Multipattern graph convolutional network-based autism spectrum disorder identification.

The early diagnosis of autism spectrum disorder (ASD) has been extensively facilitated through the utilization of resting-state fMRI (rs-fMRI). With rs-fMRI, the functional brain network (FBN) has gained much attention in diagnosing ASD. As a promising strategy, graph convolutional networks (GCN) provide an attractive approach to simultaneously extract FBN features and facilitate ASD identification, thus replacing the manual feature extraction from FBN. Previous GCN studies primarily emphasized the exploration of topological simultaneously connection weights of the estimated FBNs while only focusing on the single connection pattern. However, this approach fails to exploit the potential complementary information offered by different connection patterns of FBNs, thereby inherently limiting the performance. To enhance the diagnostic performance, we propose a multipattern graph convolution network (MPGCN) that integrates multiple connection patterns to improve the accuracy of ASD diagnosis. As an initial endeavor, we endeavored to integrate information from multiple connection patterns by incorporating multiple graph convolution modules. The effectiveness of the MPGCN approach is evaluated by analyzing rs-fMRI scans from a cohort of 92 subjects sourced from the publicly accessible Autism Brain Imaging Data Exchange database. Notably, the experiment demonstrates that our model achieves an accuracy of 91.1% and an area under ROC curve score of 0.9742. The implementation codes are available at https://github.com/immutableJackz/MPGCN.

Towards an accurate autism spectrum disorder diagnosis: multiple connectome views from fMRI data.

Functional connectome has revealed remarkable potential in the diagnosis of neurological disorders, e.g. autism spectrum disorder. However, existing studies have primarily focused on a single connectivity pattern, such as full correlation, partial correlation, or causality. Such an approach fails in discovering the potential complementary topology information of FCNs at different connection patterns, resulting in lower diagnostic performance. Consequently, toward an accurate autism spectrum disorder diagnosis, a straightforward ambition is to combine the multiple connectivity patterns for the diagnosis of neurological disorders. To this end, we conduct functional magnetic resonance imaging data to construct multiple brain networks with different connectivity patterns and employ kernel combination techniques to fuse information from different brain connectivity patterns for autism diagnosis. To verify the effectiveness of our approach, we assess the performance of the proposed method on the Autism Brain Imaging Data Exchange dataset for diagnosing autism spectrum disorder. The experimental findings demonstrate that our method achieves precise autism spectrum disorder diagnosis with exceptional accuracy (91.30%), sensitivity (91.48%), and specificity (91.11%).

Topological properties analysis and identification of mild cognitive impairment based on individual morphological brain network connectome.

Mild cognitive impairment is considered the prodromal stage of Alzheimer's disease. Accurate diagnosis and the exploration of the pathological mechanism of mild cognitive impairment are extremely valuable for targeted Alzheimer's disease prevention and early intervention. In all, 100 mild cognitive impairment patients and 86 normal controls were recruited in this study. We innovatively constructed the individual morphological brain networks and derived multiple brain connectome features based on 3D-T1 structural magnetic resonance imaging with the Jensen-Shannon divergence similarity estimation method. Our results showed that the most distinguishing morphological brain connectome features in mild cognitive impairment patients were consensus connections and nodal graph metrics, mainly located in the frontal, occipital, limbic lobes, and subcortical gray matter nuclei, corresponding to the default mode network. Topological properties analysis revealed that mild cognitive impairment patients exhibited compensatory changes in the frontal lobe, while abnormal cortical-subcortical circuits associated with cognition were present. Moreover, the combination of multidimensional brain connectome features using multiple kernel-support vector machine achieved the best classification performance in distinguishing mild cognitive impairment patients and normal controls, with an accuracy of 84.21%. Therefore, our findings are of significant importance for developing potential brain imaging biomarkers for early detection of Alzheimer's disease and understanding the neuroimaging mechanisms of the disease.

Utilizing graph convolutional networks for identification of mild cognitive impairment from single modal fMRI data: a multiconnection pattern combination approach.

