bluuebunny/crossref_metadata_2025 huggingface dataset:
Dl-3-n-Butylphthalide Alleviates Hippocampal Neuron Damage in Chronic Cerebral Hypoperfusion via Regulation of the CNTF/CNTFRα/JAK2/STAT3 Signaling Pathways
Authors: Li Wenxian , Wei Di , Zhu Zheng , Xie Xiaomei , Zhan Shuqin , Zhang Ru , Zhang Guilian , Huang Li’an
Published: January 2021

Chronic cerebral hypoperfusion (CCH) contributes to cognitive impairments, and hippocampal neuronal death is one of the key factors involved in this process. Dl-3-n-butylphthalide (D3NB) is a synthetic compound originally isolated from the seeds of Apium graveolens, which exhibits neuroprotective effects against some neurological diseases. However, the protective mechanisms of D3NB in a CCH model mimicking vascular cognitive impairment remains to be explored. We induced CCH in rats by a bilateral common carotid artery occlusion (BCCAO) operation. Animals were randomly divided into a sham-operated group, CCH 4-week group, CCH 8-week group, and the corresponding D3NB-treatment groups. Cultured primary hippocampal neurons were exposed to oxygen-glucose deprivation/reperfusion (OGD/R) to mimic CCH in vitro. We aimed to explore the effects of D3NB treatment on hippocampal neuronal death after CCH as well as its underlying molecular mechanism. We observed memory impairment and increased hippocampal neuronal apoptosis in the CCH groups, combined with inhibition of CNTF/CNTFRα/JAK2/STAT3 signaling, as compared with that of sham control rats. D3NB significantly attenuated cognitive impairment in CCH rats and decreased hippocampal neuronal apoptosis after BCCAO in vivo or OGD/R in vitro. More importantly, D3NB reversed the inhibition of CNTF/CNTFRα expression and activated the JAK2/STAT3 pathway. Additionally, JAK2/STAT3 pathway inhibitor AG490 counteracted the protective effects of D3NB in vitro. Our results suggest that D3NB could improve cognitive function after CCH and that this neuroprotective effect may be associated with reduced hippocampal neuronal apoptosis via modulation of CNTF/CNTFRα/JAK2/STAT3 signaling pathways. D3NB may be a promising therapeutic strategy for vascular cognitive impairment induced by CCH.
Estimating Brain Functional Networks Based on Adaptively-Weighted fMRI Signals for MCI Identification
Authors: Chen Huihui , Zhang Yining , Zhang Limei , Qiao Lishan , Shen Dinggang
Published: January 2021

Brain functional network (BFN) analysis is becoming a crucial way to explore the inherent organized pattern of the brain and reveal potential biomarkers for diagnosing neurological or psychological disorders. In so doing, a well-estimated BFN is of great concern. In practice, however, noises or artifacts involved in the observed data (i.e., fMRI time series in this paper) generally lead to a poor estimation of BFN, and thus a complex preprocessing pipeline is often used to improve the quality of the data prior to BFN estimation. One of the popular preprocessing steps is data-scrubbing that aims at removing “bad” volumes from the fMRI time series according to the amplitude of the head motion. Despite its helpfulness in general, this traditional scrubbing scheme cannot guarantee that the removed volumes are necessarily unhelpful, since such a step is fully independent to the subsequent BFN estimation task. Moreover, the removal of volumes would reduce the statistical power, and different numbers of volumes are generally scrubbed for different subjects, resulting in an inconsistency or bias in the estimated BFNs. To address these issues, we develop a new learning framework that conducts BFN estimation and data-scrubbing simultaneously by an alternating optimization algorithm. The newly developed algorithm adaptively weights volumes (instead of removing them directly) for the task of BFN estimation. As a result, the proposed method can not only reduce the difficulty of threshold selection involved in the traditional scrubbing scheme, but also provide a more flexible framework that scrubs the data in the subsequent FBN estimation model. Finally, we validate the proposed method by identifying subjects with mild cognitive impairment (MCI) from normal controls based on the estimated BFNs, achieving an 80.22% classification accuracy, which significantly improves the baseline methods.
NeuroExercise: The Effect of a 12-Month Exercise Intervention on Cognition in Mild Cognitive Impairment—A Multicenter Randomized Controlled Trial
Authors: Stuckenschneider Tim , Sanders Marit L. , Devenney Kate E. , Aaronson Justine A. , Abeln Vera , Claassen Jurgen A. H. R. , Guinan Emer , Lawlor Brian , Meeusen Romain , Montag Christian , Olde Rikkert Marcel G. M. , Polidori M. Cristina , Reuter Martin , Schulz Ralf-Joachim , Vogt Tobias , Weber Bernd , Kessels Roy P. C. , Schneider Stefan
Published: January 2021

