bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive Analysis of N6-Methyladenosine Regulators in the Subcluster Classification and Drug Candidates Prediction of Severe Obstructive Sleep Apnea
Authors: Li Niannian , Gao Zhenfei , Shen Jinhong , Liu Yuenan , Wu Kejia , Yang Jundong , Wang Shengming , Zhang Xiaoman , Zhu Yaxin , Zhu Jingyu , Guan Jian , Liu Feng , Yin Shankai
Published: April 2022

Background: Obstructive sleep apnea (OSA) is the most common type of sleep apnea that impacts the development or progression of many other disorders. Abnormal expression of N6-methyladenosine (m6A) RNA modification regulators have been found relating to a variety of human diseases. However, it is not yet known if m6A regulators are involved in the occurrence and development of OSA. Herein, we aim to explore the impact of m6A modification in severe OSA.

Methods: We detected the differentially expressed m6A regulators in severe OSA microarray dataset GSE135917. The least absolute shrinkage and selection operator (LASSO) and support vector machines (SVM) were used to identify the severe OSA-related m6A regulators. Receiver operating characteristic (ROC) curves were performed to screen and verify the diagnostic markers. Consensus clustering algorithm was used to identify m6A patterns. And then, we explored the character of immune microenvironment, molecular functionals, protein-protein interaction networks and miRNA-TF coregulatory networks for each subcluster. Finally, the Connectivity Map (CMap) tools were used to tailor customized treatment strategies for different severe OSA subclusters. An independent dataset GSE38792 was used for validation.

Results: We found that HNRNPA2B1, KIAA1429, ALKBH5, YTHDF2, FMR1, IGF2BP1 and IGF2BP3 were dysregulated in severe OSA patients. Among them, IGF2BP3 has a high diagnostic value in both independent datasets. Furthermore, severe OSA patients can be accurately classified into three m6A patterns (subcluster1, subcluster2, subcluster3). The immune response in subcluster3 was more active because it has high M0 Macrophages and M2 Macrophages infiltration and up-regulated human leukocyte antigens (HLAs) expression. Functional analysis showed that representative genes for each subcluster in severe OSA were assigned to histone methyltransferase, ATP synthesis coupled electron transport, virus replication, RNA catabolic, multiple neurodegeneration diseases pathway, et al. Moreover, our finding demonstrated cyclooxygenase inhibitors, several of adrenergic receptor antagonists and histamine receptor antagonists might have a therapeutic effect on severe OSA.

Conclusion: Our study presents an overview of the expression pattern and crucial role of m6A regulators in severe OSA, which may provide critical insights for future research and help guide appropriate prevention and treatment options.
Development and Validation of a Novel Gene Signature for Predicting the Prognosis of Idiopathic Pulmonary Fibrosis Based on Three Epithelial-Mesenchymal Transition and Immune-Related Genes
Authors: Zheng Jiafeng , Dong Hanquan , Zhang Tongqiang , Ning Jing , Xu Yongsheng , Cai Chunquan
Published: April 2022

Background:Increasing evidence has revealed that epithelial–mesenchymal transition (EMT) and immunity play key roles in idiopathic pulmonary fibrosis (IPF). However, correlation between EMT and immune response and the prognostic significance of EMT in IPF remains unclear.

Methods:Two microarray expression profiling datasets (GSE70866 and GSE28221) were downloaded from the Gene Expression Omnibus (GEO) database. EMT- and immune-related genes were identified by gene set variation analysis (GSVA) and the Estimation of STromal and Immune cells in MAlignant Tumors using Expression data (ESTIMATE) algorithm. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to investigate the functions of these EMT- and immune-related genes. Cox and least absolute shrinkage and selection operator (LASSO) regression analyses were used to screen prognostic genes and establish a gene signature. Gene Set Enrichment Analysis (GSEA) and Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) were used to investigate the function of the EMT- and immune-related signatures and correlation between the EMT- and immune-related signatures and immune cell infiltration. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to investigate the mRNA expression of genes in the EMT- and immune-related signatures.

Results:Functional enrichment analysis suggested that these genes were mainly involved in immune response. Moreover, the EMT- and immune-related signatures were constructed based on three EMT- and immune-related genes (IL1R2, S100A12, and CCL8), and the K–M and ROC curves presented that the signature could affect the prognosis of IPF patients and could predict the 1-, 2-, and 3-year survival well. Furthermore, a nomogram was developed based on the expression of IL1R2, S100A12, and CCL8, and the calibration curve showed that the nomogram could visually and accurately predict the 1-, 2-, 3-year survival of IPF patients. Finally, we further found that immune-related pathways were activated in the high-risk group of patients, and the EMT- and immune-related signatures were associated with NK cells activated, macrophages M0, dendritic cells resting, mast cells resting, and mast cells activated. qRT-PCR suggested that the mRNA expression of IL1R2, S100A12, and CCL8 was upregulated in whole blood of IPF patients compared with normal samples.