Mild cognitive impairment plays a crucial role in predicting the early progression of Alzheimer's disease, and it can be used as an important indicator of the disease progression. Currently, numerous studies have focused on utilizing the functional brain network as a novel biomarker for mild cognitive impairment diagnosis. In this context, we employed a graph convolutional neural network to automatically extract functional brain network features, eliminating the need for manual feature extraction, to improve the mild cognitive impairment diagnosis performance. However, previous graph convolutional neural network approaches have primarily concentrated on single modes of brain connectivity, leading to a failure to leverage the potential complementary information offered by diverse connectivity patterns and limiting their efficacy. To address this limitation, we introduce a novel method called the graph convolutional neural network with multimodel connectivity, which integrates multimode connectivity for the identification of mild cognitive impairment using fMRI data and evaluates the graph convolutional neural network with multimodel connectivity approach through a mild cognitive impairment diagnostic task on the Alzheimer's Disease Neuroimaging Initiative dataset. Overall, our experimental results show the superiority of the proposed graph convolutional neural network with multimodel connectivity approach, achieving an accuracy rate of 92.2% and an area under the Receiver Operating Characteristic (ROC) curve of 0.988.

Grass carp (Ctenopharyngodon idella) deacetylase SIRT1 targets p53 to suppress apoptosis in a KAT8 dependent or independent manner.

Sirtuin1 (SIRT1) is known as a deacetylase to control various physiological processes. In mammals, SIRT1 inhibits apoptotic process, but the detailed mechanism is not very clear. Here, our study revealed that grass carp (Ctenopharyngodon idella) SIRT1 (CiSIRT1, MN125614.1) inhibits apoptosis through targeting p53 in a KAT8-dependent or a KAT8-independent manner. In CIK cells, CiSIRT1 over-expression results in significant decrease of some apoptotic gene expressions, including Bax/Bcl2, caspase3 and caspase9, whereas CiKAT8 or Cip53 facilitates the induction of apoptosis. Because CiSIRT1 separately interacted with CiKAT8 and Cip53, we speculated that CiSIRT1 blocked apoptosis may be by virtue of KAT8-p53 axis or directly by p53. In a KAT8-dependent manner, CiSIRT1 interacted with CiKAT8, then reduced the acetylation of CiKAT8 and subsequently promoted its degradation. Then, CiKAT8 acetylated p53 and induced p53-mediated apoptosis. MYST domain of CiKAT8 was critical in this pathway. In a KAT8-independent manner, CiSIRT1 also inhibited p53-induced apoptosis by directly deacetylating p53 and promoting the degradation of p53. Generally, these findings uncovered two pathways in which CiSIRT1 decreases the acetylation of p53 via a KAT8-dependent or a KAT8-independent manner.

Grass carp (Ctenopharyngodon idella) NIK up-regulates the expression of IL-8 by activating the NF-κB canonical pathway.

NIK (NF-κB inducing kinase) belongs to the mitogen-activated protein kinase family, which activates NF-κB and plays a vital role in immunology, inflammation, apoptosis, and a series of pathological responses. In NF-κB noncanonical pathway, NIK and IKKα have been often studied in mammals and zebrafish. However, few have explored the relationship between NIK and other subunits of the IKK complex. As a classic kinase in the NF-κB canonical pathway, IKKß has never been researched with NIK in fish. In this paper, the full-length cDNA sequence of grass carp (Ctenopharyngodon idella) NIK (CiNIK) was first cloned and identified. The expression level of CiNIK in grass carp cells was increased under GCRV stimuli. Under the stimulation of GCRV, poly (I:C), and LPS, the expression of NIK in various tissues of grass carp was also increased. This suggests that CiNIK responds to viral stimuli. To study the relationship between CiNIK and CiIKKß, we co-transfected CiNIK-FLAG and CiIKKB-GFP into grass carp cells in coimmunoprecipitation and immunofluorescence experiments. The results revealed that CiNIK interacts with CiIKKß. Besides, the degree of autophosphorylation of CiNIK was enhanced under poly (I:C) stimulation. CiIKKß was phosphorylated by CiNIK and then activated the activity of p65. The activity change of p65 indicates that NF-κB downstream inflammatory genes will be functioning. CiNIK or CiIKKß up-regulated the expression of IL-8. It got higher when CiNIK and CiIKKß coexisted. This paper revealed that NF-κB canonical pathway and noncanonical pathway are not completely separated in generating benefits.

Complete genome sequence of a novel alternavirus isolated from the phytopathogenic fungus Colletotrichum fioriniae.

