bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative Genomics Reveals Evolutionary Traits, Mating Strategies, and Pathogenicity-Related Genes Variation of Botryosphaeriaceae
Authors: Yu Chengming , Diao Yufei , Lu Quan , Zhao Jiaping , Cui Shengnan , Xiong Xiong , Lu Anna , Zhang Xingyao , Liu Huixiang
Published: February 2022

Botryosphaeriaceae, as a major family of the largest class of kingdom fungi Dothideomycetes, encompasses phytopathogens, saprobes, and endophytes. Many members of this family are opportunistic phytopathogens with a wide host range and worldwide geographical distribution, and can infect many economically important plants, including food crops and raw material plants for biofuel production. To date, however, little is known about the family evolutionary characterization, mating strategies, and pathogenicity-related genes variation from a comparative genome perspective. Here, we conducted a large-scale whole-genome comparison of 271 Dothideomycetes, including 19 species in Botryosphaeriaceae. The comparative genome analysis provided a clear classification of Botryosphaeriaceae in Dothideomycetes and indicated that the evolution of lifestyle within Dothideomycetes underwent four major transitions from non-phytopathogenic to phytopathogenic. Mating strategies analysis demonstrated that at least 3 transitions were found within Botryosphaeriaceae from heterothallism to homothallism. Additionally, pathogenicity-related genes contents in different genera varied greatly, indicative of genus-lineage expansion within Botryosphaeriaceae. These findings shed new light on evolutionary traits, mating strategies and pathogenicity-related genes variation of Botryosphaeriaceae.
Computer-Aided Diagnosis of Spinal Tuberculosis From CT Images Based on Deep Learning With Multimodal Feature Fusion
Authors: Li Zhaotong , Wu Fengliang , Hong Fengze , Gai Xiaoyan , Cao Wenli , Zhang Zeru , Yang Timin , Wang Jiu , Gao Song , Peng Chao
Published: February 2022

Background

Spinal tuberculosis (TB) has the highest incidence in remote plateau areas, particularly in Tibet, China, due to inadequate local healthcare services, which not only facilitates the transmission of TB bacteria but also increases the burden on grassroots hospitals. Computer-aided diagnosis (CAD) is urgently required to improve the efficiency of clinical diagnosis of TB using computed tomography (CT) images. However, classical machine learning with handcrafted features generally has low accuracy, and deep learning with self-extracting features relies heavily on the size of medical datasets. Therefore, CAD, which effectively fuses multimodal features, is an alternative solution for spinal TB detection.

Methods

A new deep learning method is proposed that fuses four elaborate image features, specifically three handcrafted features and one convolutional neural network (CNN) feature. Spinal TB CT images were collected from 197 patients with spinal TB, from 2013 to 2020, in the People’s Hospital of Tibet Autonomous Region, China; 3,000 effective lumbar spine CT images were randomly screened to our dataset, from which two sets of 1,500 images each were classified as tuberculosis (positive) and health (negative). In addition, virtual data augmentation is proposed to enlarge the handcrafted features of the TB dataset. Essentially, the proposed multimodal feature fusion CNN consists of four main sections: matching network, backbone (ResNet-18/50, VGG-11/16, DenseNet-121/161), fallen network, and gated information fusion network. Detailed performance analyses were conducted based on the multimodal features, proposed augmentation, model stability, and model-focused heatmap.

Results

Experimental results showed that the proposed model with VGG-11 and virtual data augmentation exhibited optimal performance in terms of accuracy, specificity, sensitivity, and area under curve. In addition, an inverse relationship existed between the model size and test accuracy. The model-focused heatmap also shifted from the irrelevant region to the bone destruction caused by TB.

Conclusion

The proposed augmentation effectively simulated the real data distribution in the feature space. More importantly, all the evaluation metrics and analyses demonstrated that the proposed deep learning model exhibits efficient feature fusion for multimodal features. Our study provides a profound insight into the preliminary auxiliary diagnosis of spinal TB from CT images applicable to the Tibetan area.
Validation of a Standard Protocol to Assess the Fermentative and Chemical Properties of Saccharomyces cerevisiae Wine Strains
Authors: Romano Patrizia , Siesto Gabriella , Capece Angela , Pietrafesa Rocchina , Lanciotti Rosalba , Patrignani Francesca , Granchi Lisa , Galli Viola , Bevilacqua Antonio , Campaniello Daniela , Spano Giuseppe , Caridi Andrea , Poiana Marco , Foschino Roberto , Vigentini Ileana , Blaiotta Giuseppe , Corich Viviana , Giacomini Alessio , Cardinali Gianluigi , Corte Laura , Toffanin Annita , Agnolucci Monica , Comitini Francesca , Ciani Maurizio , Mannazzu Ilaria , Budroni Marilena , Englezos Vasileios , Rantsiou Kalliopi , Iacumin Lucilla , Comi Giuseppe , Capozzi Vittorio , Grieco Francesco , Tufariello Maria
Published: February 2022

