bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural Analysis on the Severe Acute Respiratory Syndrome Coronavirus 2 Non-structural Protein 13 Mutants Revealed Altered Bonding Network With TANK Binding Kinase 1 to Evade Host Immune System
Authors: Rashid Farooq , Suleman Muhammad , Shah Abdullah , Dzakah Emmanuel Enoch , Chen Shuyi , Wang Haiying , Tang Shixing
Published: December 2021

Mutations in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have made this virus more infectious. Previous studies have confirmed that non-structural protein 13 (NSP13) plays an important role in immune evasion by physically interacting with TANK binding kinase 1 (TBK1) to inhibit IFNβ production. Mutations have been reported in NSP13; hence, in the current study, biophysical and structural modeling methodologies were adapted to dissect the influence of major mutations in NSP13, i.e., P77L, Q88H, D260Y, E341D, and M429I, on its binding to the TBK1 and to escape the human immune system. The results revealed that these mutations significantly affected the binding of NSP13 and TBK1 by altering the hydrogen bonding network and dynamic structural features. The stability, flexibility, and compactness of these mutants displayed different dynamic features, which are the basis for immune evasion. Moreover, the binding was further validated using the MM/GBSA approach, revealing that these mutations have higher binding energies than the wild-type (WT) NSP13 protein. These findings thus justify the basis of stronger interactions and evasion for these NSP13 mutants. In conclusion, the current findings explored the key features of the NSP13 WT and its mutant complexes, which can be used to design structure-based inhibitors against the SARS-CoV-2 new variants to rescue the host immune system.
Combined With Mefloquine, Resurrect Colistin Active in Colistin-Resistant Pseudomonas aeruginosa in vitro and in vivo
Authors: Zhang Xiaodong , Zhao Yining , Feng Luozhu , Xu Mengxin , Ge Yiru , Wang Lingbo , Zhang Ying , Cao Jianming , Sun Yao , Wu Qing , Zhou Tieli
Published: December 2021

Colistin is a polymyxin antibiotic that is widely used for the treatment of multidrug resistant (MDR) Pseudomonas aeruginosa infections, as the last resort. Over the past few years, unreasonable use of antibiotics has resulted in an increase in MDR strains, including colistin-resistant P. aeruginosa. The present study aimed to explore the synergistic effects of mefloquine in combination with colistin for the treatment of colistin-resistant P. aeruginosa in vivo and in vitro. The synergistic effect of the combination of mefloquine and colistin was investigated in vitro using checkerboard method, time-killing assay, biofilm formation inhibition test, and biofilm eradication test. The study also explored the synergistic effects of this combination of drugs in vivo, using a Galleria mellonella infection model. The results for checkerboard method and time killing curve indicated that mefloquine in combination with colistin showed a good antibacterial activity. Furthermore, the combination of these two drugs inhibited biofilm formation and eradicated pre-formed mature biofilms. This synergistic effect was visualized using scanning electron microscopy (SEM), wherein the results showed that the combination of mefloquine and colistin reduced biofilm formation significantly. Further, the application of this combination of drugs to in vivo infection model significantly increased the survival rate of G. mellonella larvae. Altogether, the combination of mefloquine and colistin showed a good synergistic effect in vitro and in vivo, and highlighted its potential to be used as an alternative therapy for the treatment of colistin-resistant P. aeruginosa infection.
SPARC Overexpression Promotes Liver Cancer Cell Proliferation and Tumor Growth
Authors: Gao Zhao-wei , Liu Chong , Yang Lan , He Ting , Wu Xia-nan , Zhang Hui-zhong , Dong Ke
Published: December 2021

Background:Secreted protein acidic and rich in cysteine (SPARC) plays an important role in cancer development. The roles of SPARC in the liver hepatocellular carcinoma (LIHC) are unclear.

Methods:GEPIA2 and UALCAN were used to analyze the SPARC mRNA expression levels in LIHC based on the TCGA database. The GEO database was used to verify the analysis results. Immunohistochemical (IHC) analysis was used to investigate the SPARC protein levels in LIHC tissues. The Kaplan–Meier (KM) plotter was used to analyze the correlation between SPARC and prognosis. The serum SPARC levels were measured by ELISA. CCK8 and murine xenograft models were used to investigate the effect of SPARC on the liver cancer growthin vitroandin vivo. SPARC-correlated genes were screened by LinkedOmics.

Results:Based on the TCGA and GEO databases, the analysis showed that the SPARC mRNA expression levels were increased in tumor tissues and peripheral blood mononuclear cell (PBMC) from LIHC compared to normal controls. The IHC analysis showed an increased level of SPARC in LIHC tissues compared to adjacent non-tumor tissues. However, we found that the serum SPARC levels were lower in LIHC than those in healthy controls. The KM plotter showed that there was no significant correlation between the SPARC mRNA levels and overall survival. However, in sorafenib-treated LIHC patients, the high SPARC expression predicts favorable prognosis. Furthermore, the endogenous SPARC overexpression promotes liver cancer cell proliferationin vitroand tumor growthin vivo, while there was no significant effect of exogenous SPARC treatment on liver cancer cell proliferation. Function enrichment analysis of SPARC-correlated genes indicated a critical role of interaction with an extracellular matrix in SPARC-promoting cancer cell proliferation.

