bluuebunny/crossref_metadata_2025 huggingface dataset:
Surveying the Side-Chain Network Approach to Protein Structure and Dynamics: The SARS-CoV-2 Spike Protein as an Illustrative Case
Authors: Halder Anushka , Anto Arinnia , Subramanyan Varsha , Bhattacharyya Moitrayee , Vishveshwara Smitha , Vishveshwara Saraswathi
Published: December 2020

Network theory-based approaches provide valuable insights into the variations in global structural connectivity between different dynamical states of proteins. Our objective is to review network-based analyses to elucidate such variations, especially in the context of subtle conformational changes. We present technical details of the construction and analyses of protein structure networks, encompassing both the non-covalent connectivity and dynamics. We examine the selection of optimal criteria for connectivity based on the physical concept of percolation. We highlight the advantages of using side-chain-based network metrics in contrast to backbone measurements. As an illustrative example, we apply the described network approach to investigate the global conformational changes between the closed and partially open states of the SARS-CoV-2 spike protein. These conformational changes in the spike protein is crucial for coronavirus entry and fusion into human cells. Our analysis reveals global structural reorientations between the two states of the spike protein despite small changes between the two states at the backbone level. We also observe some differences at strategic locations in the structures, correlating with their functions, asserting the advantages of the side-chain network analysis. Finally, we present a view of allostery as a subtle synergistic-global change between the ligand and the receptor, the incorporation of which would enhance drug design strategies.
Identification of Circular RNA hsa_Circ_0003391 in Peripheral Blood Is Potentially Associated With Alzheimer's Disease
Authors: Liu Li , Chen Xi , Chen Yu-Hua , Zhang Ke
Published: December 2020

Circular RNAs (circRNAs) have recently been discovered as a novel type of endogenous non-coding RNA that may regulate gene expression in mammals. In the central nervous system (CNS), circRNAs are relevant to many neurological disorders such as Alzheimer's disease (AD). In this study, we attempted to identify an aberrant circRNA, hsa_circ_0003391, which is significantly downregulated in the peripheral blood of patients with AD, and to explore the relationship between hsa_circ_0003391 and the clinical manifestation of AD. The expression of hsa_circ_0003391 had a specific decrease in the peripheral blood of patients with AD compared to those with other types of dementia. To evaluate the potential diagnostic value of the circRNA, we performed a receiver operating characteristic (ROC) curve analysis. The area under the curve (AUC) value was 0.7283 for hsa_circ_0003391, which was statistically significant. The natural form of hsa_circ_0003391 in the peripheral blood was a loop structure with good stability. We found a potential correlation between the expression of hsa_circ_0003391 and the clinical manifestations of AD. Bioinformatic analysis was carried out to predict the latent target microRNAs (miRNA) of hsa_circ_0003391. Furthermore, microRNAs targeted by hsa_circ_0003391 were successfully detected, and miR-574-5p had an expected elevation in the AD groups, suggesting that miR-574-5p might be a potential microRNA target for hsa_circ_0003391. Our results suggest that the downregulation of hsa_circ_0003391 in the peripheral blood has a potential relationship with AD. Our findings not only provide an important latent biomarker but also highlight an important perspective for the following study into AD pathogenesis. This may promote the process of novel therapeutics targeting non-coding RNA.
Multi-parameter Behavioral Phenotyping of the MPP+ Model of Parkinson’s Disease in Zebrafish
Authors: Christensen Christian , Þorsteinsson Haraldur , Maier Valerie Helene , Karlsson Karl Ægir
Published: December 2020

Parkinson’s disease (PD) has been modeled in several animal species using the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its oxidized product 1-methyl-4-phenylpyridinium (MPP+). MPP+ selectively kills dopaminergic neurons in pars compacta of the substantia nigra, inducing parkinsonian symptoms in animals. Typically, neurotoxicity models of PD in zebrafish assess acute drug effects on locomotion. In the present study, we examined the lasting effects of MPP+ exposure and drug treatment in zebrafish larvae. Larvae were incubated in 500 μM MPP+, from 1 to 5 days post fertilization (dpf), followed by 24 h drug-free acclimation. At 6 dpf, the behavior was analyzed for locomotion, thigmotaxis, and sleep. Next, in separate assays we assessed the drug effects of brain injected glial cell-derived neurotrophic factor (GDNF) and 4-phenylbutyrate (PBA), co-incubated with MPP+. We show that MPP+ exposure consistently reduces swim distance, movement frequency, and cumulative time of movement; thus mimicking a parkinsonian phenotype of reduced movement. In contrast, MPP+ exposed larvae demonstrate reduced anxiety-like behavior and exhibit a sleep phenotype inconsistent with human PD: the larvae display longer sleep bouts, less sleep fragmentation, and more sleep. Previously reported rescuing effects of PBA were not replicated in this study. Moreover, whereas GDNF attenuated the sleep phenotype induced by MPP+, PBA augmented it. The current data suggest that MPP+ exposure generates a multifaceted phenotype in zebrafish and highlights that analyzing a narrow window of data can reveal effects that may be inconsistent with longer multi-parameter approaches. It further indicates that the model generally captures motor symptoms more faithfully than non-motor symptoms.
The Parvalbumin Hypothesis of Autism Spectrum Disorder
Authors: Filice Federica , Janickova Lucia , Henzi Thomas , Bilella Alessandro , Schwaller Beat
Published: December 2020