This paper reports on a common experiment performed by 17 Research Units of the Italian Group of Microbiology of Vine and Wine (GMVV), which belongs to the Scientific Society SIMTREA, with the aim to validate a protocol for the characterization of wine strains of Saccharomyces cerevisiae. For this purpose, two commercial S. cerevisiae strains (EC 1118 and AWRI796) were used to carry out inter-laboratory-scale comparative fermentations using both synthetic medium and grape musts and applying the same protocol to obtain reproducible, replicable, and statistically valid results. Ethanol yield, production of acetic acid, glycerol, higher alcohols, and other volatile compounds were assessed. Moreover, the Fourier transform infrared spectroscopy was also applied to define the metabolomic fingerprint of yeast cells from each experimental trial. Data were standardized as unit of compounds or yield per gram of sugar (glucose and fructose) consumed throughout fermentation, and analyzed through parametric and non-parametric tests, and multivariate approaches (cluster analysis, two-way joining, and principal component analysis). The results of experiments carried out by using synthetic must showed that it was possible to gain comparable results from three different laboratories by using the same strains. Then, the use of the standardized protocol on different grape musts allowed pointing out the goodness and the reproducibility of the method; it showed the main traits of the two yeast strains and allowed reducing variability amongst independent batches (biological replicates) to acceptable levels. In conclusion, the findings of this collaborative study contributed to the validation of a protocol in a specific synthetic medium and in grape must and showed how data should be treated to gain reproducible and robust results, which could allow direct comparison of the experimental data obtained during the characterization of wine yeasts carried out by different research laboratories.
Microbial Biofilms Along a Geochemical Gradient at the Shallow-Water Hydrothermal System of Vulcano Island, Mediterranean Sea
Authors: Sciutteri Valentina , Smedile Francesco , Vizzini Salvatrice , Mazzola Antonio , Vetriani Costantino
Published: February 2022

Shallow water hydrothermal vents represent highly dynamic environments where strong geochemical gradients can shape microbial communities. Recently, these systems are being widely used for investigating the effects of ocean acidification on biota as vent emissions can release high CO2 concentrations causing local pH reduction. However, other gas species, as well as trace elements and metals, are often released in association with CO2 and can potentially act as confounding factors. In this study, we evaluated the composition, diversity and inferred functional profiles of microbial biofilms in Levante Bay (Vulcano Island, Italy, Mediterranean Sea), a well-studied shallow-water hydrothermal vent system. We analyzed 16S rRNA transcripts from biofilms exposed to different intensity of hydrothermal activity, following a redox and pH gradient across the bay. We found that elevated CO2 concentrations causing low pH can affect the response of bacterial groups and taxa by either increasing or decreasing their relative abundance. H2S proved to be a highly selective factor shaping the composition and affecting the diversity of the community by selecting for sulfide-dependent, chemolithoautotrophic bacteria. The analysis of the 16S rRNA transcripts, along with the inferred functional profile of the communities, revealed a strong influence of H2S in the southern portion of the study area, and temporal succession affected the inferred abundance of genes for key metabolic pathways. Our results revealed that the composition of the microbial assemblages vary at very small spatial scales, mirroring the highly variable geochemical signature of vent emissions and cautioning for the use of these environments as models to investigate the effects of ocean acidification on microbial diversity.
The Verticillium dahliae Spt-Ada-Gcn5 Acetyltransferase Complex Subunit Ada1 Is Essential for Conidia and Microsclerotia Production and Contributes to Virulence
Authors: Geng Qi , Li Huan , Wang Dan , Sheng Ruo-Cheng , Zhu He , Klosterman Steven J. , Subbarao Krishna V. , Chen Jie-Yin , Chen Feng-Mao , Zhang Dan-Dan
Published: February 2022

Verticillium dahliae is a destructive soil-borne pathogen of many economically important dicots. The genetics of pathogenesis in V. dahliae has been extensively studied. Spt-Ada-Gcn5 acetyltransferase complex (SAGA) is an ATP-independent multifunctional chromatin remodeling complex that contributes to diverse transcriptional regulatory functions. As members of the core module in the SAGA complex in Saccharomyces cerevisiae, Ada1, together with Spt7 and Spt20, play an important role in maintaining the integrity of the complex. In this study, we identified homologs of the SAGA complex in V. dahliae and found that deletion of the Ada1 subunit (VdAda1) causes severe defects in the formation of conidia and microsclerotia, and in melanin biosynthesis and virulence. The effect of VdAda1 on histone acetylation in V. dahliae was confirmed by western blot analysis. The deletion of VdAda1 resulted in genome-wide alteration of the V. dahliae transcriptome, including genes encoding transcription factors and secreted proteins, suggesting its prominent role in the regulation of transcription and virulence. Overall, we demonstrated that VdAda1, a member of the SAGA complex, modulates multiple physiological processes by regulating global gene expression that impinge on virulence and survival in V. dahliae.
Reduced Inter-Voxel White Matter Integrity in Subjective Cognitive Decline: Diffusion Tensor Imaging With Tract-Based Spatial Statistics Analysis
Authors: Chao Yi-Ping , Liu Po-Ting Bertram , Wang Pei-Ning , Cheng Chia-Hsiung
Published: February 2022

Subjective cognitive decline (SCD), a self-reported worsening in cognition concurrent with normal performance on standardized neuropsychological tests, has gained much attention due to its high risks in the development of mild cognitive impairments or Alzheimer’s disease. The existing cross-sectional diffusion tensor imaging (DTI) studies in SCD have shown extremely controversial findings. Furthermore, all of these studies investigated diffusion properties within the voxel, such as fractional anisotropy, mean diffusivity, or axial diffusivity (DA). However, it remains unclear whether individuals with SCD demonstrate alterations of diffusion profile between voxels and their neighbors, as indexed by local diffusion homogeneity (LDH). We selected 30 healthy controls (HCs) and 23 SCD subjects to acquire their whole-brain DTI. Diffusion images were compared using the tract-based spatial statistics method. Diffusion indices with significant between-group tract clusters were extracted from each individual for further region-of-interest (ROI)-based comparisons. Our results showed that subjects with SCD demonstrated reduced LDH in the left superior frontal gyrus (SFG) and DA in the right anterior cingulate cortex compared with the HC group. In contrast, the SCD group showed higher LDH values in the left lingual gyrus (LG) compared with the HC group. Notably, LDH in the left SFG was significantly and negatively correlated with LDH in the left LG. In conclusion, white matter (WM) integrity in the left SFG, right ACC, and left LG is altered in SCD, suggesting that individuals with SCD exhibit detectable changes in WM tracts before they demonstrate objective cognitive deficits.
Automated Quantification of Brain Lesion Volume From Post-trauma MR Diffusion-Weighted Images
Authors: Mistral Thomas , Roca Pauline , Maggia Christophe , Tucholka Alan , Forbes Florence , Doyle Senan , Krainik Alexandre , Galanaud Damien , Schmitt Emmanuelle , Kremer Stéphane , Kastler Adrian , Troprès Irène , Barbier Emmanuel L. , Payen Jean-François , Dojat Michel
Published: February 2022

