bluuebunny/crossref_metadata_2025 huggingface dataset:
Unsupervised EEG Artifact Detection and Correction
Authors: Saba-Sadiya Sari , Chantland Eric , Alhanai Tuka , Liu Taosheng , Ghassemi Mohammad M.
Published: January 2021

Electroencephalography (EEG) is used in the diagnosis, monitoring, and prognostication of many neurological ailments including seizure, coma, sleep disorders, brain injury, and behavioral abnormalities. One of the primary challenges of EEG data is its sensitivity to a breadth of non-stationary noises caused by physiological-, movement-, and equipment-related artifacts. Existing solutions to artifactdetectionare deficient because they require experts to manually explore and annotate data for artifact segments. Existing solutions to artifactcorrectionor removal are deficient because they assume that the incidence and specific characteristics of artifacts are similar across both subjects and tasks (i.e., “one-size-fits-all”). In this paper, we describe a novel EEG noise-reduction method that uses representation learning to perform patient- and task-specific artifact detection and correction. More specifically, our method extracts 58 clinically relevant features and applies an ensemble of unsupervised outlier detection algorithms to identify EEG artifacts that are unique to a given task and subject. The artifact segments are then passed to a deep encoder-decoder network for unsupervisedartifact correction. We compared the performance of classification models trained with and without our method and observed a 10% relative improvement in performance when using our approach. Our method provides a flexible end-to-end unsupervised framework that can be applied to novel EEG data without the need for expert supervision and can be used for a variety of clinical decision tasks, including coma prognostication and degenerative illness detection. By making our method, code, and data publicly available, our work provides a tool that is of both immediate practical utility and may also serve as an important foundation for future efforts in this domain.
Summer Regional Pentad Extreme Precipitation in Eastern China and Their Possible Causes
Authors: Ji Yaqin , Sun Xuguang , Xu Yiming , Yao Jingxin , Yang Xiu-Qun
Published: January 2021

Persistent extreme precipitation covering a large area usually causes severe flooding disasters in China, but how to depict it and what are the possible causes are still open questions. With Climate Prediction Center global unified gauge-based analysis of daily precipitation and NCEP/NCAR daily reanalysis dataset from 1979 to 2019, summer regional pentad extreme precipitation (RPEP) is defined according to the threshold of the 95th percentile of pentad precipitation with more than 5% land grids coverage in eastern China. While the definition of RPEP highlights the climate features of both the persistence and the regionality of extreme precipitation, it is distinctly different from the previous definitions that mainly reflect the synoptic aspects with daily data and have strictly temporal-spatial constraints. Four categories of RPEPs are objectively identified by K-means cluster analysis, i.e., South China (SC), South of Yangtze River (SYR), Jianghuai River (JHR), and North China (NC). Along the Yangtze River (SYR and JHR), intensity and area of RPEP are positively correlated with each other, and with the increase of RPEP intensity, its center of gravity tends to move eastward in all the four cluster regions and southward in Jianghuai River and North China, respectively, and vice versa. The RPEPs mostly persist for one pentad but can reach up to two to three pentads at most, and along with the duration of RPEP, its intensity and area are both enhanced accordingly. Furthermore, the frequency of RPEP increased significantly since the late 1990s in SYR, JHR, and SC. Associated with RPEP, strong pentad-mean convergence and ascending motion occur in the middle-lower troposphere, and except for SC that is dominated by the local low-pressure and cyclone anomalies, the other three cluster regions are all forced by the western Pacific subtropical high to the southeast and weak low-pressure trough to the north, and the low-level anticyclone anomaly to the southeast transports abundant water vapors to the RPEP regions accordingly. Besides, all the RPEPs are closely in accordance with obvious subseasonal oscillations, especially the 10–30-day and 30–60-day oscillations, which can be regarded as the potential sources of RPEP predictability in eastern China.
Interface Tracking Simulation for Subcooled Flow Boiling Using VOSET Method
Authors: Ling Kong , Zhang Shuai , Liu Wenxing , Sui Xiaowei , Tao Wenquan
Published: January 2021

This article presents a numerical simulation on subcooled flow boiling at a high-pressure condition. An interface tracking method, VOSET, was used to handle the moving interface, and conjugate heat transfer between the wall and the fluid was included in the numerical model. In order to consider the evaporation on the microlayer below a growing bubble, a depletable micorlayer model was employed. Our simulation illustrated typical processes of subcooled boiling flow including bubble sliding, coalescence, detachment and annihilation, and revealed many mechanisms in increasing the heat transfer coefficient. A transition in flow regime from isolated bubbly flow to elongated bubbly flow was reproduced by our simulations. The void fraction obtained by time-averaging the volume fraction of the vapor phase under various flow conditions was analyzed.
Comparative Case Study on Oscillatory Behavior in Power Systems of Marine Vessels With High Power Converters
Authors: Tarasiuk Tomasz , Jankowski Piotr , Shagar Viknash , Piłat Andrzej , Górniak Mariusz , Nowak Jarosław
Published: January 2021