The prevalence of autism spectrum disorder (ASD)—a type of neurodevelopmental disorder—is increasing and is around 2% in North America, Asia, and Europe. Besides the known genetic link, environmental, epigenetic, and metabolic factors have been implicated in ASD etiology. Although highly heterogeneous at the behavioral level, ASD comprises a set of core symptoms including impaired communication and social interaction skills as well as stereotyped and repetitive behaviors. This has led to the suggestion that a large part of the ASD phenotype is caused by changes in a few and common set of signaling pathways, the identification of which is a fundamental aim of autism research. Using advanced bioinformatics tools and the abundantly available genetic data, it is possible to classify the large number of ASD-associated genes according to cellular function and pathways. Cellular processes known to be impaired in ASD include gene regulation, synaptic transmission affecting the excitation/inhibition balance, neuronal Ca2+ signaling, development of short-/long-range connectivity (circuits and networks), and mitochondrial function. Such alterations often occur during early postnatal neurodevelopment. Among the neurons most affected in ASD as well as in schizophrenia are those expressing the Ca2+-binding protein parvalbumin (PV). These mainly inhibitory interneurons present in many different brain regions in humans and rodents are characterized by rapid, non-adaptive firing and have a high energy requirement. PV expression is often reduced at both messenger RNA (mRNA) and protein levels in human ASD brain samples and mouse ASD (and schizophrenia) models. Although the human PVALB gene is not a high-ranking susceptibility/risk gene for either disorder and is currently only listed in the SFARI Gene Archive, we propose and present supporting evidence for the Parvalbumin Hypothesis, which posits that decreased PV level is causally related to the etiology of ASD (and possibly schizophrenia).
Pregnancy Changes the Response of the Vomeronasal and Olfactory Systems to Pups in Mice
Authors: Navarro-Moreno Cinta , Sanchez-Catalan Maria Jose , Barneo-Muñoz Manuela , Goterris-Cerisuelo Rafael , Belles Maria , Lanuza Enrique , Agustin-Pavon Carmen , Martinez-Garcia Fernando
Published: December 2020

Motherhood entails changes in behavior with increased motivation for pups, induced in part by pregnancy hormones acting upon the brain. This work explores whether this alters sensory processing of pup-derived chemosignals. To do so, we analyse the expression of immediate early genes (IEGs) in the vomeronasal organ (VNO; Egr1) and centers of the olfactory and vomeronasal brain pathways (cFos) in virgin and late-pregnant females exposed to pups, as compared to buttons (socially neutral control). In pup-exposed females, we quantified diverse behaviors including pup retrieval, sniffing, pup-directed attack, nest building and time in nest or on nest, as well as time off nest. Pups induce Egr1 expression in the VNO of females, irrespective of their physiological condition, thus suggesting the existence of VNO-detected pup chemosignals. A similar situation is found in the accessory olfactory bulb (AOB) and posteromedial part of the medial bed nucleus of the stria terminalis (BSTMPM). By contrast, in the medial amygdala and posteromedial cortical amygdala (PMCo), responses to pups-vs-buttons are different in virgin and late-pregnant females, thus suggesting altered sensory processing during late pregnancy. The olfactory system also shows changes in sensory processing with pregnancy. In the main olfactory bulbs, as well as the anterior and posterior piriform cortex, buttons activate cFos expression in virgins more than in pregnant females. By contrast, in the anterior and especially posterior piriform cortex, pregnant females show more activation by pups than buttons. Correlation between IEGs expression and behavior suggests the existence of two vomeronasal subsystems: one associated to pup care (with PMCo as its main center) and another related to pup-directed aggression observed in some pregnant females (with the BSTMPM as the main nucleus). Our data also suggest a coactivation of the olfactory and vomeronasal systems during interaction with pups in pregnant females.
Refractory Gilles de la Tourette Syndrome—Many Pieces That Define the Puzzle
Authors: Szejko Natalia , Lombroso Adam , Bloch Michael H. , Landeros-Weisenberger Angeli , Leckman James F.
Published: December 2020

Gilles de la Tourette syndrome (GTS) is a childhood onset neuropsychiatric disorder characterized by the presence of motor and vocal tics. The clinical spectrum of GTS is heterogeneous and varies from mild cases that do not require any medical attention to cases that are refractory to standard treatments. One of the unresolved issues is the definition of what constitutes treatment-refractory GTS. While for some other neuropsychiatric disorders, such as obsessive–compulsive disorder (OCD), a clear definition has been established, there is still no consensus with regard to GTS. One important issue is that many individuals with GTS also meet criteria for one or more other neurodevelopmental and neuropsychiatric disorders. In many individuals, the severity of these comorbid conditions contributes to the degree to which GTS is treatment refractory. The scope of this paper is to present the current state-of-the-art regarding refractory GTS and indicate possible approaches to define it. In closing, we discuss promising approaches to the treatment of individuals with refractory GTS.
Astrocyte HIV-1 Tat Differentially Modulates Behavior and Brain MMP/TIMP Balance During Short and Prolonged Induction in Transgenic Mice
Authors: Joshi Chaitanya R. , Stacy Satomi , Sumien Nathalie , Ghorpade Anuja , Borgmann Kathleen
Published: December 2020