Conclusion:SPARC mRNAs were increased in LIHC tumor tissues, and SPARC overexpression may promote the liver cancer growth. Further studies are needed to clarify the potential prognostic value of SPARC, both in tissues and in circulation.
Free-Living Physical Activity Measured With a Wearable Device Is Associated With Larger Hippocampus Volume and Greater Functional Connectivity in Healthy Older Adults: An Observational, Cross-Sectional Study in Northern Portugal
Authors: Domingos Célia , Picó-Pérez Maria , Magalhães Ricardo , Moreira Mariana , Sousa Nuno , Pêgo José Miguel , Santos Nadine Correia
Published: December 2021

Several studies using neuroimaging techniques have established a positive relationship between physical activity (PA) and brain structure and function in older populations. However, the use of subjective measures of PA and the lack of multimodal neuroimaging approaches have limited the understanding of this association. This study aims to explore the associations between PA and brain structure and function by objectively evaluating PA. Community-dwelling cognitively healthy older adults (without diagnosed cognitive, neurological or degenerative disease) were recruited from local health centers and local gyms. In a cross-sectional design, participants were evaluated regarding cognitive, clinical, anthropometric, physical performance, and lifestyle characteristics. A 3 T magnetic resonance imaging (MRI) was performed for structural and functional brain measures. PA time and level was assessed via a Xiaomi Mi Band 2® worn for 15 consecutive days. Participants (n = 110, after inclusion/exclusion criteria and completion of all evaluations) were 58 females (56%), with an average age of 68.42 years old (SD = 3.12), most were active. Multiple regression analysis revealed that higher time spent in vigorous PA associated with larger left parahippocampal gyrus and right hippocampus volumes. Furthermore, the analysis of the functional connectome indicated a greater functional connectivity (FC) between the frontal gyrus, cingulate gyrus, occipital inferior lobe for light, moderate, and total PA time, and sedentary time associated with lower FC in the same networks. Overall, the structural and functional findings may provide evidence on the relevant association between PA and brain health in aging.
Leisure Activity Variety and Brain Volume Among Community-Dwelling Older Adults: Analysis of the Neuron to Environmental Impact Across Generations Study Data
Authors: Iizuka Ai , Murayama Hiroshi , Machida Masaki , Amagasa Shiho , Inoue Shigeru , Fujiwara Takeo , Shobugawa Yugo
Published: December 2021

Background: Recent findings indicate that leisure activity (LA) delays cognitive decline and reduces the risk of dementia. However, the association between LA and brain volume remains unclear. This study aimed to examine the association between LA variety and brain volume with a focus on the hippocampus and gray matter.

Methods: Data were obtained from the baseline survey of the Neuron to Environmental Impact across Generations study, which had targeted community-dwelling older adults living in Niigata, Japan. We divided LAs into 10 categories, and counted the number of categories of activities in which the participants engaged. We classified them as follows: 0 (i.e., no activity), 1, 2, or ≥ 3 types. Brain volume was assessed through magnetic resonance imaging, and hippocampal and gray matter volumes were ascertained.

Results: The sample size was 482. Multiple linear regression analysis showed that hippocampal and gray matter volumes were significantly greater among participants with ≥ 3 types of LAs than among their no-activity counterparts. Hippocampal volume was significantly greater among those who engaged in one type of LA than among those who engaged in no such activity. Sex-stratified analysis revealed that hippocampal volumes were significantly greater among males who engaged in ≥ 3 types of LAs and one type of LA. However, no such association was found among females.

Conclusion: The present findings suggest that engaging in a wide range of LAs is related to hippocampal and gray matter volumes. Furthermore, there was a sex difference in the association between LA variety and brain volume.
Characteristics of Autonomic Dysfunction in Parkinson’s Disease: A Large Chinese Multicenter Cohort Study
Authors: Zhou Zhou , Zhou Xiaoting , Zhou Xiaoxia , Xiang Yaqin , Zhu Liping , Qin Lixia , Wang Yige , Pan Hongxu , Zhao Yuwen , Sun Qiying , Xu Qian , Wu Xinyin , Yan Xinxiang , Guo Jifeng , Tang Beisha , Liu Zhenhua
Published: December 2021

Autonomic dysfunction (AutD) is one of the non-motor symptoms (NMSs) in Parkinson’s disease (PD). To investigate the prevalence and clinical features of AutD in Chinese patients with PD, a large multicenter cohort of 2,556 individuals with PD were consecutively involved in the Parkinson’s Disease and Movement Disorders Multicenter Database and Collaborative Network in China (PD-MDCNC) between January 1, 2017, and December 31, 2019. The assessment of AutD was performed using the Scale for Outcomes in Parkinson’s Disease for Autonomic Symptoms (SCOPA-AUT). The evaluation of motor symptoms and other NMSs were performed using well-established scales recommended by the Movement Disorder Society. We found that out of 2,556 patients with PD, 2,333 patients with PD (91.28%) had AutD. Compared with the group of patients with PD without AutD, the group of patients with PD with AutD had older age, older age of onset, longer disease duration, more severe motor symptoms, motor complications, and more frequent NMSs. As for partial correlation analysis, the total SCOPA-AUT score was significantly and positively associated with motor severity scales [Unified Parkinson’s Disease Rating Scale (UPDRS) total score] and some of the NMSs [Rapid Eye Movement Sleep Behavior Disorder Questionnaire (RBD), Epworth Sleepiness Scale, Hamilton Depression Scale], Fatigue Severity Scale, and Parkinson’s disease questionnaire. PD Sleep Scale was significantly and negatively correlated with AutD. With logistic regression analysis for potentially related factors, age, UPDRS total score, RBD, hyposmia, depression, and fatigue may be associated with PD with AutD. In conclusion, our multicenter cohort study reported the high prevalence of AutD in Chinese PD and revealed the associated factors of PD with AutD.
BrainFD: Measuring the Intracranial Brain Volume With Fractal Dimension
Authors: Ashraf Ghulam Md , Chatzichronis Stylianos , Alexiou Athanasios , Kyriakopoulos Nikolaos , Alghamdi Badrah Saeed Ali , Tayeb Haythum Osama , Alghamdi Jamaan Salem , Khan Waseem , Jalal Manal Ben , Atta Hazem Mahmoud
Published: December 2021