Exercise intervention studies in mild cognitive impairment (MCI), a prodromal stage of Alzheimer's disease (AD), have demonstrated inconsistent yet promising results. Addressing the limitations of previous studies, this trial investigated the effects of a 12-month structured exercise program on the progression of MCI. The NeuroExercise study is a multicenter randomized controlled trial across three European countries (Ireland, Netherlands, Germany). Hundred and eighty-three individuals with amnestic MCI were included and were randomized to a 12-month exercise intervention (3 units of 45 min) of either aerobic exercise (AE; n = 60), stretching and toning exercise (ST; n = 65) or to a non-exercise control group (CG; n = 58). The primary outcome, cognitive performance, was determined by an extensive neuropsychological test battery. For the primary complete case (CC) analyses, between-group differences were analyzed with analysis of covariance under two conditions: (1) the exercise group (EG = combined AE and ST groups) compared to the CG and (2) AE compared to ST. Primary analysis of the full cohort (n = 166, 71.5 years; 51.8% females) revealed no between-group differences in composite cognitive score [mean difference (95% CI)], 0.12 [(−0.03, 0.27), p = 0.13] or in any cognitive domain or quality of life. VO2 peak was significantly higher in the EG compared to the CG after 12 months [−1.76 (−3.39, −0.10), p = 0.04]. Comparing the two intervention groups revealed a higher VO2peak level in the aerobic exercise compared to the stretching and toning group, but no differences for the other outcomes. A 12-month exercise intervention did not change cognitive performance in individuals with amnestic MCI in comparison to a non-exercise CG. An intervention effect on physical fitness was found, which may be an important moderator for long term disease progression and warrants long-term follow-up investigations.

Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT02913053, identifier: NCT02913053.
Deletion of LRP1 From Astrocytes Modifies Neuronal Network Activity in an in vitro Model of the Tripartite Synapse
Authors: Romeo Ramona , Glotzbach Kristin , Scheller Anja , Faissner Andreas
Published: January 2021

The low-density lipoprotein receptor-related protein 1 (LRP1) is a transmembrane receptor that binds over 40 potential ligands and is involved in processes such as cell differentiation, proliferation, and survival. LRP1 is ubiquitously expressed in the organism and enriched among others in blood vessels, liver, and the central nervous system (CNS). There, it is strongly expressed by neurons, microglia, immature oligodendrocytes, and astrocytes. The constitutive LRP1 knockout leads to embryonic lethality. Therefore, previous studies focused on conditional LRP1-knockout strategies and revealed that the deletion of LRP1 causes an increased differentiation of neural stem and precursor cells into astrocytes. Furthermore, astrocytic LRP1 is necessary for the degradation of Aβ and the reduced accumulation of amyloid plaques in Alzheimer’s disease. Although the role of LRP1 in neurons has intensely been investigated, the function of LRP1 with regard to the differentiation and maturation of astrocytes and their functionality is still unknown. To address this question, we generated an inducible conditional transgenic mouse model, where LRP1 is specifically deleted from GLAST-positive astrocyte precursor cells. The recombination with resulting knockout events was visualized by the simultaneous expression of the fluorescent reporter tdTomato. We observed a significantly increased number of GLT-1 expressing astrocytes in LRP1-depleted astrocytic cultures in comparison to control astrocytes. Furthermore, we investigated the influence of astrocytic LRP1 on neuronal activity and synaptogenesis using the co-culture of hippocampal neurons with control or LRP1-depleted astrocytes. These analyses revealed that the LRP1-deficient astrocytes caused a decreased number of single action potentials as well as a negatively influenced neuronal network activity. Moreover, the proportion of pre- and postsynaptic structures was significantly altered in neurons co-cultured with LPR1-depleted astrocytes. However, the number of structural synapses was not affected. Additionally, the supernatant of hippocampal neurons co-cultured with LRP1-deficient astrocytes showed an altered set of cytokines in comparison to the control condition, which potentially contributed to the altered neuronal transmission and synaptogenesis. Our results suggest astrocytic LRP1 as a modulator of synaptic transmission and synaptogenesis by altering the expression of the glutamate transporter on the cell surface on astrocytes and the release of cytokines in vitro.
P2RX7 in Dopaminergic Neurons of Ventral Periaqueductal Gray Mediates HTWP Acupuncture-Induced Consciousness in Traumatic Brain Injury
Authors: Tang Huiling , Qin Siru , Li Wei , Chen Xuyi , Ulloa Luis , Zhu Qiumei , Liu Baohu , Gong Yinan , Zhao Yadan , Wang Songtao , Li Shanshan , Guo Yongming , Xu Zhifang , Guo Yi
Published: January 2021

The induction of a coma by traumatic brain injury (TBI) is a crucial factor for poor clinical prognoses. We report that acupuncture at the hand 12 Jing-Well points (HTWP) improved consciousness and neurologic function in TBI rats. Gene chip analyses showed that HTWP acupuncture mostly activated genes modulating neuronal projections (P2rx7, P2rx3, Trpv1, Tacr1, and Cacna1d), protein secretion (Exoc1, Exoc3l1, Fgb, and Fgr), and dopamine (DA) receptor D3 (Drd3) in the ventral periaqueductal gray (vPAG), among which the expression rate of P2rx7 was the most obviously increased. Acupuncture also increased the expression and excitability of DA and P2RX7 neurons, and the DA neurons expressed P2RX7, P2RX3, and TRPV1 in the vPAG. Intracerebroventricular administration of P2RX7, P2RX3, or TRPV1 antagonists blocked acupuncture-induced consciousness, and the subsequent injection of a P2RX7 antagonist into the vPAG nucleus also inhibited this effect. Our findings provide evidence that acupuncture alleviates TBI-induced comas via DA neurons expressing P2RX7 in the vPAG, so as to reveal the cellular and molecular mechanisms of the improvement of TBI clinical outcomes by HTWP acupuncture.
Intrinsic Mechanisms Regulating Neuronal Migration in the Postnatal Brain
Authors: Bressan Cedric , Saghatelyan Armen
Published: January 2021