Despite effective antiretroviral therapy (ART), mild forms of HIV-associated neurocognitive disorders (HAND) continue to afflict approximately half of all people living with HIV (PLWH). As PLWH age, HIV-associated inflammation perturbs the balance between brain matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs), likely contributing to neuropathogenesis. The MMP/TIMP balance is associated with cognition, learning, and memory, with TIMPs eliciting neuroprotective effects. Dysregulation of the MMP/TIMP balance was evident in the brains of PLWH where levels of TIMP-1, the inducible family member, were significantly lower than non-infected controls, and MMPs were elevated. Here, we evaluated the MMP/TIMP levels in the doxycycline (DOX)-induced glial fibrillary acidic protein promoter-driven HIV-1 transactivator of transcription (Tat) transgenic mouse model. The HIV-1 protein Tat is constitutively expressed by most infected cells, even during ART suppression of viral replication. Many studies have demonstrated indirect and direct mechanisms of short-term Tat-associated neurodegeneration, including gliosis, blood-brain barrier disruption, elevated inflammatory mediators and neurotoxicity. However, the effects of acute vs. prolonged exposure on Tat-induced dysregulation remain to be seen. This is especially relevant for TIMP-1 as expression was previously shown to be differentially regulated in human astrocytes during acute vs. chronic inflammation. In this context, acute Tat expression was induced with DOX intraperitoneal injections over 3 weeks, while DOX-containing diet was used to achieve long-term Tat expression over 6 months. First, a series of behavior tests evaluating arousal, ambulation, anxiety, and cognition was performed to examine impairments analogous to those observed in HAND. Next, gene expression of components of the MMP/TIMP axis and known HAND-relevant inflammatory mediators were assessed. Altered anxiety-like, motor and/or cognitive behaviors were observed in Tat-induced (iTat) mice. Gene expression of MMPs and TIMPs was altered depending on the duration of Tat expression, which was independent of the HIV-associated neuroinflammation typically implicated in MMP/TIMP regulation. Collectively, we infer that HIV-1 Tat-mediated dysregulation of MMP/TIMP axis and behavioral changes are dependent on duration of exposure. Further, prolonged Tat expression demonstrates a phenotype comparable to asymptomatic to mild HAND manifestation in patients.
Management of Extramedullary Intradural Spinal Tumors: The Impact of Clinical Status, Intraoperative Neurophysiological Monitoring and Surgical Approach on Outcomes in a 12-Year Double-Center Experience
Authors: Cofano Fabio , Giambra Carlotta , Costa Paolo , Zeppa Pietro , Bianconi Andrea , Mammi Marco , Monticelli Matteo , Di Perna Giuseppe , Junemann Carola Vera , Melcarne Antonio , Massaro Fulvio , Ducati Alessandro , Tartara Fulvio , Zenga Francesco , Garbossa Diego
Published: December 2020

Objective: Intradural Extramedullary (IDEM) tumors are usually treated with surgical excision. The aim of this study was to investigate the impact on clinical outcomes of pre-surgical clinical conditions, intraoperative neurophysiological monitoring (IONM), surgical access to the spinal canal, histology, degree of resection and intra/postoperative complications.

Methods: This is a retrospective observational study analyzing data of patients suffering from IDEM tumors who underwent surgical treatment over a 12 year period in a double-center experience. Data were extracted from a prospectively maintained database and included: sex, age at diagnosis, clinical status according to the modified McCormick Scale (Grades I-V) at admission, discharge, and follow-up, tumor histology, type of surgical access to the spinal canal (bilateral laminectomy vs. monolateral laminectomy vs. laminoplasty), degree of surgical removal, use and type of IONM, occurrence and type of intraoperative complications, use of Ultrasonic Aspirator (CUSA), radiological follow-up.

Results: A total number of 249 patients was included with a mean follow-up of 48.3 months. Gross total resection was achieved in 210 patients (84.3%) mostly in Schwannomas (45.2%) and Meningiomas (40.4%). IONM was performed in 162 procedures (65%) and D-wave was recorded in 64.2% of all cervical and thoracic locations (99 patients). The linear regression diagram for McCormick grades before and after surgery (follow-up) showed a correlation between preoperative and postoperative clinical status. A statistically significant correlation was found between absence of worsening of clinical condition at follow-up and use of IONM at follow-up (p = 0.01) but not at discharge. No associations were found between the choice of surgical approach and the extent of resection (p = 0.79), the presence of recurrence or residual tumor (p = 0.14) or CSF leakage (p = 0.25). The extent of resection was not associated with the use of IONM (p = 0.91) or CUSA (p = 0.19).

Conclusion: A reliable prediction of clinical improvement could be made based on pre-operative clinical status. The use of IONM resulted in better clinical outcomes at follow-up (not at discharge), but no associations were found with the extent of resection. The use of minimally invasive approaches such as monolateral laminectomy showed to be effective and not associated with worse outcomes or increased complications.
Association of Brain Iron Overload With Brain Edema and Brain Atrophy After Intracerebral Hemorrhage
Authors: Liu Ran , Zhang Haoran , Cheng Shuangjuan , Sun Yuyao , Li Haijiao , Xiao Jiangxi , Huang Yining
Published: December 2020

Objective: This study evaluated iron overload after intracerebral hemorrhage (ICH) using ESWAN sequences.