A novel double-strand RNA (dsRNA) mycovirus, named "Colletotrichum fioriniae alternavirus1" (CfAV1), was isolated from the strain CX7 of Colletotrichum fioriniae, the causal agent of walnut anthracnose. The complete genome of CfAV1 is composed of three dsRNA segments: dsRNA1 (3528 bp), dsRNA2 (2485 bp), and dsRNA3 (2481 bp). The RNA-dependent RNA polymerase (RdRp) is encoded by dsRNA1, while both dsRNA2 and dsRNA3 encode hypothetical proteins. Based on multiple sequence alignments and phylogenetic analysis, CfAV1 is identified as a new member of the family Alternaviridae. This is the first report of an alternavirus that infects the phytopathogenic fungus C. fioriniae.

Wavelet transform-based frequency self-adaptive model for functional brain network.

The accurate estimation of functional brain networks is essential for comprehending the intricate relationships between different brain regions. Conventional methods such as Pearson Correlation and Sparse Representation often fail to uncover concealed information within diverse frequency bands. To address this limitation, we introduce a novel frequency-adaptive model based on wavelet transform, enabling selective capture of highly correlated frequency band sequences. Our approach involves decomposing the original time-domain signal from resting-state functional magnetic resonance imaging into distinct frequency domains, thus constructing an adjacency matrix that offers enhanced separation of features across brain regions. Comparative analysis demonstrates the superior performance of our proposed model over conventional techniques, showcasing improved clarity and distinctiveness. Notably, we achieved the highest accuracy rate of 89.01% using Sparse Representation based on Wavelet Transform, outperforming Pearson Correlation based on Wavelet Transform with an accuracy of 81.32%. Importantly, our method optimizes raw data without significantly altering feature topology, rendering it adaptable to various functional brain network estimation approaches. Overall, this innovation holds the potential to advance the understanding of brain function and furnish more accurate samples for future research and clinical applications.

Accurately predicting the risk of unfavorable outcomes after endovascular coil therapy in patients with aneurysmal subarachnoid hemorrhage: an interpretable machine learning model.

BACKGROUND: Despite endovascular coiling as a valid modality in treatment of aneurysmal subarachnoid hemorrhage (aSAH), there is a risk of poor prognosis. However, the clinical utility of previously proposed early prediction tools remains limited. We aimed to develop a clinically generalizable machine learning (ML) models for accurately predicting unfavorable outcomes in aSAH patients after endovascular coiling. METHODS: Functional outcomes at 6 months after endovascular coiling were assessed via the modified Rankin Scale (mRS) and unfavorable outcomes were defined as mRS 3-6. Five ML algorithms (logistic regression, random forest, support vector machine, deep neural network, and extreme gradient boosting) were used for model development. The area under precision-recall curve (AUPRC) and receiver operating characteristic curve (AUROC) was used as main indices of model evaluation. SHapley Additive exPlanations (SHAP) method was applied to interpret the best-performing ML model. RESULTS: A total of 371 patients were eventually included into this study, and 85.4% of them had favorable outcomes. Among the five models, the DNN model had a better performance with AUPRC of 0.645 (AUROC of 0.905). Postoperative GCS score, size of aneurysm, and age were the top three powerful predictors. The further analysis of five random cases presented the good interpretability of the DNN model. CONCLUSION: Interpretable clinical prediction models based on different ML algorithms have been successfully constructed and validated, which would serve as reliable tools in optimizing the treatment decision-making of aSAH. Our DNN model had better performance to predict the unfavorable outcomes at 6 months in aSAH patients compared with Yan's nomogram model.

PD-L1 Expression is Linked to Tumor-Infiltrating T-Cell Exhaustion and Adverse Pathological Behavior in Pheochromocytoma/Paraganglioma.