Conclusion:IL1R2, S100A12, and CCL8 might play key roles in IPF by regulating immune response and could be used as prognostic biomarkers of IPF.
The Interaction Between Autophagy and JAK/STAT3 Signaling Pathway in Tumors
Authors: Xu Jiangyan , Zhang Jinrong , Mao Qi-Fen , Wu Jian , Wang Yuan
Published: April 2022

Tumor is one of the important factors affecting human life and health in today’s world, and scientists have studied it extensively and deeply, among which autophagy and JAK/STAT3 signaling pathway are two important research directions. The JAK/STAT3 axis is a classical intracellular signaling pathway that assumes a key role in the regulation of cell proliferation, apoptosis, and vascular neogenesis, and its abnormal cell signaling and regulation are closely related to the occurrence and development of tumors. Therefore, the JAK/STAT3 pathway in tumor cells and various stromal cells in their microenvironment is often considered as an effective target for tumor therapy. Autophagy is a process that degrades cytoplasmic proteins and organelles through the lysosomal pathway. It is a fundamental metabolic mechanism for intracellular degradation. The mechanism of action of autophagy is complex and may play different roles at various stages of tumor development. Altered STAT3 expression has been found to be accompanied by the abnormal autophagy activity in many oncological studies, and the two may play a synergistic or antagonistic role in promoting or inhibiting the occurrence and development of tumors. This article reviews the recent advances in autophagy and its interaction with JAK/STAT3 signaling pathway in the pathogenesis, prevention, diagnosis, and treatment of tumors.
Roles of the m6A Modification of RNA in the Glioblastoma Microenvironment as Revealed by Single-Cell Analyses
Authors: Yuan Feng , Cai Xiangming , Cong Zixiang , Wang Yingshuai , Geng Yuanming , Aili Yiliyaer , Du Chaonan , Zhu Junhao , Yang Jin , Tang Chao , Zhang Aifeng , Zhao Sheng , Ma Chiyuan
Published: April 2022

Purpose

Glioblastoma multiforme (GBM) is a common and aggressive form of brain tumor. The N6-methyladenosine (m6A) mRNA modification plays multiple roles in many biological processes and disease states. However, the relationship between m6A modifications and the tumor microenvironment in GBM remains unclear, especially at the single-cell level.

Experimental Design

Single-cell and bulk RNA-sequencing data were acquired from the GEO and TCGA databases, respectively. We used bioinformatics and statistical tools to analyze associations between m6A regulators and multiple factors.

Results

HNRNPA2B1 and HNRNPC were extensively expressed in the GBM microenvironment. m6A regulators promoted the stemness state in GBM cancer cells. Immune-related BP terms were enriched in modules of m6A-related genes. Cell communication analysis identified genes in the GALECTIN signaling network in GBM samples, and expression of these genes (LGALS9, CD44, CD45, and HAVCR2) correlated with that of m6A regulators. Validation experiments revealed that MDK in MK signaling network promoted migration and immunosuppressive polarization of macrophage. Expression of m6A regulators correlated with ICPs in GBM cancer cells, M2 macrophages and T/NK cells. Bulk RNA-seq analysis identified two expression patterns (low m6A/high ICP and high m6A/low ICP) with different predicted immune infiltration and responses to ICP inhibitors. A predictive nomogram model to distinguish these 2 clusters was constructed and validated with excellent performance.

Conclusion

At the single-cell level, m6A modification facilitates the stemness state in GBM cancer cells and promotes an immunosuppressive microenvironment through ICPs and the GALECTIN signaling pathway network. And we also identified two m6A-ICP expression patterns. These findings could lead to novel treatment strategies for GBM patients.
Persistence of Unintegrated HIV DNA Associates With Ongoing NK Cell Activation and CD34+DNAM-1brightCXCR4+ Precursor Turnover in Vertically Infected Patients Despite Successful Antiretroviral Treatment
Authors: Taramasso Lucia , Bozzano Federica , Casabianca Anna , Orlandi Chiara , Bovis Francesca , Mora Sara , Giacomini Mauro , Moretta Lorenzo , Magnani Mauro , Di Biagio Antonio , De Maria Andrea
Published: April 2022

The quantification of proviral DNA is raising interest in view of clinical management and functional HIV eradication. Measures of all unintegrated HIV DNA (uDNA) forms in infected reservoir cells provides information on recent replication events that is not found from other proviral DNA assays. To evaluate its actual relevance in a cohort of perinatally-infected adult HIV patients (PHIV), we studied how peripheral blood mononuclear cell uDNA levels correlated with total HIV DNA (tDNA) and with overall replication or innate immune control parameters including NK cell activation/exhaustion and lymphoid turnover. Twenty-two PHIV were included, with successfully controlled HIV (HIV RNA <50 copies/mL) on combined antiretroviral therapy for mean of 8.7 ± 3.9 years. uDNA accounted for 16 [5.2-83.5] copies/µg and was strongly correlated with tDNA (ρ=0.700, p=0.001). Flow cytometric analysis of peripheral NK cells showed that CD69 expression was directly correlated uDNA (p=0.0412), but not with tDNA. Interestingly, CD56-CD16+NK cells which include newly described inflammatory precursors and terminally differentiated cells were directly correlated with uDNA levels (p<0.001), but not with tDNA, and an inverse association was observed between the proportion of NKG2D+ NK cells and uDNA (ρ=-0.548, p=0.015). In addition, CD34+DNAM-1brightCXCR4+ inflammatory precursor frequency correlated directly with uDNA levels (ρ=0.579, p=0.0075). The frequencies of CD56-CD16+ and CD34+DNAM-1brightCXCR4+ cells maintained association with uDNA levels in a multivariable analysis (p=0.045 and p=0.168, respectively). Thus, control of HIV-1 reservoir in aviremic patients on ART is an active process associated with continuous NK cell intervention and turnover, even after many years of treatment. Quantification of linear and circular uDNA provides relevant information on the requirement for ongoing innate immune control in addition to ART, on recent replication history and may help stratify patients for functional HIV eradication protocols with targeted options.
Epimicrobiome Shifts With Bleaching Disease Progression in the Brown Seaweed Saccharina japonica
Authors: Ling Fan , Egan Suhelen , Zhuang Yingrui , Chang Lirong , Xiao Luyang , Yang Qin , Wang Gaoge
Published: April 2022