A few methods and tools are available for the quantitative measurement of the brain volume targeting mainly brain volume loss. However, several factors, such as the clinical conditions, the time of the day, the type of MRI machine, the brain volume artifacts, the pseudoatrophy, and the variations among the protocols, produce extreme variations leading to misdiagnosis of brain atrophy. While brain white matter loss is a characteristic lesion during neurodegeneration, the main objective of this study was to create a computational tool for high precision measuring structural brain changes using the fractal dimension (FD) definition. The validation of the BrainFD software is based on T1-weighted MRI images from the Open Access Series of Imaging Studies (OASIS)-3 brain database, where each participant has multiple MRI scan sessions. The software is based on the Python and JAVA programming languages with the main functionality of the FD calculation using the box-counting algorithm, for different subjects on the same brain regions, with high accuracy and resolution, offering the ability to compare brain data regions from different subjects and on multiple sessions, creating different imaging profiles based on the Clinical Dementia Rating (CDR) scores of the participants. Two experiments were executed. The first was a cross-sectional study where the data were separated into two CDR classes. In the second experiment, a model on multiple heterogeneous data was trained, and the FD calculation for each participant of the OASIS-3 database through multiple sessions was evaluated. The results suggest that the FD variation efficiently describes the structural complexity of the brain and the related cognitive decline. Additionally, the FD efficiently discriminates the two classes achieving 100% accuracy. It is shown that this classification outperforms the currently existing methods in terms of accuracy and the size of the dataset. Therefore, the FD calculation for identifying intracranial brain volume loss could be applied as a potential low-cost personalized imaging biomarker. Furthermore, the possibilities measuring different brain areas and subregions could give robust evidence of the slightest variations to imaging data obtained from repetitive measurements to Physicians and Radiologists.
Protect Effects of Seafood-Derived Plasmalogens Against Amyloid-Beta (1–42) Induced Toxicity via Modulating the Transcripts Related to Endocytosis, Autophagy, Apoptosis, Neurotransmitter Release and Synaptic Transmission in SH-SY5Y Cells
Authors: Feng Junli , Song Gongshuai , Shen Qing , Chen Xi , Wang Qingcheng , Guo Shunyuan , Zhang Manman
Published: December 2021

To investigate the underlying mechanisms of decreased plasmalogens (Pls) levels in neurodegenerative diseases, here the effects of seafood-derived Pls on undifferentiated and differentiated human SH-SY5Y neuroblastoma cells exposed to amyloid-β1–42 was analyzed. Transcriptional profiles indicated that a total of 6,581 differentially expressed genes (DEGs) were significantly identified among different experimental groups, and KEGG analysis indicated that these DEGs were related to AD, endocytosis, synaptic vesicle cycle, autophagy and cellular apoptosis. After Pls treatment, the striking expression changes of ADORA2A, ATP6V1C2, CELF6, and SLC18A2 mRNA strongly suggest that Pls exerts a beneficial role in alleviating AD pathology partly by modulating the neurotransmitter release and synaptic transmission at the transcriptional level. Besides these, GPCRs are also broadly involved in Pls-signaling in neuronal cells. These results provide evidence for supporting the potential use of Pls as an effective therapeutic approach for AD.
The Neutrophil to Lymphocyte Ratio Is Associated With the Risk of Subsequent Dementia in the Framingham Heart Study
Authors: Ramos-Cejudo Jaime , Johnson Andrew D. , Beiser Alexa , Seshadri Sudha , Salinas Joel , Berger Jeffrey S. , Fillmore Nathanael R. , Do Nhan , Zheng Chunlei , Kovbasyuk Zanetta , Ardekani Babak A. , Bubu Omonigho M. , Parekh Ankit , Convit Antonio , Betensky Rebecca A. , Wisniewski Thomas M. , Osorio Ricardo S.
Published: December 2021

Objective: Active neutrophils are important contributors to Alzheimer’s disease (AD) pathology through the formation of capillary stalls that compromise cerebral blood flow (CBF) and through aberrant neutrophil signaling that advances disease progression. The neutrophil to lymphocyte ratio (NLR) is a proxy of neutrophil-mediated inflammation, and higher NLR is found in persons diagnosed with clinical AD. The objective of this study was to investigate whether increased NLR in older adults is independently associated with the risk of subsequent dementia.

Methods: We examined associations of baseline NLR with incident dementia risk in the community-based Framingham Heart Study (FHS) longitudinal cohorts. The association between NLR and risk of dementia was evaluated using the cumulative incidence function (CIF) and inverse probability-weighted Cox proportional cause-specific hazards regression models, with adjustment for age, sex, body mass index (BMI), systolic and diastolic blood pressure, diabetes, current smoking status, low-density lipoprotein (LDH), high-density lipoprotein (LDL), total cholesterol, triglycerides, and history of cardiovascular disease (CVD). Random forest survival models were used to evaluate the relative predictive value of the model covariates on dementia risk.