The chief aim of the proposed paper is to compare the behavior of supply voltage registered onboard three vessels equipped with high power converters during normal operation. The vessels considered are a chemical tanker with shaft generator working via power converter, a research-training ship with bow thruster, and a research vessel with dynamic positioning (DP) and electrical propulsion. In the case of the two latter ships, power electronic loads are present, which include a bow thruster adjustable speed drive equipped with the six pulse uncontrolled rectifier and the adjustable speed drive with an active front end (AFE) for propulsion system. For each ship, instantaneous frequency is determined and subsequently fluctuations of fundamental components and chosen harmonics are calculated using zoom-DFT. The characteristics of these irregular fluctuations are compared and commented on. Next, phase portraits and Poincare map of the registered voltages are calculated and compared. Moreover, the impact of ship rolling and pitching on the oscillatory behavior is assessed for the DP ship. The final conclusions identify reasons for oscillatory behavior in electric power systems of marine vessels containing high power converters on the source side and load side. The feasibility of using voltage trajectories as well as Poincare maps for oscillatory behavior detection is assessed.
The Effects of Weather on Avian Growth and Implications for Adaptation to Climate Change
Authors: Sauve Drew , Friesen Vicki L. , Charmantier Anne
Published: January 2021

Climate change is forecasted to generate a range of evolutionary changes and plastic responses. One important aspect of avian responses to climate change is how weather conditions may change nestling growth and development. Early life growth is sensitive to environmental effects and can potentially have long-lasting effects on adult phenotypes and fitness. A detailed understanding of both how and when weather conditions affect the entire growth trajectory of a nestling may help predict population changes in phenotypes and demography under climate change. This review covers three main topics on the impacts of weather variation (air temperature, rainfall, wind speed, solar radiation) on nestling growth. Firstly, we highlight why understanding the effects of weather on nestling growth might be important in understanding adaptation to, and population persistence in, environments altered by climate change. Secondly, we review the documented effects of weather variation on nestling growth curves. We investigate both altricial and precocial species, but we find a limited number of studies on precocial species in the wild. Increasing temperatures and rainfall have mixed effects on nestling growth, while increasing windspeeds tend to have negative impacts on the growth rate of open cup nesting species. Thirdly, we discuss how weather variation might affect the evolution of nestling growth traits and suggest that more estimates of the inheritance of and selection acting on growth traits in natural settings are needed to make evolutionary predictions. We suggest that predictions will be improved by considering concurrently changing selection pressures like urbanization. The importance of adaptive plastic or evolutionary changes in growth may depend on where a species or population is located geographically and the species’ life-history. Detailed characterization of the effects of weather on growth patterns will help answer whether variation in avian growth frequently plays a role in adaption to climate change.
Candidate Genes for Age at Menarche Are Associated With Uterine Leiomyoma
Authors: Ponomarenko Irina , Reshetnikov Evgeny , Polonikov Alexey , Verzilina Irina , Sorokina Inna , Yermachenko Anna , Dvornyk Volodymyr , Churnosov Mikhail
Published: January 2021

Age at menarche (AAM) is an important marker of the pubertal development and function of the hypothalamic–pituitary–ovarian system. It was reported as a possible factor for a risk of uterine leiomyoma (UL). However, while more than 350 loci for AAM have been determined by genome-wide association studies (GWASs) to date, no studies of these loci for their association with UL have been conducted so far. In this study, we analyzed 52 candidate loci for AAM for possible association with UL in a sample of 569 patients and 981 controls. The results of the study suggested that 23 out of the 52 studied polymorphisms had association with UL. Locus rs7759938 LIN28B was individually associated with the disease according to the dominant model. Twenty loci were associated with UL within 11 most significant models of intergenic interactions. Nine loci involved in 16 most significant models of interactions between single-nucleotide polymorphism (SNP), induced abortions, and chronic endometritis were associated with UL. Among the 23 loci associated with UL, 16 manifested association also with either AAM (7 SNPs) or height and/or body mass index (BMI) (13 SNPs). The above 23 SNPs and 514 SNPs linked to them have non-synonymous, regulatory, and expression quantitative trait locus (eQTL) significance for 35 genes, which play roles in the pathways related to development of the female reproductive organs and hormone-mediated signaling [false discovery rate (FDR) ≤ 0.05]. This is the first study reporting associations of candidate genes for AAM with UL.
The Clinical Significance and Potential Molecular Mechanism of PTTG1 in Esophageal Squamous Cell Carcinoma
Authors: Chen Shang-Wei , Zhou Hua-Fu , Zhang Han-Jie , He Rong-Quan , Huang Zhi-Guang , Dang Yi-Wu , Yang Xia , Liu Jun , Fu Zong-Wang , Mo Jun-Xian , Tang Zhong-Qing , Li Chang-Bo , Li Rong , Yang Li-Hua , Ma Jie , Yang Lin-Jie , Chen Gang
Published: January 2021

