead to milder ICP, LACP, DILI or overlapping, mostly in adults. Thus, the ABCB4 genotype has a specific correlation with the phenotype, but there are exceptions. Non-biallelic null mutations can cause severe diseases. The mechanisms underlying this genetic phenotype require further investigation.

Development and Validation of a Machine Learning-Based Model Used for Predicting Hepatocellular Carcinoma Risk in Patients with Hepatitis B-Related Cirrhosis: A Retrospective Study.

Object: Our objective was to estimate the 5-year cumulative risk of HCC in patients with HBC by utilizing an artificial neural network (ANN). Methods: We conducted this study with 1589 patients hospitalized at Beijing Ditan Hospital of Capital Medical University and People's Liberation Army Fifth Medical Center. The training cohort consisted of 913 subjects from Beijing Ditan Hospital of Capital Medical University, while the validation cohort comprised 676 subjects from People's Liberation Army Fifth Medical Center. Through univariate analysis, we identified factors that independently influenced the occurrence of HCC, which were then used to develop the ANN model. To evaluate the ANN model, we assessed its predictive accuracy, discriminative ability, and clinical net benefit using metrics such as the area under the receiver operating characteristic curve (AUC), concordance index (C-index), calibration curves. Results: In total, we included nine independent risk factors in the development of the ANN model. Remarkably, the AUC of the ANN model was 0.880, significantly outperforming the AUC values of other existing models including mPAGE-B (0.719) (95% CI 0.670-0.768), PAGE-B (0. 710) (95% CI 0.660-0.759), FIB-4 (0.693) (95% CI 0.640-0.745), and Toronto hepatoma risk index (THRI) (0.705) (95% CI 0.654-0.756) (p<0.001 for all). The ANN model effectively stratified patients into low, medium, and high-risk groups based on their 5-year In the training cohort, the positive predictive value (PPV) for low-risk patients was 26.2% (95% CI 25.0-27.4), and the negative predictive value (NPV) was 98.7% (95% CI 95.2-99.7). For high-risk patients, the PPV was 54.7% (95% CI 48.6-60.7), and the NPV was 91.6% (95% CI 89.4-93.4). These findings were validated in the independent validation cohort. Conclusion: The ANNs model has good individualized prediction performance and may be helpful to evaluate the probability of the 5-year risk of HCC in patients with HBC.

Functional cure is associated with younger age in children undergoing antiviral treatment for active chronic hepatitis B.

BACKGROUND AND AIMS: Functional cure is difficult to achieve using current antiviral therapies; moreover, limited data are available regarding treatment outcomes in children. This retrospective study aimed to assess the frequency of functional cure among children undergoing antiviral treatment for active chronic hepatitis B (CHB). METHODS: A total of 372 children aged 1-16 years, with active CHB were enrolled and underwent either nucleos(t)ide analog monotherapy or combination therapy with interferon-α (IFN-α) for 24-36 months. All children attended follow-up visits every 3 months. Functional cure was defined as evidence of hepatitis B virus (HBV) DNA loss, circulating hepatitis B e antigen (HBeAg) loss/seroconversion, and hepatitis B surface antigen (HBsAg) loss. RESULTS: After 36 months of antiviral treatment and/or follow-up visits, children with CHB aged 1- < 7 years exhibited higher rates of HBV DNA clearance, HBeAg seroconversion, and HBsAg loss than CHB children ≥ 7-16 years of age (93.75% versus [vs.] 86.21% [p < 0.0001]; 79.30% vs. 51.72% [p < 0.0001]; and 50.78% vs. 12.93% [p < 0.0001], respectively). Longitudinal investigation revealed more rapid dynamic reduction in HBV DNA, HBeAg, and HBsAg levels in children aged 1-7 years than in those aged ≥ 7-16 years with CHB. According to further age-stratified analysis, HBsAg loss rates were successively decreased in children with CHB who were 1- < 3, 3- < 7, 7- < 12, and 12-16 years of age (62.61% vs. 41.13% vs. 25.45% vs. 1.64%, respectively; p < 0.0001) at 36 months. In addition, baseline HBsAg level < 1,500 IU/mL was found to favor disease cure among these pediatric patients. No serious adverse events were observed throughout the study period. CONCLUSION: Results of the present study demonstrated that children aged 1- < 7 years, with active CHB can achieve a high functional cure rate by undergoing antiviral therapy compared to those aged ≥ 7 years, who undergo antiviral therapy. These data support the use of antiviral treatment at an early age in children with CHB. However, future prospectively randomized controlled trials are necessary to validate the findings of this study.

