bluuebunny/crossref_metadata_2025 huggingface dataset:
The Prospect of China’s Renewable Automotive Industry Upon Shrinking Subsidies
Authors: Qiu Lin-Shu , Yang Dong-Xiao , Hong Kai-Rong , Wu Wei-Ping , Zeng Wei-Kang
Published: April 2021

Increased emissions from road traffic resulting from the increase in car ownership have put enormous pressure on China’s environmental problems. To solve this problem, the Chinese government has attached great importance to the development of a new energy vehicle industry. This paper summarizes the incentive policies of China’s new energy vehicle industry. By sorting through the incentive policy system of the new energy vehicle industry, we find that the Chinese government’s promotion policy for the new energy vehicle industry is a process of gradual transformation from being government-led to being market-led. In this process, with the decrease of the subsidy amount, it is bound to cause a huge impact on the new energy vehicle industry.
Permeability Enhancement Properties of High-Pressure Abrasive Water Jet Flushing and Its Application in a Soft Coal Seam
Authors: Zhang Xinzhe , Wiśniewski Piotr , Dykas Sławomir , Zhang Guojie
Published: April 2021

High-pressure abrasive water jet flushing (HPAWJF) is an effective method used to improve coal seam permeability. In this study, based on the theories of gas flow and coal deformation, a coupled gas-rock model is established to investigate realistic failure processes by introducing equations for the evolution of mesoscopic element damage along with coal mass deformation. Numerical simulation of the failure and pressure relief processes is carried out under different coal seam permeability and flushing length conditions. Distributions of the seepage and gas pressure fields of the realistic failure process are analyzed. The effects of flushing permeability enhancement in a soft coal seam on the gas drainage from boreholes are revealed by conducting a field experiment. Conclusions can be extracted that the gas pressure of the slotted soft coal seam is reduced and that the gas drainage volume is three times higher than that of a conventional borehole. Field tests demonstrate that the gas drainage effect of the soft coal seam is significantly improved and that tunneling speed is nearly doubled. The results obtained from this study can provide guidance to gas drainage in soft coal seams regarding the theory and practice application of the HPAWJF method.
Bioinformatic Analysis of Crosstalk Between circRNA, miRNA, and Target Gene Network in NAFLD
Authors: Du Cen , Shen Lan , Ma Zhuoqi , Du Jian , Jin Shi
Published: April 2021

Background: The majority of chronic liver disease is caused by non-alcoholic fatty liver disease (NAFLD), which is one of the highly prevalent diseases worldwide. The current studies have found that non-coding RNA (ncRNA) plays an important role in the NAFLD, but few studies on circRNA. In this study, genes, microRNA (miRNA), and circular RNA (circRNA) associated with NAFLD were found by bioinformatic methods, bringing a novel perspective for the prevention and treatment of NAFLD.

Methods: Expression data of GSE63067 was acquired from Gene Expression Omnibus (GEO) database. The liver samples were collected from the people diagnosed with NAFLD or not. Differentially expressed genes (DEGs) were obtained from the steatosis vs. the control group and non-alcoholic steatohepatitis (NASH) vs. the control group using the GEO2R online tool. The overlapping genes remained for further functional enrichment analysis and protein-protein interaction network analysis. MiRNAs and circRNAs targeting these overlapping DEGs were predicted from the databases. Finally, the GSE134146 dataset was used to verify the expression of circRNA.

Results: In summary, 228 upregulated and 63 downregulated differential genes were selected. The top 10 biological processes and relative signaling pathways of the upregulated differential genes were obtained. Also, ten hub genes were performed in the Protein-protein interaction (PPI) network. One hundred thirty-nine miRNAs and 902 circRNAs were forecast for the differential genes by the database. Ultimately, the crosstalk between hsa_circ_0000313, miR-6512-3p, and PEG10 was constructed.

Conclusion: The crosstalk of hsa_circ_0000313-hsa-miR-6512-3p-PEG10 and some related non-coding RNAs may take part in NAFLD’s pathogenesis, which could be the potential biomarkers of NAFLD in the future.
NSP2 Is Important for Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus to Trigger High Fever-Related COX-2-PGE2 Pathway in Pigs
Authors: Du Li , Wang Honglei , Liu Fang , Wei Zeyu , Weng Changjiang , Tang Jun , Feng Wen-hai
Published: April 2021

In 2006, atypical porcine reproductive and respiratory syndrome (PRRS) caused by a highly pathogenic PRRSV (HP-PRRSV) strain broke out in China. Atypical PRRS is characterized by extremely high fever and high mortality in pigs of all ages. Prostaglandin E2 (PGE2) derived from arachidonic acid through the activation of the rate-limiting enzyme cyclooxygenase type 1/2 (COX-1/2) plays an important role in fever. Here, we showed that HP-PRRSV infection increased PGE2 production in microglia via COX-2 up-regulation depending on the activation of MEK1-ERK1/2-C/EBPβ signaling pathways. Then, we screened HP-PRRSV proteins and demonstrated that HP-PRRSV nonstructural protein 2 (NSP2) activated MEK1-ERK1/2-C/EBPβ signaling pathways by interacting with 14-3-3ζ to promote COX-2 expression, leading to PGE2 production. Furthermore, we identified that the amino acid residues 500-596 and 658-777 in HP-PRRSV NSP2 were essential to up-regulate COX-2 expression and PGE2 production. Finally, we made mutant HP-PRRS viruses with the deletion of residues 500-596 and/or 658-777, and found out that these viruses had impaired ability to up-regulate COX-2 and PGE2 production in vitro and in vivo. Importantly, pigs infected with the mutant viruses had relieved fever, clinical symptoms, and mortality. These data might help us understand the molecular mechanisms underlying the high fever and provide clues for the development of HP-PRRSV attenuated vaccines.
The Epigenetic Modulation of Cancer and Immune Pathways in Hepatitis B Virus-Associated Hepatocellular Carcinoma: The Influence of HBx and miRNA Dysregulation
Authors: Sartorius Kurt , An Ping , Winkler Cheryl , Chuturgoon Anil , Li Xiaodong , Makarova Julia , Kramvis Anna
Published: April 2021

Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) pathogenesis is fueled by persistent HBV infection that stealthily maintains a delicate balance between viral replication and evasion of the host immune system. HBV is remarkably adept at using a combination of both its own, as well as host machinery to ensure its own replication and survival. A key tool in its arsenal, is the HBx protein which can manipulate the epigenetic landscape to decrease its own viral load and enhance persistence, as well as manage host genome epigenetic responses to the presence of viral infection. The HBx protein can initiate epigenetic modifications to dysregulate miRNA expression which, in turn, can regulate downstream epigenetic changes in HBV-HCC pathogenesis. We attempt to link the HBx and miRNA induced epigenetic modulations that influence both the HBV and host genome expression in HBV-HCC pathogenesis. In particular, the review investigates the interplay between CHB infection, the silencing role of miRNA, epigenetic change, immune system expression and HBV-HCC pathogenesis. The review demonstrates exactly how HBx-dysregulated miRNA in HBV-HCC pathogenesis influence and are influenced by epigenetic changes to modulate both viral and host genome expression. In particular, the review identifies a specific subset of HBx induced epigenetic miRNA pathways in HBV-HCC pathogenesis demonstrating the complex interplay between HBV infection, epigenetic change, disease and immune response. The wide-ranging influence of epigenetic change and miRNA modulation offers considerable potential as a therapeutic option in HBV-HCC.
The Regulatory Mechanism of Sexual Development in Decapod Crustaceans
Authors: Farhadi Ardavan , Cui Wenxiao , Zheng Huaiping , Li Shengkang , Zhang Yueling , Ikhwanuddin Mhd , Ma Hongyu
Published: April 2021

Crustacean culture has been developing rapidly in various parts of the world. Therefore, it is important to understand their reproductive biology. Insulin-like androgenic gland hormone (IAG) secreted from the androgenic gland (AG) is widely accepted as a key regulator of sexual differentiation in male crustaceans. However, recently several sex-related genes (i.e.,CFSH,DEAD-boxfamily,Tra-2,Sxl,Dsx,Fem-1,Soxgene family,Foxl2, andDmrtgene family) have been identified via transcriptomic analysis in crustaceans, indicating that sexual differentiation in crustaceans is more complicated than previously expected. It has been found that several non-coding RNAs (i.e., miRNAs, lncRNAs, and piRNAs) and IAG receptors may be involved in the sexual development of decapods. Identification and study of the regulation mechanism of sex-related genes, non-coding RNAs, and IAG receptors will provide valuable information regarding sexual development in decapods. In this review, the roles of hormonal and genetic factors in both males and females are discussed. In males, crustacean female sex hormone (CFSH),Sxl,Dmrtgene family,Dsx,Soxgene family,GEM,Fem-1, l-GnRH-III, and corazonin play important roles inIAGregulation in the “eyestalk-IAG-testis” endocrine axis. Unlike males, the regulation mechanism and interaction of sexual genes are relatively unknown in females. However,CFSH,IAG,Fem-1,FAMeT,Slo,UCHLs,Erk2,Cdc2,EGFR,Vg,VgR, andVIHseem to play crucial roles during ovarian development. This study summarizes the available information in the field, highlights gaps, and lays the foundations for further studies and a better understanding of the regulatory mechanism of sexual development in decapods.
A COVID-19 Test Triage Tool, Predicting Negative Results and Reducing the Testing Burden on Healthcare Systems During a Pandemic
Authors: Lundon Dara J. , Kelly Brian D. , Nair Sujit , Bolton Damien M. , Patel Gopi , Reich David , Tewari Ashutosh
Published: April 2021

Background: Detecting and isolating cases of COVID-19 are amongst the key elements listed by the WHO to reduce transmission. This approach has been reported to reduce those symptomatic with COVID-19 in the population by over 90%. Testing is part of a strategy that will save lives. Testing everyone maybe ideal, but it is not practical. A risk tool based on patient demographics and clinical parameters has the potential to help identify patients most likely to test negative for SARS-CoV-2. If effective it could be used to aide clinical decision making and reduce the testing burden.

Methods: At the time of this analysis, a total of 9,516 patients with symptoms suggestive of Covid-19, were assessed and tested at Mount Sinai Institutions in New York. Patient demographics, clinical parameters and test results were collected. A robust prediction pipeline was used to develop a risk tool to predict the likelihood of a positive test for Covid-19. The risk tool was analyzed in a holdout dataset from the cohort and its discriminative ability, calibration and net benefit assessed.