Neuronal migration is a fundamental brain development process that allows cells to move from their birthplaces to their sites of integration. Although neuronal migration largely ceases during embryonic and early postnatal development, neuroblasts continue to be produced and to migrate to a few regions of the adult brain such as the dentate gyrus and the subventricular zone (SVZ). In the SVZ, a large number of neuroblasts migrate into the olfactory bulb (OB) along the rostral migratory stream (RMS). Neuroblasts migrate in chains in a tightly organized micro-environment composed of astrocytes that ensheath the chains of neuroblasts and regulate their migration; the blood vessels that are used by neuroblasts as a physical scaffold and a source of molecular factors; and axons that modulate neuronal migration. In addition to diverse sets of extrinsic micro-environmental cues, long-distance neuronal migration involves a number of intrinsic mechanisms, including membrane and cytoskeleton remodeling, Ca2+signaling, mitochondria dynamics, energy consumption, and autophagy. All these mechanisms are required to cope with the different micro-environment signals and maintain cellular homeostasis in order to sustain the proper dynamics of migrating neuroblasts and their faithful arrival in the target regions. Neuroblasts in the postnatal brain not only migrate into the OB but may also deviate from their normal path to migrate to a site of injury induced by a stroke or by certain neurodegenerative disorders. In this review, we will focus on the intrinsic mechanisms that regulate long-distance neuroblast migration in the adult brain and on how these pathways may be modulated to control the recruitment of neuroblasts to damaged/diseased brain areas.
Effects of Continuous Epidural Injection of Dexamethasone on Blood Glucose, Blood Lipids, Plasma Cortisol and ACTH in Patients With Neuropathic Pain
Authors: Liu Xiao-hui , Du Yu-min , Cong Hai-jing , Liu Guang-zhao , Ren Yu-E
Published: January 2021

Objective:To study the effects of continuous epidural injection of dexamethasone on blood glucose, blood lipids, plasma cortisol, and adrenocorticotropic hormone (ACTH) in patients with neuropathic pain.

Methods:Thirty patients with cervical spondylotic radiculopathy, lumbar disc herniation, herpes pain or postherpetic neuralgia were randomly divided into three groups and were treated with different doses of epidural injection of dexamethasone (Group S with a concentration of 25 μg/mL; Group M with a concentration of 50 μg/mL; Group L with a concentration of 100 μg/mL). Epidural catheterization placement was guided by computed tomography (CT), and was connected to the analgesic pump for 10 days. Visual Analog Score (VAS), fasting blood glucose (FBG), total cholesterol (CHOL), triglyceride (TG), 2 h postprandial blood glucose (2hPG) and the concentrations of cortisol, ACTH were measured before injection (T0), 2, 4, 6, 8, and 10 days during injection (D2, D4, D6, D8, D10), and 7, 14, 21, 28 days (W1, W2, W3, W4) after injection.

Results:During and after the treatment, VAS score was significantly decreased, and group M and L had the lowest VAS score. The concentrations of cortisol and ACTH were significantly lower during the treatment, but all of them recovered to the normal level after stopping the injection. The treatment did not affect the CHOL and TG concentrations.

Discussion:Epidural injection of dexamethasone at the concentration of 50 μg/mL is recommended for patients with neuropathic pain because of its good analgesic effect and less adverse effect on blood glucose, plasma cortisol, and ACTH.
Quantitative Evaluation of 18F-Flutemetamol PET in Patients With Cognitive Impairment and Suspected Alzheimer's Disease: A Multicenter Study
Authors: Matsuda Hiroshi , Ito Kengo , Ishii Kazunari , Shimosegawa Eku , Okazawa Hidehiko , Mishina Masahiro , Mizumura Sunao , Ishii Kenji , Okita Kyoji , Shigemoto Yoko , Kato Takashi , Takenaka Akinori , Kaida Hayato , Hanaoka Kohei , Matsunaga Keiko , Hatazawa Jun , Ikawa Masamichi , Tsujikawa Tetsuya , Morooka Miyako , Ishibashi Kenji , Kameyama Masashi , Yamao Tensho , Miwa Kenta , Ogawa Masayo , Sato Noriko
Published: January 2021

Background: In clinical practice, equivocal findings are inevitable in visual interpretation of whether amyloid positron emission tomography (PET) is positive or negative. It is therefore necessary to establish a more objective quantitative evaluation method for determining the indication for disease-modifying drugs currently under development.

Aims: We aimed to determine cutoffs for positivity in quantitative analysis of 18F-flutemetamol PET in patients with cognitive impairment and suspected Alzheimer's disease (AD). We also evaluated the clinical efficacy of amyloid PET in the diagnosis of AD. This study was registered in the Japan Registry of Clinical Trials (jRCTs, 031180321).

Methods: Ninety-three patients suspected of having AD underwent 18F-flutemetamol PET in seven institutions. A PET image for each patient was visually assessed and dichotomously rated as either amyloid-positive or amyloid-negative by two board-certified nuclear medicine physicians. If the two readers obtained different interpretations, the visual rating was rerun until they reached consensus. The PET images were quantitatively analyzed using the standardized uptake value ratio (SUVR) and standardized Centiloid (CL) scale with the whole cerebellum as a reference area.