Esophageal squamous cell carcinoma (ESCC) is the major histological type of esophageal cancers worldwide. Transcription factor PTTG1 was seen highly expressed in a variety of tumors and was related to the degree of tumor differentiation, invasion, and metastasis. However, the clinical significance of PTTG1 had yet to be verified, and the mechanism of abnormal PTTG1 expression in ESCC was not clear. In this study, the comprehensive analysis and evaluation of PTTG1 expression in ESCC were completed by synthesizing in-house immunohistochemistry (IHC), clinical sample tissue RNA-seq (in-house RNA-seq), public high-throughput data, and literature data. We also explored the possible signaling pathways and target genes of PTTG1 in ESCC by combining the target genes of PTTG1 (displayed by ChIP-seq), differentially expressed genes (DEGs) of ESCC, and PTTG1-related genes, revealing the potential molecular mechanism of PTTG1 in ESCC. In the present study, PTTG1 protein and mRNA expression levels in ESCC tissues were all significantly higher than in non-cancerous tissues. The pool standard mean difference (SMD) of the overall PTTG1 expression was 1.17 (95% CI: 0.72–1.62, P < 0.01), and the area under curve (AUC) of the summary receiver operating characteristic (SROC) was 0.86 (95% CI: 0.83–0.89). By combining the target genes displayed by ChIP-seq of PTTG1, DEGs of ESCC, and PTTG1-related genes, it was observed that PTTG1 may interact with these genes through chemokines and cytokine signaling pathways. By constructing a protein–protein interaction (PPI) network and combining ChIP-seq data, we obtained four PTTG1 potential target genes, SPTAN1, SLC25A17, IKBKB, and ERH. The gene expression of PTTG1 had a strong positive correlation with SLC25A17 and ERH, which suggested that PTTG1 might positively regulate the expression of these two genes. In summary, the high expression of PTTG1 may play an important role in the formation of ESCC. These roles may be completed by PTTG1 regulating the downstream target genes SLC25A17 and ERH.
Wfs1 and Related Molecules as Key Candidate Genes in the Hippocampus of Depression
Authors: Yang Jing , Chen Chaoqin , Jin Xiaoyuan , Liu Lu , Lin Jiajia , Kang Xianhui , Zhu Shengmei
Published: January 2021

Background

Depression is a prevalent mental disorder, which is difficult to diagnose and treat due to its unclear pathogenic mechanisms. The discovery of novel and effective therapeutic targets for depression is urgently needed. The hippocampus is a crucial region involved in depression and has been a therapeutic target for many antidepressants. Thus, it is beneficial for comprehensive research to be carried out on the molecular mechanisms of the hippocampus involved in the pathogenesis of depression. This study aims to investigate the differentially expressed genes (DEG) in the hippocampus in a chronic unpredictable mild stress (CUMS) mouse model.

Method

The study obtained GSE84183 from the GEO database. The R language screened the differential expression genes (DEG) in the hippocampus tissue of depressed mice, and the enrichment pathways of DEGs were analyzed. A protein-protein interaction (PPI) network was constructed in the STRING database and visualized in Cytoscape software. MicroRNAs for these DEGs were obtained from TarBase and mortar base databases, and transcription factors (TF) related to DEG were predicted from the ENCODE database. Both networks used the visual analysis platform NetworkAnalyst. Finally, the microRNA-TF network was integrated based on the above two networks and imported into Cytoscape for further analysis.

Results

This study screened 325 differentially expressed genes, containing 42 downregulated genes and 283 upregulated genes. Most of these genes are enriched in the cell cycle and the chemokine signaling pathway. Meanwhile, Wfs1, one of the top ten DEGs, was identified as the key regulator of the cell cycle and the participator in the highest number of modules screened out in PPI networks. Wfs1-related molecules, including UBTF, mmu-mir-17-5p, and mmu-mir-7b-5p, were therefore screened out. Furthermore, we confirmed the downregulation of Wfs1 and upregulation of UBTF/mmu-mir-17-5p/mmu-mir-7b-5p in the hippocampus of the CUMS mouse model. Our data indicate that Wfs1 and related molecules were predicted to be associated with the pathological process of depression. This research provided potential new molecular targets of stress-induced depression.
Stellate Genes and the piRNA Pathway in Speciation and Reproductive Isolation of Drosophila melanogaster
Authors: Adashev Vladimir E. , Kotov Alexei A. , Bazylev Sergei S. , Shatskikh Aleksei S. , Aravin Alexei A. , Olenina Ludmila V.
Published: January 2021

One of the main conditions of the species splitting from a common precursor lineage is the prevention of a gene flow between diverging populations. The study ofDrosophilainterspecific hybrids allows to reconstruct the speciation mechanisms and to identify hybrid incompatibility factors that maintain post-zygotic reproductive isolation between closely related species. The regulation, evolution, and maintenance of the testis-specificSte-Su(Ste)genetic system inDrosophila melanogasteris the subject of investigation worldwide. X-linked tandem testis-specificStellategenes encode proteins homologous to the regulatory β-subunit of protein kinase CK2, but they are permanently repressed in wild-type flies by the piRNA pathway via piRNAs originating from the homologous Y-linkedSu(Ste)locus. Derepression ofStellategenes caused bySu(Ste)piRNA biogenesis disruption leads to the accumulation of crystalline aggregates in spermatocytes, meiotic defects and male sterility. In this review we summarize current data about the origin, organization, evolution of theSte-Su(Ste)system, and piRNA-dependent regulation ofStellateexpression. TheSte-Su(Ste)system is fixed only in theD. melanogastergenome. According to our hypothesis, the acquisition of theSte-Su(Ste)system by a part of the ancient fly population appears to be the causative factor of hybrid sterility in crosses of female flies with males that do not carry Y-linkedSu(Ste)repeats. To support this scenario, we have directly demonstratedStellatederepression and the corresponding meiotic disorders in the testes of interspecies hybrids betweenD. melanogasterandD. mauritiana. This finding embraces our hypothesis about the contribution of theSte-Su(Ste)system and the piRNA pathway to the emergence of reproductive isolation ofD. melanogasterlineage from initial species.
Neonatal Screening and Genotype-Phenotype Correlation of 21-Hydroxylase Deficiency in the Chinese Population
Authors: Wang Xin , Wang Yanyun , Ma Dingyuan , Zhang Zhilei , Li Yahong , Yang Peiying , Sun Yun , Jiang Tao
Published: January 2021