Methods: This single-center prospective observational cohort study enrolled supratentorial ICH patients. MRI was obtained with a 3.0-T scanner at day 1, day 14, day 30, and follow-up (300 days or later). R2* mapping was generated based on the ESWAN. R2* value of the ipsilateral side represented iron deposition, and the R2* value of the contralateral side served as control. R2* value was adjusted by volume and used to assess total iron overload. Brain edema was measured on T2 FLAIR-weighted images. Brain atrophy was calculated as the contralateral hemisphere volume minus the injured hemisphere volume.

Results: Twnety-seven patients with a spontaneous supratentorial ICH were included in this analysis. The ipsilateral R2* value was 40.27 ± 11.62, 41.92 ± 13.56, and 60.89 ± 14.09 at days 1, 14, and 30, respectively. The R2* value was significantly higher in the ICH side than the contralateral side (p < 0.01). Increased R2* value was seen on day 30 compared to day 14 (p < 0.01). The R2* value showed logistic decay with the distance to the hematoma margin (p < 0.01). Brain edema at day 14 and brain atrophy at follow-up correlated with R2* value adjusted by volume at day 14 (p < 0.01).

Conclusions: After ICH, the iron deposition in the perihematomal region was progressively increased during the first month. R2* value adjusted by volume predicted acute brain edema and chronic brain atrophy.
Early Referral to an ALS Center Reduces Several Months the Diagnostic Delay: A Multicenter-Based Study
Authors: Martínez-Molina Marina , Argente-Escrig Herminia , Polo Margarita F. , Hervás David , Frasquet Marina , Cortés Victoria , Sevilla Teresa , Vázquez-Costa Juan F.
Published: December 2020

Objective: To analyze those factors contributing to the diagnostic delay in ALS.

Methods: Consecutive ALS patients were categorized as those studied in departmental hospitals and those studied in a referral ALS center. Demographic and clinical variables, together with data of the diagnostic pathway were collected. Multivariable models were used to assess their effect in the time between symptoms onset and the first neurologist visit (time symptoms-neurologist), in the time between the first neurologist visit and the diagnosis (time neurologist-diagnosis) and in the diagnostic delay.

Results: 166 ALS patients with a median diagnostic delay of 11.53 months (IQR: 6.68, 15.23) were included. The median diagnostic delay was 8.57 months (5.16, 11.61) in the referral center vs. 12.08 months (6.87, 16.8) in departmental centers. Bulbar onset, fast progression rate, upper motor neuron predominant phenotype and an early referral to the neurologist were associated with a shorter time between symptoms–neurologist. Being studied in a referral center was associated with a shorter time between neurologist–diagnosis. Comorbidities, familial ALS, bulbar onset, early referral to the neurologist and being studied in a referral center were associated with a shorter diagnostic delay. For patients studied in departmental hospitals, fast progression rate was also strongly associated with a shorter time between neurologist–diagnosis and diagnostic delay.

Conclusion: Unmodifiable factors (comorbidities, familial ALS, bulbar onset, and progression rate) as well as modifiable factors (early referral to the neurologist and the evaluation in an ALS referral center) have an independent effect in the diagnostic delay. The universalization of ALS Units is probably the most efficient measure to reduce the diagnostic delay.
Neutrophil Count, Intracranial Atherosclerotic Stenosis, and Prognosis of Ischemic Stroke After Endovascular Treatment: A Mediation Analysis
Authors: Li Tingting , Chen Zhonglun , Zhu Xuyin , Tang Xianbiao , Pan Song , Gong Fan , Xu Leyi , Wang Mingzhe , Zhang Hongzhi , Guo Yongmei , Zhang Jingsi , Qin Baofeng , Zhang Zongqi , Liu Yun , Fei Zhimin , Pan Weidong , Yu Xiaofei , Liu Dezhi
Published: December 2020

Background and Purpose: Data on the relationship among neutrophil count, intracranial atherosclerotic stenosis (ICAS), and functional outcomes after endovascular thrombectomy (EVT) for ischemic stroke patients remains unclear. We aimed to evaluate the association between neutrophil count and prognosis of EVT patients and to determine whether the association was mediated by ICAS.

Methods: We retrospectively analyzed consecutive patients who underwent EVT at two comprehensive stroke centers between June 2016 and December 2019. A remaining stenosis >70%, or a lesser degree of stenosis with a tendency toward re-occlusion or flow impairment during the procedure, was classified as ICAS. A poor outcome was defined as a 90-day modified Rankin Scale score of 3–6.

Results: Of the 221 patients (mean age, 65.9 years; males, 61.1%) included in this study, 81 (36.3%) had ICAS, and 120 (54.3%) experienced a poor outcome at 90 days, respectively. In the multivariate adjustment for potential confounders, neutrophil count (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.04–1.36; P = 0.012) and presence of ICAS (OR, 2.65; 95CI%, 1.28–5.45; P = 0.008) were risk factors of poor outcomes. Furthermore, mediation analysis indicated that total ICAS mediated the association between increased neutrophil count and worse functional outcome after EVT (the regression coefficient was changed by 11.7% for poor outcome, and 17.1% for modified Rankin Scale score, respectively).