Results: Visual interpretation obtained 61 positive and 32 negative PET scans. Receiver operating characteristic analysis determined the best agreement of quantitative assessments and visual interpretation of PET scans to have an area under curve of 0.982 at an SUVR of 1.13 and a CL of 16. Using these cutoff values, there was high agreement between the two approaches (kappa = 0.88). Five discordant cases had SUVR and CL values ranging from 1.00 to 1.22 and from 1 to 26, respectively. In these discordant cases, either diffuse or mildly focal elevation of cortical activity confused visual interpretation. The amyloid PET outcome significantly altered the diagnosis of AD (χ2 = 51.3, p < 0.0001). PET imaging elevated the proportions of the very high likelihood category from 20.4 to 46.2% and the very low likelihood category from 0 to 22.6%.

Conclusion: Quantitative analysis of amyloid PET using 18F-flutemetamol can objectively evaluate amyloid positivity using the determined cutoffs for SUVR and CL. Moreover, amyloid PET may have added value over the standard diagnostic workup in dementia patients with cognitive impairment and suspected AD.
Early-Onset Parkinson Disease Screening in Patients From Nigeria
Authors: Milanowski Lukasz M. , Oshinaike Olajumoke , Broadway Benjamin J. , Lindemann Jennifer A. , Soto-Beasley Alexandra I. , Walton Ronald L. , Hanna Al-Shaikh Rana , Strongosky Audrey J. , Fiesel Fabienne C. , Ross Owen A. , Springer Wolfdieter , Ogun Shamsideen Abayomi , Wszolek Zbigniew K.
Published: January 2021

Introduction: Nigeria is one of the most populated countries in the world; however, there is a scarcity of studies in patients with age-related neurodegenerative diseases, such as Parkinson disease (PD). The aim of this study was to screen patients with PD including a small cohort of early-onset PD (EOPD) cases from Nigeria for PRKN, PINK1, DJ1, SNCA multiplication, and LRRK2 p.G2019S.

Methods: We assembled a cohort of 109 Nigerian patients with PD from the four main Nigerian tribes: Yoruba, Igbo, Edo, and Hausa. Fifteen cases [14 from the Yoruba tribe (93.3%)] had EOPD (defined as age-at-onset <50 years). All patients with EOPD were sequenced for the coding regions of PRKN, PINK1, and DJ1. Exon dosage analysis was performed with a multiplex ligation-dependent probe amplification assay, which also included a SNCA probe and LRRK2 p.G2019S. We screened for LRRK2 p.G2019S in the entire PD cohort using a genotyping assay. The PINK1 p.R501Q functional analysis was conducted.

Results: In 15 patients with EOPD, 22 variants were observed [PRKN, 9 (40.9%); PINK1, 10 (45.5%); and DJ1, 3 (13.6%)]. Three (13.6%) rare, nonsynonymous variants were identified, but no homozygous or compound heterozygous carriers were found. No exonic rearrangements were present in the three genes, and no carriers of SNCA genomic multiplications or LRRK2 p.G2019S were identified. The PINK1 p.R501Q functional analysis revealed pathogenic loss of function.

Conclusion: More studies on age-related neurodegenerative diseases are needed in sub-Saharan African countries, including Nigeria. Population-specific variation may provide insight into the genes involved in PD in the local population but may also contribute to larger studiesperformed in White and Asian populations.
Case Report: Microglia Composition and Immune Response in an Immunocompetent Patient With an Intracranial Syphilitic Gumma
Authors: Yu Qian , Li Wei , Mo Xiaohui , Tan Fei , Yang Lianjuan
Published: January 2021

The pathogenesis of intracranial syphilitic gummas remains poorly understood. Microglia are generally considered to be the main cell type of the innate immune system in the brain. Determination of the composition of infiltrating microglia of patients with typical intracranial syphilitic gummas may contribute to the understanding of the pathological process. We report a case of an intracranial syphilitic gumma who presented with right upper limb weakness. The histological analysis showed the presence of Treponema pallidum and infiltration with histiocytes. Immunostaining indicated that cells were predominantly the M2a and M2c, which were Arg-1+ and IL-10+. These findings suggest that there is an increased number of M2a/M2c microglia in intracranial syphilitic gummas, which may be part of the immune escape mechanisms triggered by Treponema pallidum.
A Multidimensional Virtual Reality Neurorehabilitation Approach to Improve Functional Memory: Who Is the Ideal Candidate?
Authors: Di Tella Sonia , Isernia Sara , Pagliari Chiara , Jonsdottir Johanna , Castiglioni Carlotta , Gindri Patrizia , Gramigna Cristina , Canobbio Samuela , Salza Marco , Molteni Franco , Baglio Francesca
Published: January 2021

Aims: We aimed to identify the significant predictors of ecological memory amelioration after the Human Empowerment Aging and Disability (HEAD) rehabilitation program, a multidimensional treatment for chronic neurological diseases.

