bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti-inflammatory Treatment of Kawasaki Disease: Comparison of Current Guidelines and Perspectives
Authors: Buda Piotr , Friedman-Gruszczyńska Joanna , Książyk Janusz
Published: December 2021

Kawasaki disease (KD), an acute, generalized vasculitis, is associated with an increased risk of coronary heart disease and is the most common cause of acquired heart disease in childhood. The incidence of KD is increasing worldwide. There are numerous international treatment guidelines. Our study aims to perform the first one so far comparison of them. While the gold standard therapy remains still the same (intravenous immunoglobulins and aspirin), there is currently a lack of evidence for choosing optimal treatment for high-risk patients and refractory KD. In this review, we also discuss the treatment of complications of KD and Kawasaki-like phenotypes, present an anti-inflammatory treatment in the light of new scientific data, and present novel potential therapeutic targets for KD.
Reversible Bronchiectasis in COVID-19 Survivors With Acute Respiratory Distress Syndrome: Pseudobronchiectasis
Authors: Hu Qiongjie , Liu Yiwen , Chen Chong , Sun Ziyan , Wang Yujin , Xiang Min , Guan Hanxiong , Xia Liming
Published: December 2021

To retrospectively analyze whether traction bronchiectasis was reversible in coronavirus disease 2019 (COVID-19) survivors with acute respiratory distress syndrome (ARDS), and whether computed tomography (CT) findings were associated with the reversibility, 41 COVID-19 survivors with ARDS were followed-up for more than 4 months. Demographics, clinical data, and all chest CT images were collected. The follow-up CT images were compared with the previous CT scans. There were 28 (68%) patients with traction bronchiectasis (Group I) and 13 (32%) patients without traction bronchiectasis (Group II) on CT images. Traction bronchiectasis disappeared completely in 21 of the 28 (75%) patients (Group IA), but did not completely disappear in seven of the 28 (25%) patients (Group IB). In the second week after onset, the evaluation score on CT images in Group I was significantly higher than that in Group II (p = 0.001). The proportion of reticulation on the last CT images in Group IB was found higher than that in Group IA (p < 0.05). COVID-19 survivors with ARDS might develop traction bronchiectasis, which can be absorbed completely in most patients. Traction bronchiectasis in a few patients did not disappear completely, but bronchiectasis was significantly relieved. The long-term follow-up is necessary to further assess whether traction bronchiectasis represents irreversible fibrosis.
Elevated Serum Tenascin-C Predicts Mortality in Critically Ill Patients With Multiple Organ Dysfunction
Authors: Xu Yunyu , Li Nanyang , Gao Jiamin , Shang Da , Zhang Min , Mao Xiaoyi , Chen Ruiying , Zheng Jianming , Shan Ying , Chen Mingquan , Xie Qionghong , Hao Chuan-Ming
Published: December 2021

Background: Multiple organ dysfunction is a complex and lethal clinical feature with heterogeneous causes and is usually characterized by tissue injury of multiple organs. Tenascin-C (TNC) is a matricellular protein that is rarely expressed in most of the adult tissues, but re-induced following injury. This study aimed to evaluate serum TNC in predicting mortality in critically ill patients with multiple organ dysfunction.

Methods: Adult critically ill patients with at least two organs dysfunction and an increase of Sequential Organ Failure Assess (SOFA) score ≥ 2 points within 7 days were prospectively enrolled into two independent cohorts. The emergency (derivation) cohort was a consecutive series and the patients were from Emergency Department. The inpatient (validation) cohort was a convenience series and the patients were from medical wards. Their serum samples at the first 24 h after enrollment were collected and subjected to TNC measurement using ELISA. The association between serum TNC level and 28-day all-cause mortality was investigated, and then the predictive value of serum TNC was analyzed.

Results: A total of 110 patients with a median age of 64 years (53, 73) were enrolled in the emergency cohort. Compared to the survivors, serum TNC in the non-survivors was significantly higher (467.7 vs. 197.5 ng/ml, p < 0.001). Multivariate logistic regression analysis revealed that the association between serum TNC and 28-day mortality was independent of sepsis or critical illness scores such as SOFA, Acute Physiology and Chronic Health Evaluation (APACHE II), and Simplified Acute Physiology Score (SAPS II), respectively (p < 0.001 for each). The area under receiver operating characteristic curve of serum TNC for predicting mortality was 0.803 (0.717–0.888) (p < 0.001), similar with SOFA 0.808 (0.725–0.891), APACHE II 0.762 (0.667–0.857), and SAPS II 0.779 (0.685–0.872). The optimal cut-off value of serum TNC was 298.2 ng/ml. Kaplan–Meier analysis showed that the survival of patients with serum TNC ≥ 300 ng/ml was significantly worse than that of patients with serum TNC < 300 ng/ml. This result was validated in the inpatient cohort. The sensitivity and specificity of serum TNC ≥ 300 ng/ml for predicting mortality were 74.3 and 74.7% in the emergency cohort, and 63.0 and 70.1% in the inpatient cohort, respectively.

