bluuebunny/crossref_metadata_2025 huggingface dataset:
Emerging Roles of Exosomes in T1DM
Authors: Pang Haipeng , Luo Shuoming , Xiao Yang , Xia Ying , Li Xia , Huang Gan , Xie Zhiguo , Zhou Zhiguang
Published: November 2020

Type 1 diabetes mellitus (T1DM) is a complex autoimmune disorder that mainly affects children and adolescents. The elevated blood glucose level of patients with T1DM results from absolute insulin deficiency and leads to hyperglycemia and the development of life-threatening diabetic complications. Although great efforts have been made to elucidate the pathogenesis of this disease, the precise underlying mechanisms are still obscure. Emerging evidence indicates that small extracellular vesicles, namely, exosomes, take part in intercellular communication and regulate interorgan crosstalk. More importantly, many findings suggest that exosomes and their cargo are associated with the development of T1DM. Therefore, a deeper understanding of exosomes is beneficial for further elucidating the pathogenic process of T1DM. Exosomes are promising biomarkers for evaluating the risk of developingty T1DM, monitoring the disease state and predicting related complications because their number and composition can reflect the status of their parent cells. Additionally, since exosomes are natural carriers of functional proteins, RNA and DNA, they can be used as therapeutic tools to deliver these molecules and drugs. In this review, we briefly introduce the current understanding of exosomes. Next, we focus on the relationship between exosomes and T1DM from three perspectives, i.e., the pathogenic role of exosomes in T1DM, exosomes as novel biomarkers of T1DM and exosomes as therapeutic tools for T1DM.
Chimeric Antigen Receptor Based Therapy as a Potential Approach in Autoimmune Diseases: How Close Are We to the Treatment?
Authors: Sadeqi Nezhad Muhammad , Seifalian Alexander , Bagheri Nader , Yaghoubi Sajad , Karimi Mohammad Hossein , Adbollahpour-Alitappeh Meghdad
Published: November 2020

Despite significant breakthroughs in understanding of immunological and physiological features of autoimmune diseases, there is currently no specific therapeutic option with prolonged remission. Cell-based therapy using engineered-T cells has attracted tremendous attention as a practical treatment for autoimmune diseases. Genetically modified-T cells armed with chimeric antigen receptors (CARs) attack autoreactive immune cells such as B cells or antibody-secreting plasma cells. CARs can further guide the effector and regulatory T cells (Tregs) to the autoimmune milieu to traffic, proliferate, and exert suppressive functions. The genetically modified-T cells with artificial receptors are a promising option to suppress autoimmune manifestation and autoinflammatory events. Interestingly, CAR-T cells are modified to a new chimeric auto-antibody receptor T (CAAR-T) cell. This cell, with its specific-antigen, recognizes and binds to the target autoantibodies expressing autoreactive cells and, subsequently, destroy them. Preclinical studies of CAR-T cells demonstrated satisfactory outcomes against autoimmune diseases. However, the lack of target autoantigens remains one of the pivotal problems in the field of CAR-T cells. CAR-based therapy has to pass several hurdles, including stability, durability, trafficking, safety, effectiveness, manufacturing, and persistence, to enter clinical use. The primary goal of this review was to shed light on CAR-T immunotherapy, CAAR-T cell therapy, and CAR-Treg cell therapy in patients with immune system diseases.
Hydrothermal Activity at a Cretaceous Seamount, Canary Archipelago, Caused by Rejuvenated Volcanism
Authors: Klügel Andreas , Villinger Heinrich , Römer Miriam , Kaul Norbert , Krastel Sebastian , Lenz Kai-Frederik , Wintersteller Paul
Published: November 2020

Our knowledge of venting at intraplate seamounts is limited. Almost nothing is known about past hydrothermal activity at seamounts, because indicators are soon blanketed by sediment. This study provides evidence for temporary hydrothermal circulation at Henry Seamount, a re-activated Cretaceous volcano near El Hierro island, close to the current locus of the Canary Island hotspot. In the summit area at around 3000–3200 m water depth, we found areas with dense coverage by shell fragments from vesicomyid clams, a few living chemosymbiotic bivalves, and evidence for sites of weak fluid venting. Our observations suggest pulses of hydrothermal activity since some thousands or tens of thousands years, which is now waning. We also recovered glassy heterolithologic tephra and dispersed basaltic rock fragments from the summit area. Their freshness suggests eruption during the Pleistocene to Holocene, implying minor rejuvenated volcanism at Henry Seamount probably related to the nearby Canary hotspot. Heat flow values determined on the surrounding seafloor (49 ± 7 mW/m2) are close to the expected background for conductively cooled 155 Ma old crust; the proximity to the hotspot did not result in elevated basal heat flow. A weak increase in heat flow toward the southwestern seamount flank likely reflects recent local fluid circulation. We propose that hydrothermal circulation at Henry Seamount was, and still is, driven by heat pulses from weak rejuvenated volcanic activity. Our results suggest that even single eruptions at submarine intraplate volcanoes may give rise to ephemeral hydrothermal systems and generate potentially habitable environments.
Mitochondrial Complex I Core Protein Regulates cAMP Signaling via Phosphodiesterase Pde2 and NAD Homeostasis in Candida albicans
Authors: She Xiaodong , Zhang Lulu , Peng Jingwen , Zhang Jingyun , Li Hongbin , Zhang Pengyi , Calderone Richard , Liu Weida , Li Dongmei
Published: November 2020