Materials and Methods: Ninety-three patients with Parkinson disease (n = 29), multiple sclerosis (n = 26), and stroke (n = 38) underwent a multidimensional rehabilitation. We focused on changes after treatment on ecological memory (outcome measure) evaluated by Rivermead Behavioral Memory Test, Third Edition (RBMT-3). Minimal clinically important difference (MCID) after treatment were calculated for RBMT-3. The change score on RBMT-3 was categorized in positive effect, stabilization, or no effect of the treatment. Random forest classification identified who significantly benefited from treatment against who did not in terms of ecological memory functioning. Accordingly, logistic regression models were created to identify the best predictors of the treatment effect. A predicted probability value was derived, and the profile of the ideal candidate of HEAD protocol was shown by combining different ranks of significant predictors in a 3 × 3 matrix for each pair of predictors.

Results: A significant number of cases reported positive effect of the treatment on ecological memory, with an amelioration over the MCID or a stabilization. The random forest analysis highlighted a discrete accuracy of prediction (>0.60) for all the variables considered at baseline for identifying participants who significantly benefited and who did not from the treatment. Significant logistic regression model (Wald method) showed a predictive role of Montreal Cognitive Assessment (MoCA; p = 0.007), 2-Minute Walk Test (2MWT; p = 0.038), and RBMT-3 (p < 0.001) at baseline on HEAD treatment effect. Finally, we observed a high probability of success in people with higher residual cognitive functioning (MoCA; odds ratio = 1.306) or functional mobility (2MWT; odds ratio = 1.013).

Discussion: The HEAD program is a rehabilitation with effects on multiple domains, including ecological memory. Residual level of cognitive and/or motor functioning is a significant predictor of the treatment success. These findings confirm the intrinsic relationship subsisting between motor and cognitive functions and suggest the beneficial effects of physical activity on cognitive functions and vice versa.
Causal Inferences in Repetitive Transcranial Magnetic Stimulation Research: Challenges and Perspectives
Authors: Hobot Justyna , Klincewicz Michał , Sandberg Kristian , Wierzchoń Michał
Published: January 2021

Transcranial magnetic stimulation (TMS) is used to make inferences about relationships between brain areas and their functions because, in contrast to neuroimaging tools, it modulates neuronal activity. The central aim of this article is to critically evaluate to what extent it is possible to draw causal inferences from repetitive TMS (rTMS) data. To that end, we describe the logical limitations of inferences based on rTMS experiments. The presented analysis suggests that rTMS alone does not provide the sort of premises that are sufficient to warrant strong inferences about the direct causal properties of targeted brain structures. Overcoming these limitations demands a close look at the designs of rTMS studies, especially the methodological and theoretical conditions which are necessary for the functional decomposition of the relations between brain areas and cognitive functions. The main points of this article are that TMS-based inferences are limited in that stimulation-related causal effects are not equivalent to structure-related causal effects due to TMS side effects, the electric field distribution, and the sensitivity of neuroimaging and behavioral methods in detecting structure-related effects and disentangling them from confounds. Moreover, the postulated causal effects can be based on indirect (network) effects. A few suggestions on how to manage some of these limitations are presented. We discuss the benefits of combining rTMS with neuroimaging in experimental reasoning and we address the restrictions and requirements of rTMS control conditions. The use of neuroimaging and control conditions allows stronger inferences to be gained, but the strength of the inferences that can be drawn depends on the individual experiment’s designs. Moreover, in some cases, TMS might not be an appropriate method of answering causality-related questions or the hypotheses have to account for the limitations of this technique. We hope this summary and formalization of the reasoning behind rTMS research can be of use not only for scientists and clinicians who intend to interpret rTMS results causally but also for philosophers interested in causal inferences based on brain stimulation research.
Recognition of Consumer Preference by Analysis and Classification EEG Signals
Authors: Aldayel Mashael , Ykhlef Mourad , Al-Nafjan Abeer
Published: January 2021

Neuromarketing has gained attention to bridge the gap between conventional marketing studies and electroencephalography (EEG)-based brain-computer interface (BCI) research. It determines what customers actually want through preference prediction. The performance of EEG-based preference detection systems depends on a suitable selection of feature extraction techniques and machine learning algorithms. In this study, We examined preference detection of neuromarketing dataset using different feature combinations of EEG indices and different algorithms for feature extraction and classification. For EEG feature extraction, we employed discrete wavelet transform (DWT) and power spectral density (PSD), which were utilized to measure the EEG-based preference indices that enhance the accuracy of preference detection. Moreover, we compared deep learning with other traditional classifiers, such as k-nearest neighbor (KNN), support vector machine (SVM), and random forest (RF). We also studied the effect of preference indicators on the performance of classification algorithms. Through rigorous offline analysis, we investigated the computational intelligence for preference detection and classification. The performance of the proposed deep neural network (DNN) outperforms KNN and SVM in accuracy, precision, and recall; however, RF achieved results similar to those of the DNN for the same dataset.
Interpersonal Agreement and Disagreement During Face-to-Face Dialogue: An fNIRS Investigation
Authors: Hirsch Joy , Tiede Mark , Zhang Xian , Noah J. Adam , Salama-Manteau Alexandre , Biriotti Maurice
Published: January 2021