Recent bacterial induced bleaching disease events of the commercially farmed brown seaweed Saccharina japonica has resulted in significant reduction in healthy sporeling supply. However, to date the host associated epimicrobial community shifts with the disease progression have not been characterized. We investigated the dynamic shifts in the composition of the epibacterial communities of S. japonica with disease progression using 16S rRNA gene amplicon sequencing. We found that the alpha diversity was significantly higher in the control group than in the infected group over disease progression (P < 0.01). There was a significant shift in the composition and predicted functions of the epibacterial communities in both control and infected groups. Indicator species, belonging to Stenotrophomonas, Pseudomonas and Sphingomona were significantly higher in the control group than infected group, suggesting that these taxa are associated with healthy S. japonica. In contrast, Vibrio, Pseudoalteromonas and Colwellia were keystone taxa in the infected group at 24 h, and thus maybe considered to be the secondary opportunistic pathogens. Our study describes the changes of epibacterial communities associated with the progression of bleaching disease in S. japonica. This new information not only extends our baseline knowledge of the S. japonica epimicrobiome, but also paves the way for developing measures to mitigate disease outbreaks for the sustainable aquaculture of S. japonica.
Evaluation of Non-Uniform Thermal Aging of XLPE Cable Based on Modified Debye Model
Authors: Zhang Yiyi , Gu Guangfeng , Liu Jiefeng , Jiang Fengyu , Fan Yufan , Zha Junwei
Published: April 2022

The polarization/depolarization curve (PDC), which contains abundant insulation information, is widely used to evaluate the insulation condition of the cross-linked polyethylene (XLPE) cables. However, the insulation condition assessing the result of the XLPE cables is usually inaccurate using the PDC technology because the parameters of the current Debye model are determined in a uniform aging hypothesis, instead of a real non-uniform situation. To solve this problem, the modified Debye model considering the real non-uniform situation is proposed, and the effectiveness of the modified model is proved by the comparison of the PDC test results with non-uniform and uniform aging materials. It is found that the parameters of the extended Debye model tend to overestimate the cable insulation performance, while the characteristic parameters obtained by the modified Debye model better reflect the real situation of cable non-uniform aging. Result analysis shows that the proposed method has better accuracy in the insulation condition evaluation of cables.
Infrared Heating for Rapid and Localized Shape Transformations of Additively Manufactured Polymer Parts
Authors: Oh Seo-Hyeon , Goo Bona , Park Keun
Published: April 2022

Four-dimensional (4D) printing is an advanced application of additive manufacturing which enables additional shape transformations over time in response to external stimuli. For appropriate shape transformation, dedicated materials such as shape memory polymers or 3D printers supporting multi-material printing have been used. Recently, a facile 4D printing method was developed which used a fused filament fabrication type 3D printer and a plain thermoplastic filament. This method used the anisotropic thermal deformation of the FFF-printed part to intentionally impose anisotropy by programming orthogonal printing paths, which resulted in thermoresponsive shape transformation upon a thermal stimulation. While the previous studies used convective heating as the thermal stimulus and thus required a long heating time of more than 10 min, this study uses an infrared (IR) heating to enable rapid thermoresponsive shape transformation. An infrared heating system was developed which included an optical focusing unit, a masking unit and a movable heating stage. To investigate the speed of shape transformation, IR heating was performed on a rectangular strip (60 × 6 × 1.6 mm) and the relevant shape transformation time was compared with the previous convective heating result. The shape transformation proceeded rapidly, and after 70 s formed a fully-closed circular shape, corresponding to the 1/10 reduction compared with the convection type heating (more than 13 min). The IR heating was further applied to 2D-to-3D shape transformations of 2D star-shape and flower-shape specimens. For each specimen, a profiled mask was used to selectively irradiate IR on predefined regions and thus to localize the relevant thermoresponsive shape transformation. The global and local IR irradiations were then compared in terms of heating capability and the variability in shape transformations.
Comparative Analysis of Long Non-Coding RNA Expression and Immune Response in Mild and Severe COVID-19
Authors: Zhang Yongting , Shi Fan , Wang Yuchong , Meng Yuting , Zhang Qiong , Wang Kaihang , Zeng Ping , Diao Hongyan
Published: April 2022

Background: Coronavirus disease 2019 (COVID-19) is a worldwide emergency, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Long non-coding RNAs (lncRNAs) do not encode proteins but could participate in immune response.

Methods: In our study, 39 COVID-19 patients were enrolled. The microarray of peripheral blood mononuclear cells from healthy and COVID-19 patients was applied to identify the expression profiles of lncRNAs and mRNAs. Identified differentially expressed (DE) lncRNAs were validated by qRT-PCR. Then, the lncRNA–mRNA network was constructed and visualized using Cytoscape (3.6.1) based on the Pearson correlation coefficient. The enrichment of DE mRNAs was analyzed using Metascape. The difference in frequencies of immune cells and cytokines was detected using CIBERSORT and ImmPort based on DE mRNAs.