Background: Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders encompassing enzyme deficiencies in the adrenal steroidogenesis pathway that leads to impaired cortisol biosynthesis. 21-hydroxylase deficiency (21-OHD) is the most common type of CAH. Severe cases of 21-OHD may result in death during the neonatal or infancy periods or sterility in later life. The early detection and timely treatment of 21-OHD are essential. This study aimed to summarize the clinical and genotype characteristics of 21-OHD patients detected by neonatal screening in Nanjing, Jiangsu province of China from 2000 to 2019.

Methods: Through a retrospective analysis of medical records, the clinical presentations, laboratory data, and molecular characteristics of 21-OHD patients detected by neonatal screening were evaluated.

Results: Of the 1,211,322 newborns who were screened, 62 cases were diagnosed with 21-OHD with an incidence of 1:19858. 58 patients were identified with the classical salt-wasting type (SW) 21-OHD and four patients were identified with simple virilizing type (SV) 21-OHD. Amongst these patients, 19 cases patients accepted genetic analysis, and another 40 cases were received from other cities in Eastern China. Eighteen different variants were found in the CYP21A2 gene. The most frequent variants was c.293-13A/C>G (36.29%). The most severe clinical manifestations were caused by large deletions or conversions of CYP21A2.

Conclusions: This study suggested that neonatal screening effectively leads to the early diagnosis of 21-OHD and reduces fatal adrenal crisis. Our data provide additional information on the occurrence and genotype-phenotype correlation of 21-OHD in the Chinese population which can be used to better inform treatment and improve prognosis.
Podocyte Injury Through Interaction Between Tlr8 and Its Endogenous Ligand miR-21 in Obstructed and Its Collateral Kidney
Authors: Masum Md. Abdul , Ichii Osamu , Elewa Yaser Hosny Ali , Kon Yasuhiro
Published: January 2021

While chronic kidney disease is prevalent in adults, obstructive nephropathy (ON) has been reported in both young and old patients. In ON, tubulointerstitial lesions (TILs) have been widely investigated, but glomerular lesions (GLs) have been largely neglected. Here, we show a novel mechanism underlying GL development in ON in young and old mice. TILs develop earlier than GLs owing to infiltration of inflammatory cells in the tubulointerstitium, but GLs develop following the activation of Toll-like receptor 8 (Tlr8) even though the absence of inflammatory cells infiltrating the glomerulus. TLR8 and interleukin 1 beta (IL1β) proteins colocalize with reducing podocyte function markers (PFMs), indicating the activation of TLR8 signaling in injured podocytes. Furthermore, glomerular and serum levels of miR-21, an endogenous ligand for Tlr8, were higher in the ON mouse model than in the sham control. The glomerular expression of Tlr8 positively correlates with miR-21 and the downstream cytokines Il1b and Il6 and negatively correlated with PFMs (Nphs1 and Synpo). We also show the colocalization of TLR8 and IL1β proteins with reducing PFMs in both obstructed and collateral kidney of young and old mice. Furthermore, in vitro study results revealed higher expression of Tlr8 and its downstream cytokines in glomeruli from obstructed kidneys following treatment with miR-21 mimic than in the control. In conclusion, the overexpression of Tlr8 may serve as a plausible mechanism underlying GL development in ON through podocyte injury.
Living in a Hostile World: Inflammation, New Drug Development, and Coronavirus
Authors: Dobson Geoffrey P. , Biros Erik , Letson Hayley L. , Morris Jodie L.
Published: January 2021

We present a brief history of the immune response and show that Metchnikoff’s theory of inflammation and phagocytotic defense was largely ignored in the 20thcentury. For decades, the immune response was believed to be triggered centrally, until Lafferty and Cunningham proposed the initiating signal came from the tissues. This shift opened the way for Janeway’s pattern recognition receptor theory, and Matzinger’s danger model. All models failed to appreciate that without inflammation, there can be no immune response. The situation changed in the 1990s when cytokine biology was rapidly advancing, and the immune system’s role expanded from host defense, to the maintenance of host health. An inflammatory environment, produced by immune cells themselves, was now recognized as mandatory for their attack, removal and repair functions after an infection or injury. We explore the cellular programs of the immune response, and the role played by cytokines and other mediators to tailor the right response, at the right time. Normally, the immune response is robust, self-limiting and restorative. However, when the antigen load or trauma exceeds the body’s internal tolerances, as witnessed in some COVID-19 patients, excessive inflammation can lead to increased sympathetic outflows, cardiac dysfunction, coagulopathy, endothelial and metabolic dysfunction, multiple organ failure and death. Currently, there are few drug therapies to reduce excessive inflammation and immune dysfunction. We have been developing an intravenous (IV) fluid therapy comprising adenosine, lidocaine and Mg2+(ALM) that confers a survival advantage by preventing excessive inflammation initiated by sepsis, endotoxemia and sterile trauma. The multi-pronged protection appears to be unique and may provide a tool to examine the intersection points in the immune response to infection or injury, and possible ways to prevent secondary tissue damage, such as that reported in patients with COVID-19.
Optimal Planting Distance in a Simple Model of Habitat Restoration With an Allee Effect
Authors: Hammann Liv , Silliman Brian , Blasius Bernd
Published: January 2021