Although the neural systems that underlie spoken language are well-known, how they adapt to evolving social cues during natural conversations remains an unanswered question. In this work we investigate the neural correlates of face-to-face conversations between two individuals using functional near infrared spectroscopy (fNIRS) and acoustical analyses of concurrent audio recordings. Nineteen pairs of healthy adults engaged in live discussions on two controversial topics where their opinions were either in agreement or disagreement. Participants were matched according to their a priori opinions on these topics as assessed by questionnaire. Acoustic measures of the recorded speech including the fundamental frequency range, median fundamental frequency, syllable rate, and acoustic energy were elevated during disagreement relative to agreement. Consistent with both the a priori opinion ratings and the acoustic findings, neural activity associated with long-range functional networks, rather than the canonical language areas, was also differentiated by the two conditions. Specifically, the frontoparietal system including bilateral dorsolateral prefrontal cortex, left supramarginal gyrus, angular gyrus, and superior temporal gyrus showed increased activity while talking during disagreement. In contrast, talking during agreement was characterized by increased activity in a social and attention network including right supramarginal gyrus, bilateral frontal eye-fields, and left frontopolar regions. Further, these social and visual attention networks were more synchronous across brains during agreement than disagreement. Rather than localized modulation of the canonical language system, these findings are most consistent with a model of distributed and adaptive language-related processes including cross-brain neural coupling that serves dynamic verbal exchanges.
Searching Far and Genome-Wide: The Relevance of Association Studies in Amyotrophic Lateral Sclerosis
Authors: Rich Kelly A. , Roggenbuck Jennifer , Kolb Stephen J.
Published: January 2021

Genome-wide association studies (GWAS) and rare variant association studies (RVAS) are applied across many areas of complex disease to analyze variation in whole genomes of thousands of unrelated patients. These approaches are able to identify variants and/or biological pathways which are associated with disease status and, in contrast to traditional linkage studies or candidate gene approaches, do so without requiring multigenerational affected families, prior hypotheses, or known genes of interest. However, the novel associations identified by these methods typically have lower effect sizes than those found in classical family studies. In the motor neuron disease amyotrophic lateral sclerosis (ALS), GWAS, and RVAS have been used to identify multiple disease-associated genes but have not yet resulted in novel therapeutic interventions. There is significant urgency within the ALS community to identify additional genetic markers of disease to uncover novel biological mechanisms, stratify genetic subgroups of disease, and drive drug development. Given the widespread and increasing application of genetic association studies of complex disease, it is important to recognize the strengths and limitations of these approaches. Here, we review ALS gene discovery via GWAS and RVAS.
Nicotine Increases Spontaneous Glutamate Release in the Rostromedial Tegmental Nucleus
Authors: Castillo-Rolón Diego , Ramírez-Sánchez Enrique , Arenas-López Gabina , Garduño Julieta , Hernández-González Omar , Mihailescu Stefan , Hernández-López Salvador
Published: January 2021

The rostromedial tegmental nucleus (RMTg) is a bilateral structure localized in the brainstem and comprise of mainly GABAergic neurons. One of the main functions of the RMTg is to regulate the activity of dopamine neurons of the mesoaccumbens pathway. Therefore, the RMTg has been proposed as a modulator of the reward system and adaptive behaviors associated to reward learning. The RMTg receives an important glutamatergic input from the lateral habenula. Also, it receives cholinergic inputs from the laterodorsal and pedunculopontine tegmental nuclei. Previously, it was reported that nicotine increases glutamate release, evoked by electric stimulation, in the RMTg nucleus. However, the mechanisms by which nicotine induces this effect were not explored. In the present work, we performed electrophysiological experiments in brainstem slices to study the effect of nicotine on spontaneous excitatory postsynaptic currents recorded from immunocytochemically identified RMTg neurons. Also, we used calcium imaging techniques to explore the effects of nicotine on multiple RMTg neurons simultaneously. We found that nicotine promotes the persistent release of glutamate through the activation of α7 nicotinic acetylcholine receptors present on glutamatergic afferents and by a mechanism involving calcium release from intracellular stores. Through these mechanisms, nicotine increases the excitability and synchronizes the activity of RMTg neurons. Our results suggest that the RMTg nucleus mediates the noxious effects of the nicotine, and it could be a potential therapeutic target against tobacco addiction.
Hemisphere-Specific Functional Remodeling and Its Relevance to Tumor Malignancy of Cerebral Glioma Based on Resting-State Functional Network Analysis
Authors: Cai Siqi , Shi Zhifeng , Jiang Chunxiang , Wang Kai , Chen Liang , Ai Lin , Zhang Lijuan
Published: January 2021

Background: Functional remodeling may vary with tumor aggressiveness of glioma. Investigation of the functional remodeling is expected to provide scientific relevance of tumor characterization and disease management of glioma. In this study, we aimed to investigate the functional remodeling of the contralesional hemisphere and its utility in predicting the malignant grade of glioma at the individual level with multivariate logistic regression (MLR) analysis. Subjects and Methods: One hundred and twenty-six right-handed subjects with histologically confirmed cerebral glioma were included with 80 tumors located in the left hemisphere (LH) and 46 tumors located in the right hemisphere (RH). Resting-state functional networks of the contralesional hemisphere were constructed using the human brainnetome atlas based on resting-state fMRI data. Functional connectivity and topological features of functional networks were quantified. The performance of functional features in predicting the glioma grade was evaluated using area under (AUC) the receiver operating characteristic curve (ROC). The dataset was divided into training and validation datasets. Features with high AUC values in malignancy classification in the training dataset were determined as predictive features. An MLR model was constructed based on predictive features and its classification performance was evaluated on the training and validation datasets with 10-fold cross validation. Results: Predictive functional features showed apparent hemispheric specifications. MLR classification models constructed with age and predictive functional connectivity features (AUC of 0.853 ± 0.079 and 1.000 ± 0.000 for LH and RH group, respectively) and topological features (AUC of 0.788 ± 0.150 and 0.897 ± 0.165 for LH and RH group, respectively) achieved efficient performance in predicting the malignant grade of gliomas. Conclusion: Functional remodeling of the contralesional hemisphere was hemisphere-specific and highly predictive of the malignant grade of glioma. Network approach provides a novel pathway that may innovate glioma characterization and management at the individual level.
Looking for Novelty in an “Old” Receptor: Recent Advances Toward Our Understanding of GABAARs and Their Implications in Receptor Pharmacology
Authors: Castellano David , Shepard Ryan David , Lu Wei
Published: January 2021