The cyclic adenosine 3′,5′-monophosphate (cAMP)/protein kinase A (PKA) pathway ofCandida albicansresponds to nutrient availability to coordinate a series of cellular processes for its replication and survival. The elevation of cAMP for PKA signaling must be both transitory and tightly regulated. Otherwise, any abnormal cAMP/PKA pathway would disrupt metabolic potential and ergosterol synthesis and promote a stress response. One possible mechanism for controlling cAMP levels is direct induction of the phosphodiesterasePDE2gene by cAMP itself. Our earlier studies have shown that most single-gene-deletion mutants of the mitochondrial electron transport chain (ETC) complex I (CI) are hypersensitive to fluconazole. To understand the fluconazole hypersensitivity observed in these mutants, we focused upon the cAMP/PKA-mediated ergosterol synthesis in CI mutants. Two groups of the ETC mutants were used in this study. Group I includes CI mutants. Group II is composed of CIII and CIV mutants; group II mutants are known to have greater respiratory loss. All mutants are not identical in cAMP/PKA-mediated ergosterol response. We found that ergosterol levels are decreased by 47.3% in thendh51Δ (CI core subunit mutant) and by 23.5% ingoa1Δ (CI regulator mutant). Both mutants exhibited a greater reduction of cAMP and excessive trehalose production compared with other mutants. Despite the normal cAMP level, ergosterol content decreased by 33.0% in the CIII mutantqce1Δ as well, thereby displaying a cAMP/PKA-independent ergosterol response. While the two CI mutants have some unique cAMP/PKA-mediated ergosterol responses, we found that the degree of cAMP reduction correlates linearly with a decrease in total nicotinamide adenine dinucleotide (NAD) levels in all mutants, particularly in the seven CI mutants. A mechanism study demonstrates that overactivePDE2and cPDE activity must be the cause of the suppressive cAMP-mediated ergosterol response in thendh51Δ andgoa1Δ. While the purpose of this study is to understand the impact of ETC proteins on pathogenesis-associated cellular events, our results reveal the importance of Ndh51p in the regulation of the cAMP/PKA pathway through Pde2p inhibition in normal physiological environments. As a direct link between Ndh51p and Pde2p remains elusive, we suggest that Ndh51p participates in NAD homeostasis that might regulate Pde2p activity for the optimal cAMP pathway state.
Spatiotemporal Dynamics of Vibrio Communities and Abundance in Dongshan Bay, South of China
Authors: Xu Wei , Gong LinFeng , Yang Shuai , Gao Yuanhao , Ma Xiaowan , Xu Limei , Chen Haisheng , Luo Zhuhua
Published: November 2020

The Vibrio genus inhabit estuarine and marine ecosystem throughout the world and can cause severe infections in humans and animals. Previous studies have demonstrated the dynamics of Vibrio at both community and population levels and assessed the close relationship between environmental factors and Vibrio diversity and abundance, such as temperature, salinity, and dissolved oxygen. It is also generally believed that aquaculture is the fastest-growing food sector, which is also applying great environmental impacts on microbial communities in aquatic ecosystems. However, our understanding of the spatiotemporal quantification of Vibrio throughout the four seasons in the aquaculture zone and response to environmental factors remains poor. To explore the spatiotemporal distribution and abundance of the Vibrio community with their related environmental factors and detect the relationships among them, we collected 10 seawater sites spanning four seasons across the whole year in Dongshan Bay for investigating the Vibrio community dynamics. Marked differences in diversity and abundance of the Vibrio community were observed between seasons, which were mainly driven by temperature, dissolved oxygen, nitrate, and nitrite. qPCR analysis showed that Vibrio abundance was most abundant in the summer (5.37 × 106 copies/L), compared with the autumn (4.58 × 106 copies/L), spring (1.18 × 106 copies/L), and winter (1.55 × 104 copies/L). A total of 22 Vibrio operational taxonomic units (OTUs) and 28 species were identified by universal bacteria 16S rRNA gene and cultivation methods, with Vibrio fortis the dominant in these aquaculture areas. To summarize, our present study is one of the few studies to research the occurrence of Vibrio in marine aquaculture of South China, and the results indicate that Vibrio are widely distributed in aquaculture environment and that a further risk assessment is needed to be conducted.
Discovery of an Antibiotic-Related Small Protein of Biocontrol Strain Pseudomonas sp. Os17 by a Genome-Mining Strategy
Authors: Takeuchi Kasumi , Tsuchiya Wataru , Fujimoto Zui , Yamada Kosumi , Someya Nobutaka , Yamazaki Toshimasa
Published: November 2020

Many root-colonizing Pseudomonas spp. exhibiting biocontrol activities produce a wide range of secondary metabolites that exert antibiotic effects against other microbes, nematodes, and insects in the rhizosphere. The expression of these secondary metabolites depends on the Gac/Rsm signal transduction pathway. Based on the findings of a previous genomic study on newly isolated biocontrol pseudomonad strains, we herein investigated the novel gene cluster OS3, which consists of four genes (Os1348–Os1351) that are located upstream of putative efflux transporter genes (Os1352–Os1355). Os1348 was predicted to encode an 85-aa small precursor protein, the expression of which was under the control of GacA, and an X-ray structural analysis suggested that the Os1348 protein formed a dimer. The mutational loss of the Os1348 gene decreased the antibiotic activity of Pseudomonas sp. Os17 without changing its growth rate. The Os1349–1351 genes were predicted to be involved in post-translational modifications. Intracellular levels of the Os1348 protein in the deficient mutant of each gene differed from that in wild-type cells. These results suggest that Os1348 is involved in antibiotic activity and that the structure or expression of this protein is under the control of downstream gene products.
Differences in Noradrenaline Receptor Expression Across Different Neuronal Subtypes in Macaque Frontal Eye Field
Authors: Lee Max , Mueller Adrienne , Moore Tirin
Published: November 2020