Objectives

Determining the volume of brain lesions after trauma is challenging. Manual delineation is observer-dependent and time-consuming and cannot therefore be used in routine practice. The study aimed to evaluate the feasibility of an automated atlas-based quantification procedure (AQP) based on the detection of abnormal mean diffusivity (MD) values computed from diffusion-weighted MR images.

Methods

The performance of AQP was measured against manual delineation consensus by independent raters in two series of experiments based on: (i) realistic trauma phantoms (n = 5) where low and high MD values were assigned to healthy brain images according to the intensity, form and location of lesion observed in real TBI cases; (ii) severe TBI patients (n = 12 patients) who underwent MR imaging within 10 days after injury.

Results

In realistic TBI phantoms, no statistical differences in Dice similarity coefficient, precision and brain lesion volumes were found between AQP, the rater consensus and the ground truth lesion delineations. Similar findings were obtained when comparing AQP and manual annotations for TBI patients. The intra-class correlation coefficient between AQP and manual delineation was 0.70 in realistic phantoms and 0.92 in TBI patients. The volume of brain lesions detected in TBI patients was 59 ml (19–84 ml) (median; 25–75th centiles).

Conclusions

Our results support the feasibility of using an automated quantification procedure to determine, with similar accuracy to manual delineation, the volume of low and high MD brain lesions after trauma, and thus allow the determination of the type and volume of edematous brain lesions. This approach had comparable performance with manual delineation by a panel of experts. It will be tested in a large cohort of patients enrolled in the multicenter OxyTC trial (NCT02754063).
Migraine: A Review on Its History, Global Epidemiology, Risk Factors, and Comorbidities
Authors: Amiri Parastoo , Kazeminasab Somayeh , Nejadghaderi Seyed Aria , Mohammadinasab Reza , Pourfathi Hojjat , Araj-Khodaei Mostafa , Sullman Mark J. M. , Kolahi Ali-Asghar , Safiri Saeid
Published: February 2022

Migraine affects more than one billion individuals each year across the world, and is one of the most common neurologic disorders, with a high prevalence and morbidity, especially among young adults and females. Migraine is associated with a wide range of comorbidities, which range from stress and sleep disturbances to suicide. The complex and largely unclear mechanisms of migraine development have resulted in the proposal of various social and biological risk factors, such as hormonal imbalances, genetic and epigenetic influences, as well as cardiovascular, neurological, and autoimmune diseases. This review presents a comprehensive review of the most up-to-date literature on the epidemiology, and risk factors, as well as highlighting the gaps in our knowledge.
Diagnostic Impact of Monitoring Visual Evoked Potentials to Prevent Visual Complications During Endovascular Treatment for Intracranial Aneurysm
Authors: Nakagawa Ichiro , Park HunSoo , Kotsugi Masashi , Yokoyama Shohei , Omoto Kouji , Myochin Kaoru , Takeshima Yasuhiro , Matsuda Ryosuke , Nishimura Fumihiko , Yamada Shuichi , Takatani Tsunenori , Nakase Hiroyuki
Published: February 2022

Introduction

The present study aimed to determine the incidence of intraprocedural visual-evoked potential (VEP) changes and to identify correlations with intraprocedural ischemic complications during endovascular treatment in patients with intracranial aneurysm related to visual function.

Methods

This study analyzed data from 104 consecutive patients who underwent endovascular coil embolization to treat intracranial aneurysms related to visual function under VEP and transcranial motor evoked potential (MEP) monitoring. We analyzed associations between significant changes in MEP and VEP, defined as a >50% decrease in amplitude, and both intraprocedural complications and postoperative neurological deficits. Factors associated with postoperative neurological deficits were also assessed.

Results

Treated aneurysms were predominantly located in the internal carotid artery (95%). Five (5%) were located in the posterior cerebral artery (PCA). Significant decreases in intraprocedural VEP occurred in four patients (4%), although one of those four patients did not show concomitant MEP decreases during procedures. Immediate salvage procedures avoided postoperative visual disturbances. All VEP decreases were transient and not associated with postoperative visual impairment. One of three cases who underwent intraoperative balloon occlusion test showed tolerance to balloon occlusion of the proximal PCA under VEP assessment; parent artery occlusion was performed without postoperative visual disturbance in that case.

Conclusion

Although significant VEP decreases occurred 4% during neuro-endovascular aneurysm treatment related to visual function, intraprocedural VEP monitoring identifies ischemic changes associated with visual pathways and facilitates prompt initiation of salvage procedures.
Long-Term Deutetrabenazine Treatment for Tardive Dyskinesia Is Associated With Sustained Benefits and Safety: A 3-Year, Open-Label Extension Study
Authors: Hauser Robert A. , Barkay Hadas , Fernandez Hubert H. , Factor Stewart A. , Jimenez-Shahed Joohi , Gross Nicholas , Marinelli Leslie , Wilhelm Amanda , Alexander Jessica , Gordon Mark Forrest , Savola Juha-Matti , Anderson Karen E.
Published: February 2022

Background

Deutetrabenazine is a vesicular monoamine transporter 2 inhibitor approved for the treatment of tardive dyskinesia (TD) in adults. In two 12-week pivotal studies, deutetrabenazine demonstrated statistically significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores, with favorable safety/tolerability in TD patients. This study reports long-term efficacy and safety of deutetrabenazine in a 3-year, single-arm, open-label extension (OLE) study.