Diverse populations of GABAA receptors (GABAARs) throughout the brain mediate fast inhibitory transmission and are modulated by various endogenous ligands and therapeutic drugs. Deficits in GABAAR signaling underlie the pathophysiology behind neurological and neuropsychiatric disorders such as epilepsy, anxiety, and depression. Pharmacological intervention for these disorders relies on several drug classes that target GABAARs, such as benzodiazepines and more recently neurosteroids. It has been widely demonstrated that subunit composition and receptor stoichiometry impact the biophysical and pharmacological properties of GABAARs. However, current GABAAR-targeting drugs have limited subunit selectivity and produce their therapeutic effects concomitantly with undesired side effects. Therefore, there is still a need to develop more selective GABAAR pharmaceuticals, as well as evaluate the potential for developing next-generation drugs that can target accessory proteins associated with native GABAARs. In this review, we briefly discuss the effects of benzodiazepines and neurosteroids on GABAARs, their use as therapeutics, and some of the pitfalls associated with their adverse side effects. We also discuss recent advances toward understanding the structure, function, and pharmacology of GABAARs with a focus on benzodiazepines and neurosteroids, as well as newly identified transmembrane proteins that modulate GABAARs.
Neurobiological and Hormonal Mechanisms Regulating Women’s Sleep
Authors: Dorsey Alanna , de Lecea Luis , Jennings Kimberly J.
Published: January 2021

Sleep is crucial for optimal well-being, and sex differences in sleep quality have significant implications for women’s health. We review the current literature on sex differences in sleep, such as differences in objective and subjective sleep measures and their relationship with aging. We then discuss the convincing evidence for the role of ovarian hormones in regulating female sleep, and survey how these hormones act on a multitude of brain regions and neurochemicals to impact sleep. Lastly, we identify several important areas in need of future research to narrow the knowledge gap and improve the health of women and other understudied populations.
Estimating Dining Plate Size From an Egocentric Image Sequence Without a Fiducial Marker
Authors: Jia Wenyan , Wu Zekun , Ren Yiqiu , Cao Shunxin , Mao Zhi-Hong , Sun Mingui
Published: January 2021

Despite the extreme importance of food intake in human health, it is currently difficult to conduct an objective dietary assessment without individuals' self-report. In recent years, a passive method utilizing a wearable electronic device has emerged. This device acquires food images automatically during the eating process. These images are then analyzed to estimate intakes of calories and nutrients, assisted by advanced computational algorithms. Although this passive method is highly desirable, it has been thwarted by the requirement of a fiducial marker which must be present in the image for a scale reference. The importance of this scale reference is analogous to the importance of the scale bar in a map which determines distances or areas in any geological region covered by the map. Likewise, the sizes or volumes of arbitrary foods on a dining table covered by an image cannot be determined without the scale reference. Currently, the fiducial marker (often a checkerboard card) serves as the scale reference which must be present on the table before taking pictures, requiring human efforts to carry, place and retrieve the fiducial marker manually. In this work, we demonstrate that the fiducial marker can be eliminated if an individual's dining location is fixed and a one-time calibration using a circular plate of known size is performed. When the individual uses another circular plate of an unknown size, our algorithm estimates its radius using the range of pre-calibrated distances between the camera and the plate from which the desired scale reference is determined automatically. Our comparative experiment indicates that the mean absolute percentage error of the proposed estimation method is ~10.73%. Although this error is larger than that of the manual method of 6.68% using a fiducial marker on the table, the new method has a distinctive advantage of eliminating the manual procedure and automatically generating the scale reference.
Analysis of Human Faecal Host Proteins: Responsiveness to 10-Week Dietary Intervention Modifying Dietary Protein Intake in Elderly Males
Authors: Gathercole Jessica L. , Grosvenor Anita J. , Lee Erin , Thomas Ancy , Mitchell Cameron J. , Zeng Nina , D'Souza Randall F. , Ramzan Farha , Sharma Pankaja , Knowles Scott O. , Roy Nicole C. , Sjödin Anders , Wagner Karl-Heinz , Milan Amber M. , Mitchell Sarah M. , Cameron-Smith David
Published: January 2021