Conclusion: Serum TNC was associated with mortality in critically ill patients with multiple organ dysfunction, and would be used as a prognostic tool for predicting mortality in this population.
Metabolomic Profiling of Amino Acids in Human Plasma Distinguishes Diabetic Kidney Disease From Type 2 Diabetes Mellitus
Authors: Zhou Chunyu , Zhang Qing , Lu Liqian , Wang Jiao , Liu Dongwei , Liu Zhangsuo
Published: December 2021

Background: Diabetic kidney disease (DKD) is a highly prevalent complication in patients with type 2 diabetes mellitus (T2DM). Patients with DKD exhibit changes in plasma levels of amino acids (AAs) due to insulin resistance, reduced protein intake, and impaired renal transport of AAs. The role of AAs in distinguishing DKD from T2DM and healthy controls has yet to be elucidated. This study aimed to investigate the metabolomic profiling of AAs in the plasma of patients with DKD.

Methods: We established an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method to detect the plasma levels of the 20 AAs in healthy controls (n = 112), patients with T2DM (n = 101), and patients with DKD (n = 101). The key AAs associated with DKD were identified by orthogonal partial least-squares discriminant analysis (OPLS-DA) models with loading plots, shared and unique structures (SUS) plots, and variable importance in projection (VIP) values. The discrimination accuracies of these key AAs were then determined by analyses of receiver-operating characteristic (ROC) curves.

Results: Metabolomic profiling of plasma revealed significant alterations in levels of the 20 AAs in patients with DKD when compared to those in either patients with T2DM or healthy controls. Metabolomic profiling of the 20 AAs showed a visual separation of patients with DKD from patients with T2DM and healthy controls in OPLS-DA models. Based on loading plots, SUS plots, and VIP values in the OPLS-DA models, we identified valine and cysteine as potential contributors to the progression of DKD from patients with T2DM. Histidine was identified as a key mediator that could distinguish patients with DKD from healthy controls. Plasma levels of histidine and valine were decreased significantly in patients with DKD with a decline in kidney function, and had excellent performance in distinguishing patients with DKD from patients with T2DM and healthy controls according to ROC curves.

Conclusion: Plasma levels of histidine and valine were identified as the main AAs that can distinguish patients with DKD. Our findings provide new options for the prevention, treatment, and management of DKD.
Does Preoperative Halo-Gravity Traction Reduce the Degree of Deformity and Improve Pulmonary Function in Severe Scoliosis Patients With Pulmonary Insufficiency? A Systematic Review and Meta-Analysis
Authors: Yang Zhao , Liu Yang , Qi Longtao , Wu Shanshan , Li Jingwen , Wang Yu , Jiang Bin
Published: December 2021

Background: Halo-gravity traction is a commonly used clinical intervention to reduce surgical risk in patients with scoliosis before surgical correction. Some previous studies have focused on the application of halo-gravity traction on patients with severe spinal deformity and pulmonary insufficiency, but the overall effect of halo-gravity traction has not been fully understood. The object of the present study was to perform a meta-analysis exploring the efficacy of preoperative halo-gravity traction on radiographic measurement and pulmonary function in severe scoliosis patients with pulmonary insufficiency.

Methods: We searched the medical works of literature completed before January 17, 2021, in the databases of Pubmed, Embase, and Cochrane Library. Studies that quantitatively analyzed the effects of halo-gravity traction on the deformity and pulmonary functions of patients with severe scoliosis were included. Two researchers independently conducted the literature search, data extraction, and quality assessment. We used the Review Manager Software (version 5.4) for statistical analysis and data analysis. Mean difference (MD) with 95% confidence intervals (CIs) were calculated to evaluate the effects of halo-gravity traction.

Results: Seven studies involving 189 patients received halo-gravity traction therapy preoperatively were analyzed in our study. Preoperative halo-gravity traction significantly ameliorated the degree of deformity in severe scoliosis patients with pulmonary insufficiency, especially reduced coronal Cobb angle and sagittal Cobb angle effectively [mean deviation (MD) = 2 7.28 (95%CI 21.16–33.4), p < 0.001; MD = 22.02 (95%CI 16.8–27.23), p < 0.001]. Preoperative halo-gravity traction also improved the pulmonary functions in patients, especially increasing %FVC and %FEV1 [MD = −0.0662 (95%CI −0.0672–−0.0652), p < 0.001; MD = −0.0824 (95%CI −0.0832–−0.081), p < 0.001].

Conclusions: Preoperative halo-gravity traction for severe scoliosis patients shows significant improvement in the degree of deformity and pulmonary functions. Halo-gravity traction is an effective method to improve the tolerance of patients to surgery in the perioperative period.
Dialysis Adequacy and Risk of Dementia in Elderly Hemodialysis Patients
Authors: Kim Hyung Woo , Jhee Jong Hyun , Joo Young Su , Yang Ki Hwa , Jung Jin Ju , Shin Ji Hyeon , Han Seung Hyeok , Yoo Tae-Hyun , Kang Shin-Wook , Park Jung Tak
Published: December 2021

Objective: Dementia is prevalent among elderly patients undergoing hemodialysis. However, the association between dialysis adequacy and the risk of dementia is uncertain.

Methods: A total of 10,567 patients aged >65 years undergoing maintenance hemodialysis who participated in a national hemodialysis quality assessment program were analyzed. The patients were classified into quartile groups based on single-pool Kt/V levels. The associations between single-pool Kt/V and the development of dementia, Alzheimer's disease (AD), and vascular dementia (VD) were examined.