Results: Over 48% of those tested in this cohort, had a positive result. The derived model had an AUC of 0.77, provided reliable risk prediction, and demonstrated a superior net benefit than a strategy of testing everybody. When a risk cut-off of 70% was applied, the model had a negative predictive value of 96%.

Conclusion: Such a tool could be used to help aide but not replace clinical decision making and conserve vital resources needed to effectively tackle this pandemic.
Active Management Reduces the Incidence of Recurrent Pre-eclampsia and Improves Maternal and Fetal Outcomes in Women With Recurrent Pre-eclampsia
Authors: Dong Xin , Han Min , Zeb Shahn , Tong Mancy , Li Xuelan , Chen Qi
Published: April 2021

Background: Women with previous pre-eclampsia are at an increased risk of developing recurrent pre-eclampsia. Intervention with low dose aspirin had been recommended to reduce the incidence of recurrent pre-eclampsia. However, the association between interventions and maternal and neonatal outcomes in subsequent pregnancies in women with previous pre-eclampsia has not been fully studied.

Methods: In this prospective study, a total of 41 patients with previous pre-eclampsia received low dose aspirin and active management (including psychological and physiological intervention), between 10 to 28 weeks until 32 to 34 weeks in our regional referral hospital. The recurrence of pre-eclampsia, and maternal and neonatal outcomes in this pregnancy were analyzed and compared to our previous study which reported a 60% recurrence of pre-eclampsia in our regional referral hospital.

Results: Thirteen women with previous pre-eclampsia developed recurrent pre-eclampsia. The time of onset or severity of pre-eclampsia in the previous pregnancy was not associated with the incidence of recurrent pre-eclampsia. The time of onset of previous pre-eclampsia was also not associated with the time of onset in subsequent pre-eclampsia. However, the number of severe recurrent pre-eclampsia was significantly reduced, compared to their first pregnancies. The number of SGA and stillbirth/neonatal death was also significantly reduced in recurrent pre-eclampsia that was actively managed, compared to their first pregnancies.

Conclusion: Despite the small sample size included in this study, our study demonstrates that active obstetric management reduces the incidence of recurrent pre-eclampsia, compared to our previous study, and reduces the severity of recurrent pre-eclampsia. It also improves neonatal outcomes in recurrent pre-eclampsia. However, because of no controls in this study, our findings need to confirmed by a case-control or randomized clinical trial study.
Correlation of Breed, Growth Performance, and Rumen Microbiota in Two Rustic Cattle Breeds Reared Under Different Conditions
Authors: Daghio Matteo , Ciucci Francesca , Buccioni Arianna , Cappucci Alice , Casarosa Laura , Serra Andrea , Conte Giuseppe , Viti Carlo , McAmmond Breanne M. , Van Hamme Jonathan D. , Mele Marcello
Published: April 2021

The use of rustic cattle is desirable to face challenges brought on by climate change. Maremmana (MA) and Aubrac (AU) are rustic cattle breeds that can be successfully used for sustainable production. In this study, correlations between two rearing systems (feedlot and grazing) and the rumen microbiota, the lipid composition of rumen liquor (RL), and the growth performance of MA and AU steers were investigated. Bacterial community composition was characterized by high-throughput sequencing of 16S rRNA gene amplicons, and the RL lipid composition was determined by measuring fatty acid (FA) and the dimethyl acetal profiles. The main factor influencing bacterial community composition was the cattle breed. Some bacterial groups were positively correlated to average daily weight gain for the two breeds (i.e., Rikenellaceae RC9 gut group, Fibrobacter and Succiniclasticum in the rumen of MA steers, and Succinivibrionaceae UCG-002 in the rumen of AU steers); despite this, animal performance appeared to be influenced by short chain FAs production pathways and by the presence of H2 sinks that divert the H2 to processes alternative to the methanogenesis.
A Deep Graph Network–Enhanced Sampling Approach to Efficiently Explore the Space of Reduced Representations of Proteins
Authors: Errica Federico , Giulini Marco , Bacciu Davide , Menichetti Roberto , Micheli Alessio , Potestio Raffaello
Published: April 2021

The limits of molecular dynamics (MD) simulations of macromolecules are steadily pushed forward by the relentless development of computer architectures and algorithms. The consequent explosion in the number and extent of MD trajectories induces the need for automated methods to rationalize the raw data and make quantitative sense of them. Recently, an algorithmic approach was introduced by some of us to identify the subset of a protein’s atoms, or mapping, that enables the most informative description of the system. This method relies on the computation, for a given reduced representation, of the associated mapping entropy, that is, a measure of the information loss due to such simplification; albeit relatively straightforward, this calculation can be time-consuming. Here, we describe the implementation of a deep learning approach aimed at accelerating the calculation of the mapping entropy. We rely on Deep Graph Networks, which provide extreme flexibility in handling structured input data and whose predictions prove to be accurate and-remarkably efficient. The trained network produces a speedup factor as large as 105 with respect to the algorithmic computation of the mapping entropy, enabling the reconstruction of its landscape by means of the Wang–Landau sampling scheme. Applications of this method reach much further than this, as the proposed pipeline is easily transferable to the computation of arbitrary properties of a molecular structure.
Terminal Epitope-Dependent Branch Preference of Siglecs Toward N-Glycans
Authors: Wang Shuaishuai , Chen Congcong , Guan Minhui , Liu Ding , Wan Xiu-Feng , Li Lei
Published: April 2021