Pheochromocytoma/paraganglioma (PPGL) is an endocrine-related tumor associated with excessive catecholamine release and has limited treatment options once metastasis occurs. Although recent phase 2 clinical trials of immune checkpoint inhibitors in the treatment of PPGL have preliminarily shown promising results, the fundamentals of immunotherapy for PPGL have not yet been established. In the early research, using bulk RNA sequencing of tumor samples from 7 PPGL patients, we found that PPGL tumor tissues exhibited high PD-L1 mRNA expression compared with adjacent normal adrenal medulla tissues, and this was related to T-cell exhaustion biomarkers. To further validate the association, in this study (n = 60), we first stratified all PPGL samples according to PD-L1 expression as determined by immunohistochemical staining, and then subjected 23 fresh PPGL tumor samples from the cohort to a quantitative polymerase chain reaction (n = 16), flow cytometry (n = 7), and multiplex-immunofluorescence staining. Subsequently, we evaluated the pathological manifestations of all 60 PPGL tumor samples and analyzed the correlation among PD-L1 expression, adverse pathological behavior, various clinicopathological data, and genotypes in PPGL. The results showed that PD-L1-positive expression correlated with the exhaustion of tumor-infiltrating T cells, preoperative abnormal elevation of plasma norepinephrine, high Ki67 index, and adverse pathological behavior in PPGL but not with genetic mutation or metastatic disease, possibly due to the limitation of the small number of patients with metastatic disease (n = 4) in the study cohort. In conclusion, our findings reveal that PD-L1 expression is associated with T-cell exhaustion and adverse pathological behavior in PPGL. These results are expected to provide a new theoretical basis and clinical guidance for the treatment of PPGL.

Visualized Lateral Flow Assay for Dual Viral RNA Fragment Detection.

In this technical note, we report an easy-to-produce, reverse-transcription-free, and protein-enzyme-free lateral flow assay for detection of viral RNA fragments by taking SARS-CoV-2 ORF1ab and N as target models. Catalytic hairpin assembly is utilized for dual RNA fragment orthogonal reaction to generate copious amounts of opened hairpin duplexes, which bridge DNA-modified gold nanoparticles and capture strands on the strip to induce coloration. The dual RNA fragments are simultaneously visualized during one time of sample flow, and single-base-mismatched nontarget sequences can be differentiated. The test strip can be flexibly adapted to detect evolutional SARS-CoV-2 variants such as Delta and Omicron. It also shows potential in visually detecting long-sequence virus simulants and achieves a sensitivity comparable to that of RT-qPCR by incorporation with upstream sample amplification. The lateral flow assay should offer a convenient and reliable technique for viral nucleic acid detection.

Grass carp (Ctenopharyngodon idella) Mex3B positively regulates innate immunity by promoting the K63-linked ubiquitination of TLR3.

As a member of Mex3 (muscle excess protein-3) family, Mex3B (Mex-3 RNA binding family member B) is crucial in cell proliferation and migration in mammals. In this study, an ortholog of mammalian Mex3B (denominated CiMex3B, MT276802.1) was cloned and identified in grass carp (Ctenopharyngodon idella). CiMex3B is 1578 bp in length and encodes a polypeptide of 525 amino acids. Consistent with its mammalian counterpart, CiMex3B also contains one C-terminal RING domain and two N-terminal conserved tandem KH domains. CiMex3B up-regulates the expressions of IFN1, ISG15, MX2, as well as the expressions of inflammatory cytokines such as IL6, IL8 and TNFα in response to poly(I:C). A screening test for identifying potential targets indicated that CiMex3B is associated with TLR3 and TRIF. CiMex3B co-localizes with TLR3 in the late endosome, mitochondria and endoplasmic reticulum after poly(I:C) stimulation, whereas they are rarely discovered in the lysosomes. CiMex3B serves as a positive regulator in the phosphorylation of IRF3 and induces IFN1 expression. In addition, two truncation mutants of CiMex3B (1-220 and 221-525) were constructed to better understand the molecular mechanism of CiMex3B-mediated ubiquitination of TLR3. In line with wild-type protein, CiMex3B mutant (1-220) was found mainly in the cytoplasm; however, CiMex3B mutant (221-525) resided in the cytoplasm and the nucleus as well, and it was further confirmed that CiMex3B mutant (221-525) still interacts with TLR3. We also observed that CiMex3B promotes the K63-linked ubiquitination of TLR3, while neither of the truncation mutants (1-220 or 221-525) retains this activity. To sum up, this study revealed that CiMex3B potentiates the K63-linked ubiquitination of TLR3, and then elicits the IRF3-mediated antiviral innate immune responses.

Characterization of a novel hypovirus isolated from the phytopathogenic fungus Colletotrichum camelliae.