Results: All patients with COVID-19 displayed lymphopenia, especially in T cells, and hyper-inflammatory responses, including IL-6 and TNF-α. Four immune-related lncRNAs in COVID-19 were found and further validated, including AC136475.9, CATG00000032642.1, G004246, and XLOC_013290. Functional analysis enriched in downregulation of the T-cell receptor and the antigen processing and presentation as well as increased apoptotic proteins, which could lead to T-cell cytopenia. In addition, they participated in monocyte remodeling, which contributed to releasing cytokines and chemokines and then recruiting more monocytes and aggravating the clinical severity of COVID-19 patients.

Conclusion: Taken together, four lncRNAs were in part of immune response in COVID-19, which was involved in the T-cell cytopenia by downregulating the antigen processing and presentation, the T-cell receptor, and an increased proportion of monocytes, with a distinct change in cytokines and chemokines.
The Roles of Long-Term Hyperhomocysteinemia and Micronutrient Supplementation in the AppNL–G–F Model of Alzheimer’s Disease
Authors: Nieraad Hendrik , de Bruin Natasja , Arne Olga , Hofmann Martine C. J. , Pannwitz Nina , Resch Eduard , Luckhardt Sonja , Schneider Ann-Kathrin , Trautmann Sandra , Schreiber Yannick , Gurke Robert , Parnham Michael J. , Till Uwe , Geisslinger Gerd
Published: April 2022

A causal contribution of hyperhomocysteinemia to cognitive decline and Alzheimer’s disease (AD), as well as potential prevention or mitigation of the pathology by dietary intervention, have frequently been subjects of controversy. In the present in vivo study, we attempted to further elucidate the impact of elevated homocysteine (HCys) and homocysteic acid (HCA) levels, induced by dietary B-vitamin deficiency, and micronutrient supplementation on AD-like pathology, which was simulated using the amyloid-based AppNL–G–F knock-in mouse model. For this purpose, cognitive assessment was complemented by analyses of ex vivo parameters in whole blood, serum, CSF, and brain tissues from the mice. Furthermore, neurotoxicity of HCys and HCA was assessed in a separate in vitro assay. In confirmation of our previous study, older AppNL–G–F mice also exhibited subtle phenotypic impairment and extensive cerebral amyloidosis, whereas dietary manipulations did not result in significant effects. As revealed by proximity extension assay-based proteome analysis, the AppNL–G–F genotype led to an upregulation of AD-characteristic neuronal markers. Hyperhomocysteinemia, in contrast, indicated mainly vascular effects. Overall, since there was an absence of a distinct phenotype despite both a significant amyloid-β burden and serum HCys elevation, the results in this study did not corroborate the pathological role of amyloid-β according to the “amyloid hypothesis,” nor of hyperhomocysteinemia on cognitive performance. Nevertheless, this study aided in further characterizing the AppNL–G–F model and in elucidating the role of HCys in diverse biological processes. The idea of AD prevention with the investigated micronutrients, however, was not supported, at least in this mouse model of the disease.
Caveolin-1 Promoted Collateral Vessel Formation in Patients With Moyamoya Disease
Authors: Zhao Jinbing , Yu Zhiqiang , Zhang Yanping , Qiu Cheng , Zhang Guangxu , Chen Lijiu , He Shengxue , Ma Jun
Published: April 2022

Background

Caveolin-1 (Cav-1) plays pivotal roles in the endothelial function and angiogenesis postischemia. Moyamoya disease (MMD) is characterized by progressive artery stenosis with unknown etiology. We aim to determine whether serum Cav-1 levels of patients with MMD were associated with collateral vessel formation after bypass surgery.

Methods

We studied serum Cav-1 levels of 130 patients with MMD (16 with RNF213 p.R4810K mutation and 114 without RNF213 p.R4810K mutation), 15 patients with acute stroke, and 33 healthy controls. Cerebral perfusion and collateral circulation were evaluated preoperation and at 6 months after operation using pseudocontinuous arterial spin labeling MRI (pCASL-MRI) and digital subtraction angiography (DSA), respectively. Endothelial expression of Cav-1 was verified in the superficial temporal artery (STA) wall of patients with MMD by immunofluorescence double staining. We also investigated whether overexpression of Cav-1 affects cell migration and tube formation using human microvascular endothelial cells (HMECs).

Results

The serum Cav-1 level of patients with MMD intermediated between the stroke group and healthy controls and it was enhanced after the bypass surgery (681.87 ± 311.63 vs. 832.91 ± 464.41 pg/ml, p = 0.049). By 6 months after bypass surgery, patients with MMD with better collateral compensation manifested higher postoperative/preoperative Cav-1 ratio (rCav-1) than bad compensation patients. Consistently, cerebral blood flow (CBF) determined by pCASL-MRI (nCBFMCA ratio) was positively in line with rCav-1 ratio (r = 0.8615, p < 0.0001). Cav-1 was expressed in the endothelial cells of the STA vessels of patients with MMD. Overexpression of Cav-1 by plasmid transfection in HMECs promoted tube formation and cell migration.