Siglecs are sialic acid–binding immunoglobulin-like lectins that play vital roles in immune cell signaling. Siglecs help the immune system distinguish between self and nonself through the recognition of glycan ligands. While the primary binding specificities of Siglecs are known to be divergent, their specificities for complex glycans remain unclear. Herein, we determined N-glycan binding profiles of a set of Siglecs by using a complex asymmetric N-glycan microarray. Our results showed that Siglecs had unique terminal epitope-dependent branch preference when recognizing asymmetric N-glycans. Specifically, human Siglec-3, -9, and -10 prefer the α1-3 branch when Siaα2-6Galβ1-4GlcNAc terminal epitope serves as the binding ligand but prefer the opposite α1-6 branch when Siaα2-3Galβ1-4GlcNAc epitope serves as the ligand. Interestingly, Siglec-10 exhibited dramatic binding divergence toward a pair of Neu5Ac-containing asymmetric N-glycan isomers, as well as their Neu5Gc-containing counterparts. This new information on complex glycan recognition by Siglecs provides insights into their biological roles and applications.
Hiding in Plain Sight: Formation and Function of Stress Granules During Microbial Infection of Mammalian Cells
Authors: Tweedie Alistair , Nissan Tracy
Published: April 2021

Stress granule (SG) formation is a host cell response to stress-induced translational repression. SGs assemble with RNA-binding proteins and translationally silent mRNA. SGs have been demonstrated to be both inhibitory to viruses, as well as being subverted for viral roles. In contrast, the function of SGs during non-viral microbial infections remains largely unexplored. A handful of microbial infections have been shown to result in host SG assembly. Nevertheless, a large body of evidence suggests SG formation in hosts is a widespread response to microbial infection. Diverse stresses caused by microbes and their products can activate the integrated stress response in order to inhibit translation initiation through phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α). This translational response in other contexts results in SG assembly, suggesting that SG assembly can be a general phenomenon during microbial infection. This review explores evidence for host SG formation in response to bacterial, fungal, and protozoan infection and potential functions of SGs in the host and for adaptations of the pathogen.
Profiling Thermus thermophilus Argonaute Guide DNA Sequence Preferences by Functional Screening
Authors: Hunt Eric A. , Tamanaha Esta , Bonanno Kevin , Cantor Eric J. , Tanner Nathan A.
Published: April 2021

Prokaryotic Argonautes (pAgo) are an increasingly well-studied class of guided endonucleases, and the underlying mechanisms by which pAgo generate nucleic acid guides in vivo remains an important topic of investigation. Recent insights into these mechanisms for the Argonaute protein from Thermus thermophilus has drawn attention to global sequence and structural feature preferences involved in oligonucleotide guide selection. In this work, we approach the study of guide sequence preferences in T. thermophilus Argonaute from a functional perspective. Screening a library of 1,968 guides against randomized single- and double-stranded DNA substrates, endonuclease activity associated with each guide was quantified using high-throughput capillary electrophoresis, and localized sequence preferences were identified which can be used to improve guide design for molecular applications. The most notable preferences include: a strong cleavage enhancement from a first position dT independent of target sequence; a significant decrease in activity with dA at position 12; and an impact of GC dinucleotides at positions 10 and 11. While this method has been useful in characterizing unique preferences of T. thermophilus Argonaute and criteria for creating efficient guides, it could be expanded further to rapidly characterize more recent mesophilic variants reported in the literature and drive their utility toward molecular tools in biology and genome editing applications.
From Prokaryotes to Eukaryotes: Insights Into the Molecular Structure of Glycogen Particles
Authors: Liu Qing-Hua , Tang Jia-Wei , Wen Peng-Bo , Wang Meng-Meng , Zhang Xiao , Wang Liang
Published: April 2021

Glycogen is a highly-branched polysaccharide that is widely distributed across the three life domains. It has versatile functions in physiological activities such as energy reserve, osmotic regulation, blood glucose homeostasis, and pH maintenance. Recent research also confirms that glycogen plays important roles in longevity and cognition. Intrinsically, glycogen function is determined by its structure that has been intensively studied for many years. The recent association of glycogen α-particle fragility with diabetic conditions further strengthens the importance of glycogen structure in its function. By using improved glycogen extraction procedures and a series of advanced analytical techniques, the fine molecular structure of glycogen particles in human beings and several model organisms such asEscherichia coli,Caenorhabditis elegans,Mus musculus, andRat rattushave been characterized. However, there are still many unknowns about the assembly mechanisms of glycogen particles, the dynamic changes of glycogen structures, and the composition of glycogen associated proteins (glycogen proteome). In this review, we explored the recent progresses in glycogen studies with a focus on the structure of glycogen particles, which may not only provide insights into glycogen functions, but also facilitate the discovery of novel drug targets for the treatment of diabetes mellitus.
Increased MANF Expression in the Inferior Temporal Gyrus in Patients With Alzheimer Disease
Authors: Liu Xue-Chun , Qi Xiu-Hong , Fang Hui , Zhou Ke-Qing , Wang Qing-Song , Chen Gui-Hai
Published: April 2021