Some members of genus Colletotrichum are important plant pathogens. Here, we report a novel positive single-stranded RNA virus, Colletotrichum camelliae hypovirus 1 (CcHV1), from strain GXNN11-2 of Colletotrichum camelliae. The complete genome of CcHV1 is 9907 nucleotides (nt) in length and contains a single large open reading frame (ORF) from nt 352 to 9006. This ORF encodes a polyprotein with four conserved domains, namely UDP-glycosyltransferase, RNA-dependent RNA polymerase (RdRp), peptidase, and DEAD-like helicase. The CcHV1 polyprotein shares the highest similarity with Fusarium concentricum hypovirus 1. Phylogenetic analysis indicated that CcHV1 clustered with members of the genus Betahypovirus within the family Hypoviridae. This is the first report of a hypovirus in a member of the genus Colletotrichum.

Physiological and clinical variables identify ARDS classes and therapeutic heterogeneity to glucocorticoids: a retrospective study.

OBJECTIVE: We aimed to identify new classes in acute respiratory distress syndrome (ARDS) using physiological and clinical variables and to explore heterogeneity in the effects of glucocorticoid therapy between classes. METHODS: Using the Medical Information Mart for Intensive Care-IV database, we identified patients with ARDS. Potential profile analysis was used to identify classes with physiological and clinical data as delineating variables. Baseline characteristics and clinical outcomes were compared between classes. The effect of glucocorticoid treatment was explored by stratifying by class and glucocorticoid treatment. RESULTS: From 2008 to 2019, 1104 patients with ARDS were enrolled in the study. The 2-class potential analysis model had the best fit (P < 0.0001), with 78% of patients falling into class 1 and 22% into class 2. Additional classes did not improve the model fit. Patients in class 2 had higher anion gap, lactate, creatinine, and glucose levels and lower residual base, blood pressure, and bicarbonate compared with class 1. In-hospital mortality and 28-day mortality were significantly higher among patients in class 2 than those in class 1 (P < 0.001). Heterogeneity of glucocorticoid treatment was observed, stratified by class and treatment, with no significant effect in class 1 (P = 0.496), increased mortality in class 2 (P = 0.001), and a significant interaction (P = 0.0381). In class 2, 28-day survival was significantly lower with glucocorticoid treatment compared with no hormone treatment (P = 0.001). CONCLUSION: We used clinical and physiological variables to identify two classes of non-COVID-19-associated ARDS with different baseline characteristics and clinical outcomes. The response to glucocorticoid therapy varied among different classes of patients.

Chlorphoxim induces neurotoxicity in zebrafish embryo through activation of oxidative stress.

It is known that chlorphoxim is a broad-spectrum and high-effective pesticide. With the wide use in agricultural practice, chlorphoxim residue is also frequently detected in water, but its potential toxicity to aquatic life is still unclear. In this study, zebrafish is used as a model to detect the toxicity of chlorphoxim. Our results showed that exposure of high concentration of chlorphoxim at 96 h post-fertilization (hpf) resulted in a high mortality and pericardium edema rate, a low hatchability rate and heart rate. The nervous system damage, swimming behavior alteration and acetylcholinesterase (AChE) inhibition were measured in zebrafish embryos after a 6 days post-fertilization (dpf) of chlorphoxim exposure. The expression of neural-related genes is abnormal in zebrafish embryos. Chlorphoxim exposure significantly increases oxidative stress in zebrafish embryos by inhibiting antioxidant enzyme (SOD and CAT) and activating reactive oxygen species (ROS). As expected, chlorphoxim exposure induces apoptosis by enhancing the expression of apoptotic genes (Bax, Bcl2, and p53). Astaxanthin (ATX), an effective antioxidant, was found to be able to rescue the neurotoxicity of chlorphoxim through relieving oxidative stress and apoptosis. Altogether, the results showed that chlorphoxim exposure led to severe neurotoxicity to zebrafish embryos, which was contributed to a more comprehensive understanding of the safety use of the organophosphorus pesticide.

First report of Colletotrichum fioriniae Causing Anthracnose Disease of Rhus chinensis in China.