Methods

Patients who completed the pivotal studies could enroll in this single-arm OLE study, titrating up to 48 mg/day based on dyskinesia control and tolerability. Efficacy was assessed based on change from baseline in total motor AIMS score, Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change (PGIC), and quality of life (QOL) assessments. Safety evaluation included adverse event (AE) incidence, reported using exposure-adjusted incidence rates, and safety scales.

Results

343 patients enrolled in the study (6 patients were excluded). At Week 145 (mean dose: 39.4 ± 0.83 mg/day), mean ± SE change from baseline in total motor AIMS score was −6.6 ± 0.37 and 67% of patients achieved ≥50% improvement in total motor AIMS score. Based on CGIC and PGIC, 73% and 63% of patients achieved treatment success, respectively. QOL improvements were also observed. Deutetrabenazine was generally well tolerated, with low rates of mild-to-moderate AEs and no new safety signals; most safety scales remained unchanged over time.

Conclusions

Long-term deutetrabenazine treatment was associated with sustained improvement in AIMS scores, indicative of clinically meaningful long-term benefit, and was generally well tolerated. Results suggest deutetrabenazine may provide increasing benefit over time without increases in dose.
Up-Regulated Expression of Interferon-Gamma, Interleukin-6 and Tumor Necrosis Factor-Alpha in the Endolymphatic Sac of Meniere's Disease Suggesting the Local Inflammatory Response Underlies the Mechanism of This Disease
Authors: Huang Chao , Wang Qin , Pan Xueying , Li Wei , Liu Wei , Jiang Wenqi , Huang Li , Peng Anquan , Zhang Zhiwen
Published: February 2022

Background

Immune mediated inflammatory changes affecting the endolymphatic sac (ES) may underlie the pathology of Meniere's disease (MD). The aim of the present study was to explore the differentially expressed cytokines in ES luminal fluid (ELF) of patients with MD, and the correlation between the expression of cytokines in the ELF with that in the serum was determined by quantitatively analyzing the cytokines in human ELF and serum.

Methods

Human ELF, serum and ES tissues were collected from patients with unilateral MD and patients with acoustic neuroma (AN) during surgery. The Simoa Cytokine 6-Plex Panel kit was used to analyze the levels of cytokines in the ELF and blood samples of the patients. Immunohistochemistry and immunofluorescence were subsequently used to validate the relative expression levels of the cytokines in MD.

Results

Significant differences were identified in the expression levels of interferon-γ (IFN-γ) (P < 0.001), interleukin (IL)-6 (P = 0.008) and tumor necrosis factor-α (TNF-α) (P = 0.036) in the luminal fluid of the ES comparing between the MD and AN groups. By contrast, the levels of IFN-γ, IL-10, IL-12p70, IL-17A, IL-6 and TNF-α in the serum of the MD group were not significantly different from those of either the AN group or healthy control subjects. In addition, no significant correlations in the expression levels of cytokines compared between the ELF and serum were found for the patients in either the MD or the AN group. Finally, the detection of positive expression of TNF-α, IL-6 and IFN-γ in the epithelial cells of the majority of ES specimens from patients with MD confirmed the up-regulated expression of these cytokines in the ES of patients with MD.

Conclusions

The identification of up-regulated expression levels of TNF-α, IL-6 and IFN-γ in the ELF in the present study has provided direct evidence for an increased immunologic activity in the microenvironment of the ES in patients with unilateral MD, may suggest the local inflammatory response underlies the mechanism of this disease.
Altered Brain Morphometry in Cerebral Small Vessel Disease With Cerebral Microbleeds: An Investigation Combining Univariate and Multivariate Pattern Analyses
Authors: Li Jing , Wen Hongwei , Wang Shengpei , Che Yena , Zhang Nan , Guo Lingfei
Published: February 2022

Purpose

The objective of this study was to evaluate whether altered gray matter volume (GMV) and white matter volume (WMV) are associated with the presence of cerebral microbleeds (CMBs) in cerebral small vessel disease (CSVD).

Materials and Methods

In this study, we included 26 CSVD patients with CMBs (CSVD-c), 43 CSVD patients without CMBs (CSVD-n) and 39 healthy controls. All participants underwent cognitive assessment testing. Both univariate analysis and multivariate pattern analysis (MVPA) approaches were applied to investigate differences in brain morphometry among groups.

Results

In univariate analysis, GMV and WMV differences were compared among groups using voxel-based morphometry (VBM) with diffeomorphic anatomical registration through exponentiated lie algebra (DARTEL). Compared to healthy controls, the CSVD-c group and CSVD-n group showed significantly lower GMV than the control group in similar brain clusters, mainly including the right superior frontal gyrus (medial orbital), left anterior cingulate gyrus, right inferior frontal gyrus (triangular part) and left superior frontal gyrus (medial), while the CSVD-n group also showed significantly lower WMV in the cluster of the left superior frontal gyrus (medial). No significant GMV or WMV differences were found between the CSVD-c group and the CSVD-n group. Specifically, we applied the multiple kernel learning (MKL) technique in MVPA to combine GMV and WMV features, yielding an average of >80% accuracy for three binary classification problems, which was a considerable improvement over the individual modality approach. Consistent with the univariate analysis, the MKL weight maps revealed default mode network and subcortical region damage associated with CSVD compared to controls. On the other hand, when classifying the CSVD-c group and CSVD-n group in the MVPA analysis, we found that some WMVs were highly weighted regions (left olfactory cortex and right middle frontal gyrus), which hinted at the presence of different white matter alterations in the CSVD-c group.