Results: The mean age of the patients was 72.9 years, and 43.4% were female. The mean baseline single-pool Kt/V level was 1.6 ± 0.3. During a median follow-up of 45.6 (45.6–69.9) months, there were 27.6, 23.9, and 2.8 events/1,000 person-years of overall dementia, AD, and VD, respectively. The incidences of overall dementia, AD, and VD were lowest in the highest single-pool Kt/V quartile group. Compared with the lowest single-pool Kt/V quartile, the risks of incident overall dementia and AD were significantly lower in the highest quartile [sub-distribution hazard ratio (sHR): 0.69, 95% confidence interval (CI): 0.58–0.82 for overall dementia; sHR: 0.69, 95% CI: 0.57–0.84 for AD]. Inverse relationships were found between the risks of developing overall dementia and AD, and single-pool Kt/V. However, no significant relationship was observed between single-pool Kt/V levels and VD development.

Conclusions: Increased dialysis clearance was associated with a lower risk of developing dementia in elderly hemodialysis patients.
Effects of Baduanjin Exercise on Physical Function and Health-Related Quality of Life in Peritoneal Dialysis Patients: A Randomized Trial
Authors: Zhang Fan , Liao Jing , Zhang Weihong , Wang Hui , Huang Liuyan , Shen Qiyun , Zhang Huachun
Published: December 2021

Background and Aims: Exercise is an efficient non-pharmacological intervention for chronic kidney disease. The study aims to evaluate the effects of Baduanjin exercise on physical function and health-related quality of life (HRQOL) in peritoneal dialysis (PD) patients.

Methods: Seventy PD patients were randomly assigned to either the Baduanjin exercise group or the control group. Fifty-seven patients completed the study (exercise group, 25; control group, 32). The exercise group received the Baduanjin exercise program for 12 weeks. The control group received usual care. Three well-established performance-based tests determined physical function: five times sit-to-stand test (FTSST), timed up and go test (TUGT), and handgrip strength (HGS). HRQOL was assessed by the Kidney Disease Quality of Life-Short Form.

Results: At baseline, no differences in physical function and HRQOL were observed between the Baduanjin exercise and the control group. At follow-up, the Baduanjin exercise group showed a marginally significant improvement in FTSST (P = 0.008) and TUGT (P = 0.040) over the 12 weeks compared to the control group. HRQOL in the Baduanjin exercise group was significantly higher than that of the control group.

Conclusions: A 12-week Baduanjin exercise program may improve physical function and HRQOL in PD patients. Longer follow-up is needed to determine if these findings will translate into clinical application.
Multigene Phylogeny, Diversity and Antimicrobial Potential of Endophytic Sordariomycetes From Rosa roxburghii
Authors: Zhang Hong , Wei Tian-Peng , Li Lin-Zhu , Luo Ming-Yan , Jia Wei-Yu , Zeng Yan , Jiang Yu-Lan , Tao Guang-Can
Published: December 2021

Rosa roxburghii Tratt. is widely applied in food, cosmetics, and traditional medicine, and has been demonstrated to possess diverse bioactivities. Plant endophytic fungi are important microbial resources with great potential for application in many fields. They not only establish mutualistic symbiosis with host plants but also produce a variety of bioactive compounds. Therefore, in the present study, endophytic fungi were isolated from R. roxburghii, the diversity and antimicrobial activities were evaluated. As a result, 242 strains of endophytic Sordariomycetes were successfully isolated. Multigene phylogenetic analyses showed that these isolates included eight orders, 19 families, 33 genera. The dominant genera were Diaporthe (31.4%), Fusarium (14.4%), Chaetomium (7.9%), Dactylonectria (7.0%), Graphium (4.5%), Colletotrichum (4.1%), and Clonostachys (4.1%). For different tissues of R. roxburghii, alpha diversity analysis revealed that the diversity of fungal communities decreased in the order of root, fruit, stem, flower, leaf, and seed, and Clonostachys and Dactylonectria exhibited obvious tissue specificity. Meanwhile, functional annotation of 33 genera indicated that some fungi have multitrophic lifestyles combining endophytic, pathogenic, and saprophytic behavior. Additionally, antimicrobial activities of endophytic Sordariomycetes against Lasiodiplodia theobromae, Botryosphaeria dothidea, Colletotrichum capsici, Pyricularia oryzae, Rhizoctonia solani, Fusarium oxysporum, Pseudomonas syringae, Pantoea agglomerans, Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa were screened. Dual culture test assays showed that there were 40 different endophytic species with strong inhibition of at least one or moderate inhibition of two or more against the 12 tested strains. The results from the filter paper diffusion method suggested that extracellular metabolites may be more advantageous than intracellular metabolites in the development of antimicrobial agents. Eleven isolates with good activities were screened. In particular, Hypomontagnella monticulosa HGUP194009 and Nigrospora sphaerica HGUP191020 have shown promise in both broad-spectrum and intensity. Finally, some fungi that commonly cause disease have been observed to have beneficial biological activities as endophytic fungi. In conclusion, this study showed the species composition, alpha diversity, and lifestyle diversity of endophytic Sordariomycetes from R. roxburghii and demonstrated these isolates are potential sources for exploring antimicrobial agents.
Abundance of Lipopolysaccharide Heptosyltransferase I in Human Gut Microbiome and Its Association With Cardiovascular Disease and Liver Cirrhosis
Authors: Lin Shujin , Zhang Hui , Wang Xueke , Lin Ting , Chen Zihan , Liu Jingfeng , Wang Jianmin
Published: December 2021