Rhus chinensis, a tree of major economic importance in China, belongs to the Anacardiaceae. It is the summer host of the aphid Melaphis chinensis which produces a leaf gall utilized for medicinal purposes (Li et al. 2022). In August 2021 and June 2022, dark brown spots were observed on young branches of R. chinensis in Wufeng, Hubei province, China. The plantations of R. chinensis in Wufeng County had different degrees of disease. We focused our survey on three plantations, each with an area of 1.5 hectares and 1600 R. chinensis plants per hectare, and the incidence of the disease was found to be around 70%. Symptoms began as small brown spots that expanded with time and eventually led to large, irregular, dark brown and sunken lesions. Under high temperature and humidity, orange conidiomata appeared on top of the lesions. As the disease progressed, branches rotted, broke, and leaves died and dropped, eventually causing the death of trees. The fungus was isolated from infected branches. Branch pieces were cut and surface disinfested in 75% (v/v) alcohol for 30 sec, then sterilized in 4% sodium hypochlorite for 1 min, and washed three times with sterile distilled water before incubated on potato dextrose agar (PDA) at 25℃.Ten isolates were obtained by a single-spore culturing method, considering HTK-3 isolate showed more pathogenic and grew faster than other isolates, it was selected for further research. After culturing for 7 days on PDA medium, the colony of isolate HTK-3 was cottony with white-to-gray aerial mycelium. The mycelial growth rate was 8.7 mm/day at 25℃. Conidia were single-celled, colorless, smooth-walled, fusiform with acute ends, and measured 7.7 to 14.3 × 3.2 to 5.3µm (mean 11.8 ± 1.3 to 4.2 ± 0.5µm, n = 50). Appressoria were single, medium brown, ovate to ellipsoid, 5.8 to 8.5× 3.7 to 6.1µm (mean 7.2 ± 0.7 × 4.9 ± 0.4 µm, n=50). Microscopic examinations showed conidia of the HTK-3 were hyaline, aseptate, and sub-cylindrical, with obtuse apices and tapering bases. Mycelium of which was hyaline, branched and septate. Based on these morphological features, the fungus was tentatively identified as belonging to Colletotrichum acutatum species complex (Damm et al. 2012). For molecular identification, the ITS region, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), chitin synthase (CHS-1), beta-tubulin 2 (TUB2), and actin (ACT) were amplified and sequenced (Liu et al., 2022). The obtained sequences were deposited into the GenBank [accession numbers: OP630818 (ITS); OP649736 (GAPDH); OP649735 (TUB2); OP649738 (CHS-1); OP649737 (ACT)]. For all of these genes, isolates HTK-3 had a 99-100% similarity to multiple C. fioriniae accessions. A maximum likelihood tree was generated from a multiple sequence alignment of reported isolates (Liu et al. 2022) and HTK-3 was identified as C. fioriniae. To fulfill Koch's postulates, ten healthy branches were inoculated with 5-mm-diameter mycelial plugs of each of ten fungal isolates (Wang et al., 2022). PDAs plug without mycelium was used as control. Six days post-inoculation, all branches developed anthracnose symptoms similar to those observed in the field, while the control remained healthy. The pathogenicity tests were repeated twice with the same results. C. fioriniae was re-isolated from the disease branches and the morphology was consistent with original, fulfilling Koch's postulates. The species of C. fioriniae has been reported to cause severe anthracnose of many species of plants (Eaton et al. 2021). To our knowledge, this is the first report of C. fioriniae as a pathogen of R. chinensis in China. The results will help to target the screening of control agents and provide guidance for disease prevention and control.

Effect of downregulated citrate synthase on oxidative phosphorylation signaling pathway in HEI-OC1 cells.

BACKGROUND: Citrate Synthase (Cs) gene mutation (locus ahL4) has been found to play an important role in progressive hearing loss of A/J mice. HEI-OC1 cells have been widely used as an in vitro system to study cellular and molecular mechanisms related to hearing lose. We previously reported the increased apoptosis and the accumulation of reactive oxygen species in shRNACs-1429 cells, a Cs low-expressed cell model from HEI-OCI. The details of the mechanism of ROS production and apoptosis mediated by the abnormal expression of Cs needed to research furtherly. METHODS: iTRAQ proteomics was utilized to detect the differentially expressed proteins (DEPs) caused by low expression of Cs. The GO and KEGG pathways analysis were performed for annotation of the differentially expressed proteins. Protein-protein interaction network was constructed by STRING online database. Immunoblotting was utilized to confirm the protein levels of the the differentially expressed proteins. RESULTS: The differentially expressed proteins were significantly enriched in various signaling pathways mainly related to mitochondrial dysfunction diseases including Parkinson's disease, Alzheimer's disease, Huntington's disease, et al. Most noteworthy, the oxidative phosphorylation pathway was most significantly suppressed in the shRNACs-1429 cells,, in which a total of 10 differentially expressed proteins were enriched and were all downregulated by the abnormal expression of Cs. The downregulations of Ndufb5, Ndufv1 and Uqcrb were confirmed by immunoblotting. Meanwhile, the ATP levels of shRNACs-1429 cells were also reduced. CONCLUSIONS: These results suggest that low level expression of Cs induces the inhibition of oxidative phosphorylation pathway, which is responsible for the high level production of reactive oxygen species and low level of ATP, leading to the apoptosis of cochlear cells. This study may provide new theories for understanding and therapy of progressive hearing loss.