Results: The final study sample included 1,648 participants with FHS (average age, 69 years; 56% women). During follow-up (median, 5.9 years), we observed 51 cases of incident dementia, of which 41 were AD cases. Results from weighted models suggested that the NLR was independently associated with incident dementia, and it was preceded in predictive value only by age, history of CVD, and blood pressure at baseline.

Conclusion: Our study shows that individuals with higher NLR are at a greater risk of subsequent dementia during a 5.9-year follow-up period. Further evaluating the role of neutrophil-mediated inflammation in AD progression may be warranted.
Factors That Influence Non-Motor Impairment Across the ALS-FTD Spectrum: Impact of Phenotype, Sex, Age, Onset and Disease Stage
Authors: Devenney Emma M. , McErlean Kate , Tse Nga Yan , Caga Jashelle , Dharmadasa Thanuja , Huynh William , Mahoney Colin J. , Zoing Margaret , Mazumder Srestha , Dobson-Stone Carol , Kwok John B. , Halliday Glenda M. , Hodges John R. , Piguet Olivier , Ahmed Rebekah M. , Kiernan Matthew C.
Published: December 2021

Objective: This study aimed to establish (1) the pattern and severity of neuropsychiatric symptoms and other non-motor symptoms of sleep and mood, across ALS phenotypes in comparison to bvFTD and (2) the contribution of non-modifiable factors including age, sex and disease state to the severity of symptoms experienced by ALS patients.

Methods: Consecutive participants were recruited to the study and underwent a detailed clinical, cognitive, behavioral and neuroimaging assessment. Neuropsychiatric and other non-motor symptoms were determined using the Cambridge Behavioral Inventory, the CBI-R. The scores were converted to define impairment in terms of mild, moderate and severe symptoms for each subscale. Rate, severity and contribution of King's staging and modifiable factors were also determined and a regression model identified predictors of symptom severity.

Results: In total, 250 participants (115 ALS, 98 bvFTD, and 37 ALS-FTD patients) were recruited. A similar pattern of neuropsychiatric symptom severity was identified (apathy, disinhibition and stereotypic behavior) for all behavioral phenotypes of ALS compared to bvFTD (all p > 0.05). Neuropsychiatric symptoms were also present in cases defined as ALSpure and the cognitive phenotype of ALS (ALSci) although they occurred less frequently and were at the milder end of the spectrum. Disordered sleep and disrupted mood were common across all phenotypes (all p < 0.05). The severity of sleep dysfunction was influenced by both sex and age (all p < 0.05). Neuropsychiatric symptoms, sleep and mood disorders were common early in the disease process and deteriorated in line with progression on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; all p < 0.05). Diagnostic phenotype, disease duration and global cognition scores were the strongest predictors of non-motor and neuropsychiatric impairments.

Conclusion: The current findings reveal strikingly similar patterns of changes across the subgroups of ALS and bvFTD, supporting the concept of the ALS-FTD spectrum. The findings further highlight the impact of non-motor and neuropsychiatric symptoms in patients with ALS, that are often as severe as that seen in ALS-FTD and bvFTD. This study advances understanding across the ALS-FTD spectrum that may accelerate the early identification of patient needs, to ensure prompt recognition of symptoms and thereby to improve clinical awareness, patient care and management.
Synaptic Loss in Multiple Sclerosis: A Systematic Review of Human Post-mortem Studies
Authors: Möck E. E. Amelie , Honkonen Eveliina , Airas Laura
Published: December 2021

Background: Gray matter pathology plays a central role in the progression of multiple sclerosis (MS). The occurrence of synaptic loss appears to be important but, to date, still poorly investigated aspect of MS pathology. In this systematic review, we drew from the recent knowledge about synaptic loss in human post-mortem studies.

Methods: We conducted a systematic search with PubMed to identify relevant publications. Publications available from15 June 2021 were taken into account. We selected human post-mortem studies that quantitatively assessed the synapse number in MS tissue.

Results: We identified 14 relevant publications out of which 9 reported synaptic loss in at least one investigated subregion. The most commonly used synaptic marker was synaptophysin; non-etheless, we found substantial differences in the methodology and the selection of reference tissue. Investigated regions included the cortex, the hippocampus, the cerebellum, the thalamus, and the spinal cord.

Conclusion: Synaptic loss seems to take place throughout the entire central nervous system. However, the results are inconsistent, probably due to differences in the methodology. Moreover, synaptic loss appears to be a dynamic process, and thus the nature of this pathology might be captured using in vivo synaptic density measurements.
Response to Thalamic Ventralis Intermedius Nucleus Deep Brain Stimulation in Essential Tremor vs. Essential Tremor-Plus
Authors: Gilmour Gabriela S. , Martino Davide , Hunka Karen , Lawrence Pia , Kiss Zelma H. T. , Bruno Veronica
Published: December 2021

Introduction: Essential tremor (ET) is a tremor syndrome characterized by bilateral, upper limb action tremor. Essential tremor-plus (ET-plus) describes ET patients with additional neurologic signs. It is unknown whether there is a difference in response to treatment with ventralis intermedius nucleus deep brain stimulation (VIM DBS) in patients with ET and ET-plus. Due to potential variability in underlying etiology in ET-plus, there is a concern that ET-plus patients may have worse outcomes. The aim of this study was to identify whether patients with ET-plus have worse tremor outcomes after VIM DBS than patients with ET.