Conclusion

Our findings not only suggested that the localized alterations in GMV and WMV appeared to be associated with the pathophysiology of CSVD but also indicated that altered brain morphometry could be a potential discriminative pattern to detect CSVD at the individual level.
Serum Neurofilament Light Chain Levels May Be a Marker of Lower Motor Neuron Damage in Amyotrophic Lateral Sclerosis
Authors: Zhang Linjing , Ji Tuo , Wu Chujun , Zhang Shuo , Tang Lu , Zhang Nan , Liu Xiangyi , Fan Dongsheng
Published: February 2022

Objectives The aims of this study were to investigate whether serum neurofilament light chain (NfL) levels were correlated with the severity of the axonal degeneration of lower motor neurons (LMNs) in the early symptomatic phase of amyotrophic lateral sclerosis (ALS). Methods In this prospective study, the serum samples used for NfL measurement were obtained from 103 sporadic ALS outpatients within 2 years of disease duration. The severity of axonal degeneration was assessed by assessing the decrease in the compound muscle action potentials (CMAPs) within a 1-month interval from serum sampling. Results The NfL levels showed a significant positive correlation with the relative score as a proxy for the axonal damage of LMNs in patients with ALS (coefficient: 0.264, p = 0.009). Furthermore, this correlation became stronger (coefficient: 0.582, p = 0.037) when estimated only among patients with disease subtypes that involve only LMNs, that is, patients with flail arm or leg syndrome (FAS or FLS). The levels of NfL increased with the severity of axonal damage of LMNs (F = 6.694, P = 0.0001). Conclusions Serum NfL levels mirrored the severity of the axonal degeneration of LMNs, particularly in patients with signs of predominant LMN involvement. These results may have a profound effect on the selection of patients and the monitoring of treatment efficacy in future disease-modifying clinical trials.
Multimodal Neuroimaging in Rett Syndrome With MECP2 Mutation
Authors: Kong Yu , Li Qiu-bo , Yuan Zhao-hong , Jiang Xiu-fang , Zhang Gu-qing , Cheng Nan , Dang Na
Published: February 2022

Rett syndrome (RTT) is a rare neurodevelopmental disorder characterized by severe cognitive, social, and physical impairments resulting from de novo mutations in the X-chromosomal methyl-CpG binding protein gene 2 (MECP2). While there is still no cure for RTT, exploring up-to date neurofunctional diagnostic markers, discovering new potential therapeutic targets, and searching for novel drug efficacy evaluation indicators are fundamental. Multiple neuroimaging studies on brain structure and function have been carried out in RTT-linked gene mutation carriers to unravel disease-specific imaging features and explore genotype-phenotype associations. Here, we reviewed the neuroimaging literature on this disorder. MRI morphologic studies have shown global atrophy of gray matter (GM) and white matter (WM) and regional variations in brain maturation. Diffusion tensor imaging (DTI) studies have demonstrated reduced fractional anisotropy (FA) in left peripheral WM areas, left major WM tracts, and cingulum bilaterally, and WM microstructural/network topology changes have been further found to be correlated with behavioral abnormalities in RTT. Cerebral blood perfusion imaging studies using single-photon emission CT (SPECT) or PET have evidenced a decreased global cerebral blood flow (CBF), particularly in prefrontal and temporoparietal areas, while magnetic resonance spectroscopy (MRS) and PET studies have contributed to unraveling metabolic alterations in patients with RTT. The results obtained from the available reports confirm that multimodal neuroimaging can provide new insights into a complex interplay between genes, neurotransmitter pathway abnormalities, disease-related behaviors, and clinical severity. However, common limitations related to the available studies include small sample sizes and hypothesis-based and region-specific approaches. We, therefore, conclude that this field is still in its early development phase and that multimodal/multisequence studies with improved post-processing technologies as well as combined PET–MRI approaches are urgently needed to further explore RTT brain alterations.
Application of Three-Dimensional Pseudocontinuous Arterial Spin Labeling Perfusion Imaging in the Brains of Children With Autism
Authors: Tang Shilong , Liu Xianfan , Ran Qiying , Nie Lisha , Wu Lan , Pan Zhengxia , He Ling
Published: February 2022

Objective

To explore the application of three-dimensional pseudocontinuous arterial spin labeling (3D-PCASL) perfusion imaging in the brains of children with autism and to understand the characteristics of cerebral blood perfusion in children with autism.

Methods

A total of 320 children with autism (160 men and 160 women) aged between 2 and 18 years and 320 age- and sex-matched healthy children participated in the study. All children were scanned by 3.0 T magnetic resonance axial T1 fluid-attenuated inversion recovery (FLAIR), T2 FLAIR, 3D-T1, and 3D-PCASL sequences. After postprocessing, cerebral blood flow (CBF) values in each brain region of children with autism and healthy children at the same age were compared and analyzed. Furthermore, CBF characteristics in each brain region of autistic children at various ages were determined.

Results

The CBF values of the frontal lobe, hippocampus, temporal lobe, and caudate nucleus of children with autism are lower than those of healthy children (P < 0.05). Additionally, as the ages of children with autism increase, the number of brain regions with decreased CBF values gradually increases. A receiver operating characteristic (ROC) analysis results show that the CBF values of the frontal lobe, hippocampus, temporal lobe, and caudate nucleus can distinguish children with autism [area under the ROC curve (AUC) > 0.05, P < 0.05].