Ecological restoration is emerging as an important strategy to improve the recovery of degraded lands and to combat habitat and biodiversity loss worldwide. One central unresolved question revolves around the optimal spatial design for outplanted propagules that maximizes restoration success. Essentially, two contrasting paradigms exist: the first aims to plant propagules in dispersed arrangements to minimize competitive interactions. In contrast, ecological theory and recent field experiments emphasize the importance of positive species interactions, suggesting instead clumped planting configurations. However, planting too many propagules too closely is likely to waste restoration resources as larger clumps have less edges and have relatively lower spread rates. Thus, given the constraint of limited restoration efforts, there should be an optimal planting distance that both is able to harness positive species interactions but at the same time maximizes spread in the treated area. To explore these ideas, here we propose a simple mathematical model that tests the influence of positive species interactions on the optimal design of restoration efforts. We model the growth and spatial spread of a population starting from different initial conditions that represent either clumped or dispersed configurations of planted habitat patches in bare substrate. We measure the spatio-temporal development of the population, its relative and absolute growth rates as well as the time-discounted population size and its dependence on the presence of an Allee effect. Finally, we assess whether clumped or dispersed configurations perform better in our models and qualitatively compare the simulation outcomes with a recent wetland restoration experiment in a coastal wetland. Our study shows that intermediate clumping is likely to maximize plant spread under medium and high stress conditions (high occurrence of positive interactions) while dispersed designs maximize growth under low stress conditions where competitive interactions dominate. These results highlight the value of mathematical modeling for optimizing the efficiency of restoration efforts and call for integration of this theory into practice.
Protein Kinase R Restricts the Intracellular Survival of Mycobacterium tuberculosis by Promoting Selective Autophagy
Authors: Smyth Robin , Berton Stefania , Rajabalee Nusrah , Chan Therese , Sun Jim
Published: January 2021

Tuberculosis (TB) is a deadly infectious lung disease caused by the pathogenic bacteriumMycobacterium tuberculosis(Mtb). The identification of macrophage signaling proteins exploited by Mtb during infection will enable the development of alternative host-directed therapies (HDT) for TB. HDT strategies will boost host immunity to restrict the intracellular replication of Mtb and therefore hold promise to overcome antimicrobial resistance, a growing crisis in TB therapy. Protein Kinase R (PKR) is a key host sensor that functions in the cellular antiviral response. However, its role in defense against intracellular bacterial pathogens is not clearly defined. Herein, we demonstrate that expression and activation of PKR is upregulated in macrophages infected with Mtb. Immunological profiling of human THP-1 macrophages that overexpress PKR (THP-PKR) showed increased production of IP-10 and reduced production of IL-6, two cytokines that are reported to activate and inhibit IFNγ-dependent autophagy, respectively. Indeed, sustained expression and activation of PKR reduced the intracellular survival of Mtb, an effect that could be enhanced by IFNγ treatment. We further demonstrate that the enhanced anti-mycobacterial activity of THP-PKR macrophages is mediated by a mechanism dependent on selective autophagy, as indicated by increased levels of LC3B-II that colocalize with intracellular Mtb. Consistent with this mechanism, inhibition of autophagolysosome maturation with bafilomycin A1 abrogated the ability of THP-PKR macrophages to limit replication of Mtb, whereas pharmacological activation of autophagy enhanced the anti-mycobacterial effect of PKR overexpression. As such, PKR represents a novel and attractive host target for development of HDT for TB, and our data suggest value in the design of more specific and potent activators of PKR.
Visual Abnormalities Associate With Hippocampus in Mild Cognitive Impairment and Early Alzheimer's Disease
Authors: Zhao Aonan , Fang Fang , Li Binyin , Chen Yan , Qiu Yinghui , Wu Yanli , Xu Wei , Deng Yulei
Published: January 2021

Background and Objective:Alzheimer's disease (AD) has been shown to affect vision in human patients and animal models. This study was conducted to explore ocular abnormalities in the primary visual pathway and their relationship with hippocampal atrophy in patients with AD and mild cognitive impairment (MCI). The aim of this study was to investigate the potential value of ocular examinations as a biomarker during the AD progression.

Methods:Patients with MCI (n= 23) or AD (n= 17) and age-matched cognitively normal controls (NC;n= 19) were enrolled. Pattern visual-evoked potentials (PVEP), flash electroretinogram (FERG) recordings and optical coherence tomography (OCT) were performed for all participants. Hippocampal volumes were measured by 3T magnetic resonance imaging. Cognitive function was assessed by Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA) and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). Pearson correlation was employed to analyze the potential associations between ocular abnormalities and hippocampal volumes. Hierarchical regression models were conducted to determine associations between cognitive performances and ocular abnormalities as well as hippocampal volumes after adjusting for confounding factors including age, sex, cognitive reserve, and APOE4 status.