Faecal proteomics targeting biomarkers of immunity and inflammation have demonstrated clinical application for the identification of changes in gastrointestinal function. However, there are limited comprehensive analyses of the host faecal proteome and how it may be influenced by dietary factors. To examine this, the Homo sapiens post-diet proteome of older males was analysed at the completion of a 10-week dietary intervention, either meeting the minimum dietary protein recommendations (RDA; n = 9) or twice the recommended dietary allowance (2RDA, n = 10). The host faecal proteome differed markedly between individuals, with only a small subset of proteins present in ≥ 60% of subjects (14 and 44 proteins, RDA and 2RDA, respectively, with only 7 common to both groups). No differences were observed between the diet groups on the profiles of host faecal proteins. Faecal proteins were detected from a wide range of protein classes, with high inter-individual variation and absence of obvious impact in response to diets with markedly different protein intake. This suggests that well-matched whole food diets with two-fold variation in protein intake maintained for 10 weeks have minimal impact on human faecal host proteins.
Development and Validation of a Novel Risk Stratification Model for Cancer-Specific Survival in Diffuse Large B-Cell Lymphoma
Authors: Zhong Qiaofeng , Shi Yuankai
Published: January 2021

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogenous disease. Identifying more precise and individual survival prognostic models are still needed. This study aimed to develop a predictive nomogram and a web-based survival rate calculator that can dynamically predict the long-term cancer-specific survival (CSS) of DLBCL patients. A total of 3,573 eligible patients with DLBCL from 2004 to 2015 were extracted from the Surveillance, Epidemiology and End Results (SEER) database. The entire group was randomly divided into the training (n = 2,504) and validation (n = 1,069) cohorts. We identified six independent predictors for survival including age, sex, marital status, Ann Arbor stage, B symptom, and chemotherapy, which were used to construct the nomogram and the web-based survival rate calculator. The C-index of the nomogram was 0.709 (95% CI, 0.692–0.726) in the training cohort and 0.700 (95% CI, 0.671–0.729) in the validation cohort. The AUC values of the nomogram for predicting the 1-, 5-, and 10- year CSS rates ranged from 0.704 to 0.765 in both cohorts. All calibration curves revealed optimal consistency between predicted and actual survival. A risk stratification model generated based on the nomogram showed a favorable level of predictive accuracy compared with the IPI, R-IPI, and Ann Arbor stage in both cohorts according to the AUC values (training cohort: 0.715 vs 0.676, 0.652, and 0.648; validation cohort: 0.695 vs 0.692, 0.657, and 0.624) and K-M survival curves. In conclusion, we have established and validated a novel nomogram risk stratification model and a web-based survival rate calculator that can dynamically predict the long-term CSS in DLBCL, which revealed more discriminative and predictive accuracy than the IPI, R-IPI, and Ann Arbor stage in the rituximab era.
A Novel Insecticidal Spider Peptide that Affects the Mammalian Voltage-Gated Ion Channel hKv1.5
Authors: Alvarado Diana , Cardoso-Arenas Samuel , Corrales-García Ligia-Luz , Clement Herlinda , Arenas Iván , Montero-Dominguez Pavel Andrei , Olamendi-Portugal Timoteo , Zamudio Fernando , Csoti Agota , Borrego Jesús , Panyi Gyorgy , Papp Ferenc , Corzo Gerardo
Published: January 2021

Spider venoms include various peptide toxins that modify the ion currents, mainly of excitable insect cells. Consequently, scientific research on spider venoms has revealed a broad range of peptide toxins with different pharmacological properties, even for mammal species. In this work, thirty animal venoms were screened against hKv1.5, a potential target for atrial fibrillation therapy. The whole venom of the spider Oculicosa supermirabilis, which is also insecticidal to house crickets, caused voltage-gated potassium ion channel modulation in hKv1.5. Therefore, a peptide from the spider O. supermirabilis venom, named Osu1, was identified through HPLC reverse-phase fractionation. Osu1 displayed similar biological properties as the whole venom; so, the primary sequence of Osu1 was elucidated by both of N-terminal degradation and endoproteolytic cleavage. Based on its primary structure, a gene that codifies for Osu1 was constructed de novo from protein to DNA by reverse translation. A recombinant Osu1 was expressed using a pQE30 vector inside the E. coli SHuffle expression system. recombinant Osu1 had voltage-gated potassium ion channel modulation of human hKv1.5, and it was also as insecticidal as the native toxin. Due to its novel primary structure, and hypothesized disulfide pairing motif, Osu1 may represent a new family of spider toxins.
Allium macrostemon Saponin Inhibits Activation of Platelet via the CD40 Signaling Pathway
Authors: Ling Sisi , Jin Lijun , Li Shizheng , Zhang Fangcheng , Xu Qiong , Liu Mingke , Chen Xuke , Liu Xiaolin , Gu Jielei , Liu Shiming , Liu Ningning , Ou Wenchao
Published: January 2021

Allium macrostemon saponin is a traditional Chinese medicine that exhibits anti-atherosclerosis effects. However, the mechanism of its action has not been fully clarified. Platelet activation induced by CD40L plays an important role in the process of atherosis. In the present study, we demonstrate for the first time that A. macrostemon saponin inhibits platelet activation induced by CD40L. Moreover, the effects of saponin on platelet activation were achieved by activation of the classical CD40L-associated pathway, including the PI3K/Akt, MAPK and NF-κB proteins. In addition, the present study further demonstrated that saponin exhibited an effect on the TRAF2-mediated ubiquitination degradation, which contributed to the inhibition of the CD40 pathway and its downstream members. The findings determine that A. macrostemon saponin inhibits activation of platelets via activation of downstream proteins of the CD40 pathway. This in turn affected TRAF2-associated ubiquitination degradation and caused an anti-thrombotic effect.