Conclusion

The 3D-PCASL shows lower brain CBF values in children with autism.

Clinical Trial Registration

www.ClinicalTrials.gov, identifier: ChiCTR2000034356.
DNA Methylation Markers and Prediction Model for Depression and Their Contribution for Breast Cancer Risk
Authors: Wang Ning , Sun Jing , Pang Tao , Zheng Haohao , Liang Fengji , He Xiayue , Tang Danian , Yu Tao , Xiong Jianghui , Chang Suhua
Published: February 2022

Background

Major depressive disorder (MDD) has become a leading cause of disability worldwide. However, the diagnosis of the disorder is dependent on clinical experience and inventory. At present, there are no reliable biomarkers to help with diagnosis and treatment. DNA methylation patterns may be a promising approach for elucidating the etiology of MDD and predicting patient susceptibility. Our overarching aim was to identify biomarkers based on DNA methylation, and then use it to propose a methylation prediction score for MDD, which we hope will help us evaluate the risk of breast cancer.

Methods

Methylation data from 533 samples were extracted from the Gene Expression Omnibus (GEO) database, of which, 324 individuals were diagnosed with MDD. Statistical difference of DNA Methylation between Promoter and Other body region (SIMPO) score for each gene was calculated based on the DNA methylation data. Based on SIMPO scores, we selected the top genes that showed a correlation with MDD in random resampling, then proposed a methylation-derived Depression Index (mDI) by combining the SIMPO of the selected genes to predict MDD. A validation analysis was then performed using additional DNA methylation data from 194 samples extracted from the GEO database. Furthermore, we applied the mDI to construct a prediction model for the risk of breast cancer using stepwise regression and random forest methods.

Results

The optimal mDI was derived from 426 genes, which included 245 positive and 181 negative correlations. It was constructed to predict MDD with high predictive power (AUC of 0.88) in the discovery dataset. In addition, we observed moderate power for mDI in the validation dataset with an OR of 1.79. Biological function assessment of the 426 genes showed that they were functionally enriched in Eph Ephrin signaling and beta-catenin Wnt signaling pathways. The mDI was then used to construct a predictive model for breast cancer that had an AUC ranging from 0.70 to 0.67.

Conclusion

Our results indicated that DNA methylation could help to explain the pathogenesis of MDD and assist with its diagnosis.
Chemical Variation of Chenpi (Citrus Peels) and Corresponding Correlated Bioactive Compounds by LC-MS Metabolomics and Multibioassay Analysis
Authors: Yang Mei , Jiang Zongde , Wen Mingchun , Wu Zhenfeng , Zha Minyu , Xu Wen , Zhang Liang
Published: February 2022

The peel of Citrus reticulata “Chachi” (CP) possesses various health-promoting benefits and is not only one of the most famous Chinese herbal medicine, but also an ingredient in fermented foods. In the present study, the effects of storage years (1-, 3-, 4-, 5-, 6-, and 11-years) on the chemical profiling and potential bioactive compounds of CP were compared by metabolomics and in vitro bioactivity analysis. With the increase of storage time, the content of hesperidin significantly decreased, but nobiletin, 3,5,6,7,8,3′,4′-heptamethoxyflavone, and tangeretin were increased. Meanwhile, the antioxidant activity of CP was enhanced. Phenolic acids, flavonol glycosides, fatty acids, and alkyl glycosides were marker compounds that were responsible for distinguishing the storage time of CP. Correlation analysis suggested that some polyphenols including quercetin-glucoside, quinic acid, trihydroxydimethoxyflavone, and rutin were potential antioxidant compounds in CP. The dichloromethane and n-butanol fractions showed the better antioxidant capacity and inhibitory effects on glucose-hydrolysis enzymes. They mainly contained ferulic acid, nobiletin, 3,5,6,7,8,3′,4′-heptamethoxyflavone, kaempferol, and hesperidin.
Tspan9 Induces EMT and Promotes Osteosarcoma Metastasis via Activating FAK-Ras-ERK1/2 Pathway
Authors: Shao Shijie , Piao Lianhua , Wang Jiangsong , Guo Liwei , Wang Jiawen , Wang Luhui , Tong Lei , Yuan Xiaofeng , Han Xu , Fang Sheng , Zhu Junke , Wang Yimin
Published: February 2022

Object

At present, there are few effective treatment options available to patients suffering from osteosarcoma (OS). Clarifying the signaling pathways that govern OS oncogenesis may highlight novel approaches to treating this deadly form of cancer. Recent experimental evidence suggests that the transmembrane protein tetraspanin-9 (Tspan9) plays a role in tumor development. This study was thus formulated to assess the molecular role of Tspan9 as a regulator of OS cell metastasis.

Methods

Gene expression in OS cell lines was evaluated via qRT-PCR, while CCK-8, colony formation, Transwell, and wound healing assays were used to explore the in vitro proliferative, invasive, and migratory activities of OS cells. The relationship between Tspan9 and in vivo OS cell metastasis was assessed by injecting these cells into the tail vein of nude mice. Interactions between the Tspan9 and integrin β1 proteins were explored through mass spectrometric and co-immunoprecipitation, and Western blotting to assess the functional mechanisms whereby Tspan9 shapes OS pathogenesis.