Characteristics analysis of hepatitis B core-related antigen in children with hepatitis B e antigen-positive chronic viral hepatitis B infection.

BACKGROUND: The objective of antiviral therapy for chronic viral hepatitis B infection (CHB) is to achieve a functional cure. An important viral marker in the serum of patients with CHB is the serum hepatitis B core-related antigen (HBcrAg). However, there is limited research on HBcrAg in juvenile patients with CHB. In this study, we aimed to investigate the correlation between serum HBcrAg and other hepatitis B virus (HBV) markers in children with CHB and its predictive significance for prognosis during antiviral therapy. METHODS: A single-center retrospective study was conducted involving 79 children with CHB, aged between 0 and 16 years. All the children were treated with interferon [or combined nucleos(t)ide analogs] for 48 weeks. HBcrAg, hepatitis B surface antigen (HBsAg), and HBV DNA were measured before treatment, and at 12 and 48 weeks after treatment. The enrolled children were classified into the seroclearance group and the nonseroclearance group based on the therapeutic outcome. RESULTS: HBsAg seroclearance was observed in 28 out of 79 patients and hepatitis B e antigen seroconversion without HBsAg seroclearance was observed in 14 out of 79 patients following the conclusion of the treatment, with baseline HBcrAg titer levels showing no statistical significance in both the seroclearance and nonseroclearance groups ( P  = 0.277). HBsAg and HBV DNA were positively correlated with HBcrAg in children with CHB ( R2  = 0.3289, 0.4388). The area under the receiver operating characteristic curve of the decrease in HBcrAg at 12 weeks of treatment as a predictor of seroclearance at 48 weeks of treatment, exhibited a value of 0.77. CONCLUSION: A decrease in serum HBcrAg levels in children with hepatitis B serves as a prognostic indicator.

[Effects on DNA damage and apoptosis and P53 protein expression induced by phoxim in rat bone marrow stem cells].

OBJECTIVE: To study the DNA damage and oxidative damage and apoptosis and P53 protein expression in rat bone marrow stem cells cultured in vitro induced by phoxim. METHODS: Rat bone marrow stem cells of P3 cultured in vitro were treated with phoxim of different concentrations (0, 0.2, 2 and 20 microg/L) for 24 h after 48 h cultured. The total activity of SOD, CAT and MDA content, survival rate in cell were detected by spectrophotometry,and the DNA damage were detected by single cell gel electrophoresis. The cell apoptosis were detected by flow cytometry,and the P53 protein expression were detected by Western blot. RESULTS: With the 0.2 and 20 microg/L of phoxim concentrations treated for 24 h in culture media, the total activity of SOD and CAT were significantly decreased compared with the controls (P < 0.05). With the increase of phoxim concentration in culture media, the MDA contents, DNA damage, apoptosis rates and P53 protein expression of rat bone marrow stem cells was increased significantly compared with the controls (P < 0.05). CONCLUSION: Phoxim can increase the rates of DNA damage, oxidative damage and induce apoptosis and expression of P53 in rat bone marrow stem cells, and there exists a rise tendency with the increase concentration of phoxim.

A review of studies on the implication of NLRP3 inflammasome for Parkinson's disease and related candidate treatment targets.

Parkinson's disease (PD) is a neurodegenerative disease for which the prevalence is second only to Alzheimer's disease (AD). This disease primarily affects people of middle and old age, significantly impacting their health and quality of life. The main pathological features include the degenerative nigrostriatal dopaminergic (DA) neuron loss and Lewy body (LB) formation. Currently, available PD medications primarily aim to alleviate clinical symptoms, however, there is no universally recognized therapy worldwide that effectively prevents, clinically treats, stops, or reverses the disease. Consequently, the evaluation and exploration of potential therapeutic targets for PD are of utmost importance. Nevertheless, the pathophysiology of PD remains unknown, and neuroinflammation mediated by inflammatory cytokines that prompts neuron death is fundamental for the progression of PD. The nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is a key complex of proteins linking the neuroinflammatory cascade in PD. Moreover, mounting evidence suggests that traditional Chinese medicine (TCM) alleviates PD by suppressing the NLRP3 inflammasome. This article aims to comprehensively review the available studies on the composition and activating mechanism of the NLRP3 inflammasome, along with its significance in PD pathogenesis and potential treatment targets. We also review natural products or synthetic compounds which reduce neuroinflammation via modulating NLRP3 inflammasome activity, aiming to identify new targets for future PD diagnosis and treatment through the exploration of NLRP3 inhibitors. Additionally, this review offers valuable references for developing new PD treatment methods.