Conclusion

This study indicated that Cav-1 may be a potential driver to promote angiogenesis and collateral formation after bypass surgery in patients with MMD, providing a better understanding of MMD pathophysiology and potential non-surgical targets of MMD.
Children With PANS May Manifest POTS
Authors: Chan Avis , Gao Jaynelle , Houston Madison , Willett Theresa , Farhadian Bahare , Silverman Melissa , Tran Paula , Jaradeh Safwan , Thienemann Margo , Frankovich Jennifer
Published: April 2022

Objectives

Pediatric acute-onset neuropsychiatric syndrome (PANS) is characterized by an abrupt-onset of severe psychiatric symptoms including OCD, anxiety, cognitive difficulties, and sleep issues which is thought to be a post-infection brain inflammatory disorder. We observed postural orthostatic tachycardia syndrome (POTS) which resolved with immunomodulation in a patient with Pediatric acute-onset neuropsychiatric syndrome (PANS). Here, we aim to present a case of POTS and to examine the prevalence of (POTS) in our PANS cohort, and compare the clinical characteristics of patients with and without POTS.

Study Design

We conducted this cohort study of patients meeting PANS criteria who had at least three clinic visits during the study period. We included data from prospectively collected questionnaires and medical record review. We present a case followed by statistical comparisons within our cohort and a Kaplan-Meier analysis to determine the time-dependent risk of a POTS diagnosis.

Results

Our study included 204 patients: mean age of PANS onset was 8.6 years, male sex (60%), non-Hispanic White (78%). Evidence of POTS was observed in 19/204 patients (9%) with 5/19 having persistent POTS defined as persistent abnormal orthostatic vitals, persistent POTS symptoms, and/or continued need for pharmacotherapy for POTS symptoms for at least 6 months). In this PANS cohort, patients with POTS were more likely to have comorbid joint hypermobility (63 vs 37%, p = 0.04), chronic fatigue (42 vs 18%, p = 0.03), and a family history of chronic fatigue, POTS, palpitations and syncope. An unadjusted logistic regression model showed that a PANS flare (abrupt neuropsychiatric deterioration) was significantly associated with an exacerbation of POTS symptoms (OR 3.3, 95% CI 1.4–7.6, p < 0.01).

Conclusions

Our study describes a high prevalence of POTS in patients with PANS (compared to the general population) and supports an association between POTS presentation and PANS flare within our cohort.
Sensitivity of Diffusion MRI to White Matter Pathology: Influence of Diffusion Protocol, Magnetic Field Strength, and Processing Pipeline in Systemic Lupus Erythematosus
Authors: Kornaropoulos Evgenios N. , Winzeck Stefan , Rumetshofer Theodor , Wikstrom Anna , Knutsson Linda , Correia Marta M. , Sundgren Pia C. , Nilsson Markus
Published: April 2022

There are many ways to acquire and process diffusion MRI (dMRI) data for group studies, but it is unknown which maximizes the sensitivity to white matter (WM) pathology. Inspired by this question, we analyzed data acquired for diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) at 3T (3T-DTI and 3T-DKI) and DTI at 7T in patients with systemic lupus erythematosus (SLE) and healthy controls (HC). Parameter estimates in 72 WM tracts were obtained using TractSeg. The impact on the sensitivity to WM pathology was evaluated for the diffusion protocol, the magnetic field strength, and the processing pipeline. Sensitivity was quantified in terms of Cohen's d for group comparison. Results showed that the choice of diffusion protocol had the largest impact on the effect size. The effect size in fractional anisotropy (FA) across all WM tracts was 0.26 higher when derived by DTI than by DKI and 0.20 higher in 3T compared with 7T. The difference due to the diffusion protocol was larger than the difference due to magnetic field strength for the majority of diffusion parameters. In contrast, the difference between including or excluding different processing steps was near negligible, except for the correction of distortions from eddy currents and motion which had a clearly positive impact. For example, effect sizes increased on average by 0.07 by including motion and eddy correction for FA derived from 3T-DTI. Effect sizes were slightly reduced by the incorporation of denoising and Gibbs-ringing removal (on average by 0.011 and 0.005, respectively). Smoothing prior to diffusion model fitting generally reduced effect sizes. In summary, 3T-DTI in combination with eddy current and motion correction yielded the highest sensitivity to WM pathology in patients with SLE. However, our results also indicated that the 3T-DKI and 7T-DTI protocols used here may be adjusted to increase effect sizes.
Diabetes: Chronic Metformin Treatment and Outcome Following Acute Stroke
Authors: Akhtar Naveed , Singh Rajvir , Kamran Saadat , Babu Blessy , Sivasankaran Shobana , Joseph Sujatha , Morgan Deborah , Shuaib Ashfaq
Published: April 2022

Aim

To evaluate if in patients with known diabetes, pretreatment metformin will lead to less severe stroke, better outcome, and lower mortality following acute stroke.

Methods

The Qatar stroke database was interrogated for stroke severity and outcome in patients with ischemic stroke. Outcome was compared in nondiabetic vs. diabetic patients and in diabetic patients on metformin vs. other hypoglycemic agents. The National Institute of Health Stroke Scale was used to measure stroke severity and 90-day modified Rankin scale (mRS) score to determine outcome following acute stroke.