Cognitive functions such as attention and working memory are modulated by noradrenaline receptors in the prefrontal cortex (PFC). The frontal eye field (FEF) has been shown to play an important role in visual spatial attention. However, little is known about the underlying circuitry. The aim of this study was to characterize the expression of noradrenaline receptors on different pyramidal neuron and inhibitory interneuron subtypes in macaque FEF. Using immunofluorescence, we found broad expression of noradrenaline receptors across all layers of the FEF. Differences in the expression of different noradrenaline receptors were observed across different inhibitory interneuron subtypes. No significant differences were observed in the expression of noradrenaline receptors across different pyramidal neuron subtypes. However, we found that putative long-range projecting pyramidal neurons expressed all noradrenaline receptor subtypes at a much higher proportion than any of the other neuronal subtypes. Nearly all long-range projecting pyramidal neurons expressed all types of noradrenaline receptor, suggesting that there is no receptor-specific machinery acting on these long-range projecting pyramidal neurons. This pattern of expression among long-range projecting pyramidal neurons suggests a mechanism by which noradrenergic modulation of FEF activity influences attention and working memory.
Developmental Genes and Malformations in the Hypothalamus
Authors: Diaz Carmen , Puelles Luis
Published: November 2020

The hypothalamus is a heterogeneous rostral forebrain region that regulates physiological processes essential for survival, energy metabolism, and reproduction, mainly mediated by the pituitary gland. In the updated prosomeric model, the hypothalamus represents the rostralmost forebrain, composed of two segmental regions (terminal and peduncular hypothalamus), which extend respectively into the non-evaginated preoptic telencephalon and the evaginated pallio-subpallial telencephalon. Complex genetic cascades of transcription factors and signaling molecules rule their development. Alterations of some of these molecular mechanisms acting during forebrain development are associated with more or less severe hypothalamic and pituitary dysfunctions, which may be associated with brain malformations such as holoprosencephaly or septo-optic dysplasia. Studies on transgenic mice with mutated genes encoding critical transcription factors implicated in hypothalamic-pituitary development are contributing to understanding the high clinical complexity of these pathologies. In this review article, we will analyze first the complex molecular genoarchitecture of the hypothalamus resulting from the activity of previous morphogenetic signaling centers and secondly some malformations related to alterations in genes implicated in the development of the hypothalamus.
Whole-Brain Three-Dimensional Profiling Reveals Brain Region Specific Axon Vulnerability in 5xFAD Mouse Model
Authors: Zhang Jianping , Long Ben , Li Anan , Sun Qingtao , Tian Jiaojiao , Luo Ting , Ding Zhangheng , Gong Hui , Li Xiangning
Published: November 2020

Axonopathy is a pathological feature observed in both Alzheimer’s disease (AD) patients and animal models. However, identifying the temporal and regional progression of axonopathy during AD development remains elusive. Using the fluorescence micro-optical sectioning tomography system, we acquired whole-brain datasets in the early stage of 5xFAD/Thy1-GFP-M mice. We reported that among GFP labeled axons, GFP-positive axonopathy first formed in the lateral septal nucleus, subiculum, and medial mammillary nucleus. The axonopathy further increased in most brain regions during aging. However, most of the axonopathic varicosities disappeared significantly in the medial mammillary nucleus after 8 weeks old. Continuous three-dimensional datasets showed that axonopathy in the medial mammillary nucleus was mainly located on axons from hippocampal GFP-positive neurons. Using the rabies viral tracer in combination with immunohistochemistry, we found that axons in the medial mammillary nucleus from the subiculum were susceptible to lesions that prior to the occurrence of behavioral disorders. In conclusion, we created an early-stage spatiotemporal map of axonopathy in 5xFAD/Thy1-GFP-M mice and identified specific neural circuits which are vulnerable to axon lesions in an AD mouse model. These findings underline the importance of early interventions for AD, and may contribute to the understanding of its progression and its early symptom treatment.
Reinforcement Q-Learning Control With Reward Shaping Function for Swing Phase Control in a Semi-active Prosthetic Knee
Authors: Hutabarat Yonatan , Ekkachai Kittipong , Hayashibe Mitsuhiro , Kongprawechnon Waree
Published: November 2020

In this study, we investigated a control algorithm for a semi-active prosthetic knee based on reinforcement learning (RL). Model-free reinforcement Q-learning control with a reward shaping function was proposed as the voltage controller of a magnetorheological damper based on the prosthetic knee. The reward function was designed as a function of the performance index that accounts for the trajectory of the subject-specific knee angle. We compared our proposed reward function to a conventional single reward function under the same random initialization of a Q-matrix. We trained this control algorithm to adapt to several walking speed datasets under one control policy and subsequently compared its performance with that of other control algorithms. The results showed that our proposed reward function performed better than the conventional single reward function in terms of the normalized root mean squared error and also showed a faster convergence trend. Furthermore, our control strategy converged within our desired performance index and could adapt to several walking speeds. Our proposed control structure has also an overall better performance compared to user-adaptive control, while some of its walking speeds performed better than the neural network predictive control from existing studies.
Association Between Cumulative Exposure to Increased Low-Density Lipoprotein Cholesterol and the Prevalence of Asymptomatic Intracranial Atherosclerotic Stenosis
Authors: Kang Kaijiang , Wang Yu , Wu Jianwei , Wang Anxin , Zhang Jia , Xu Jie , Ju Yi , Zhao Xingquan
Published: November 2020

Background and Purpose: Intracranial atherosclerosis has gained increasing attention due to the high risk of recurrent clinical or subclinical ischemic events, while the relationship between low-density lipoprotein cholesterol (LDL-C) measured at a single time point and intracranial atherosclerotic stenosis (ICAS) is inconsistent. This study aims to assess the association between cumulative exposure to increased LDL-C and the prevalence of asymptomatic ICAS.