Alzheimer disease (AD) is an aging-related disorder linked to endoplasmic reticulum (ER) stress. The main pathologic feature of AD is the presence of extracellular senile plaques and intraneuronal neurofibrillary tangles (NFTs) in the brain. In neurodegenerative diseases, the unfolded protein response (UPR) induced by ER stress ensures cell survival. Mesencephalic astrocyte-derived neurotrophic factor (MANF) protects against ER stress and has been implicated in the pathogenesis of AD. MANF is expressed in neurons of the brain and spinal cord. However, there have been no investigations on MANF expression in the brain of AD patients. This was addressed in the present study by immunohistochemistry, western blotting, and quantitative analyses of postmortem brain specimens. We examined the localization and expression levels of MANF in the inferior temporal gyrus of the cortex (ITGC) in AD patients (n = 5), preclinical (pre-)AD patients (n = 5), and age-matched non-dementia controls (n = 5) by double immunofluorescence labeling with antibodies against the neuron-specific nuclear protein neuronal nuclei (NeuN), ER chaperone protein 78-kDa glucose-regulated protein (GRP78), and MANF. The results showed that MANF was mainly expressed in neurons of the ITGC in all 3 groups; However, the number of MANF-positive neurons was significantly higher in pre-AD (Braak stage III/IV) and AD (Braak stage V/VI) patients than that in the control group. Thus, MANF is overexpressed in AD and pre-AD, suggesting that it can serve as a diagnostic marker for early stage disease.
A Proposed Hypothesis on Dementia: Inflammation, Small Vessel Disease, and Hypoperfusion Is the Sequence That Links All Harmful Lifestyles to Cognitive Impairment
Authors: Hakim Antoine M.
Published: April 2021

There is growing consensus that certain lifestyles can contribute to cognitive impairment and dementia, but the physiological steps that link a harmful lifestyle to its negative impact are not always evident. It is also unclear whether all lifestyles that contribute to dementia do so through the same intermediary steps. This article will focus on three lifestyles known to be risk factors for dementia, namely obesity, sedentary behavior, and insufficient sleep, and offer a unifying hypothesis proposing that lifestyles that negatively impact cognition do so through the same sequence of events: inflammation, small vessel disease, decline in cerebral perfusion, and brain atrophy. The hypothesis will then be tested in a recently identified risk factor for dementia, namely hearing deficit. If further studies confirm this sequence of events leading to dementia, a significant change in our approach to this debilitating and costly condition may be necessary, possible, and beneficial.
In vivo Morphometry of Inner Plexiform Layer (IPL) Stratification in the Human Retina With Visible Light Optical Coherence Tomography
Authors: Zhang Tingwei , Kho Aaron M. , Srinivasan Vivek J.
Published: April 2021

From the bipolar cells to higher brain visual centers, signals in the vertebrate visual system are transmitted along parallel on and off pathways. These two pathways are spatially segregated along the depth axis of the retina. Yet, to our knowledge, there is no way to directly assess this anatomical stratification in vivo. Here, employing ultrahigh resolution visible light Optical Coherence Tomography (OCT) imaging in humans, we report a stereotyped reflectivity pattern of the inner plexiform layer (IPL) that parallels IPL stratification. We characterize the topography of this reflectivity pattern non-invasively in a cohort of normal, young adult human subjects. This proposed correlate of IPL stratification is accessible through non-invasive ocular imaging in living humans. Topographic variations should be carefully considered when designing studies in development or diseases of the visual system.
Novel Tools and Investigative Approaches for the Study of Oligodendrocyte Precursor Cells (NG2-Glia) in CNS Development and Disease
Authors: Galichet Christophe , Clayton Richard W. , Lovell-Badge Robin
Published: April 2021

Oligodendrocyte progenitor cells (OPCs), also referred to as NG2-glia, are the most proliferative cell type in the adult central nervous system. While the primary role of OPCs is to serve as progenitors for oligodendrocytes, in recent years, it has become increasingly clear that OPCs fulfil a number of other functions. Indeed, independent of their role as stem cells, it is evident that OPCs can regulate the metabolic environment, directly interact with and modulate neuronal function, maintain the blood brain barrier (BBB) and regulate inflammation. In this review article, we discuss the state-of-the-art tools and investigative approaches being used to characterize the biology and function of OPCs. From functional genetic investigation to single cell sequencing and from lineage tracing to functional imaging, we discuss the important discoveries uncovered by these techniques, such as functional and spatial OPC heterogeneity, novel OPC marker genes, the interaction of OPCs with other cells types, and how OPCs integrate and respond to signals from neighboring cells. Finally, we review the use of in vitro assay to assess OPC functions. These methodologies promise to lead to ever greater understanding of this enigmatic cell type, which in turn will shed light on the pathogenesis and potential treatment strategies for a number of diseases, such as multiple sclerosis (MS) and gliomas.
The Modulatory Effects of Intermittent Theta Burst Stimulation in Combination With Mirror Hand Motor Training on Functional Connectivity: A Proof-of-Concept Study
Authors: Zhang Jack Jiaqi , Fong Kenneth N. K.
Published: April 2021