Lipopolysaccharide (LPS) is a potent endotoxin on the outer membrane of gram-negative bacteria. Heptosyltransferase I (HpeI) takes part in the synthesis of LPS. In this study, we first collected the protein sequences of HpeI homologs from the human microbiome. The collected HpeI sequences was classified based on sequence similarity, and seven clusters of HpeI were obtained. Among these clusters, proteins from Cluster 3 were abundant in the human mouth, while Clusters 1, 6, and 7 were abundant in the human gut. In addition, proteins from Cluster 1 were mainly from the order of Enterobacterales, while Cluster 6 and 7 were from Burkholderiales. The correlation analysis indicated that the total abundance of HpeIs was increased in patients with cardiovascular disease and liver cirrhosis, and HpeI in Cluster 1 contributed to this increase. These data suggest that HpeI homologs in Cluster 1 can be recognized as biomarkers for cardiovascular disease and liver cirrhosis, and that reducing the bacterial load in Cluster 1 may contribute to disease therapy.
Cell-Extrinsic Priming Increases Permissiveness of CD4+ T Cells to Human Immunodeficiency Virus Infection by Increasing C–C Chemokine Receptor Type 5 Co-receptor Expression and Cellular Activation Status
Authors: Pedersen Jesper G. , Egedal Johanne H. , Packard Thomas A. , Thavachelvam Karthiga , Xie Guorui , van der Sluis Renée Marije , Greene Warner C. , Roan Nadia R. , Jakobsen Martin R.
Published: December 2021

The chemokine receptor CCR5 is expressed on multiple cell types, including macrophages, dendritic cells, and T cells, and is the major co-receptor used during HIV transmission. Using a standard αCD3/CD28in vitrostimulation protocol to render CD4+ T cells from PBMCs permissive to HIV infection, we discovered that the percentage of CCR5+T cells was significantly elevated in CD4+ T cells when stimulated in the presence of peripheral blood mononuclear cells (PBMCs) as compared to when stimulated as purified CD4+ T cells. This indicated that environmental factors unique to the T-PBMCs condition affect surface expression of CCR5 on CD4+ T cells. Conditioned media from αCD3/CD28-stimulated PBMCs induced CCR5 expression in cultures of unstimulated cells. Cytokine profile analysis of these media suggests IL-12 as an inducer of CCR5 expression. Mass cytometric analysis showed that stimulated T-PBMCs exhibited a uniquely activated phenotype compared to T-Pure. In line with increased CCR5 expression and activation status in stimulated T-PBMCs, CD4+ T cells from these cultures were more susceptible to infection by CCR5-tropic HIV-1 as compared with T-Pure cells. These results suggest that in order to increaseex vivoinfection rates of blood-derived CD4+ T cells, standard stimulation protocols used in HIV infection studies should implement T-PBMCs or purified CD4+ T cells should be supplemented with IL-12.
LRMP Associates With Immune Infiltrates and Acts as a Prognostic Biomarker in Lung Adenocarcinoma
Authors: Jin Xin , Chen Liwei , Zhou Ning , Ni Hong , Zu Lingling , He Jinling , Yang Lingqi , Zhu Yifan , Sun Xiaoyue , Li Xiaojiang , Xu Song
Published: December 2021

Background:Lymphoid-restricted membrane protein (LRMP) is an endoplasmic reticulum-associated protein that is expressed in a developmentally regulated manner in both B and T cell lineages. However, the role of LRMP in the growth, prognosis and immune infiltration in lung adenocarcinoma (LUAD) remains unclear.

Method:The expression levels ofLRMPmRNA in tumor and normal tissues were analyzed using Tumor Immune Estimation Resource 2.0 (TIMER 2.0) and Gene Expression Profiling Interactive Analysis 2 (GEPIA 2). LRMP protein expression was examined using the Human Protein Atlas.In vitroexperiments, including qRT-PCR Western blot and immunohistochemistry staining were also performed to investigate LRMP expression. GEPIA2 and Kaplan-Meier plotter databases were used to analyze the clinical prognostic significance of LRMP. To further confirm the underlying function of LRMP, the data were analyzed using gene set enrichment analysis. Moreover, we also constructed plasmids to overexpress LRMP and explored the effect of LRMP in A549 cell line. Additionally, Tumor Immune single-cell Hub was used to investigate the distribution of LRMP in the LUAD immune microenvironment; TIMER and CIBERSORT were used to investigate the relationships amongLRMP,LRMPco-expressed genes, and tumor-infiltrating immune cells; Finally, the correlations between LRMP and immune checkpoints were analyzed using TIMER 2.0.

Results:The expression ofLRMPwas significantly lower in LUAD tissues and cell lines. HighLRMPexpression is associated with a better prognosis in patients with LUAD.In vitroexperimental studies demonstrated that overexpression of LRMP could decrease the proliferation, migration and invasion in A549 cells, and downregulated multiple oncogenic signaling pathways, including p-STAT3, p-PI3K-p-AKT, p-MEK and EMT pathways. GSEA results showed that immuno-related and cell adhesion pathways were enriched in samples with high LRMP expression. LRMP and its co-expressed genes were positively correlated with various tumor-infiltrating immune cells and their markers. Additionally, LRMP positively correlated with immune checkpoints.