Results

Both primary OS tumors and OS cell lines commonly exhibited Tspan9 upregulation, and the knockdown of this tetraspanin suppressed the migration, invasion, and epithelial-mesenchymal transition (EMT) activity in OS cells, whereas Tspan9 overexpression resulted in opposite phenotypes. Tumor lung metastasis were significantly impaired in mice implanted with HOS cells in which Tspan9 was downregulated as compared to mice implanted with control HOS cells. Tspan9 was also found to interact with β1 integrin and to contribute to OS metastasis via the amplification of integrin-mediated downstream FAK/Ras/ERK1/2 signaling pathway.

Conclusion

These data suggest that Tspan9 can serve as a promising therapeutic target in OS.
Non-Myeloablative Chemotherapy as Consolidation Strategy After High-Dose Methotrexate-Based Chemoimmunotherapy in Patients With Primary CNS Lymphoma: A Retrospective Single Center Study in China
Authors: Sun Xuefei , Wu Yuchen , Xing Ruixian , Bai Xueyan , Qian Jun , Zhu Hong , Cui Qu , Chen Yuedan , Liu Qing , Lai Wenyuan , Li Junhong , Wang Yaming , Sun Shengjun , Gao Chunji , Ji Nan , Liu Yuanbo
Published: February 2022

Primary central nervous system lymphoma (PCNSL) remains a disease with poor outcome and high recurrence rate. We retrospectively analyzed the clinical data of 243 immunocompetent patients with PCNSL in Beijing Tiantan Hospital. The median age of PCNSL patients was 57 years (range 10-95 years). For induction therapy, 94.7% of patients received high-dose methotrexate (HD-MTX) containing regimens, and 59.3% received rituximab, which increased over time. The overall response rate was 72.8%, with 58.8% achieving complete response. With a median follow-up of 27.0 months (95% confidence interval 23.6-30.4), the median progression-free survival (PFS) time was 14.0 months (95% CI 9.45-18.55), and the 2-year PFS rate was 33.2%. The median overall survival (OS) was not reached (NR), with an estimated overall survival rate at 4 years of 61.6%. Among 95 patients who completed sequential consolidation chemotherapy with either pemetrexed or etoposide plus cytarabine, the median PFS was 28 months (95% CI 17.11-38.89), and the estimated overall survival at 4 years was 78.7%. In conclusion, HD-MTX based induction chemotherapy with non-myeloablative sequential consolidation chemotherapy is an alternative feasible treatment option.
Differentiation Between Benign and Metastatic Breast Lymph Nodes Using Apparent Diffusion Coefficients
Authors: Fardanesh Reza , Thakur Sunitha B. , Sevilimedu Varadan , Horvat Joao V. , Gullo Roberto Lo , Reiner Jeffrey S. , Eskreis-Winkler Sarah , Thakur Nikita , Pinker Katja
Published: February 2022

The aim of this study was to determine the range of apparent diffusion coefficient (ADC) values for benign axillary lymph nodes in contrast to malignant axillary lymph nodes, and to define the optimal ADC thresholds for three different ADC parameters (minimum, maximum, and mean ADC) in differentiating between benign and malignant lymph nodes. This retrospective study included consecutive patients who underwent breast MRI from January 2017–December 2020. Two-year follow-up breast imaging or histopathology served as the reference standard for axillary lymph node status. Area under the receiver operating characteristic curve (AUC) values for minimum, maximum, and mean ADC (min ADC, max ADC, and mean ADC) for benign vs malignant axillary lymph nodes were determined using the Wilcoxon rank sum test, and optimal ADC thresholds were determined using Youden’s Index. The final study sample consisted of 217 patients (100% female, median age of 52 years (range, 22–81), 110 with benign axillary lymph nodes and 107 with malignant axillary lymph nodes. For benign axillary lymph nodes, ADC values (×10−3 mm2/s) ranged from 0.522–2.712 for mean ADC, 0.774–3.382 for max ADC, and 0.071–2.409 for min ADC; for malignant axillary lymph nodes, ADC values (×10−3 mm2/s) ranged from 0.796–1.080 for mean ADC, 1.168–1.592 for max ADC, and 0.351–0.688 for min ADC for malignant axillary lymph nodes. While there was a statistically difference in all ADC parameters (p<0.001) between benign and malignant axillary lymph nodes, boxplots illustrate overlaps in ADC values, with the least overlap occurring with mean ADC, suggesting that this is the most useful ADC parameter for differentiating between benign and malignant axillary lymph nodes. The mean ADC threshold that resulted in the highest diagnostic accuracy for differentiating between benign and malignant lymph nodes was 1.004×10−3 mm2/s, yielding an accuracy of 75%, sensitivity of 71%, specificity of 79%, positive predictive value of 77%, and negative predictive value of 74%. This mean ADC threshold is lower than the European Society of Breast Imaging (EUSOBI) mean ADC threshold of 1.300×10−3 mm2/s, therefore suggesting that the EUSOBI threshold which was recently recommended for breast tumors should not be extrapolated to evaluate the axillary lymph nodes.
Transcriptional Expressions of ALDH1A1/B1 as Independent Indicators for the Survival of Thyroid Cancer Patients
Authors: Cui Ying , Liu Yao , Mu Lan , Li Yang , Wu Gang
Published: February 2022

Background

Aldehyde dehydrogenase (ALDH) 1 is an important enzyme involved in the regulation of several cellular mechanisms via aldehyde detoxification. High ALDH1 levels were correlated with tumorigenesis and stemness maintenance in cancer.

Methods

We used UALCAN, Human Protein Atlas, Kaplan–Meier plotter, TISIDB, TIMER, and KOBAS databases to investigate the expression and role of ALDH1 in thyroid cancer progression. In addition, quantitative real-time polymerase chain reaction was performed to detect the expression of the target genes in thyroid cancer cell lines and cancer tissues.