Mirror training (MT) is an observation-based motor learning strategy. Intermittent theta burst stimulation (iTBS) is an accelerated form of excitatory repetitive transcranial magnetic stimulation (rTMS) that has been used to enhance the cortical excitability of the motor cortices. This study aims to investigate the combined effects of iTBS with MT on the resting state functional connectivity at alpha frequency band in healthy adults. Eighteen healthy adults were randomized into one of three groups—Group 1: iTBS plus MT, Group 2: iTBS plus sham MT, and Group 3: sham iTBS plus MT. Participants in Groups 1 and 3 observed the mirror illusion of the moving (right) hand in a plain mirror for four consecutive sessions, one session/day, while participants in Group 2 received the same training with a covered mirror. Real or sham iTBS was applied daily over right motor cortex prior to the training. Resting state electroencephalography (EEG) at baseline and post-training was recorded when participants closed their eyes. The mixed-effects model demonstrated a significant interaction effect in the coherence between FC4 and C4 channels, favoring participants in Group 1 over Group 3 (Δβ = −0.84, p = 0.048). A similar effect was also found in the coherence between FC3 and FC4 channels favoring Group 1 over Group 3 (Δβ = −0.43, p = 0.049). In contrast to sham iTBS combined with MT, iTBS combined with MT may strengthen the functional connectivity between bilateral premotor cortices and ipsilaterally within the motor cortex of the stimulated hemisphere. In contrast to sham MT, real MT, when combined with iTBS, might diminish the connectivity among the contralateral parietal–frontal areas.
Validation of a Deep Learning Tool in the Detection of Intracranial Hemorrhage and Large Vessel Occlusion
Authors: McLouth Joel , Elstrott Sebastian , Chaibi Yasmina , Quenet Sarah , Chang Peter D. , Chow Daniel S. , Soun Jennifer E.
Published: April 2021

Purpose: Recently developed machine-learning algorithms have demonstrated strong performance in the detection of intracranial hemorrhage (ICH) and large vessel occlusion (LVO). However, their generalizability is often limited by geographic bias of studies. The aim of this study was to validate a commercially available deep learning-based tool in the detection of both ICH and LVO across multiple hospital sites and vendors throughout the U.S.

Materials and Methods: This was a retrospective and multicenter study using anonymized data from two institutions. Eight hundred fourteen non-contrast CT cases and 378 CT angiography cases were analyzed to evaluate ICH and LVO, respectively. The tool's ability to detect and quantify ICH, LVO, and their various subtypes was assessed among multiple CT vendors and hospitals across the United States. Ground truth was based off imaging interpretations from two board-certified neuroradiologists.

Results: There were 255 positive and 559 negative ICH cases. Accuracy was 95.6%, sensitivity was 91.4%, and specificity was 97.5% for the ICH tool. ICH was further stratified into the following subtypes: intraparenchymal, intraventricular, epidural/subdural, and subarachnoid with true positive rates of 92.9, 100, 94.3, and 89.9%, respectively. ICH true positive rates by volume [small (<5 mL), medium (5–25 mL), and large (>25 mL)] were 71.8, 100, and 100%, respectively. There were 156 positive and 222 negative LVO cases. The LVO tool demonstrated an accuracy of 98.1%, sensitivity of 98.1%, and specificity of 98.2%. A subset of 55 randomly selected cases were also assessed for LVO detection at various sites, including the distal internal carotid artery, middle cerebral artery M1 segment, proximal middle cerebral artery M2 segment, and distal middle cerebral artery M2 segment with an accuracy of 97.0%, sensitivity of 94.3%, and specificity of 97.4%.

Conclusion: Deep learning tools can be effective in the detection of both ICH and LVO across a wide variety of hospital systems. While some limitations were identified, specifically in the detection of small ICH and distal M2 occlusion, this study highlights a deep learning tool that can assist radiologists in the detection of emergent findings in a variety of practice settings.
Computational Methods for Continuous Eye-Tracking Perimetry Based on Spatio-Temporal Integration and a Deep Recurrent Neural Network
Authors: Grillini Alessandro , Hernández-García Alex , Renken Remco J. , Demaria Giorgia , Cornelissen Frans W.
Published: April 2021

The measurement of retinal sensitivity at different visual field locations–perimetry–is a fundamental procedure in ophthalmology. The most common technique for this scope, the Standard Automated Perimetry, suffers from several issues that make it less suitable to test specific clinical populations: it can be tedious, it requires motor manual feedback, and requires from the patient high levels of compliance. Previous studies attempted to create user-friendlier alternatives to Standard Automated Perimetry by employing eye movements reaction times as a substitute for manual responses while keeping the fixed-grid stimuli presentation typical of Standard Automated Perimetry. This approach, however, does not take advantage of the high spatial and temporal resolution enabled by the use of eye-tracking. In this study, we introduce a novel eye-tracking method to perform high-resolution perimetry. This method is based on the continuous gaze-tracking of a stimulus moving along a pseudo-random walk interleaved with saccadic jumps. We then propose two computational methods to obtain visual field maps from the continuous gaze-tracking data: the first is based on the spatio-temporal integration of ocular positional deviations using the threshold free cluster enhancement (TFCE) algorithm; the second is based on using simulated visual field defects to train a deep recurrent neural network (RNN). These two methods have complementary qualities: the TFCE is neurophysiologically plausible and its output significantly correlates with Standard Automated Perimetry performed with the Humphrey Field Analyzer, while the RNN accuracy significantly outperformed the TFCE in reconstructing the simulated scotomas but did not translate as well to the clinical data from glaucoma patients. While both of these methods require further optimization, they show the potential for a more patient-friendly alternative to Standard Automated Perimetry.
Evaluation of Zn, Cu, and Se Levels in the North American Autism Spectrum Disorder Population
Authors: Mehta Sunil Q. , Behl Supriya , Day Patrick L. , Delgado Adriana M. , Larson Nicholas B. , Stromback Lindsay R. , Huebner Andrea R. , DeGrado Timothy R. , Davis Jessica M. , Jannetto Paul J. , Howie Flora , Pandey Mukesh K.
Published: April 2021