Methods: The Asymptomatic Polyvascular Abnormalities Community study was investigated on the epidemiology of asymptomatic polyvascular abnormalities in Chinese adults. In this study, we included 4,523 participants with LDL-C measured at 3 examinations in 2006, 2008, and 2010. Cumulative exposure to increased LDL-C was calculated as following: LDL-C burden2006−2008 = [(LDL-C2006-1.8) + (LDL-C2008-1.8)]/2 * time2006−2008; LDL-C burden = LDL-C burden2006−2008 + LDL-C burden2008−2010. Transcranial doppler ultrasonography was performed in 2010 to detecting the ICAS.

Results: Of the 4,347 patients, 13.3% (580/4,347) were diagnosed with ICAS. In univariate analysis, the association between LDL-C burden and ICAS prevalence was significant, the odds ratios (95% confidence interval) from the lowest to the highest quartile were 1 (reference), 1.30 (0.99–1.70), 1.32 (1.01–1.73), and 2.14 (1.66–2.75), respectively (P < 0.05). After adjustment for potential confounding factors, the same result was reached.

Conclusions: Cumulative exposure to increased LDL-C is concentration-dependently associated with increased prevalence of asymptomatic ICAS, especially in those under the age of 65 y or free of hypertension, diabetes mellitus, and hyperlipidemia.
Later-Onset Hypertension Is Associated With Higher Risk of Dementia in Mild Cognitive Impairment
Authors: Qin Hongyun , Zhu Binggen , Hu Chengping , Zhao Xudong
Published: November 2020

To investigate the correlation between hypertension development and the progression of mild cognitive impairment (MCI) to dementia in middle-aged and elderly people. A population-based longitudinal cognition survey of people aged 55+ was conducted. The hypertension onset age was estimated by self-reported information and medical insurance card records. To study the effect of later-onset hypertension on dementia, the incidence of dementia was compared between the two groups. Of 277 hypertensive MCI participants without dementia, 56 (20.22%) progressed to dementia (MCIp) over the 6-year follow-up. The proportion of MCIp participants in the old-age-onset hypertension group (≥65 years) was higher than that in the middle-age-onset hypertension group (27.0 vs. 15.4%, respectively; X2 = 5.538, P = 0.019). In the old-age-onset hypertension group, the proportion of MCIp without diabetes mellitus was higher than those with diabetes mellitus (24.7 vs. 12.6%, respectively; X2 = 5.321, P = 0.021) and those with increased pulse pressure was higher than those without increased pulse pressure (33.3 vs. 15.4%, respectively; X2 = 3.902, P = 0.048). However, the cox proportional hazard showed that older age was the only risk factor for MCIp (HR = 0.618, p = 0.000). These results suggest that individuals with later-onset hypertension may have greater cognition decline, even with blood pressure maintained at 130/80 mmHg with antihypertensive management.
Anti-N-methyl-D-Aspartate Receptor Encephalitis Mimicking Sporadic Creutzfeldt–Jakob Disease
Authors: Liu Jiao , Chen Liyan , Yang Jing , Wang Lan , Shang Huifang , Chen Xueping
Published: November 2020

Objectives: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and sporadic Creutzfeldt–Jakob disease (sCJD) share similar clinical features. Here, we present two unusual cases of anti-NMDAR encephalitis who were misdiagnosed as sCJD at first.

Methods: We described two patients' clinical manifestations, as well as the string of symptomatological evolution, treatments, and follow-up results.

Results: Our patients presented with rapidly progressive dementia, memory problems, psychiatric symptoms, and movement disorders, and we considered all these symptoms as a presenting feature of sCJD at first, but the cerebrospinal fluid examination showed positive results for both the 14-3-3 protein and antibodies against NMDAR. Immunomodulatory treatment led to a resolution of these deficits, and both of them remained in remission after treatment.

Conclusion: Anti-NMDAR encephalitis can present with rapidly progressive cognitive decline, and sometimes laboratory investigations can be misleading. The examination for the presence of NMDAR antibodies is necessary, even with the presence of 14-3-3 protein. Early immunomodulatory therapy should be considered, especially for patients with high titers of NMDAR antibodies.
Gilles de la Tourette Syndrome—A Disorder of Action-Perception Integration
Authors: Kleimaker Alexander , Kleimaker Maximilian , Bäumer Tobias , Beste Christian , Münchau Alexander
Published: November 2020