Conclusions: Our study demonstrated that a higher neutrophil count might increase the risk of a poor outcome among ischemic stroke patients who underwent EVT, which was partially mediated by ICAS.
Case Report: Endovascular Treatment of a Giant Distal PICA Aneurysm in Association With a Cerebellar AVM: A Report on Treatment Considerations and a Literature Review
Authors: Khayat Hassan A. , Hawkes Christine M. , Algird Almunder R.
Published: December 2020

Background: Distal posterior inferior cerebellar artery (PICA) aneurysms are uncommon intracranial vascular lesions. The coincidence of these aneurysms and Arteriovenous malformation (AVM) is even more rare. Since 1956, a total of 57 cases of distal PICA aneurysms associated with AVM have been reported with clear and adequate description. None of these reports describe a giant prenidal aneurysm at this particular location. The paucity of natural history data as well as lack of consensus about treatment strategies in such cases present a significant challenge that requires an individualized management approach.

Case Description: A 68-year-old male presented with recurrent episodes of nausea and vomiting precipitated by physical exertion and change of head position. An MRI of the brain demonstrated a giant partially thrombosed right posterior inferior cerebellar artery (PICA) aneurysm with mass effect on the floor of the fourth ventricle. A conventional cerebral angiogram revealed a giant (3.1 x 3.1 x 2.8cm) distal right PICA pre-nidal aneurysm with two smaller distal PICA aneurysms. An AVM (Spetzler-Martin Grade 1) supplied by the right PICA as well as the right superior cerebellar artery (SCA) was also identified on cerebral angiography (not seen on an MRI). Endovascular coil embolization with parent vessel sacrifice was performed to occlude the giant aneurysm. Due to the asymptomatic nature, low risk of rupture, and the patient's age, AVM treatment was deferred.

Conclusion: This paper presents the first case of a giant PICA aneurysm associated with cerebellar AVM. For PICA aneurysm-AVM complexes, meticulous evaluation of the morphology, associated anatomy, and comparative risk analysis for both lesions are key for treatment planning. Distal PICA aneurysms can be treated safely with parent vessel occlusion, particularly in the case of prenidal aneurysms.
Signal-Space Projection Suppresses the tACS Artifact in EEG Recordings
Authors: Vosskuhl Johannes , Mutanen Tuomas P. , Neuling Toralf , Ilmoniemi Risto J. , Herrmann Christoph S.
Published: December 2020

Background

To probe the functional role of brain oscillations, transcranial alternating current stimulation (tACS) has proven to be a useful neuroscientific tool. Because of the excessive tACS-caused artifact at the stimulation frequency in electroencephalography (EEG) signals, tACS + EEG studies have been mostly limited to compare brain activity between recordings before and after concurrent tACS. Critically, attempts to suppress the artifact in the data cannot assure that the entire artifact is removed while brain activity is preserved. The current study aims to evaluate the feasibility of specific artifact correction techniques to clean tACS-contaminated EEG data.

New Method

In the first experiment, we used a phantom head to have full control over the signal to be analyzed. Driving pre-recorded human brain-oscillation signals through a dipolar current source within the phantom, we simultaneously applied tACS and compared the performance of different artifact-correction techniques: sine subtraction, template subtraction, and signal-space projection (SSP). In the second experiment, we combined tACS and EEG on one human subject to demonstrate the best-performing data-correction approach in a proof of principle.

Results

The tACS artifact was highly attenuated by SSP in the phantom and the human EEG; thus, we were able to recover the amplitude and phase of the oscillatory activity. In the human experiment, event-related desynchronization could be restored after correcting the artifact.

Comparison With Existing Methods

The best results were achieved with SSP, which outperformed sine subtraction and template subtraction.

Conclusion

Our results demonstrate the feasibility of SSP by applying it to a phantom measurement with pre-recorded signal and one human tACS + EEG dataset. For a full validation of SSP, more data are needed.
Sensorimotor Functional Connectivity: A Neurophysiological Factor Related to BCI Performance
Authors: Vidaurre Carmen , Haufe Stefan , Jorajuría Tania , Müller Klaus-Robert , Nikulin Vadim V.
Published: December 2020

Brain-Computer Interfaces (BCIs) are systems that allow users to control devices using brain activity alone. However, the ability of participants to command BCIs varies from subject to subject. About 20% of potential users of sensorimotor BCIs do not gain reliable control of the system. The inefficiency to decode user's intentions requires the identification of neurophysiological factors determining “good” and “poor” BCI performers. One of the important neurophysiological aspects in BCI research is that the neuronal oscillations, used to control these systems, show a rich repertoire of spatial sensorimotor interactions. Considering this, we hypothesized that neuronal connectivity in sensorimotor areas would define BCI performance. Analyses for this study were performed on a large dataset of 80 inexperienced participants. They took part in a calibration and an online feedback session recorded on the same day. Undirected functional connectivity was computed over sensorimotor areas by means of the imaginary part of coherency. The results show that post- as well as pre-stimulus connectivity in the calibration recording is significantly correlated to online feedback performance in μ and feedback frequency bands. Importantly, the significance of the correlation between connectivity and BCI feedback accuracy was not due to the signal-to-noise ratio of the oscillations in the corresponding post and pre-stimulus intervals. Thus, this study demonstrates that BCI performance is not only dependent on the amplitude of sensorimotor oscillations as shown previously, but that it also relates to sensorimotor connectivity measured during the preceding training session. The presence of such connectivity between motor and somatosensory systems is likely to facilitate motor imagery, which in turn is associated with the generation of a more pronounced modulation of sensorimotor oscillations (manifested in ERD/ERS) required for the adequate BCI performance. We also discuss strategies for the up-regulation of such connectivity in order to enhance BCI performance.
Meta-Analysis of Differentially Expressed Genes in the Substantia Nigra in Parkinson’s Disease Supports Phenotype-Specific Transcriptome Changes
Authors: Phung Duong My , Lee Jinwoo , Hong SangKyoon , Kim Young Eun , Yoon Jeehee , Kim Yun Joong
Published: December 2020

Background

Studies regarding differentially expressed genes (DEGs) in Parkinson’s disease (PD) have focused on common upstream regulators or dysregulated pathways or ontologies; however, the relationships between DEGs and disease-related or cell type-enriched genes have not been systematically studied. Meta-analysis of DEGs (meta-DEGs) are expected to overcome the limitations, such as replication failure and small sample size of previous studies.