Results

In total, 4,897 acute stroke patients [nondiabetic: 2,740 (56%) and diabetic: 2,157 (44%)] were evaluated. There were no significant differences in age, risk factors, stroke severity and type, or thrombolysis between the two groups. At 90 days, mRS (shift analysis) showed significantly poor outcome in diabetic patients (p < 0.001) but no differences in mortality. In the diabetic group, 1,132 patients were on metformin and 1,025 on other hypoglycemic agents. mRS shift analysis showed a significantly better outcome in metformin-treated patients (p < 0.001) and lower mortality (8.1 vs. 4.6% p < 0.001). Multivariate negative binomial analyses showed that the presence of diabetes negatively affected the outcome (90-day mRS) by factor 0.17 (incidence risk ratio, IRR, 1.17; CI [1.08–1.26]; p < 0.001) when all independent variables were held constant. In diabetic patients, pre-stroke treatment with metformin improved the outcome (90-day mRS) by factor 0.14 (IRR 0.86 [CI 0.75–0.97] p = 0.006).

Conclusion

Similar to previous reports, our study shows that diabetes adversely affects stroke outcome. The use of prior metformin is associated with better outcome in patients with ischemic stroke and results in lower mortality. The positive effects of metformin require further research to better understand its mechanism.
Sleep and Temporal Lobe Epilepsy – Associations, Mechanisms and Treatment Implications
Authors: Garg Divyani , Charlesworth Laurel , Shukla Garima
Published: April 2022

In this systematic review, we aim to describe the association between temporal lobe epilepsy (TLE) and sleep, with bidirectional links in mechanisms and therapeutic aspects. Sleep stages may variably impact seizure occurrence, secondary generalization and the development, frequency and distribution of interictal epileptiform discharges. Conversely, epilepsy affects sleep micro- and macroarchitecture. TLE, the most frequent form of drug resistant epilepsy (DRE), shares an enduring relationship with sleep, with some intriguing potential mechanisms specific to anatomic localization, linking the two. Sleep characteristics of TLE may also inform localizing properties in persons with DRE, since seizures arising from the temporal lobe seem to be more common during wakefulness, compared to seizures of extratemporal origin. Polysomnographic studies indicate that persons with TLE may experience excessive daytime somnolence, disrupted sleep architecture, increased wake after sleep onset, frequent shifts in sleep stages, lower sleep efficiency, decreased rapid eye movement (REM) sleep, and possibly, increased incidence of sleep apnea. Limited literature suggests that effective epilepsy surgery may remedy many of these objective and subjective sleep-related concerns, via multipronged effects, apart from reduced seizure frequency. Additionally, sleep abnormalities also seem to influence memory, language and cognitive-executive function in both medically controlled and refractory TLE. Another aspect of the relationship pertains to anti-seizure medications (ASMs), which may contribute significantly to sleep characteristics and abnormalities in persons with TLE. Literature focused on specific aspects of TLE and sleep is limited, and heterogeneous. Future investigations are essential to understand the pathogenetic mechanisms linking sleep abnormalities on epilepsy outcomes in the important sub-population of TLE.
Immune Activation in Functional Dyspepsia: Bystander Becoming the Suspect
Authors: Ceulemans Matthias , Jacobs Inge , Wauters Lucas , Vanuytsel Tim
Published: April 2022

Disorders of gut-brain interaction (DGBI), formerly termed functional gastrointestinal disorders (FGID), are highly prevalent although exact pathophysiological mechanisms remain unclear. Intestinal immune activation has been recognized, but increasing evidence supports a pivotal role for an active inflammatory state in these disorders. In functional dyspepsia (FD), marked eosinophil and mast cell infiltration has been repeatedly demonstrated and associations with symptoms emphasize the relevance of an eosinophil-mast cell axis in FD pathophysiology. In this Review, we highlight the importance of immune activation in DGBI with a focus on FD. We summarize eosinophil biology in both homeostasis and inflammatory processes. The evidence for immune activation in FD is outlined with attention to alterations on both cellular and molecular level, and how these may contribute to FD symptomatology. As DGBI are complex and multifactorial conditions, we shed light on factors associated to, and potentially influencing immune activation, including bidirectional gut-brain interaction, allergy and the microbiota. Crucial studies reveal a therapeutic benefit of treatments targeting immune activation, suggesting that specific anti-inflammatory therapies could offer renewed hope for at least a subset of DGBI patients. Lastly, we explore the future directions for DGBI research that could advance the field. Taken together, emerging evidence supports the recognition of FD as an immune-mediated organic-based disorder, challenging the paradigm of a strictly functional nature.
Trapezius Motor Evoked Potentials From Transcranial Electrical Stimulation and Transcranial Magnetic Stimulation: Reference Data, Characteristic Differences and Intradural Motor Velocities in Horses
Authors: Journée Sanne Lotte , Journée Henricus Louis , Berends Hanneke Irene , Reed Steven Michael , Bergmann Wilhelmina , de Bruijn Cornelis Marinus , Delesalle Cathérine John Ghislaine
Published: April 2022

Reason for Performing Study

So far, only transcranial motor evoked potentials (MEP) of the extensor carpi radialis and tibialis cranialis have been documented for diagnostic evaluation in horses. These allow for differentiating whether lesions are located in either the thoraco-lumbar region or in the cervical myelum and/or brain. Transcranial trapezius MEPs further enable to distinguish between spinal and supraspinal located lesions. No normative data are available. It is unclear whether transcranial electrical stimulation (TES) and transcranial magnetic stimulation (TMS) are interchangeable modalities.

Objectives

To provide normative data for trapezius MEP parameters in horses for TES and TMS and to discern direct and indirect conduction routes by neurophysiological models that use anatomical geometric characteristics to relate latency times with peripheral (PCV) and central conduction velocities (CCV).