Gilles de la Tourette syndrome is a multifaceted and complex neuropsychiatric disorder. Given that tics as motor phenomena are the defining and cardinal feature of Tourette syndrome, it has long been conceptualized as a motor/movement disorder. However, considering premonitory urges preceding tics, hypersensitivity to external stimuli and abnormalities in sensorimotor integration perceptual processes also seem to be relevant in the pathophysiology of Tourette syndrome. In addition, tic expression depends on attention and tics can, at least partly and transiently, be controlled, so that cognitive processes need to be considered as well. Against this background, explanatory concepts should encompass not only the motor phenomenon tic but also perceptual and cognitive processes. Representing a comprehensive theory of the processing of perceptions and actions paying particular attention to their interdependency and the role of cognitive control, the Theory of Event Coding seems to be a suitable conceptual framework for the understanding of Tourette syndrome. In fact, recent data suggests that addressing the relation between actions (i.e., tics) and perceptions (i.e., sensory phenomena like premonitory urges) in the context of event coding allows to gaining relevant insights into perception-action coding in Tourette syndrome indicating that perception action binding is abnormally strong in this disorder.
Dynamics of Internalization and Intracellular Interaction of Tau Antibodies and Human Pathological Tau Protein in a Human Neuron-Like Model
Authors: Shamir Dov B. , Deng Yan , Wu Qian , Modak Swananda , Congdon Erin E. , Sigurdsson Einar M.
Published: November 2020

We and others have shown in various in vivo, ex vivo and cell culture models that several tau antibodies interact with pathological tau within neurons. To further clarify this interaction in a dynamic human model, we differentiated SH-SY5Y cells with retinoic acid and BDNF to create a neuron-like model. Therein, tau antibodies were primarily taken up by receptor-mediated endocytosis, and prevented toxicity of human brain-derived paired helical filament-enriched tau (PHF). Subsequently, we monitored in real-time the interaction of antibodies and PHF within endocytic cellular compartments. Cells were pre-treated with fluorescently-tagged PHF and then incubated with tau antibodies, 4E6, 6B2, or non-specific isotype control IgG1 labeled with a pH sensitive dye. The uptake and binding of the efficacious antibody, 4E6, to PHF occurred mainly within the soma, whereas the ineffective antibody, 6B2, and ineffective control IgG1, were visualized via the processes and showed limited colocalization with PHF within this period. In summary, we have developed a neuron-like model that clarifies the early intracellular dynamics of the interaction of tau antibodies with pathological tau, and identifies features associated with efficacy. Since the model is entirely human, it is suitable to verify the therapeutic potential of humanized antibodies prior to extensive clinical trials.
Clinical Characteristics and Long-Term Outcome of Headaches Associated With Moyamoya Disease in the Chinese Population—A Cohort Study
Authors: Gao Bin , Kang Kaijiang , Zhang Jia , Zhang Dong , Zhao Xingquan
Published: November 2020

Background: Headache associated with Moyamoya disease (HAMD) in the Chinese population is not well-described. The long-term outcome of surgical revascularization and natural course of HAMD has not been disclosed either.

Methods: A headache screening questionnaire in China based on the ICHD2 and a face-to-face interview performed by an experienced neurologist were used to investigate headache characteristics and frequency and pain intensity in the 3 months before admission, and a telephone interview was used for the follow-up of a large cohort of 119 Chinese patients with HAMD.

Results: Headache intensity was rated as scores of 5.9 ± 2.0 on a visual analog scale (VAS), ranging from 0 to 10, in the 3 months before admission. Forty-six patients (38.6%) were categorized as having migraine-like headaches, 29 patients (24.3%) were categorized as having tension type-like headaches, and 44 patients (36.9%) had a combination of both. The majority of patients had migraine-like headaches (n = 34, 73.9%) with a migrainous aura. Both the frequency and intensity of the headache improved significantly in patients treated with surgical revascularization (n = 96, 80.7%) or the conservative treatment (n = 23, 19.3%) in a long-term follow-up.

Conclusion: HAMD frequently presented with a migraine-like headache (75.5% in total). A tension type headache was present in 60.9% of patients. The symptom of dizziness is common in patients with HAMD (60.5%), and 19 of them (26.4%) met the diagnose of vestibular migraine. Both intensity and frequency of HAMD show a trend of spontaneous remission in a long-term follow-up, and there is no difference in long-term outcomes of HAMD between surgical revascularization and conservative treatment, which indicates that the effect of bypass intervention on HAMD may be a placebo effect.
Integration of Convergent Sensorimotor Inputs Within Spinal Reflex Circuits in Healthy Adults
Authors: Lopez Alejandro J. , Xu Jiang , Hoque Maruf M. , McMullen Carly , Kesar Trisha M. , Borich Michael R.
Published: November 2020