Conclusions:Our data suggest that LRMP may act as a tumor suppressor gene and indicates a better prognosis. Moreover, LRMP is associated with immune infiltrates which may be involved in immunotherapy response in LUAD. Further studies are needed to validate these findings.
A Nomogram Model for Predicting the Response to Transcatheter Arterial Embolization in Patients With Symptomatic Hepatic Hemangioma
Authors: Liu Qinqin , You Nan , Zhu Jiangqin , Li Jing , Wu Ke , Wang Zheng , Wang Liang , Zhu Yinan , Gu Huiying , Peng Xuehui , Zheng Lu
Published: December 2021

Background:Transcatheter arterial embolization (TAE) is regarded as an effective treatment for patients with symptomatic hepatic hemangioma. However, few studies have evaluated the efficacy of TAE alone for treating hepatic hemangioma. The aim of this study was to identify the factors that influence the response to TAE and formulate a quantitative nomogram to optimize the individualized management of hepatic hemangioma.

Methods:We retrospectively studied 276 patients treated with TAE for hepatic hemangioma at our center from January 2011 to December 2019. The full cohort was randomly divided into training and validation cohorts. After assessing the potential predictive factors for the efficacy of TAE in the training cohort, a nomogram model was established and evaluated by discrimination and calibration.

Results:During follow-up, the symptom relief rate was 100%. The tumor blood supply (p< 0.001), tumor number (p= 0.004), and tumor size (p= 0.006) were identified as significant predictors of the failure of tumor shrinkage in response to TAE. The nomogram model showed favorable discrimination and calibration, with a C-index of 0.775 (95% CI, 0.705–0.845) in the training cohort, which was further confirmed in the validation cohort (C-index 0.768; 95% CI, 0.680–0.856). The side effects of TAE were relatively minor and included mainly abdominal pain, nausea, vomiting, fever, and the presence of elevated hepatic transaminases.

Conclusion:TAE is a safe and effective treatment for symptomatic hepatic hemangioma. The established nomogram performed well for the estimation of the effect of TAE in patients with hepatic hemangioma and can facilitate the selection of patients who would benefit most from the treatment.
1H -NMR Metabolomics Study of the Effect of Cisplatin and Casiopeina IIgly on MDA-MB-231 Breast Tumor Cells
Authors: Resendiz-Acevedo Karen , García-Aguilera Martha E. , Esturau-Escofet Nuria , Ruiz-Azuara Lena
Published: December 2021

The knowledge of the metabolic processes of designed metallodrugs for cancer treatment is an area that has been not profoundly studied. Casiopeina IIgly (CasIIgly), which belongs to the Casiopeínas® family, is a copper (II) coordination compound that has shown good biological activity against several cancer cells, low toxicity in normal cells, and antineoplastic activity in in vivo murine and xenografted models. In this work we employed a triple-negative highly metastatic breast carcinoma line (MDA-MB-231), which is one of the cancer types with a great mortality index, for 1H-NMR metabolomic analysis using cisplatin and CasIIgly, in order to quantify the effect of metallodrugs in the metabolic profile of this cell tumor line as a consequence of treatment at different times. Our findings indicate that cisplatin mainly contributes to phospholipid biosynthesis while CasIIgly affects processes such as carbohydrates and nucleotides metabolism. Also, we observed that CasIIgly treatment has an important and fast effect over MDA-MB-231 cell metabolism, which makes it a good alternative for treatment in this type of cancer.
Potential Biomarkers to Predict Acute Ischemic Stroke in Type 2 Diabetes
Authors: Moin Abu Saleh Md , Nandakumar Manjula , Al-Qaissi Ahmed , Sathyapalan Thozhukat , Atkin Stephen L. , Butler Alexandra E.
Published: December 2021

Background and Purpose: Patients with type 2 diabetes (T2D) have increased risk of cardiovascular disease (CVD), encompassing myocardial infarction, stroke, and peripheral vascular disease. We hypothesized that those biomarkers indicative of acute ischemic stroke (AIS) seen in large vessel occlusion (LVO) may also be elevated in T2D and further enhanced by stress conditions; therefore, these proteins represent potentially predictive biomarkers for those T2D patients at high risk of AIS.

Methods: We performed an exploratory proteomic analysis in control subjects (n = 23) versus those with type 2 diabetes (T2D) (n = 23) who underwent a hyperinsulinemic clamp study to transient severe hypoglycemia [blood glucose <2.0 mmol/L (36 mg/dl)] in a prospective case-control study. We compared these proteins described as diagnostic and prognostic biomarkers for AIS due to LVO: lymphatic vessel endothelial hyaluronic acid receptor-1 (LYVE1), thrombospondin-1 (THBS1), pro-platelet basic protein (PPBP), and cadherin 1 (CDH1).

Results: At baseline (BL), PPBP (p < 0.05), THBS1 (p < 0.05), and CDH1 (p < 0.01) were elevated in T2D; LYVE1 was not different between controls and T2D subjects at BL or at subsequent timepoints. PPBP and THBS1 tended to increase at hypoglycemia in both cohorts, though reached significance only in controls (p < 0.05), returning to BL levels post-hypoglycemia. CDH1 levels were higher in T2D at BL, at hypoglycemia and up to 2-h posthypoglycemia, thereafter reverting to BL levels.

Conclusion: Elevated levels of PPBP, THBS1, and CDH1, circulatory proteins suggested as biomarkers of AIS due to LVO, may, in T2D patients, be prognostically indicative of a cohort of T2D patients at increased risk of ischaemic stroke. Prospective studies are needed to determine if this reflects future clinical risk.