Methods: This is a retrospective chart and video review evaluating VIM DBS outcomes by comparing changes from baseline in the Fahn-Tolosa-Marin Tremor Rating Scale Part B (FTM-B) for the treated limb between patients with ET and ET-plus at follow-up examinations. Patients were re-classified as having ET or ET-plus using pre-operative examination videos by two independent movement disorders neurologists blinded to patient characteristics. As a secondary outcome, we evaluated for correlations and potential predictors of treatment response.

Results: Twenty-six patients were included: 13 with ET, 13 with ET-plus. There were no significant differences in the change in FTM-B scores between the ET and ET-plus patients at each follow-up examination. None of the included patients developed new symptoms compatible with dystonia, parkinsonism or gait disturbances.

Conclusions: Patients with ET-plus had tremor improvement from VIM DBS, with no differences when compared to those with ET, without emergence of postoperative neurological issues. Patients with ET-plus should still be considered good candidates for VIM DBS for treatment of tremor.
Mental State Detection Using Riemannian Geometry on Electroencephalogram Brain Signals
Authors: Wriessnegger Selina C. , Raggam Philipp , Kostoglou Kyriaki , Müller-Putz Gernot R.
Published: December 2021

The goal of this study was to implement a Riemannian geometry (RG)-based algorithm to detect high mental workload (MWL) and mental fatigue (MF) using task-induced electroencephalogram (EEG) signals. In order to elicit high MWL and MF, the participants performed a cognitively demanding task in the form of the letter n-back task. We analyzed the time-varying characteristics of the EEG band power (BP) features in the theta and alpha frequency band at different task conditions and cortical areas by employing a RG-based framework. MWL and MF were considered as too high, when the Riemannian distances of the task-run EEG reached or surpassed the threshold of the baseline EEG. The results of this study showed a BP increase in the theta and alpha frequency bands with increasing experiment duration, indicating elevated MWL and MF that impedes/hinders the task performance of the participants. High MWL and MF was detected in 8 out of 20 participants. The Riemannian distances also showed a steady increase toward the threshold with increasing experiment duration, with the most detections occurring toward the end of the experiment. To support our findings, subjective ratings (questionnaires concerning fatigue and workload levels) and behavioral measures (performance accuracies and response times) were also considered.
Automatic Diagnosis of Schizophrenia in EEG Signals Using CNN-LSTM Models
Authors: Shoeibi Afshin , Sadeghi Delaram , Moridian Parisa , Ghassemi Navid , Heras Jónathan , Alizadehsani Roohallah , Khadem Ali , Kong Yinan , Nahavandi Saeid , Zhang Yu-Dong , Gorriz Juan Manuel
Published: December 2021

Schizophrenia (SZ) is a mental disorder whereby due to the secretion of specific chemicals in the brain, the function of some brain regions is out of balance, leading to the lack of coordination between thoughts, actions, and emotions. This study provides various intelligent deep learning (DL)-based methods for automated SZ diagnosisviaelectroencephalography (EEG) signals. The obtained results are compared with those of conventional intelligent methods. To implement the proposed methods, the dataset of the Institute of Psychiatry and Neurology in Warsaw, Poland, has been used. First, EEG signals were divided into 25 s time frames and then were normalized byz-score or norm L2. In the classification step, two different approaches were considered for SZ diagnosisviaEEG signals. In this step, the classification of EEG signals was first carried out by conventional machine learning methods, e.g., support vector machine,k-nearest neighbors, decision tree, naïve Bayes, random forest, extremely randomized trees, and bagging. Various proposed DL models, namely, long short-term memories (LSTMs), one-dimensional convolutional networks (1D-CNNs), and 1D-CNN-LSTMs, were used in the following. In this step, the DL models were implemented and compared with different activation functions. Among the proposed DL models, the CNN-LSTM architecture has had the best performance. In this architecture, the ReLU activation function with thez-score and L2-combined normalization was used. The proposed CNN-LSTM model has achieved an accuracy percentage of 99.25%, better than the results of most former studies in this field. It is worth mentioning that to perform all simulations, thek-fold cross-validation method withk= 5 has been used.
Epigenetic Heterogeneity in Friedreich Ataxia Underlies Variable FXN Reactivation
Authors: Rodden Layne N. , Gilliam Kaitlyn M. , Lam Christina , Lynch David R. , Bidichandani Sanjay I.
Published: December 2021

Friedreich ataxia (FRDA) is typically caused by homozygosity for an expanded GAA triplet-repeat in intron 1 of theFXNgene. The expanded repeat induces repressive histone changes and DNA hypermethylation, which result in epigenetic silencing andFXNtranscriptional deficiency. A class I histone deacetylase inhibitor (HDACi-109) reactivates the silencedFXNgene, although with considerable inter-individual variability, which remains etiologically unexplained. Because HDAC inhibitors work by reversing epigenetic silencing, we reasoned that epigenetic heterogeneity among patients may help to explain this inter-individual variability. As a surrogate measure for epigenetic heterogeneity, a highly quantitative measurement of DNA hypermethylation via bisulfite deep sequencing, with single molecule resolution, was used to assess the prevalence of unmethylated, partially methylated, and fully methylated somaticFXNmolecules in PBMCs from a prospective cohort of 50 FRDA patients. Treatment of the same PBMCs from this cohort with HDACi-109 significantly increasedFXNtranscript to levels seen in asymptomatic heterozygous carriers, albeit with the expected inter-individual variability. Response to HDACi-109 correlated significantly with the prevalence of unmethylated and partially methylatedFXNmolecules, supporting the model thatFXNreactivation involves a proportion of genes that are amenable to correction in non-dividing somatic cells, and that heavily methylatedFXNmolecules are relatively resistant to reactivation.FXNreactivation is a promising therapeutic strategy in FRDA, and inter-individual variability is explained, at least in part, by somatic epigenetic heterogeneity.
Excitation/Inhibition Modulators in Autism Spectrum Disorder: Current Clinical Research
Authors: Canitano Roberto , Palumbi Roberto
Published: December 2021