Methods

Transcranial electrical stimulation-induced trapezius MEPs were obtained from twelve horses. TES and TMS-MEPs (subgroup 5 horses) were compared intra-individually. Trapezius MEPs were measured bilaterally twice at 5 intensity steps. Motoneurons were localized using nerve conduction models of the cervical and spinal accessory nerves (SAN). Predicted CCVs were verified by multifidus MEP data from two horses referred for neurophysiological assessment.

Results

Mean MEP latencies revealed for TES: 13.5 (11.1–16.0)ms and TMS: 19.7 (12–29.5)ms, comprising ∼100% direct routes and for TMS mixed direct/indirect routes of L:23/50; R:14/50. Left/right latency decreases over 10 > 50 V for TES were: –1.4/–1.8 ms and over 10 > 50% for TMS: –1.7/–3.5 ms. Direct route TMS-TES latency differences were 1.88–4.30 ms. 95% MEP amplitudes ranges for TES were: L:0.26–22 mV; R:0.5–15 mV and TMS: L:0.9 – 9.1 mV; R:1.1–7.9 mV.

Conclusion

This is the first study to report normative data characterizing TES and TMS induced- trapezius MEPs in horses. The complex trapezius innervation leaves TES as the only reliable stimulation modality. Differences in latency times along the SAN route permit for estimation of the location of active motoneurons, which is of importance for clinical diagnostic purpose. SAN route lengths and latency times are governed by anatomical locations of motoneurons across C2-C5 segments. TES intensity-dependent reductions of trapezius MEP latencies are similar to limb muscles while MEP amplitudes between sides and between TES and TMS are not different. CCVs may reach 180 m/s.
The Association Between Gait Speed and Sleep Problems Among Chinese Adults Aged 50 and Greater
Authors: Wang Lili , Zou Benxu
Published: April 2022

Objective

The relationship between sleep problems and walking speed has been less explored. The present cross-sectional study was to investigate the association between sleep quality and sleep duration and gait speed in Chinese adults.

Methods

A total of 13,367 participants were recruited in this cross-sectional study, retrieving the data from the Global Aging and Adult Health Survey (SAGE). Gait speed was measured using the 4-m walking test. Age, sex, education years, smoking status, alcohol consumption, physical activity, chronic disease, sleep problems were self-reported by participants. To explore the association between sleep problems and gait speed, multivariate linear regression models were employed.

Results

In the adjusted model, poor sleep quality and longer sleep duration were significantly associated with slower normal walking speed in Chinese adults (p < 0.001). Moreover, there were negatively significant associations between normal gait speed and sleep quality in male adults (p < 0.01).

Conclusion

The findings suggest that slower normal walking speed was associated with poor sleep quality and longer sleep duration (>8 h) in Chinese male adults.
Motor Unit Discharge Patterns in Response to Focal Tendon Vibration of the Lower Limb in Cats and Humans
Authors: Thompson Christopher K. , Johnson Michael D. , Negro Francesco , Farina Dario , Heckman C. J.
Published: April 2022

High-frequency vibration of the tendon provides potent activation of Ia afferents time-locked to the stimulation frequency and provides excitatory ionotropic activation of homonymous motor pools. In cats, the evoked motor unit discharge is constrained to discharge at integer multiples of the vibration frequency, resulting in a probability of discharge that is highly punctuated. Here we quantify the robustness of this punctuated response in the cat and evaluate whether it is present in the human. Soleus electromyography (EMG) was collected from eight cats using 64 channel electrodes during three modes of motoneuron activation. First, tendon vibration parameters were modified. Second, secondary reflex inputs are applied concurrently with tendon vibration. Third, the state of the spinal cord was altered through pharmacological or surgical manipulations. Analogous surface high-density EMG was collected from the lower leg of six humans during both vibration evoked and matched volitional contractions. Array EMG signals from both the cat and human were decomposed into corresponding motor unit action potential spike trains, and the punctuation in discharge was quantified. In the cat, regardless of vibration parameters, secondary synaptic drive, and state of spinal circuitry, focal tendon vibration evoked punctuated motor unit discharge. However, in the human lower limb, the vibration-evoked contractions do not produce punctuated motor unit discharge.
Acute Cerebral Ischemia Increases a Set of Brain-Specific miRNAs in Serum Small Extracellular Vesicles
Authors: Zhou Xin , Xu Chenxue , Chao Dachong , Chen Zixin , Li Shuyuan , Shi Miaomiao , Pei Yuqiang , Dai Yujuan , Ji Juling , Ji Yuhua , Ji Qiuhong
Published: April 2022