Clinical trial reg. no: NCT03102801.
Development and Validation of Ten-RNA Binding Protein Signature Predicts Overall Survival in Osteosarcoma
Authors: Zhang Jian , Miao Xinxin , Wu Tianlong , Jia Jingyu , Cheng Xigao
Published: December 2021

Osteosarcoma is a malignant tumor that originates in the bones with the characteristics of high malignancy, predisposition to metastasis, and poor prognosis. RNA binding proteins (RBPs) are closely related to various tumors, but their relationship with osteosarcoma remains unclear. Based on GTEx and TARGET RNA sequencing data, we applied differential analysis to obtain RBP genes that are differentially expressed in osteosarcoma, and analyzed the functions of these RBPs. After applying univariate and LASSO Cox regression analysis, 10 key prognostic RBPs (TDRD6, TLR8, NXT2, EIF4E3, RPS27L, CPEB3, RBM34, TERT, RPS29, and ZC3HAV1) were screened, and an RBP prognostic risk assessment model for patients with osteosarcoma was established. The independent cohort GSE21257 was used for external verification, and the results showed that the signature has an excellent ability to predict prognosis. In addition, a nomogram that can be used for clinical evaluation was constructed. Finally, the expression levels of 10 prognostic RBPs in osteosarcoma cells and tissues were confirmed through experiments. Our study identified a ten-gene prognostic marker related to RBP, which is of great significance for adjusting the treatment strategy of patients with osteosarcoma and exploring prognostic markers.
Water Accessibility Refinement of the Extended Structure of KirBac1.1 in the Closed State
Authors: Amani Reza , Schwieters Charles D. , Borcik Collin G. , Eason Isaac R. , Han Ruixian , Harding Benjamin D. , Wylie Benjamin J.
Published: December 2021

NMR structures of membrane proteins are often hampered by poor chemical shift dispersion and internal dynamics which limit resolved distance restraints. However, the ordering and topology of these systems can be defined with site-specific water or lipid proximity. Membrane protein water accessibility surface area is often investigated as a topological function via solid-state NMR. Here we leverage water-edited solid-state NMR measurements in simulated annealing calculations to refine a membrane protein structure. This is demonstrated on the inward rectifier K+ channel KirBac1.1 found in Burkholderia pseudomallei. KirBac1.1 is homologous to human Kir channels, sharing a nearly identical fold. Like many existing Kir channel crystal structures, the 1p7b crystal structure is incomplete, missing 85 out of 333 residues, including the N-terminus and C-terminus. We measure solid-state NMR water proximity information and use this for refinement of KirBac1.1 using the Xplor-NIH structure determination program. Along with predicted dihedral angles and sparse intra- and inter-subunit distances, we refined the residues 1–300 to atomic resolution. All structural quality metrics indicate these restraints are a powerful way forward to solve high quality structures of membrane proteins using NMR.
Replenishing the Aged Brains: Targeting Oligodendrocytes and Myelination?
Authors: Zhang Xi , Huang Nanxin , Xiao Lan , Wang Fei , Li Tao
Published: December 2021

Aging affects almost all the aspects of brain functions, but the mechanisms remain largely undefined. Increasing number of literatures have manifested the important role of glial cells in regulating the aging process. Oligodendroglial lineage cell is a major type of glia in central nervous system (CNS), composed of mature oligodendrocytes (OLs), and oligodendroglia precursor cells (OPCs). OLs produce myelin sheaths that insulate axons and provide metabolic support to meet the energy demand. OPCs maintain the population throughout lifetime with the abilities to proliferate and differentiate into OLs. Increasing evidence has shown that oligodendroglial cells display active dynamics in adult and aging CNS, which is extensively involved in age-related brain function decline in the elderly. In this review, we summarized present knowledge about dynamic changes of oligodendroglial lineage cells during normal aging and discussed their potential roles in age-related functional decline. Especially, focused on declined myelinogenesis during aging and underlying mechanisms. Clarifying those oligodendroglial changes and their effects on neurofunctional decline may provide new insights in understanding aging associated brain function declines.
Multiple Functions of Draxin/Netrin-1 Signaling in the Development of Neural Circuits in the Spinal Cord and the Brain
Authors: Ahmed Giasuddin , Shinmyo Yohei
Published: December 2021

Axon guidance proteins play key roles in the formation of neural circuits during development. We previously identified an axon guidance cue, named draxin, that has no homology with other axon guidance proteins. Draxin is essential for the development of various neural circuits including the spinal cord commissure, corpus callosum, and thalamocortical projections. Draxin has been shown to not only control axon guidance through netrin-1 receptors, deleted in colorectal cancer (Dcc), and neogenin (Neo1) but also modulate netrin-1-mediated axon guidance and fasciculation. In this review, we summarize the multifaceted functions of draxin and netrin-1 signaling in neural circuit formation in the central nervous system. Furthermore, because recent studies suggest that the distributions and functions of axon guidance cues are highly regulated by glycoproteins such as Dystroglycan and Heparan sulfate proteoglycans, we discuss a possible function of glycoproteins in draxin/netrin-1-mediated axon guidance.
Effects of Chronic Social Defeat Stress on Behavior and Dopamine Receptors in Adolescent Mice With 6-Hydroxydopamine Lesions of the Medial Prefrontal Cortex
Authors: Zhao Tong , Gao XiaoLei , Huang Guang-Biao
Published: December 2021

Background: Social stress factors in schizophrenia have long-term effects, but will only induce symptoms in a portion of individuals, even if exposed to identical stress.