Metal ion dyshomeostasis and disparate levels of biometals like zinc (Zn), copper (Cu), and selenium (Se) have been implicated as a potential causative factor for Autism Spectrum Disorder (ASD). In this study, we have enrolled 129 children (aged 2–4 years) in North America, of which 64 children had a diagnosis of ASD and 65 were controls. Hair, nail, and blood samples were collected and quantitatively analyzed for Zn, Cu and Se using inductively coupled plasma mass spectrometry (ICP-MS). Of the analyzed biometals, serum Se (116.83 ± 14.84 ng/mL) was found to be significantly lower in male ASD cases compared to male healthy controls (128.21 ± 9.11 ng/mL; p < 0.005). A similar trend was found for nail Se levels in ASD (1.01 ± 0.15 mcg/g) versus that of controls (1.11 ± 0.17 mcg/g) with a p-value of 0.0132 using a stratified Wilcoxon rank sum testing. The level of Se in ASD cohort was co-analyzed for psychometric correlation and found a negative correlation between total ADOS score and serum Se levels. However, we did not observe any significant difference in Zn, Cu, and Zn/Cu ratio in ASD cases versus controls in this cohort of North American children. Further studies are recommended to better understand the biology of the relationship between Se and ASD status.
The Challenges of Designing and Implementing Clinical Trials With Broccoli Sprouts… and Turning Evidence Into Public Health Action
Authors: Fahey Jed W. , Kensler Thomas W.
Published: April 2021

Broccoli sprouts are a convenient and rich source of the glucosinolate glucoraphanin, which can generate the chemopreventive agent sulforaphane through the catalytic actions of plant myrosinase or β-thioglucosidases in the gut microflora. Sulforaphane, in turn, is an inducer of cytoprotective enzymes through activation of Nrf2 signaling, and a potent inhibitor of carcinogenesis in multiple murine models. Sulforaphane is also protective in models of diabetes, neurodegenerative disease, and other inflammatory processes, likely reflecting additional actions of Nrf2 and interactions with other signaling pathways. Translating this efficacy into the design and implementation of clinical chemoprevention trials, especially food-based trials, faces numerous challenges including the selection of the source, placebo, and dose as well as standardization of the formulation of the intervention material. Unlike in animals, purified sulforaphane has had very limited use in clinical studies. We have conducted a series of clinical studies and randomized clinical trials to evaluate the effects of composition (glucoraphanin-rich [± myrosinase] vs. sulforaphane-rich or mixture beverages), formulation (beverage vs. tablet) and dose, on the efficacy of these broccoli sprout-based preparations to evaluate safety, pharmacokinetics, pharmacodynamic action, and clinical benefit. While the challenges for the evaluation of broccoli sprouts in clinical trials are themselves formidable, further hurdles must be overcome to bring this science to public health action.
Advanced Diagnostic Technology of Volatile Organic Compounds Real Time analysis Analysis From Exhaled Breath of Gastric Cancer Patients Using Proton-Transfer-Reaction Time-of-Flight Mass Spectrometry
Authors: Jung Yoon Ju , Seo Ho Seok , Kim Ji Hyun , Song Kyo Young , Park Cho Hyun , Lee Han Hong
Published: April 2021

Background

Screening endoscopy is considered to be the most accurate tool for early detection of gastric cancer, but it is both invasive and costly. It is therefore essential to develop cost-effective and non-invasive diagnostic tools for gastric cancer. The aim of this study is to investigate the presence of certain volatile organic compounds (VOCs) associated with gastric cancer and to survey the usefulness of VOCs as screening tools of gastric cancer.

Methods

The present study was conducted prospectively to identify the relationship between gastric cancer and specific VOCs quantified by mass spectrometry. Exhaled breath samples from a total of 43 participants were analysed. This study was approved by the Institutional Review Board of the College of Medicine, Catholic University of Korea (KC16TISI0598), and registered to clinical research information service (KCT0004356).

Results

Nine VOCs differed significantly between the control and cancer patient groups. When participants were divided into control, early gastric cancer (EGC), and advanced gastric cancer (AGC) groups, seven VOCs remained significantly different. Of these, four (propanal, aceticamide, isoprene and 1,3 propanediol) showed gradual increases as cancer advanced, from normal control to EGC to AGC. In receiver operating characteristic curves for these four VOCs, the area under the curve for gastric cancer prediction was highest (0.842) when more than two VOCs were present.