Purpose

Meta-DEGs were performed to investigate dysregulated genes enriched with neurodegenerative disorder causative or risk genes in a phenotype-specific manner.

Methods

Six microarray datasets from PD patients and controls, for which substantia nigra sample transcriptome data were available, were downloaded from the NINDS data repository. Meta-DEGs were performed using two methods, combining p-values and combing effect size, and common DEGs were used for secondary analyses. Gene sets of cell type-enriched or disease-related genes for PD, Alzheimer’s disease (AD), and hereditary progressive ataxia were constructed by curation of public databases and/or published literatures.

Results

Our meta-analyses revealed 449 downregulated and 137 upregulated genes. Overrepresentation analyses with cell type-enriched genes were significant in neuron-enriched genes but not in astrocyte- or microglia-enriched genes. Meta-DEGs were significantly enriched in causative genes for hereditary disorders accompanying parkinsonism but not in genes associated with AD or hereditary progressive ataxia. Enrichment of PD-related genes was highly significant in downregulated DEGs but insignificant in upregulated genes.

Conclusion

Downregulated meta-DEGs were associated with PD-related genes, but not with other neurodegenerative disorder genes. These results highlight disease phenotype-specific changes in dysregulated genes in PD.
TLR4 Targeting as a Promising Therapeutic Strategy for Alzheimer Disease Treatment
Authors: Zhou Yongji , Chen Yanxing , Xu Congcong , Zhang Hao , Lin Caixiu
Published: December 2020

Alzheimer disease (AD) is a devastating neurodegenerative disorder characterized by extracellular accumulation of amyloid-beta and formation of intracellular neurofibrillary tangles. Microglia activation and neuroinflammation play important roles in the pathogenesis of AD; Toll-like receptor 4 (TLR4)—a key component of the innate immune system—in microglia is also thought to be involved based on the observed association between TLR gene polymorphisms and AD risk. TLR4 has been shown to exert both detrimental and beneficial effects on AD-related pathologies. In preclinical models, experimental manipulations targeting TLR4 were shown to improve learning and memory, which was related to inhibition of pro-inflammatory cytokine release and reduction of oxidative stress. In this review, we summarize the key evidence supporting TLR4 as a promising therapeutic target in AD treatment.
Investigation of Deep-Learning-Driven Identification of Multiple Sclerosis Patients Based on Susceptibility-Weighted Images Using Relevance Analysis
Authors: Lopatina Alina , Ropele Stefan , Sibgatulin Renat , Reichenbach Jürgen R. , Güllmar Daniel
Published: December 2020

The diagnosis of multiple sclerosis (MS) is usually based on clinical symptoms and signs of damage to the central nervous system, which is assessed using magnetic resonance imaging. The correct interpretation of these data requires excellent clinical expertise and experience. Deep neural networks aim to assist clinicians in identifying MS using imaging data. However, before such networks can be integrated into clinical workflow, it is crucial to understand their classification strategy. In this study, we propose to use a convolutional neural network to identify MS patients in combination with attribution algorithms to investigate the classification decisions. The network was trained using images acquired with susceptibility-weighted imaging (SWI), which is known to be sensitive to the presence of paramagnetic iron components and is routinely applied in imaging protocols for MS patients. Different attribution algorithms were used to the trained network resulting in heatmaps visualizing the contribution of each input voxel to the classification decision. Based on the quantitative image perturbation method, we selected DeepLIFT heatmaps for further investigation. Single-subject analysis revealed veins and adjacent voxels as signs for MS, while the population-based study revealed relevant brain areas common to most subjects in a class. This pattern was found to be stable across different echo times and also for a multi-echo trained network. Intensity analysis of the relevant voxels revealed a group difference, which was found to be primarily based on the T1w magnitude images, which are part of the SWI calculation. This difference was not observed in the phase mask data.
GABA Measurement in a Neonatal Fragile X Syndrome Mouse Model Using 1H-Magnetic Resonance Spectroscopy and Mass Spectrometry
Authors: Reyes Samantha T. , Mohajeri Sanaz , Krasinska Karolina , Guo Scarlett G. , Gu Meng , Pisani Laura , Rosenberg Jarrett , Spielman Daniel M. , Chin Frederick T.
Published: December 2020