Methods: In the current experiment, we examined mice with 6-hydroxydopamine (6-OHDA)-induced medial prefrontal cortical (mPFC) injury to select for members of a “stress-susceptible group,” and observed the changes in their behavior and the expression of D1 and D2 dopamine receptors in the amygdala and hippocampus.

Results: We observed that after chronic social defeat stress, 72.6% of the 6-OHDA lesioned mice exhibited stress response to aggressors, compared to 52.3% of the blank control group. Both the 6-OHDA lesion + social defeat and social defeat groups exhibited anxiety and depression-like behavior. However, social cognitive impairment in the mice from the 6-OHDA lesion + social defeat group was more significant and the D1 expression levels in the amygdala were significantly decreased.

Conclusion: These results suggest that the reason that adolescent mice with cortical injury were highly sensitive to defeat stress and had more prominent social cognitive impairment may be the decreased selectivity of D1 in the amygdala.
Training-Dependent Change in Content of Association in Appetitive Pavlovian Conditioning
Authors: Kim Hea-jin , Koh Hae-Young
Published: December 2021

In appetitive Pavlovian conditioning, experience with a conditional relationship between a cue [conditioned stimulus (CS)] and a reward [unconditioned stimulus (US)] bestows CS with the ability to promote adaptive behavior patterns. Different features of US (e.g., identity-specific sensory, general motivational) can be encoded by CS based on the nature of the CS-US relationship experienced (e.g., temporal factors such as training amount) and the content of association may determine the influence of CS over behavior (e.g., mediated learning, conditioned reinforcement). The content of association changed with varying conditioning factors, thereby altering behavioral consequences, however, has never been addressed in relevant brain signals evoked by CS. Our previous study found that phospholipase C β1-knockout (PLCβ1-KO) mice display persistent mediated learning over the extended course of odor-sugar conditioning, and that wild-type (WT) mice lose mediated learning sensitivity after extended training. In this study, in order to see whether this behavioral difference between these two genotypes comes from a difference in the course of association content, we examined whether odor CS can evoke the taste sensory representation of an absent sugar US after minimal- and extended training in these mice. In contrast to WT, which lost CS-evoked neural activation (c-Fos expression) in the gustatory cortex after extended training, KO mice displayed persistent association with the sensory feature of sugar, suggesting that sensory encoding is reliably linked to mediated learning sensitivity and there is a training-dependent change in the content of association in WT. PLCβ1 knockdown in the left medial prefrontal cortex (mPFC) resulted in mediated learning sensitivity and CS-evoked gustatory cortical activation after extended training, proposing a molecular component of the neural system underlying this Pavlovian conditioning process. We also discuss how disruption of this process is implicated for hallucination-like behaviors (impaired reality testing).
Induction of Relaxation by Autonomous Sensory Meridian Response
Authors: Sakurai Noriko , Ohno Ken , Kasai Satoshi , Nagasaka Kazuaki , Onishi Hideaki , Kodama Naoki
Published: December 2021

Background: Autonomous sensory meridian response (ASMR) is used by young people to induce relaxation and sleep and to reduce stress and anxiety; it comprises somatosensation caused by audiovisual stimuli (triggers) that lead to positive emotions. Auditory stimuli play the most important role among the triggers involved in ASMR and have been reported to be more triggering than visual stimuli. On the other hand, classical music is also known to have a relaxing effect. This is the first study to clarify the difference in brain activation associated with relaxation effects between ASMR and classical music by limiting ASMR to auditory stimulation alone.

Methods: Thirty healthy subjects, all over 20 years of age, underwent fMRI while listening to ASMR and classical music. We compared the differences in brain activation associated with classical music and ASMR stimulation. After the experiment, the subjects were administered a questionnaire on somatosensation and moods. After the experiment, the participants were asked whether they experienced ASMR somatosensation or frisson. They were also asked to rate the intensity of two moods during stimulation: “comfortable mood,” and “tingling mood”.

Result: The results of the questionnaire showed that none of the participants experienced any ASMR somatosensation or frisson. Further, there was no significant difference in the ratings given to comfort mood, but there was a significant difference in those given to tingling mood. In terms of brain function, classical music and ASMR showed significant activation in common areas, while ASMR showed activation in more areas, with the medial prefrontal cortex being the main area of activation during ASMR.

Conclusion: Both classical music and the ASMR auditory stimulus produced a pleasant and relaxed state, and ASMR involved more complex brain functions than classical music, especially the activation of the medial prefrontal cortex. Although ASMR was limited to auditory stimulation, the effects were similar to those of listening to classical music, suggesting that ASMR stimulation can produce a pleasant state of relaxation even if it is limited to the auditory component, without the somatic sensation of tingling. ASMR stimulation is easy to use, and appropriate for wellness purposes and a wide range of people.
Delay Discounting in Established and Proposed Behavioral Addictions: A Systematic Review and Meta-Analysis
Authors: Weinsztok Sarah , Brassard Sarah , Balodis Iris , Martin Laura E. , Amlung Michael
Published: December 2021