Succinate dehydrogenase complex subunit C: Role in cellular physiology and disease.

Succinate dehydrogenase complex subunit C (SDHC) is a subunit of mitochondrial complex II (MCII), which is also known as succinate dehydrogenase (SDH) or succinate: ubiquinone oxidoreductase. Mitochondrial complex II is the smallest respiratory complex in the respiratory chain and contains four subunits. SDHC is a membrane-anchored subunit of SDH, which connects the tricarboxylic acid cycle and the electron transport chain. SDH regulates several physiological processes within cells, plays an important role in generating energy to maintain normal cell growth, and is involved in apoptosis. Currently, SDHC is generally recognized as a tumor-suppressor gene. SDHC mutations can cause oxidative damage in the body. It is closely related to the occurrence and development of cancer, neurodegenerative diseases, and aging-related diseases. Here, we review studies on the structure, biological function, related diseases of SDHC, and the mev-1 Animal Model of SDHC Mutation and its potential use as a therapeutic target of certain human diseases.

Bifidobacterium animalis A12, a Probiotic Strain That Promotes Glucose and Lipid Metabolism, Improved the Texture and Aroma of the Fermented Sausage.

Bifidobacterium animalis A12 was used for the development of fermented sausage. The growth activity, tolerance, and enzyme activity of B. animalis A12 and its contribution to the texture and flavour of fermented sausages were evaluated. Additionally, the sensory texture, flavour components, and amino acid nutrients during the fermentation process were assessed. B. animalis had high tolerance to NaCl and nitrite, and B. animalis A12 had protease and lipase activities. The pH value of sausage fermented with B. animalis A12 was lower than that of sausage fermented without any fermentation strain. Hexanal, heptanal, decanal, cis-2-decanal, and 4-methoxy-benzaldehyde are the unique aldehydes flavour components of fermented sausages in the A12 group. The highest content of volatile flavour substances and amino acids, and the color and texture characteristics of fermented sausage in the experimental group at 18 h were better than those at other times. These results suggest that B. animalis A12 has the potential to be used as a starter culture for im-proving flavour and texture in fermented sausage.

Cdk5 phosphorylation-dependent C9orf72 degradation promotes neuronal death in Parkinson's disease models.

AIMS: Chromosome 9 open reading frame 72 (C9orf72) is one of the most dazzling molecules in neurodegenerative diseases, albeit that its role in Parkinson's disease (PD) remains unknown. This article aimed to explore the potential mechanism of C9orf72 involved in the pathogenesis of PD. METHODS: The expression and phosphorylation levels of C9orf72 were examined by Western blotting, RT-PCR, and immunoprecipitation using PD models. Multiple bioinformatics software was used to predict the potential phosphorylation sites of C9orf72 by Cdk5, followed by verification of whether Cdk5-inhibitor ROSCOVITINE could reverse the degradation of C9orf72 in PD. By constructing the sh-C9orf72-knockdown adenovirus and overexpressing the FLAG-C9orf72 plasmid, the effects of C9orf72 knockdown and overexpression, respectively, were determined. A short peptide termed Myr-C9orf72 was used to verify whether interfering with Cdk5 phosphorylation at the Ser9 site of the C9orf72 protein could alleviate autophagy disorder, neuronal death, and movement disorder in PD models. RESULTS: The expression level of the C9orf72 protein was significantly reduced, albeit the mRNA expression was not changed in the PD models. Moreover, the phosphorylation level was enhanced, and its reduction was mainly degraded by the ubiquitin-proteasome pathway. The key nervous system kinase Cdk5 directly phosphorylated the S9 site of the C9orf72 protein, which promoted the degradation of the C9orf72 protein. The knockdown of C9orf72 aggravated autophagy dysfunction and increased neuronal loss and motor dysfunction in substantia nigra neurons of PD mice. The overexpression of C9orf72 alleviated autophagy dysfunction in PD neurons. Specifically, interference with Cdk5 phosphorylation at the S9 site of C9orf72 alleviated autophagy dysfunction, neuronal death, and motor dysfunction mediated by C9orf72 protein degradation during PD. CONCLUSIONS: Cumulatively, our findings illustrate the importance of the role of C9orf72 in the regulation of neuronal death during PD progression via the Cdk5-dependent degradation.