Results

Expression of ALDH1A1/B1 was significantly decreased based on individual cancer stages and tumor histology, and high levels of ALDH1A1/B1 were associated with poor overall survival in thyroid cancer patients. Moreover, ALDH1A1/B1 expression was negatively correlated with immune-stimulating genes, major histocompatibility complex, chemokines, and receptors.

Conclusions

These results suggest that ALDH1A1/B1 might serve as potential prognostic biomarkers for thyroid cancer diagnosis.
NCAPG as a Novel Prognostic Biomarker in Glioma
Authors: Jiang Xiulin , Shi Yulin , Chen Xi , Xu Haitao , Liu Bohu , Zhou Fan , Huang Xiaobin , Cho William C. , Li Lihua , Pu Jun
Published: February 2022

Background

Non-SMC condensin I complex subunit G (NCAPG) is expressed in various human cancers, including gliomas. However, its biological function in glioma remains unclear. The present study was designed to determine the biological functions of NCAPG in glioma and to evaluate the association of NCAPG expression with glioma progression.

Methods

Clinical data on patients with glioma were obtained from The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), the Gene Expression Omnibus (GEO), and the Rembrandt and Gravendeel databases. The correlations among NCAPG expression, pathological characteristics, and clinical outcome were evaluated. In addition, the correlations of NCAPG expression with immune cell infiltration and glioma progression were analyzed.

Results

NCAPG expression was higher in gliomas than in adjacent normal tissues. Higher expression of NCAPG in gliomas correlated with poorer prognosis, unfavorable histological features, absence of mutations in the isocitrate dehydrogenase gene (IDH), absence of chromosome 1p and 19q deletions, and responses to chemoradiotherapy. Univariate and multivariate Cox analysis demonstrated, in addition to patient age, tumor grade, absence of IDH mutations, and absence of chromosome 1p and 19q deletions, NCAPG expression was independently prognostic of overall survival, disease-free survival, and progression-free survival in patients with glioma. In addition, high expression of NCAPG correlated with tumor infiltration of B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells. Gene set enrichment analysis (GSEA) indicated that high NCAPG expression was associated with cell proliferation and immune response-related signaling pathways. NCAPG knockdown in glioma cell lines significantly reduced cell survival, proliferation, and migration.

Conclusion

NCAPG expression correlates with glioma progression and immune cell infiltration, suggesting that NCAPG expression may be a useful prognostic biomarker for glioma.
Prognostic Significance of Galectin-1 but Not Galectin-3 in Patients With Lung Adenocarcinoma After Radiation Therapy
Authors: Huang Chun-Chieh , Chuang I-Chieh , Su Yu-Li , Luo Hao-Lun , Chang Ya-Chun , Chen Jo-Ying , Hsiao Chang-Chun , Huang Eng-Yen
Published: February 2022

Introduction

To investigate the role of tumor galectin-1 and galectin-3 in patients with lung adenocarcinoma after definitive radiation therapy.

Methods

A total of 41 patients with localized lung adenocarcinoma undergoing thoracic radiation therapy without concurrent chemotherapy were enrolled. Their paraffin-embedded lung tissues were sent for immunohistochemical staining for galectin-1 and galectin-3. The clinical treatment outcomes, including overall (OS), locoregional progression-free (LRPFS), and distant metastasis-free (DMFS) survivals, were evaluated. Univariable and multivariable Cox regression analyses were applied.

Results

Overexpression of tumor galectin-1 and galectin-3 were found in 26.8% and 19.5% of patients, respectively. Overexpression of tumor galectin-1 was the most significant prognosticator to predict worse LRPFS in both univariable (p = 0.007) and multivariable analyses (p = 0.022). Besides, patients with overexpression of tumor galectin-1 had a trend of worse OS (p = 0.066) than those with low expression in multivariable analysis, and worse DMFS (p = 0.035) in univariable analysis. The overexpression of tumor galectin-3 had no significant effect on survival outcomes.

Conclusions

The overexpression of tumor galectin-1, but not galectin-3, is associated with poor LRPFS of patients with lung adenocarcinoma after thoracic radiation therapy. Future research on the mechanism of galectin-1 affecting radiation response in lung adenocarcinoma may be worth exploring.
Comprehensive Analysis of the Transcriptome-Wide m6A Methylome in Endometrioid Ovarian Cancer
Authors: Yang Li , Chen Xin , Qian Xiang , Zhang Jiejie , Wu Meijuan , Yu Aijun
Published: February 2022

Emerging studies have revealed that N6-methyladenosine modification is involved in the development of various cancers. However, the m6A modification pattern of endometrioid ovarian cancer (EOC) has not been demonstrated. In the present study, high-throughput sequencing combined with methylated RNA immunoprecipitation (MeRIP-seq) and RNA sequencing were used to obtain the transcriptome-wide m6A modifications of endometrioid ovarian cancer for the first time. The roles of methyltransferase-like 3 (METTL3) in EOC cell line COV362 were explored. In total, 39,237 m6A-modified peaks related to 17,082 genes were identified in the EOC group, and 52,848 m6A peaks representing 19,349 genes were detected in endometriosis group. Functional enrichment analysis revealed that m6A enriched genes were associated with tight junctions, cell adhesion molecules, platinum drug resistance, adherens junction, and more. METTL3 knockdown in the COV362 cells significantly decreased cell proliferation, promoted cell apoptosis, and induced cell cycle arrest at the G0/G1 phase. Our study presented the transcriptome-wide m6A modifications of endometrioid ovarian cancer for the first time and revealed various differentially expressed genes with methylated m6A modifications. This study may provide new directions for in-depth research of the underlying molecular mechanisms and signaling pathways of EOC development and progression.