The output from motor neuron pools is influenced by the integration of synaptic inputs originating from descending corticomotor and spinal reflex pathways. In this study, using paired non-invasive brain and peripheral nerve stimulation, we investigated how descending corticomotor pathways influence the physiologic recruitment order of the soleus Hoffmann (H-) reflex. Eleven neurologically unimpaired adults (9 females; mean age 25 ± 3 years) completed an assessment of transcranial magnetic stimulation (TMS)-conditioning of the soleus H-reflex over a range of peripheral nerve stimulation (PNS) intensities. Unconditioned H-reflex recruitment curves were obtained by delivering PNS pulses to the posterior tibial nerve. Subsequently, TMS-conditioned H-reflex recruitment curves were obtained by pairing PNS with subthreshold TMS at short (−1.5 ms) and long (+10 ms) intervals. We evaluated unconditioned and TMS-conditioned H-reflex amplitudes along the ascending limb, peak, and descending limb of the H-reflex recruitment curve. Our results revealed that, for long-interval facilitation, TMS-conditioned H-reflex amplitudes were significantly larger than unconditioned H-reflex amplitudes along the ascending limb and peak of the H-reflex recruitment curve. Additionally, significantly lower PNS intensities were needed to elicit peak H-reflex amplitude (Hmax) for long-interval facilitation compared to unconditioned. These findings suggest that the influence of descending corticomotor pathways, particularly those mediating long-interval facilitation, contribute to changing the recruitment gain of the motor neuron pool, and can inform future methodological protocols for TMS-conditioning of H-reflexes. By characterizing and inducing short-term plasticity in circuitry mediating short- and long-interval TMS-conditioning of H-reflex amplitudes, future studies can investigate supraspinal and spinal circuit contributions to abnormal motor control, as well as develop novel therapeutic targets for neuromodulation.
Brain Metabolite Levels in Sedentary Women and Non-contact Athletes Differ From Contact Athletes
Authors: Schranz Amy L. , Dekaban Gregory A. , Fischer Lisa , Blackney Kevin , Barreira Christy , Doherty Timothy J. , Fraser Douglas D. , Brown Arthur , Holmes Jeff , Menon Ravi S. , Bartha Robert
Published: November 2020

White matter tracts are known to be susceptible to injury following concussion. The objective of this study was to determine whether contact play in sport could alter white matter metabolite levels in female varsity athletes independent of changes induced by long-term exercise. Metabolite levels were measured by single voxel proton magnetic resonance spectroscopy (MRS) in the prefrontal white matter at the beginning (In-Season) and end (Off-Season) of season in contact (N = 54, rugby players) and non-contact (N = 23, swimmers and rowers) varsity athletes. Sedentary women (N = 23) were scanned once, at a time equivalent to the Off-Season time point. Metabolite levels in non-contact athletes did not change over a season of play, or differ from age matched sedentary women except that non-contact athletes had a slightly lower myo-inositol level. The contact athletes had lower levels of myo-inositol and glutamate, and higher levels of glutamine compared to both sedentary women and non-contact athletes. Lower levels of myo-inositol in non-contact athletes compared to sedentary women indicates long-term exercise may alter glial cell profiles in these athletes. The metabolite differences observed between contact and non-contact athletes suggest that non-contact athletes should not be used as controls in studies of concussion in high-impact sports because repetitive impacts from physical contact can alter white matter metabolite level profiles. It is imperative to use athletes engaged in the same contact sport as controls to ensure a matched metabolite profile at baseline.
Expected Valence Predicts Choice in a Recurrent Decision Task
Authors: Jäger Daniel T. , Boltzmann Melanie , Rollnik Jens D. , Rüsseler Jascha
Published: November 2020

There is empirical evidence that expected yet not current affect predicts decisions. However, common research designs in affective decision-making show consistent methodological problems (e.g., conceptualization of different emotion concepts; measuring only emotional valence, but not arousal). We developed a gambling task that systematically varied learning experience, average feedback balance and feedback consistency. In Experiment 1 we studied whether predecisional current affect or expected affect predict recurrent gambling responses. Furthermore, we exploratively examined how affective information is represented on a neuronal level in Experiment 2. Expected and current valence and arousal ratings as well as Blood Oxygen Level Dependent (BOLD) responses were analyzed using a within-subject design. We used a generalized mixed effect model to predict gambling responses with the different affect variables. Results suggest a guiding function of expected valence for decisions. In the anticipation period, we found activity in brain areas previously associated with valence-general processing (e.g., anterior cingulate cortex, nucleus accumbens, thalamus) mostly independent of contextual factors. These findings are discussed in the context of the idea of a valence-general affective work-space, a goal-directed account of emotions, and the hypothesis that current affect might be used to form expectations of future outcomes. In conclusion, expected valence seems to be the best predictor of recurrent decisions in gambling tasks.
Molecular Mechanisms of Glutamate Toxicity in Parkinson’s Disease
Authors: Wang Ji , Wang Fushun , Mai Dongmei , Qu Shaogang
Published: November 2020

Parkinson’s disease (PD) is a common neurodegenerative disease, the pathological features of which include the presence of Lewy bodies and the neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta. However, until recently, research on the pathogenesis and treatment of PD have progressed slowly. Glutamate and dopamine are both important central neurotransmitters in mammals. A lack of enzymatic decomposition of extracellular glutamate results in glutamate accumulating at synapses, which is mainly absorbed by excitatory amino acid transporters (EAATs). Glutamate exerts its physiological effects by binding to and activating ligand-gated ion channels [ionotropic glutamate receptors (iGluRs)] and a class of G-protein-coupled receptors [metabotropic glutamate receptors (mGluRs)]. Timely clearance of glutamate from the synaptic cleft is necessary because high levels of extracellular glutamate overactivate glutamate receptors, resulting in excitotoxic effects in the central nervous system. Additionally, increased concentrations of extracellular glutamate inhibit cystine uptake, leading to glutathione depletion and oxidative glutamate toxicity. Studies have shown that oxidative glutamate toxicity in neurons lacking functional N-methyl-D-aspartate (NMDA) receptors may represent a component of the cellular death pathway induced by excitotoxicity. The association between inflammation and excitotoxicity (i.e., immunoexcitotoxicity) has received increased attention in recent years. Glial activation induces neuroinflammation and can stimulate excessive release of glutamate, which can induce excitotoxicity and, additionally, further exacerbate neuroinflammation. Glutamate, as an important central neurotransmitter, is closely related to the occurrence and development of PD. In this review, we discuss recent progress on elucidating glutamate as a relevant neurotransmitter in PD. Additionally, we summarize the relationship and commonality among glutamate excitotoxicity, oxidative toxicity, and immunoexcitotoxicity in order to posit a holistic view and molecular mechanism of glutamate toxicity in PD.
Modulation of β-Amyloid Fibril Formation in Alzheimer’s Disease by Microglia and Infection
Authors: Brown Madeleine R. , Radford Sheena E. , Hewitt Eric W.
Published: November 2020