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by social and communication abnormalities. Heterogeneity in the expression and severity of the core and associated symptoms poses difficulties in classification and the overall clinical approach. Synaptic abnormalities have been observed in preclinical ASD models. They are thought to play a major role in clinical functional abnormalities and might be modified by targeted interventions. An imbalance in excitatory to inhibitory neurotransmission (E/I imbalance), through altered glutamatergic and GABAergic neurotransmission, respectively, is thought to be implicated in the pathogenesis of ASD. Glutamatergic and GABAergic agents have been tested in clinical trials with encouraging results as to efficacy and tolerability. Further studies are needed to confirm the role of E/I modulators in the treatment of ASD and on the safety and efficacy of the current agents.
Turbo Gradient and Spin Echo PROPELLER-Diffusion Weighted Imaging for Orbital Tumors: A Comparative Study With Readout-Segmented Echo-Planar Imaging
Authors: Fu Qing , Kong Xiang-chuang , Liu Ding-Xi , Zhou Kun , Guo Yi-hao , Lei Zi-Qiao , Zheng Chuan-sheng , Yang Fan
Published: December 2021

Purpose: To qualitatively and quantitatively compare the image quality and diagnostic performance of turbo gradient and spin echo PROPELLER diffusion-weighted imaging (TGSE-PROPELLER-DWI) vs. readout-segmented echo-planar imaging (rs-EPI) in the evaluation of orbital tumors.

Materials and Methods: A total of 43 patients with suspected orbital tumors were enrolled to perform the two DWIs with comparable spatial resolution on 3T. The overall image qualities, geometric distortions, susceptibility artifacts, and lesion conspicuities were scored by using a four-point scale (1, poor; 4, excellent). Quantitative measurements, including contrast-to-noise ratios (CNRs), apparent diffusion coefficients (ADCs), geometric distortion rates (GDRs), and lesion sizes, were calculated and compared. The two ADCs for differentiating malignant from benign orbital tumors were evaluated. Wilcoxon signed-rank test, Kappa statistic, and receiver operating characteristics (ROC) curves were used.

Results: TGSE-PROPELLER-DWI performed superior in all subjective scores and quantitative GDR evaluation than rs-EPI (p < 0.001), and excellent interobserver agreement was obtained for Kappa value ranging from 0.876 to 1.000. ADClesion of TGSE-PROPELLER-DWI was significantly higher than those of rs-EPI (p < 0.001). Mean ADC of malignant tumors was significantly lower than that of benign tumors both in two DWIs. However, the AUC for differentiating malignant and benign tumors showed no significant difference in the two DWIs (0.860 vs. 0.854, p = 0.7448). Sensitivity and specificity could achieve 92.86% and 72.73% for TGSE-PROPELLER-DWI with a cutoff value of 1.23 × 10–3 mm2/s, and 85.71% and 81.82% for rs-EPI with a cutoff value of 0.99 × 10–3 mm2/s.

Conclusion: Compared with rs-EPI, TGSE-PROPELLER-DWI showed minimized geometric distortion and susceptibility artifacts significantly improved the image quality for orbital tumors and achieved comparable diagnostic performance in differentiating malignant and benign orbital tumors.
Federated Morphometry Feature Selection for Hippocampal Morphometry Associated Beta-Amyloid and Tau Pathology
Authors: Wu Jianfeng , Dong Qunxi , Zhang Jie , Su Yi , Wu Teresa , Caselli Richard J. , Reiman Eric M. , Ye Jieping , Lepore Natasha , Chen Kewei , Thompson Paul M. , Wang Yalin
Published: December 2021

Amyloid-β (Aβ) plaques and tau protein tangles in the brain are now widely recognized as the defining hallmarks of Alzheimer’s disease (AD), followed by structural atrophy detectable on brain magnetic resonance imaging (MRI) scans. One of the particular neurodegenerative regions is the hippocampus to which the influence of Aβ/tau on has been one of the research focuses in the AD pathophysiological progress. This work proposes a novel framework, Federated Morphometry Feature Selection (FMFS) model, to examine subtle aspects of hippocampal morphometry that are associated with Aβ/tau burden in the brain, measured using positron emission tomography (PET). FMFS is comprised of hippocampal surface-based feature calculation, patch-based feature selection, federated group LASSO regression, federated screening rule-based stability selection, and region of interest (ROI) identification. FMFS was tested on two Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohorts to understand hippocampal alterations that relate to Aβ/tau depositions. Each cohort included pairs of MRI and PET for AD, mild cognitive impairment (MCI), and cognitively unimpaired (CU) subjects. Experimental results demonstrated that FMFS achieves an 89× speedup compared to other published state-of-the-art methods under five independent hypothetical institutions. In addition, the subiculum and cornu ammonis 1 (CA1 subfield) were identified as hippocampal subregions where atrophy is strongly associated with abnormal Aβ/tau. As potential biomarkers for Aβ/tau pathology, the features from the identified ROIs had greater power for predicting cognitive assessment and for survival analysis than five other imaging biomarkers. All the results indicate that FMFS is an efficient and effective tool to reveal associations between Aβ/tau burden and hippocampal morphometry.
Compulsive Eating in a Rat Model of Binge Eating Disorder Under Conditioned Fear and Exploration of Neural Mechanisms With c-fos mRNA Expression
Authors: Li Zhi Fei , Chometton Sandrine , Guèvremont Geneviève , Timofeeva Elena , Timofeev Igor
Published: December 2021