Glucose and H2O2 Dual-Responsive Nanocomplex Grafted with Insulin Prodrug for Blood Glucose Regulation.

Although "closed-loop" smart insulin delivery systems have been extensively investigated, the majority of them suffer from low insulin loading efficiency and slow glucose response. Here, we constructed a novel nanocomplex (NC), which was prepared by electrostatic interaction between negatively charged insulin prodrug nanoparticles (NPs) and positively charged polycaprolactone-polyethylenimine (PCL-PEI) micelles. The insulin prodrug was linked to acetalated dextran (AD) via borate ester bonds to form IAD NPs, and glucose oxidase (GOx) was encapsulated in PCL-PEI micelles. The NC was negatively charged with a high insulin grafting rate (0.473 mg/mg), and in vitro experiments revealed that IAD was sensitive to hyperglycemia and H2O2, whereas GOx significantly improved the response to glucose by altering the microenvironment to promote sustained insulin release. Furthermore, compared with free insulin and IAD NPs, subcutaneously injected NCs in diabetic rats had long-term hypoglycemic effects, showing excellent biocompatibility in vitro and in vivo, which had good potential in insulin self-regulation delivery.

Differences in clinical presentation and management between pre- and postsurgical diagnoses of urinary bladder paraganglioma: is there clinical relevance? A systematic review.

PURPOSE: Paraganglioma of the urinary bladder (UBPGL) is a rare neuroendocrine tumor diagnosed in many patients only after surgery. We, therefore, assessed clinical clues relevant to presurgical diagnosis and clinical consequences in patients with a missed presurgical diagnosis of UBPGL. MATERIALS AND METHODS: Case reports describing a UBPGL (published from 1-1-2001 and 31-12-2020) were identified in Pubmed. Two authors independently performed data extraction and assessed data quality according to the PRISMA guideline. Patients were divided into two groups: UBPGL diagnosis before and after surgery. RESULTS: We included 177 articles reporting 194 cases. In 90 (46.4%) patients, the UBPGL was diagnosed before and in 104 (53.6%) after surgery. In presurgically diagnosed UBPGL, hypertension and catecholamine-associated symptoms were 2- to 3-fold (p < 0.001) more frequent than in postsurgically diagnosed patients whereas hematuria was twofold (p = 0.003) more prevalent in those with postsurgical diagnosis. Hypertension was an independent factor for presurgical biochemical testing (OR 4.45, 95% CI 1.66-11.94) while hematuria (OR 0.23, 95% CI 0.09-0.60) was an independent factor for not performing presurgical biochemical testing. Most patients diagnosed after surgery were not pretreated with alpha-adrenoceptor blockade (95.2%), underwent more frequently transurethral resection instead of cystectomy (70.2% vs. 23.1%) and had more frequent peroperative complications and residual tumor mass. CONCLUSIONS: In nearly half of all patients with a UBPGL, the diagnosis was not established before surgery. Hypertension and hematuria contributed independently to a presurgical diagnosis. Postsurgical diagnosis, which was associated with suboptimal presurgical and surgical management, resulted in more peroperative complications and incomplete tumor resections.

An Improved Protocol for the Stereoselective Synthesis of ß-d-Glycosyl Fluorides from 2-O-Acyl Thioglycosides.

A safe and operationally simple protocol for the preparation of ß-d-glycosyl fluorides is presented. We demonstrate that a precise combination of XtalFluor-M, N-bromosuccinimide, and Et3N·3HF can mediate facile, high-yielding, and diastereoselective conversions of 2-O-acyl thioglycosides to ß-d- and other 1,2-trans glycosyl fluorides. The key roles of these reagents are dissected in this work, as is the impact of their interplay on the fluorination stereoselectivity.