Fragile X syndrome (FXS) is the leading monogenetic cause of autism spectrum disorder and inherited cause of intellectual disability that affects approximately one in 7,000 males and one in 11,000 females. In FXS, the Fmr1 gene is silenced and prevents the expression of the fragile X mental retardation protein (FMRP) that directly targets mRNA transcripts of multiple GABAA subunits. Therefore, FMRP loss adversely impacts the neuronal firing of the GABAergic system which creates an imbalance in the excitatory/inhibitory ratio within the brain. Current FXS treatment strategies focus on curing symptoms, such as anxiety or decreased social function. While treating symptoms can be helpful, incorporating non-invasive imaging to evaluate how treatments change the brain’s biology may explain what molecular aberrations are associated with disease pathology. Thus, the GABAergic system is suitable to explore developing novel therapeutic strategies for FXS. To understand how the GABAergic system may be affected by this loss-of-function mutation, GABA concentrations were examined within the frontal cortex and thalamus of 5-day-old wild type and Fmr1 knockout mice using both 1H magnetic resonance imaging (1H-MRS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Our objective was to develop a reliable scanning method for neonatal mice in vivo and evaluate whether 1H-MRS is suitable to capture regional GABA concentration differences at the front end of the critical cortical period where abnormal neurodevelopment occurs due to FMRP loss is first detected. 1H-MRS quantified GABA concentrations in both frontal cortex and thalamus of wild type and Fmr1 knockout mice. To substantiate the results of our 1H-MRS studies, in vitro LC-MS/MS was also performed on brain homogenates from age-matched mice. We found significant changes in GABA concentration between the frontal cortex and thalamus within each mouse from both wild type and Fmr1 knockout mice using 1H-MRS and LC-MS/MS. Significant GABA levels were also detected in these same regions between wild type and Fmr1 knockout mice by LC-MS/MS, validating that FMRP loss directly affects the GABAergic system. Thus, these new findings support the need to develop an effective non-invasive imaging method to monitor novel GABAergic strategies aimed at treating patients with FXS.
SynapsEM: Computer-Assisted Synapse Morphometry
Authors: Watanabe Shigeki , Davis M. Wayne , Kusick Grant F. , Iwasa Janet , Jorgensen Erik M.
Published: December 2020

The structural features of a synapse help determine its function. Synapses are extremely small and tightly packed with vesicles and other organelles. Visualizing synaptic structure requires imaging by electron microscopy, and the features in micrographs must be quantified, a process called morphometry. Three parameters are typically assessed from each specimen: (1) the sizes of individual vesicles and organelles; (2) the absolute number and densities of organelles; and (3) distances between organelles and key features at synapses, such as active zone membranes and dense projections. For data to be meaningful, the analysis must be repeated from hundreds to thousands of images from several biological replicates, a daunting task. Here we report a custom computer program to analyze key structural features of synapses: SynapsEM. In short, we developed ImageJ/Fiji macros to record x,y-coordinates of segmented structures. The coordinates are then exported as text files. Independent investigators can reload the images and text files to reexamine the segmentation using ImageJ. The Matlab program then calculates and reports key synaptic parameters from the coordinates. Since the values are calculated from coordinates, rather than measured from each micrograph, other parameters such as locations of docked vesicles relative to the center of an active zone can be extracted in Matlab by additional scripting. Thus, this program can accelerate the morphometry of synapses and promote a more comprehensive analysis of synaptic ultrastructure.
Anti-CXCR4 Single-Chain Variable Fragment Antibodies Have Anti-Tumor Activity
Authors: Liang Guang-Quan , Liu Jing , Zhou Xiao-Xin , Lin Ze-Xiong , Chen Tao , Chen Guo , Wei Henry
Published: December 2020

Monoclonal antibodies (mAbs) are large and have limitations as cancer therapeutics. Human single-chain variable fragment (scFv) is a small antibody as a good alternative. It can easily enter cancer tissues, has no immunogenicity and can be produced in bacteria to decrease the cost. The chemokine receptor CXCR4 is overexpressed in different cancer cells. It plays an important role in tumor growth and metastasis. Its overexpression is associated with poor prognosis in cancer patients and is regarded as an attractive target for cancer treatment. In this study, a peptide on the CXCR4 extracellular loop 2 (ECL2) was used as an antigen for screening a human scFv antibody library by yeast two-hybrid method. Three anti-CXCR4 scFv antibodies were isolated. They could bind to CXCR4 protein and three cancer cell lines (DU145, PC3, and MDA-MB-231) and not to 293T and 3T3 cells as negative controls. These three scFvs could decrease the proliferation, migration, and invasion of these cancer cells and promote their apoptosis. The two scFvs were further examined in a mouse xenograft model, and they inhibited the tumor growth. Tumor immunohistochemistry also demonstrated that the two scFvs decreased cancer cell proliferation and tumor angiogenesis and increased their apoptosis. These results show that these anti-CXCR4 scFvs can decrease cancer cell proliferation and inhibit tumor growth in mice, and may provide therapy for various cancers.
Prognostic Role of ABO Blood Type in Operable Esophageal Cancer: Analysis of 2179 Southern Chinese Patients
Authors: Zhang Shuishen , Jia Minghan , Cai Xiaoli , Yang Weixiong , Liao Shufen , Liu Zhenguo , Wen Jing , Luo Kongjia , Cheng Chao
Published: December 2020

Background

The prognostic value of ABO blood types is not well clarified for esophageal carcinoma (EC). This study attempted to elucidate the associations between different ABO blood types and disease-free survival (DFS) and overall survival (OS) of EC.

Methods

This study was a retrospective review of the records of 2179 patients with EC who received surgery from December 2000 to December 2008. The prognostic impact of ABO blood group on DFS and OS were estimated using the Kaplan-Meier method and cox proportional hazard models.