Compulsive eating is the most obstinate feature of binge eating disorder. In this study, we observed the compulsive eating in our stress-induced binge-like eating rat model using a conflicting test, where sucrose and an aversively conditioned stimulus were presented at the same time. In this conflicting situation, the binge-like eating prone rats (BEPs), compared to the binge-like eating resistant rats (BERs), showed persistent high sucrose intake and inhibited fear response, respectively, indicating a deficit in palatability devaluation and stronger anxiolytic response to sucrose in the BEPs. We further analyzed the neuronal activation with c-fos mRNA in situ hybridization. Surprisingly, the sucrose access under conditioned fear did not inhibit the activity of amygdala; instead, it activated the central amygdala. In the BEPs, sucrose reduced the response of the paraventricular hypothalamic nucleus (PVN), while enhancing activities in the lateral hypothalamic area (LHA) to the CS. The resistance to devaluating the palatable food in the BEPs could be a result of persistent Acb response to sucrose intake and attenuated recruitment of the medial prefrontal cortex (mPFC). We interpret this finding as that the reward system of the BEPs overcame the homeostasis system and the stress-responding system.
Examination of Athlete Triad Symptoms Among Endurance-Trained Male Athletes: A Field Study
Authors: Moore Erin M. , Drenowatz Clemens , Stodden David F. , Pritchett Kelly , Brodrick Thaddus C. , Williams Brittany T. , Goins Justin M. , Torres-McGehee Toni M.
Published: December 2021

Background: Studies examining the physiological consequences associated with deficits in energy availability (EA) for male athletes are sparse.

Purpose: To examine male athlete triad components; low energy availability (LEA) with or without an eating disorder risk (ED), reproductive hormone [testosterone (T)], and bone mineral density (BMD) in endurance-trained male athletes during different training periods.

Methods: A cross-sectional design with 14 participants (age: 26.4 ± 4.2 years; weight: 70.6 ± 6.4 kg; height: 179.5 ± 4.3 cm; BMI: 21.9 ± 1.8 kg/m2) were recruited from the local community. Two separate training weeks [low (LV) and high (HV) training volumes] were used to collect the following: 7-day dietary and exercise logs, and blood concentration of T. Anthropometric measurements was taken prior to data collection. A one-time BMD measure (after the training weeks) and VO2max-HR regressions were utilized to calculate EEE.

Results: Overall, EA presented as 27.6 ± 10.7 kcal/kgFFM·d-1 with 35% (n = 5) of participants demonstrating increased risk for ED. Examining male triad components, 64.3% presented with LEA (≤ 30 kcal/kgFFM·d-1) while participants presented with T (1780.6 ± 1672.6 ng/dl) and BMD (1.31 ±.09 g/cm2) within normal reference ranges. No differences were found across the 2 training weeks for EI, with slight differences for EA and EEE. Twenty-five participants (89.3%) under-ingested CHO across both weeks, with no differences between weeks.

Conclusion: Majority of endurance-trained male athletes presented with one compromised component of the triad (LEA with or without ED risk); however, long-term negative effects on T and BMD were not demonstrated. Over 60% of the participants presented with an EA ≤ 30 kcal/kgFFM·d-1, along with almost 90% not meeting CHO needs. These results suggest male endurance-trained athletes may be at risk to negative health outcomes similar to mechanistic behaviors related to EA with or without ED in female athletes.
Association of Maternal Dietary Patterns With Birth Weight and the Mediation of Gestational Weight Gain: A Prospective Birth Cohort
Authors: Li Yan , Zhou Xuezhen , Zhang Yu , Zhong Chunrong , Huang Li , Chen Xi , Chen Renjuan , Wu Jiangyue , Li Qian , Sun Guoqiang , Yin Heng , Xiong Guoping , Hao Liping , Yang Nianhong , Yang Xuefeng
Published: December 2021

The associations among maternal diet, birth weight, and gestational weight gain are still inconclusive. This study aimed to investigate the associations between maternal dietary patterns and birth weight, and further explore whether GWG mediates these associations. A total of 3,334 pregnant women who completed a validated semi-quantitative food frequency questionnaire from the Tongji Maternal and Child Health Cohort were included. Dietary patterns were extracted by using principal component analysis. Regression models and mediation analyses were performed to explore the associations between dietary patterns and birth weight and the effects of GWG on these associations. Five dietary patterns were identified: “Beans-vegetables,” “Fish-meat-eggs,” “Nuts-whole grains,” “Organ-poultry-seafood” and “Rice-wheat-fruits.” Only women following the “Beans-vegetables” pattern had heavier newborns (β = 47.39; 95% CI: 12.25, 82.54). Women following the “Beans-vegetables” pattern had significantly lower GWG (β = −0.7; 95% CI: −1.15, −0.25) and had a 16% lower risk of excessive GWG and 11% higher odd of adequate GWG. The association between the “Beans-vegetables” pattern and birth weight was negatively mediated by GWG. A dietary pattern enriched in beans and vegetables is beneficial for effectively controlling GWG and increasing birth weight. GWG serves.