Small extracellular vesicles (sEVs) miRNAs are promising diagnosis and prognosis biomarkers for ischemic stroke (IS). This study aimed to determine the impact of IS on the serum sEVs miRNA profile of IS patients and a transient middle cerebral artery occlusion (tMCAO) mouse model. Small RNAseq was used to define the serum sEVs miRNA profile in IS patients and healthy controls (HC), and tMCAO mice and sham controls. Among the 1,444 and 1,373 miRNAs identified in human and mouse serum sEVs, the expression of 424 and 37 miRNAs was significantly altered in the IS patients and tMCAO mice, respectively (| Log2FC| ≥ 1, p < 0.01). Notably, five of the top 25 upregulated miRNAs in IS patients were brain-specific or enriched, including hsa-miR-9-3p, hsa-miR-124-3p, hsa-miR-143-3p, hsa-miR-98-5p, and hsa-miR-93-5p. Upregulation of these four miRNAs was further validated by qPCR. Nine of the 20 upregulated miRNAs in tMCAO mice were also brain-specific or enriched miRNAs. Temporal analysis indicated that the dynamics of mmu-miR-9-5p, mmu-miR-124-3p, mmu-miR-129-5p, and mmu-miR-433-3p were closely correlated with the evolution of ischemic brain injury, as their expression increased at 0.5 days after the onset of ischemia, peaked at day 1 or 3, and returned to normal levels at day 7 and 14. Notably, with the exceptions of mmu-miR-128-3p, the expression of the other eight miRNAs in the mouse serum sEVs was unaffected in the lipopolysaccharide (LPS)-induced neuroinflammation model. Together, in this study, we provided a comprehensive view of the influences of IS on the serum sEVs miRNA profile of IS patients and tMCAO mice and demonstrated the increment of a set of brain-specific miRNAs in serum sEVs after acute cerebral ischemia, which could be promising candidates directly reflecting the ischemic brain injury.
A Radiomics Nomogram for Distinguishing Benign From Malignant Round-Like Breast Tumors
Authors: Wang Lanyun , Ding Yi , Yang Wenjun , Wang Hao , Shen Jinjiang , Liu Weiyan , Xu Jingjing , Wei Ran , Hu Wenjuan , Ge Yaqiong , Zhang Bei , Song Bin
Published: April 2022

Objective

The objective of this study is to develop a radiomics nomogram for the presurgical distinction of benign and malignant round-like solid tumors.

Methods

This retrospective trial enrolled patients with round-like tumors who had received preoperative digital mammography (DM) no sooner than 20 days prior to surgery. Breast tumors were segmented manually on DM images in order to extract radiomic features. Four machine learning classification models were constructed, and their corresponding areas under the receiver operating characteristic (ROC) curves (AUCs) for differential tumor diagnosis were calculated. The optimal classifier was then selected for the validation set. After this, predictive machine learning models that employed radiomic features and/or patient features were applied for tumor assessment. The models’ AUC, accuracy, negative (NPV) and positive (PPV) predictive values, sensitivity, and specificity were then derived.

Results

In total 129 cases with benign and malignant tumors confirmed by pathological analysis were enrolled in the study, including 91 and 38 in the training and test sets, respectively. The DM images yielded 1,370 features per patient. For the machine learning models, the Least Absolute Shrinkage and Selection Operator for Gradient Boosting Classifier turned out to be the optimal classifier (AUC=0.87, 95% CI 0.76-0.99), and ROC curves for the radiomics nomogram and the DM-only model were statistically different (P<0.001). The radiomics nomogram achieved an AUC of 0.90 (95% CI 0.80-1.00) in the test cohort and was statistically higher than the DM-based model (AUC=0.67, 95% CI 0.51-0.84). The radiomics nomogram was highly efficient in detecting malignancy, with accuracy, sensitivity, specificity, PPV, and NPV in the validation set of 0.868, 0.950, 0.778, 0.826, and 0.933, respectively.

Conclusions

This radiomics nomogram that combines radiomics signatures and clinical characteristics represents a noninvasive, cost-efficient presurgical prediction technique.
A Phase I Trial to Determine the Safety and Tolerability of Autophagy Inhibition Using Chloroquine or Hydroxychloroquine in Combination With Carboplatin and Gemcitabine in Patients With Advanced Solid Tumors
Authors: Karim Nagla Abdel , Ullah Asad , Ahmad Imran , Bahassi Elmustapha , Olowokure Olugbenga , Khaled Ahmed , Davis Harold , Morris John C.
Published: April 2022

Background

Autophagy is a catabolic process that is triggered in cells during periods of metabolic or hypoxic stress, which enables their survival during this challenge. Autophagy may also impart survival advantage to tumors cells undergoing attack from chemotherapy or radiation. Inhibition of early-stage autophagy can rescue cancer cells, while inhibition of late-stage autophagy enhances cell death due to accumulation of damaged organelles. The antiparasitic drugs chloroquine (CQ) and hydroxychloroquine (HCQ) inhibit late-phase autophagy. We assessed the safety, tolerability, and efficacy of combining CQ or HCQ with carboplatin and gemcitabine (CG) in patients with refractory advanced solid tumors.

Methods

This single institution phase 1 dose-escalation study was designed to evaluate the maximum tolerated dose (MTD) of CQ/HCQ, in combination with CG, in patients with advanced solid tumors. Secondary objectives were to determine overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). A starting dose of CQ or HCQ 50 mg was used in conjunction with standard starting doses of CG and increased in increments of 50 mg in each patient dose cohort. Grade 3 or greater toxicity that is treatment related, and was not self-limited, or not controlled in <7 days was considered dose-limiting toxicity (DLT).

Results

Twenty-two patients were enrolled. All patients had at least one prior treatment, and 11 of them had 3 prior regimens. CQ/HCQ 100 mg daily was found to be the MTD in combination with CG with thrombocytopenia and/or neutropenia dose limiting. The median overall (OS) was 11 months, and the 1- and 3-year OS were 30% and 7%, respectively. Median progression-free survival was 5 months, and the 6-, 12-, and 18-month progression-free survivals were 48%, 21%, and 14%, respectively.

Conclusion

The MTD identified for CQ/HCQ was lower than previously reported with concomitant use of chemotherapeutic regimes likely due to the myelosuppressive nature of CG in previously treated patients.