Results:PVEP amplitude of P100 waveform was significantly decreased in AD patients compared to MCI and normal individuals. In FERG test, delayed latencies of rod response, rod cone response and 3.0 flicker time were found in cognitively impaired groups, indicating dysfunctions of both the rod and cone systems in the disease progression. OCT test revealed reduced macular retinal nerve fiber layer (m-RNFL) thickness in MCI and AD patients, which significantly correlated with brain structure of hippocampus particularly vulnerable during the progression of AD. Interestingly, P100 amplitude showed a significant association with hippocampal volumes even after adjusting confounding factors including age, sex, and cognitive reserve. Hierarchical regression analysis further demonstrated that m-RNFL thickness, as well as hippocampal volumes, significantly associated with ADAS-cog scores.

Conclusion:P100 amplitude and m-RNFL thickness showed significant correlations with brain structure involved in AD-related neurodegeneration, and therefore proved to be potential indicators of brain imaging pathologies.
Puberty is a Critical Period for Vomeronasal Organ Mediation of Socio-sexual Behavior in Mice
Authors: Cross Sarah K. J. , Martin Yellow H. , Salia Stephanie , Gamba Iain , Major Christina A. , Hassan Suhail , Parsons Katelyn A. , Swift-Gallant Ashlyn
Published: January 2021

Genetic disruption of the vomeronasal organ (VNO), an organ responsible for pheromone processing, drastically alters socio-sexual behavior in mice. However, it is not known whether the VNO has a role during the pubertal organizational period when sex-typical socio-sexual behaviors emerge, or if disruption of the organ in adulthood is sufficient to alter socio-sexual behavior. To bypass the lifelong VNO disruption of genetic knockout models, we surgically ablated the VNO of male and female mice either during the peripubertal period [postnatal day (PND) 28–30] or adulthood (PND 58–60), with sham controls at both ages. We ruled out anosmia via the buried food test and assessed sexual odor preferences by simultaneously exposing mice to same- and opposite-sex soiled-bedding. We then measured territorial aggression with the resident-intruder paradigm and assessed sexual behavior in response to an encounter with an estrus-induced female. Neural activity approximated by FOS-immunoreactivity along the VNO-accessory olfactory pathway was measured in response to opposite-sex odors. We found that peripubertal VNO ablation decreased sexual odor preferences and neural activity in response to opposite-sex odors, and drastically reduced territorial aggression in male mice. Conversely, adult VNO ablation resulted in subtle differences in sexual odor preferences compared with sham controls. Regardless of the VNO condition, mice displayed sex-typical copulatory behaviors. Together, these results suggest that puberty is a critical period in development whereby the VNO contributes to the sexual differentiation of behavior and neural response to conspecific odors.
Behavioral and Molecular Effects Induced by Cannabidiol and Valproate Administration in the GASH/Sal Model of Acute Audiogenic Seizures
Authors: Cabral-Pereira Giselda , Sánchez-Benito David , Díaz-Rodríguez Sandra M. , Gonçalves Jaime , Sancho Consuelo , Castellano Orlando , Muñoz Luis J. , López Dolores E. , Gómez-Nieto Ricardo
Published: January 2021

Despite evidence that supports cannabidiol (CBD) as an anticonvulsant agent, there remains controversy over the antiseizure efficacy, possible adverse effects, and synergistic interactions with classic antiepileptics such as valproate (VPA). The genetic audiogenic seizure hamster from the University of Salamanca (GASH/Sal) is a reliable experimental model of generalized tonic–clonic seizures in response to intense sound stimulation. The present study examines the behavioral and molecular effects of acute and chronic intraperitoneal administrations of VPA (300 mg/kg) and CBD (100 mg/kg) on the GASH/Sal audiogenic seizures, as well as the coadministration of both drugs. The GASH/Sal animals were examined prior to and after the corresponding treatment at 45 min, 7 days, and 14 days for seizure severity and neuroethology, open-field behaviors, body weight variations, and various hematological and biochemical parameters. Furthermore, the brain tissue containing the inferior colliculus (so-called epileptogenic nucleus) was processed for reverse transcription–quantitative polymerase chain reaction analysis to determine the treatment effects on the gene expression of neuronal receptors associated with drug actions and ictogenesis. Our results indicated that single dose of VPA helps prevent the animals from getting convulsions, showing complete elimination of seizures, whereas 7 days of chronic VPA treatment had few effects in seizure behaviors. Acute CBD administration showed subtle attenuation of seizure behaviors, increasing seizure latency and decreasing the duration of the convulsion phase, but without entirely seizure abolition. Chronic CBD treatments had no significant effects on sound-induced seizures, although some animals slightly improved seizure severity. Acute and chronic CBD treatments have no significant adverse effects on body weight, hematological parameters, and liver function, although locomotor activity was reduced. The combination of VPA and CBD did not alter the therapeutic outcome of the VPA monotherapy, showing no apparent synergistic effects. As compared to sham animals, chronic treatments with CBD caused abnormal mRNA expression levels forTrpv1, Adora1, Slc29a1, andCnr1genes, whereas no differences in gene expression were found forHtr1aandSigmar1. Our study shed light on the behavioral and molecular effects of CBD and VPA on the GASH/Sal model and constituted the basis to develop further studies on the pharmacological effects of CBD and its interactions with other anticonvulsants.
Megalencephalic Leukoencephalopathy: Insights Into Pathophysiology and Perspectives for Therapy
Authors: Bosch Assumpció , Estévez Raúl
Published: January 2021