Amyloid plaques are a pathological hallmark of Alzheimer’s disease. The major component of these plaques are highly ordered amyloid fibrils formed by amyloid-β (Aβ) peptides. However, whilst Aβ amyloid fibril assembly has been subjected to detailed and extensive analysis in vitro, these studies may not reproduce how Aβ fibrils assemble in the brain. This is because the brain represents a highly complex and dynamic environment, and in Alzheimer’s disease multiple cofactors may affect the assembly of Aβ fibrils. Moreover, in vivo amyloid plaque formation will reflect the balance between the assembly of Aβ fibrils and their degradation. This review explores the roles of microglia as cofactors in Aβ aggregation and in the clearance of amyloid deposits. In addition, we discuss how infection may be an additional cofactor in Aβ fibril assembly by virtue of the antimicrobial properties of Aβ peptides. Crucially, by understanding the roles of microglia and infection in Aβ amyloid fibril assembly it may be possible to identify new therapeutic targets for Alzheimer’s disease.
Comparative Efficacy of Pharmacological and Nonpharmacological Interventions for Acne Vulgaris: A Network Meta-Analysis
Authors: Shi Qingyang , Tan Lizi , Chen Zhe , Ge Long , Zhang Xiaoyan , Yang Fengwen , Liu Chunxiang , Zhang Junhua
Published: November 2020

Acne has several effects on physical symptoms, but the main impacts are on the quality of life, which can be improved by treatment. There are several acne treatments but less evidence comparing their relative efficacy. Thus, we assessed the comparative efficacy of pharmacological and nonpharmacological interventions for acne. We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials from inception to April 2019, to include randomized controlled trials for acne that compared topical antibiotics (TA), benzoyl peroxide (BPO), topical retinoids (TR), oral antibiotics (OA), lasers, light devices including LED device (LED), photodynamic therapy (PDT), and intense pulsed light, chemical peels (CP), miscellaneous therapies or complementary and alternative medicine (MTCAM), or their combinations. We performed Bayesian network meta-analysis with random effects for all treatments compared with placebo and each other. Mean differences (MDs) of lesions count and risk ratios of adverse events with their 95% credible intervals (CrIs) were calculated, and all interventions were ranked by the Surface Under the Cumulative Ranking (SUCRA) values. Additional frequentist additive network meta-analysis was performed to detect the robustness of results and potential interaction effects. Sensitivity analyses were carried out with different priors, and metaregression was to adjust for nine potential effect modifiers. In the result, seventy-three randomized controlled trials (27,745 patients with mild to moderate acne), comparing 30 grouped intervention categories, were included with low to moderate risk of bias. For adverse effects, OA had more risk in combination treatment with others. For noninflammatory lesions reduction, seventeen interventions had significant differences comparing with placebo and three interventions (TR+BPO: MD = −21.89, 95%CrI [−28.97, −14.76]; TR+BPO+MTCAM: −22.48 [−34.13, −10.70]; TA+BPO+CP: −20.63 [−33.97, −7.13]) were superior to others with 94, 94, and 91% SUCRA values, respectively. For inflammatory lesions reduction, nineteen interventions were significantly better than placebo, and three interventions (TR+BPO: MD = −12.13, 95%CrI [−18.41, −5.80]; TR+BPO+MTCAM: −13.21 [−.39, −3.04]; LED: −11.30 [−18.34, −4.42]) were superior to others (SUCRA: 81, 81, and 77%, respectively). In summary of noninflammatory and inflammatory lesions results, TR+BPO and TA+BPO were the best options compared to others. The frequentist model showed similar results as above. In summary, current evidence supports the suggestion that TR+BPO and TA+BPO are the best options for mild to moderate acne. LED is another option for inflammatory lesions when drug resistance occurs. All the combinations involved with OA showed more risk of adverse events than others. However, the evidence of this study should be cautiously used due to the limitations.
Inhibition of Tryptophan Hydroxylases and Monoamine Oxidase-A by the Proton Pump Inhibitor, Omeprazole—In Vitro and In Vivo Investigations
Authors: Betari Nibal , Sahlholm Kristoffer , Morató Xavier , Godoy-Marín Héctor , Jáuregui Olga , Teigen Knut , Ciruela Francisco , Haavik Jan
Published: November 2020