Clinical Trial Registry: This trial was registered at ClinicalTrials.gov (NCT03099837).
Systemic Immune-Inflammation Index Is a Prognostic Factor for Breast Cancer Patients After Curative Resection
Authors: Li Wen , Ma Guangzhi , Deng Yunfu , Chen Wenjie , Liu Zhenkun , Chen Fang , Wu Qiang
Published: December 2021

Background

The preoperative systemic immune-inflammation index (SII) is correlated with prognosis in several malignancies. The aim of this study was to investigate the prognosis value of SII in patients with resected breast cancer.

Materials and Methods

A total of 784 breast cancer patients who underwent surgical resection were consecutively investigated. The optimal cutoff value of SII was evaluated using the receiver operating characteristic (ROC) curve. The collection of SII with clinicopathological characteristic and prognosis was further evaluated.

Results

The optimal cutoff value for SII in the prediction of survival was 514 according to ROC curve analysis. A high SII was significantly correlated with younger age (P= 0.037), PR status (P< 0.001), and HER2 status (P= 0.035). Univariate analysis revealed that SII (P< 0.001), T-stage (P< 0.001), lymph node involvement post-surgery (P= 0.024), and histological grade (P< 0.001) were significantly related to DFS, and SII (P< 0.001), T-stage (P= 0.003), lymph node involvement post-surgery (P= 0.006), and histological grade (P< 0.001) were significantly associated with OS. In multivariate analysis, a high SII was an independent worse prognostic factor for DFS (HR, 4.530; 95% CI, 3.279-6.258;P< 0.001) and OS (HR, 3.825; 95% CI, 2.594-5.640;P< 0.001) in all the enrolled patients. Furthermore, subgroup analysis of molecular subtype revealed that SII was significantly associated with prognosis in all subtypes.

Conclusion

Preoperative SII is a simple and useful prognostic factor for predicting long-term outcomes for breast cancer patients undergoing surgery.
Effectiveness and Safety of Targeted Agents Combined With Chemoradiotherapy for the Treatment of Esophageal Cancer: A Network Meta-Analysis
Authors: Liu Peng , Wang Guo-Fei , Peng Hua , Zhang Lei , Li Xiao-Yan , Zeng Qiao-Miao , Li Qian , Zhou Jian-Hui
Published: December 2021

Background

Concurrent chemoradiotherapy (CRT) is the preferred treatment strategy for inoperable esophageal cancer (EC). However, the effect of CRT needs to be improved.

Methods

This study comprehensively analyzed targeted agents combined with CRT for the treatment of EC by a network meta-analysis. The search was performed in public databases from incipient to 5 August 2021. Randomized controlled trials comparing the effect of targeted agents combined with CRT and CRT alone on EC patients were included.

Results

Ten studies were included. For progression-free survival (PFS), nivolumab (67.4%) and erlotinib (64.6%) had advantages based on Cox analysis. Regarding the frequency of PFS, cetuximab (OR: 1.39; 95% CI: 1.01, 1.91; p=0.042) and nivolumab (OR: 1.81; 95% CI: 1.34, 2.44; p<0.01) were significantly superior to the control. For overall survival (OS), nivolumab (71.6%) in Cox analysis and nimotuzumab (69.7%) in frequency analysis were found to have relative advantages. Nimotuzumab combined with CRT was significantly better than the control with regard to endoscopic and the pathologic complete response (epCR; OR: 2.81; 95% CI: 1.28, 6.14; p=0.011) and objective response rate (ORR; 4.71; 95% CI: 1.45, 15.29; p=0.008). The targeted drugs were not associated with significant SEA risk.

Conclusion

In conclusion, compared to CRT alone, cetuximab and nivolumab combined with CRT were found to significantly improve the PFS rate only based on the frequency results. However, there was no benefit in terms of OS. For epCR and ORR, nimotuzumab was better than the blank control. Considering the limitations in this study, more well-designed RCTs are needed in the future to validate the results.
Impact of Fatty Pancreas on Postoperative Pancreatic Fistulae: A Meta-Analysis
Authors: Zhou Lu , Xiao Wei-ming , Li Cheng-peng , Gao Yi-wen , Gong Wei-juan , Lu Guo-tao
Published: December 2021

Background

Soft pancreas is widely recognized as an important risk factor for the development of postoperative pancreatic fistula (POPF). Although fatty pancreas (FP) has not been formally defined as a cause of pancreatic fistula, existing research has shown that it can increase the incidence of POPF by increasing pancreatic tenderness; therefore, it may be a potential risk factor. This study aimed to discern whether FP was associated with POPF.

Method

Two reviewers independently performed literature searches from five electronic databases. According to the established inclusion criteria, we extracted necessary data from the studies that met the criteria for further analysis. We pooled the odds ratios (ORs) from individual studies using a random-effects model to investigate the associations between POPF and the prognosis of FP.

Result

A total of 11 studies involving 2484 individuals were included. The pooled prevalence of POPF was 18% (95% CI: 12-24%). Body mass index (BMI) was associated with a significantly increased risk of POPF (OR=3.55; 95% CI: 1.83, 6.86; P=0.0002; I²=0). FP was obviously associated with the occurrence of POPF (OR=3.75; 95% CI: 1.64, 8.58; P=0.002; I²=78).

Conclusion

FP is closely associated with the development of POPF, and the early identification of these high-risk patients can help to reduce the incidence of POPF.

Systematic Review Registration

The Registration URL link is (https://www.crd.york.ac.uk/PROSPERO/). The ID is “CRD42021265141”.