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare genetic disorder belonging to the group of vacuolating leukodystrophies. It is characterized by megalencephaly, loss of motor functions, epilepsy, and mild mental decline. In brain biopsies of MLC patients, vacuoles were observed in myelin and in astrocytes surrounding blood vessels. It is mainly caused by recessive mutations in MLC1 and HEPACAM (also called GLIALCAM) genes. These disease variants are called MLC1 and MLC2A with both types of patients sharing the same clinical phenotype. Besides, dominant mutations in HEPACAM were also identified in a subtype of MLC patients (MLC2B) with a remitting phenotype. MLC1 and GlialCAM proteins form a complex mainly expressed in brain astrocytes at the gliovascular interface and in Bergmann glia at the cerebellum. Both proteins regulate several ion channels and transporters involved in the control of ion and water fluxes in glial cells, either directly influencing their location and function, or indirectly regulating associated signal transduction pathways. However, the MLC1/GLIALCAM complex function and the related pathological mechanisms leading to MLC are still unknown. It has been hypothesized that, in MLC, the role of glial cells in brain ion homeostasis is altered in both physiological and inflammatory conditions. There is no therapy for MLC patients, only supportive treatment. As MLC2B patients show an MLC reversible phenotype, we speculated that the phenotype of MLC1 and MLC2A patients could also be mitigated by the re-introduction of the correct gene even at later stages. To prove this hypothesis, we injected in the cerebellar subarachnoid space of Mlc1 knockout mice an adeno-associated virus (AAV) coding for human MLC1 under the control of the glial-fibrillary acidic protein promoter. MLC1 expression in the cerebellum extremely reduced myelin vacuolation at all ages in a dose-dependent manner. This study could be considered as the first preclinical approach for MLC. We also suggest other potential therapeutic strategies in this review.
Top-Down Inference in the Auditory System: Potential Roles for Corticofugal Projections
Authors: Asilador Alexander , Llano Daniel A.
Published: January 2021

It has become widely accepted that humans use contextual information to infer the meaning of ambiguous acoustic signals. In speech, for example, high-level semantic, syntactic, or lexical information shape our understanding of a phoneme buried in noise. Most current theories to explain this phenomenon rely on hierarchical predictive coding models involving a set of Bayesian priors emanating from high-level brain regions (e.g., prefrontal cortex) that are used to influence processing at lower-levels of the cortical sensory hierarchy (e.g., auditory cortex). As such, virtually all proposed models to explain top-down facilitation are focused on intracortical connections, and consequently, subcortical nuclei have scarcely been discussed in this context. However, subcortical auditory nuclei receive massive, heterogeneous, and cascading descending projections at every level of the sensory hierarchy, and activation of these systems has been shown to improve speech recognition. It is not yet clear whether or how top-down modulation to resolve ambiguous sounds calls upon these corticofugal projections. Here, we review the literature on top-down modulation in the auditory system, primarily focused on humans and cortical imaging/recording methods, and attempt to relate these findings to a growing animal literature, which has primarily been focused on corticofugal projections. We argue that corticofugal pathways contain the requisite circuitry to implement predictive coding mechanisms to facilitate perception of complex sounds and that top-down modulation at early (i.e., subcortical) stages of processing complement modulation at later (i.e., cortical) stages of processing. Finally, we suggest experimental approaches for future studies on this topic.
Selective Participation of Single Cortical Neurons in Neuronal Avalanches
Authors: Bellay Timothy , Shew Woodrow L. , Yu Shan , Falco-Walter Jessica J. , Plenz Dietmar
Published: January 2021

Neuronal avalanches are scale-invariant neuronal population activity patterns in the cortex that emerge in vivo in the awake state and in vitro during balanced excitation and inhibition. Theory and experiments suggest that avalanches indicate a state of cortex that improves numerous aspects of information processing by allowing for the transient and selective formation of local as well as system-wide spanning neuronal groups. If avalanches are indeed involved with information processing, one might expect that single neurons would participate in avalanche patterns selectively. Alternatively, all neurons could participate proportionally to their own activity in each avalanche as would be expected for a population rate code. Distinguishing these hypotheses, however, has been difficult as robust avalanche analysis requires technically challenging measures of their intricate organization in space and time at the population level, while also recording sub- or suprathreshold activity from individual neurons with high temporal resolution. Here, we identify repeated avalanches in the ongoing local field potential (LFP) measured with high-density microelectrode arrays in the cortex of awake nonhuman primates and in acute cortex slices from young and adult rats. We studied extracellular unit firing in vivo and intracellular responses of pyramidal neurons in vitro. We found that single neurons participate selectively in specific LFP-based avalanche patterns. Furthermore, we show in vitro that manipulating the balance of excitation and inhibition abolishes this selectivity. Our results support the view that avalanches represent the selective, scale-invariant formation of neuronal groups in line with the idea of Hebbian cell assemblies underlying cortical information processing.
Early Stages of Alzheimer's Disease: Evolving the Care Team for Optimal Patient Management
Authors: Galvin James E. , Aisen Paul , Langbaum Jessica B. , Rodriguez Eric , Sabbagh Marwan , Stefanacci Richard , Stern Robert A. , Vassey Elizabeth A. , de Wilde Arno , West Neva , Rubino Ivana
Published: January 2021