Serotonin (5-HT) is a hormone and neurotransmitter that modulates neural activity as well as a wide range of other physiological processes including cardiovascular function, bowel motility, and platelet aggregation. 5-HT synthesis is catalyzed by tryptophan hydroxylase (TPH) which exists as two distinct isoforms; TPH1 and TPH2, which are responsible for peripheral and central 5-HT, respectively. Due to the implication of 5-HT in a number of pathologies, including depression, anxiety, autism, sexual dysfunction, irritable bowel syndrome, inflammatory bowel disease, and carcinoid syndrome, there has been a growing interest in finding modulators of these enzymes in recent years. We thus performed high-throughput screening (HTS) using a fluorescence-based thermal shift assay (DSF) to search the Prestwick Chemical Library containing 1,280 compounds, mostly FDA-approved drugs, for TPH1 binders. We here report the identification of omeprazole, a proton pump inhibitor, as an inhibitor of TPH1 and TPH2 with low micromolar potency and high selectivity over the other aromatic amino acid hydroxylases. The S-enantiomer of omeprazole, esomeprazole, has recently also been described as an inhibitor of monoamine oxidase-A (MAO-A), the main enzyme responsible for 5-HT degradation, albeit with lower potency compared to the effect on TPH1 and TPH2. In order to investigate the net effect of simultaneous inhibition of TPH and MAO-A in vivo, we administered high-dose (100 mg/kg) omeprazole to CD-1 mice for 4 days, after which the animals were subjected to the tail suspension test. Finally, central (whole brain) and peripheral (serum) 5-HT content was measured using liquid chromatography-mass spectrometry (LC-MS). Omeprazole treatment significantly increased 5-HT concentrations, both in brain and in serum, and reduced the time spent immobile in the tail suspension test relative to vehicle control. Thus, the MAO-A inhibition afforded by high-dose omeprazole appears to overcome the opposing effect on 5-HT produced by inhibition of TPH1 and TPH2. Further modification of proton pump inhibitor scaffolds may yield more selective modulators of 5-HT metabolism.
Gap Junction Intercellular Communication Negatively Regulates Cadmium-Induced Autophagy and Inhibition of Autophagic Flux in Buffalo Rat Liver 3A Cells
Authors: Zou Hui , Yuan Junzhao , Zhang Yi , Wang Tao , Chen Yan , Yuan Yan , Bian Jianchun , Liu Zongping
Published: November 2020

Cadmium is an important environmental pollutant that poses a serious threat to the health of humans and animals. A large number of studies have shown that the liver is one of the important target organs of cadmium. Stimulation of cells can lead to rapid changes in gap junction intercellular communication (GJIC) and autophagy. Previous studies have shown that cadmium can inhibit GJIC and induce autophagy. In order to understand the dynamic changes of GJIC and autophagy in the process of cadmium-induced hepatotoxic injury and the effects of GJIC on autophagy, a time-gradient model of cadmium cytotoxicity was established. The results showed that within 24 h of cadmium exposure, 5 μmol/L cadmium inhibited GJIC by down regulating the expression levels of connexin 43 (Cx43) and disturbing the localization of Cx43 in Buffalo rat liver 3A (BRL 3A) cells. In addition, cadmium induced autophagy and then inhibited autophagic flux in the later stage. During this process, inhibiting of GJIC could exacerbate the cytotoxic damage of cadmium and induce autophagy, but further blocked autophagic flux, promoting GJIC in order to obtain the opposite results.
Efficacy and Safety of Socheongryong-Tang Among Atopic Dermatitis Patients With Respiratory Disorders: A Double-Blinded, Randomized, Placebo-Controlled Clinical Trial
Authors: Lee Ju Hyun , Jo Eun Heui , Jung Jee Youn , Kim Young-Eun , Son Mi-Ju , Kang Su Jin , Yang Geum Jin , Shim Yu Hwa , Park Min Cheol
Published: November 2020

Atopic dermatitis is a chronic inflammatory skin disease that affects the growth and development of children. The prevalence of atopic dermatitis has been continually increasing, and this has also been accompanied by rising socioeconomic costs. Interest has been growing in alternative medicine as a means of alleviating the burden of atopic dermatitis. This was a single-center, double-blinded, randomized, placebo-controlled investigator-led clinical trial including 60 atopic dermatitis patients. The participants were classified into an experimental group (30 persons) and a control group (30 persons), who were administered, respectively, socheongryong-tang or a placebo for 4 weeks. After 4 weeks of treatment, the participants visited the trial center again and assess their efficacy and safety. The researchers performed statistical comparisons of the changes in the SCORAD Index, amount and frequency of ointment use, and height and weight to assess the efficacy. To assess the safety, diagnostic tests and vital sign checks were performed at each visit, and the presence or absence of adverse events was observed. As a result, the frequency and the amount of steroid ointment application in both groups increased, but the experimental group showed less tendency (p = 0.081). Results of analyzing the children in the experimental group in relation to growth showed a significantly greater height growth than the control group (p < 0.05). In addition, all study participants did not show any remarkable abnormal signs in the safety evaluation. In conclusion, compared to the control group, the experimental group, who took socheongryong-tang showed a tendency to be less dependent on steroid ointment and statistically significant increase in height.
In Vivo Positron Emission Tomography Imaging of Adenosine A2A Receptors
Authors: Sun Meng-Juan , Liu Fang , Zhao Ya-Fei , Wu Xiao-Ai
Published: November 2020

As an invasive nuclear medical imaging technology, positron emission tomography (PET) possess the possibility to imaging the distribution as well as the density of selective receptors via specific PET tracers. Inspired by PET, the development of radio-chemistry has greatly promoted the progress of innovative imaging PET tracers for adenosine receptors, in particular adenosine A2A receptors (A2ARs). PET imaging of A2A receptors play import roles in the research of adenosine related disorders. Several radio-tracers for A2A receptors imaging have been evaluated in human studies. This paper reviews the recent research progress of PET tracers for A2A receptors imaging, and their applications in the diagnosis and treatment of related disease, such as cardiovascular diseases, autoimmune diseases, neurodegenerative and psychiatric disease. The future development of A2A PET tracers were also discussed.