Steep delay discounting, or a greater preference for smaller-immediate rewards over larger-delayed rewards, is a common phenomenon across a range of substance use and psychiatric disorders. Non-substance behavioral addictions (e.g., gambling disorder, internet gaming disorder, food addiction) are of increasing interest in delay discounting research. Individual studies have reported steeper discounting in people exhibiting various behavioral addictions compared to controls or significant correlations between discounting and behavioral addiction scales; however, not all studies have found significant effects. To synthesize the published research in this area and identify priorities for future research, we conducted a pre-registered systematic review and meta-analysis (following PRISMA guidelines) of delay discounting studies across a range of behavioral addiction categories. The final sample included 78 studies, yielding 87 effect sizes for the meta-analysis. For studies with categorical designs, we found statistically significant, medium-to-large effect sizes for gambling disorder (Cohen’s d = 0.82) and IGD (d = 0.89), although the IGD effect size was disproportionately influenced by a single study (adjusted d = 0.53 after removal). Categorical internet/smartphone studies were non-significant (d = 0.16, p = 0.06). Aggregate correlations in dimensional studies were statistically significant, but generally small magnitude for gambling (r = 0.22), internet/smartphone (r = 0.13) and food addiction (r = 0.12). Heterogeneity statistics suggested substantial variability across studies, and publication bias indices indicated moderate impact of unpublished or small sample studies. These findings generally suggest that some behavioral addictions are associated with steeper discounting, with the most robust evidence for gambling disorder. Importantly, this review also highlighted several categories with notably smaller effect sizes or categories with too few studies to be included (e.g., compulsive buying, exercise addiction). Further research on delay discounting in behavioral addictions is warranted, particularly for categories with relatively few studies.
Deep Cross-Corpus Speech Emotion Recognition: Recent Advances and Perspectives
Authors: Zhang Shiqing , Liu Ruixin , Tao Xin , Zhao Xiaoming
Published: December 2021

Automatic speech emotion recognition (SER) is a challenging component of human-computer interaction (HCI). Existing literatures mainly focus on evaluating the SER performance by means of training and testing on a single corpus with a single language setting. However, in many practical applications, there are great differences between the training corpus and testing corpus. Due to the diversity of different speech emotional corpus or languages, most previous SER methods do not perform well when applied in real-world cross-corpus or cross-language scenarios. Inspired by the powerful feature learning ability of recently-emerged deep learning techniques, various advanced deep learning models have increasingly been adopted for cross-corpus SER. This paper aims to provide an up-to-date and comprehensive survey of cross-corpus SER, especially for various deep learning techniques associated with supervised, unsupervised and semi-supervised learning in this area. In addition, this paper also highlights different challenges and opportunities on cross-corpus SER tasks, and points out its future trends.
Block Phenomena During Electric Micro-Stimulation of Pyramidal Cells and Retinal Ganglion Cells
Authors: Sajedi Sogand , Fellner Andreas , Werginz Paul , Rattay Frank
Published: December 2021

Electric micro-stimulation of the nervous system is a means to restore various body functions. The stimulus amplitude necessary to generate action potentials, the lower threshold (LT), is well characterized for many neuronal populations. However, electric overstimulation above an upper threshold (UT) prevents action potential generation and therefore hinders optimal neuro-rehabilitation. Previous studies demonstrated the impact of the UT in micro-stimulation of retinal ganglion cells (RGCs). The observed phenomenon is mostly explained by (i) reversed sodium ion flow in the soma membrane, and (ii) anodal surround block that hinders spike conduction in strongly hyperpolarized regions of the axon at high stimulus intensities. However, up to now, no detailed study of the nature of these phenomena has been presented, particularly for different cell types. Here, we present computational analyses of LT and UT for layer 5 pyramidal cells (PCs) as well as alpha RGCs. Model neurons were stimulated in close vicinity to the cell body and LTs and UTs as well as the ratio UT/LT were compared. Aside from a simple point source electrode and monophasic stimuli also realistic electrode and pulse configurations were examined. The analysis showed: (i) in RGCs, the soma contributed to action potential initiation and block for small electrode distances, whereas in PCs the soma played no role in LTs or UTs. (ii) In both cell types, action potential always initiated within the axon initial segment at LT. (iii) In contrast to a complete block of spike conductance at UT that occurred in RGCs, an incomplete block of spiking appeared in PC axon collaterals. (iv) PC axon collateral arrangement influenced UTs but had small impact on LTs. (v) Population responses of RGCs change from circular regions of activation to ring-shaped patterns for increasing stimulus amplitude. A better understanding of the stimulation window that can reliably activate target neurons will benefit the future development of neuroprostheses.
Nuclear Factor Erythroid-2-Related Factor 2 Signaling in the Neuropathophysiology of Inherited Metabolic Disorders
Authors: Seminotti Bianca , Grings Mateus , Tucci Paolo , Leipnitz Guilhian , Saso Luciano
Published: December 2021

Inherited metabolic disorders (IMDs) are rare genetic conditions that affect multiple organs, predominantly the central nervous system. Since treatment for a large number of IMDs is limited, there is an urgent need to find novel therapeutical targets. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor that has a key role in controlling the intracellular redox environment by regulating the expression of antioxidant enzymes and several important genes related to redox homeostasis. Considering that oxidative stress along with antioxidant system alterations is a mechanism involved in the neuropathophysiology of many IMDs, this review focuses on the current knowledge about Nrf2 signaling dysregulation observed in this group of disorders characterized by neurological dysfunction. We review here Nrf2 signaling alterations observed in X-linked adrenoleukodystrophy, glutaric acidemia type I, hyperhomocysteinemia, and Friedreich’s ataxia. Additionally, beneficial effects of different Nrf2 activators are shown, identifying a promising target for treatment of patients with these disorders. We expect that this article stimulates research into the investigation of Nrf2 pathway involvement in IMDs and the use of potential pharmacological modulators of this transcription factor to counteract oxidative stress and exert neuroprotection.