Alzheimer's disease (AD) is a progressive, neurodegenerative disease that creates complex challenges and a significant burden for patients and caregivers. Although underlying pathological changes due to AD may be detected in research studies decades prior to symptom onset, many patients in the early stages of AD remain undiagnosed in clinical practice. Increasing evidence points to the importance of an early and accurate AD diagnosis to optimize outcomes for patients and their families, yet many barriers remain along the diagnostic journey. Through a series of international working group meetings, a diverse group of experts contributed their perspectives to create a blueprint for a patient-centered diagnostic journey for individuals in the early stages of AD and an evolving, transdisciplinary care team. Here, we discuss key learnings, implications, and recommendations.
Electrical Stimulation-Induced Seizures and Breathing Dysfunction: A Systematic Review of New Insights Into the Epileptogenic and Symptomatogenic Zones
Authors: Ochoa-Urrea Manuela , Dayyani Mojtaba , Sadeghirad Behnam , Tandon Nitin , Lacuey Nuria , Lhatoo Samden D.
Published: January 2021

Objective: Electrical stimulation (ES) potentially delineates epileptogenic cortex through induction of typical seizures. Although frequently employed, its value for epilepsy surgery remains controversial. Similarly, ES is used to identify symptomatogenic zones, but with greater success and a long-standing evidence base. Recent work points to new seizure symptoms such as ictal central apnea (ICA) that may enhance presurgical hypotheses. The aims of this review are 2-fold: to determine the value of ES-induced seizures (ESIS) in epilepsy surgery and to analyze current evidence on ICA as a new surrogate of symptomatogenic cortex.

Methods: Three databases were searched for ESIS. Investigators independently selected studies according to pre-specified criteria. Studies reporting postoperative outcome in patients with ESIS were included in a meta-analysis. For ES-induced apnea, a thorough search was performed and reference list searching was employed.

Results: Of 6,314 articles identified for ESIS, 25 were considered eligible to be reviewed in full text. Fourteen studies were included in the qualitative synthesis (1,069 patients); six studies were included in the meta-analysis (530 patients). The meta-analysis showed that favorable outcome is associated with ESIS prior to surgery (OR: 2.02; 95% CI: 1.332–3.08). In addition, the overall estimation of the occurrence of favorable outcome among cases with ESIS is 68.13% (95% CI: 56.62–78.7). On the other hand, recent studies have shown that stimulation of exclusively mesial temporal lobe structures elicits central apnea and represents symptomatogenic anatomic substrates of ICA. This is in variance with traditional teaching that mesial temporal ES is non-symptomatogenic.

Conclusions: ES is a tool highly likely to aid in the delineation of the epileptogenic zone, since ESIS is associated with favorable postoperative outcomes (Engel I). There is an urgent need for prospective evaluation of this technique, including effective stimulation parameters and surgical outcomes, that will provide knowledge base for practice. In addition, ES-induced apnea studies suggest that ICA, especially when it is the first or only clinical sign, is an important semiological feature in localizing the symptomatogenic zone to mesial temporal lobe structures, which must be considered in SEEG explorations where this is planned, and in surgical resection strategies.
Jia-Ji Electro-Acupuncture Improves Locomotor Function With Spinal Cord Injury by Regulation of Autophagy Flux and Inhibition of Necroptosis
Authors: Hongna Yin , Hongzhao Tian , Quan Li , Delin Feng , Guijun Liu , Xiaolin Lv , Fulin Guan , Zhongren Sun
Published: January 2021

Jia-Ji electro-acupuncture (EA) has been widely applied in clinic to exhibit curative effects on spinal cord injury (SCI). However, its underlying mechanisms leading to improvement of motor function after SCI remain unclear. Allen’s method was made by NYU Impactor M-III equipment to create the SCI rats model. Rats were randomly divided into four groups: Sham (only laminectomy), Model (SCI group), EA (SCI + Jia-Ji EA treatment), EA + CQ (SCI + Jia-Ji EA treatment + inhibitor chloroquine). Basso-Beattie-Bresnahan assessment showed improvement of hind limb motor function after Jia-Ji electro-acupuncture treatment. Histological change of injured spinal cord tissue was alleviated after treatment, observed by hematoxylin-eosin and Nissl staining. The mRNA and protein expression levels of RIPK1, RIPK3 and MLKL were decreased in EA group. Besides, the increased expression of LC3 and reduced expression of P62 after treatment compared with Model group, confirmed that Jia-Ji electro-acupuncture could enhance the autophagy flux. Electron microscopy imaging showed increasing the number of lysosomes, autophagosomes, and autolysosomes after Jia-Ji electro-acupuncture treatment. Furthermore, inhibition of lysosome function with CQ led to partly eliminate the effect of EA on reducing necroptosis. These data make the case that Jia-Ji electro-acupuncture treatment may improve locomotor function by promoting autophagy flux and inhibiting necroptosis.