Results

Univariate analyses found significant differences in DFS and OS among the four blood types. Multivariate analyses showed ABO blood type independently predicted DFS (P=0.001) and OS (P=0.002). Furthermore, patients with non-B blood types had a significantly shorter DFS (HR=1.22, 95%CI:1.07–1.38, P=0.002) and OS (HR=1.22, 95%CI:1.07–1.38, P=0.003) than patients with blood type B, and patients with non-O blood types had a significantly better DFS (HR=0.86, 95%CI:0.77–0.96, P=0.006) and OS (HR=0.86, 95%CI:0.77–0.96, P=0.007) than patients with blood type O. Subgroup analyses found that blood type B had a better DFS and OS than non-B in patients who were male, younger, early pathological stages and had squamous-cell carcinomas (ESCC). Blood type O had a worse DFS and OS than non-O in patients who were male, younger, and had ESCC (P<0.05).

Conclusions

The results demonstrate that ABO blood group is an independent prognostic factor of survival, and that type B predicts a favorable prognosis, whereas type O predicts an unfavorable prognosis for survival in patients with EC, especially those with ESCC.
Bilirubin Nanoparticles Reduce Diet-Induced Hepatic Steatosis, Improve Fat Utilization, and Increase Plasma β-Hydroxybutyrate
Authors: Hinds Terry D. , Creeden Justin F. , Gordon Darren M. , Stec Donald F. , Donald Matthew C. , Stec David E.
Published: December 2020

The inverse relationship of plasma bilirubin levels with liver fat accumulation has prompted the possibility of bilirubin as a therapeutic for non-alcoholic fatty liver disease. Here, we used diet-induced obese mice with non-alcoholic fatty liver disease treated with pegylated bilirubin (bilirubin nanoparticles) or vehicle control to determine the impact on hepatic lipid accumulation. The bilirubin nanoparticles significantly reduced hepatic fat, triglyceride accumulation, de novo lipogenesis, and serum levels of liver dysfunction marker aspartate transaminase and ApoB100 containing very-low-density lipoprotein. The bilirubin nanoparticles improved liver function and activated the hepatic β-oxidation pathway by increasing PPARα and acyl-coenzyme A oxidase 1. The bilirubin nanoparticles also significantly elevated plasma levels of the ketone β-hydroxybutyrate and lowered liver fat accumulation. This study demonstrates that bilirubin nanoparticles induce hepatic fat utilization, raise plasma ketones, and reduce hepatic steatosis, opening new therapeutic avenues for NAFLD.
Suppression of mICAT in Mouse Small Intestinal Myocytes by General Anaesthetic Ketamine and its Recovery by TRPC4 Agonist (-)-englerin A
Authors: Melnyk Mariia I. , Dryn Dariia O. , Al Kury Lina T. , Dziuba Dmytro O. , Zholos Alexander V.
Published: December 2020

A better understanding of the negative impact of general anesthetics on gastrointestinal motility requires thorough knowledge of their molecular targets. In this respect the muscarinic cationic current (mICAT carried mainly via TRPC4 channels) that initiates cholinergic excitation-contraction coupling in the gut is of special interest. Here we aimed to characterize the effects of one of the most commonly used “dissociative anesthetics”, ketamine, on mICAT. Patch-clamp and tensiometry techniques were used to investigate the mechanisms of the inhibitory effects of ketamine on mICAT in single mouse ileal myocytes, as well as on intestinal motility. Ketamine (100 µM) strongly inhibited both carbachol- and GTPγS-induced mICAT. The inhibition was slow (time constant of about 1 min) and practically irreversible. It was associated with altered voltage dependence and kinetics of mICAT. In functional tests, ketamine suppressed both spontaneous and carbachol-induced contractions of small intestine. Importantly, inhibited by ketamine mICAT could be restored by direct TRPC4 agonist (-)-englerin A. We identified mICAT as a novel target for ketamine. Signal transduction leading to TRPC4 channel opening is disrupted by ketamine mainly downstream of muscarinic receptor activation, but does not involve TRPC4 per se. Direct TRPC4 agonists may be used for the correction of gastrointestinal disorders provoked by general anesthesia.
COVID-19 Disease and Vitamin D: A Mini-Review
Authors: Boulkrane Mohamed Said , Ilina Victoria , Melchakov Roman , Fedotova Julia , Drago Filippo , Gozzo Lucia , Das Undurti Narasimha , Abd El-Aty A. M. , Baranenko Denis
Published: December 2020

Novel coronavirus disease (COVID-19) pandemic caused by SARS-CoV-2, for which there is no effective treatment except employing prevention strategies, has already instituted significant number of deaths. In this review, we provide a scientific view on the potential role of vitamin D in SARS-CoV-2 virus/COVID-19 disease. Vitamin D is well-known to play a significant role in maintaining the immune health of an individual. Moreover, it induces antimicrobial peptide expression that can decrease viral replication and regulate the levels of pro-inflammatory/anti-inflammatory cytokines. Therefore, supplementation of vitamin D has the potential to reduce the incidence, severity and the risk of death from pneumonia resulting from the cytokine storm of many viral infections including COVID-19. We suggest that supplementation of subjects at high risk of COVID-19 with vitamin D (1.000 to 3.000 IU) to maintain its optimum serum concentrations may be of significant benefit for both in the prevention and treatment of the COVID-19.