Conclusions

The present study offers potential directions for non-invasive gastric cancer screening, and may inspire advanced diagnostic technologies in the era of smart home healthcare. However, despite the high accuracy, cancer-specific VOCs from several studies on different populations, and analytic methods show inconsistency, it is necessary to establish standards for each analytical method, and to validate on each population.
Efficacy of Combination Docetaxel and Nintedanib in Advanced Non-Small Cell Lung Cancer in Thailand: A Multicenter Study
Authors: Korphaisarn Krittiya , Danchaivijitr Pongwut , Reungwetwattana Thanyanan , Chewaskulyong Busayamas , Thongthieang Luangyot , Chindaprasirt Jarin , Maneenil Kunlatida , Sathitruangsak Chirawadee , Vinayanuwattikun Chanida
Published: April 2021

Introduction

The mainstay systemic treatment for non-oncogenic addictive advanced stage non-small cell lung cancer is chemotherapy. Anti-angiogenic agents are additive compounds that enhance disease control and lead to improvement of overall survival benefit. Recently PD-(L)1 blockage, a checkpoint inhibitor, has been adopted as another line of treatment. A sequential strategy to enhance the efficacy of combination docetaxel and nintedanib after immunotherapy, correlated with genomic mutation, has been explored.

Method

A retrospective cohort study of 56 patients from 8 centers in Thailand who received combination docetaxel and nintedanib via the Thai nintedanib Named Patient Use program was conducted. Demographic characteristics, treatment details, and treatment responses were retrieved from medical records.

Results

The majority of patients were male (62.5%) with adenocarcinoma subtype (88%). Thirty-five percent had sensitizing EGFR mutation. Combination docetaxel and nintedanib was given as second to fourth line of treatment. Median PFS of docetaxel/nintedanib was 5.6 months [95% CI 4.8-6.9]. Median OS of the entire cohort was 22.5 months [95% CI 20.2-31.1]. Among them, only four patients received this combination after immunotherapy which limited the validity of efficacy analysis. Median PFS of those four patients was 7.9 months [range 5.2-9.1] which was slightly higher than the remaining cohort (median PFS 4.5 months, 95% CI: 4.0-6.0, p-value 0.09). Among the adenocarcinoma subtype, a relapse-time of platinum-doublet chemotherapy of more than 6 months was solely indicated as a benefit of combination docetaxel/nintedanib treatment compared to the relapse-time of platinum-doublet chemotherapy of less than 6 months by multivariate HR of PFS 0.32 [95% CI: 0.14-0.68, p-value 0.003].

Conclusion

Combination docetaxel and nintedanib provided more benefit in relapse-time of platinum-doublet chemotherapy of more than 6 months in advanced stage adenocarcinoma lung cancer. Neither EGFR nor ALK alteration influenced the outcome of treatment.
Alternative Splicing Events in Tumor Immune Infiltration in Colorectal Cancer
Authors: Shi Jian-yu , Bi Yan-yan , Yu Bian-fang , Wang Qing-feng , Teng Dan , Wu Dong-ning
Published: April 2021

Despite extensive research, the exact mechanisms involved in colorectal cancer (CRC) etiology and pathogenesis remain unclear. This study aimed to examine the correlation between tumor-associated alternative splicing (AS) events and tumor immune infiltration (TII) in CRC. We analyzed transcriptome profiling and clinical CRC data from The Cancer Genome Atlas (TCGA) database and lists of AS-related and immune-related signatures from the SpliceSeq and Innate databases, respectively to develop and validate a risk model of differential AS events and subsequently a TII risk model. We then conducted a two-factor survival analysis to study the association between TII and AS risk and evaluated the associations between immune signatures and six types of immune cells based on the TIMER database. Subsequently, we studied the distribution of six types of TII cells in high- and low-risk groups for seven AS events and in total. We obtained the profiles of AS events/genes for 484 patients, which included 473 CRC tumor samples and 41 corresponding normal samples, and detected 22581 AS events in 8122 genes. Exon Skip (ES) (8446) and Mutually Exclusive Exons (ME) (74) exhibited the most and fewest AS events, respectively. We then classified the 433 patients with CRC into low-risk (n = 217) and high-risk (n = 216) groups based on the median risk score in different AS events. Compared with patients with low-risk scores (mortality = 11.8%), patients with high-risk scores were associated with poor overall survival (mortality = 27.6%). The risk score, cancer stage, and pathological stage (T, M, and N) were closely correlated with prognosis in patients with CRC (P < 0.001). We identified 6479 differentially expressed genes from the transcriptome profiles of CRC and intersected 468 differential immune-related signatures. High-AS-risk and high-TII-risk predicted a poor prognosis in CRC. Different AS types were associated with different TII risk characteristics. Alternate Acceptor site (AA) and Alternate Promoter (AP) events directly affected the concentration of CD4T cells, and the level of CD8T cells was closely correlated with Alternate Terminator (AT) and Exon Skip (ES) events. Thus, the concentration of CD4T and CD8T cells in the CRC immune microenvironment was not specifically modulated by AS. However, B cell, dendritic cell, macrophage, and neutrophilic cell levels were strongly correlated with AS events. These results indicate adverse associations between AS event risk levels and immune cell infiltration density. Taken together, our findings show a clear association between tumor-associated alternative splicing and immune cell infiltration events and patient outcome and could form a basis for the identification of novel markers and therapeutic targets for CRC and other cancers in the future.