bluuebunny/crossref_metadata_2025 huggingface dataset:
Neutrophil and Eosinophil DNA Extracellular Trap Formation: Lessons From Pathogenic Fungi
Authors: Silva Juliana da Costa , Thompson-Souza Glaucia de Azevedo , Barroso Marina Valente , Neves Josiane Sabbadini , Figueiredo Rodrigo Tinoco
Published: February 2021

Fungal infections represent a worldwide health problem. Fungal pathogens are responsible for a variety of conditions, including superficial diseases, allergic pathologies and potentially lethal invasive infections. Neutrophils and eosinophils have been implicated as effector cells in several pathologies. Neutrophils are major effector cells involved in the control of fungal infections and exhibit a plethora of antifungal mechanisms, such as phagocytosis, reactive oxygen species production, degranulation, extracellular vesicle formation, and DNA extracellular trap (ET) release. Eosinophils are polymorphonuclear cells classically implicated as effector cells in the pathogenesis of allergic diseases and helminthic infections, although their roles as immunomodulatory players in both innate and adaptive immunity are currently recognized. Eosinophils are also endowed with antifungal activities and are abundantly found in allergic conditions associated with fungal colonization and sensitization. Neutrophils and eosinophils have been demonstrated to release their nuclear and mitochondrial DNA in response to many pathogens and pro-inflammatory stimuli. ETs have been implicated in the killing and control of many pathogens, as well as in promoting inflammation and tissue damage. The formation of ETs by neutrophils and eosinophils has been described in response to pathogenic fungi. Here, we provide an overview of the mechanisms involved in the release of neutrophil and eosinophil ETs in response to fungal pathogens. General implications for understanding the formation of ETs and the roles of ETs in fungal infections are discussed.
Applications of Machine Learning in Human Microbiome Studies: A Review on Feature Selection, Biomarker Identification, Disease Prediction and Treatment
Authors: Marcos-Zambrano Laura Judith , Karaduzovic-Hadziabdic Kanita , Loncar Turukalo Tatjana , Przymus Piotr , Trajkovik Vladimir , Aasmets Oliver , Berland Magali , Gruca Aleksandra , Hasic Jasminka , Hron Karel , Klammsteiner Thomas , Kolev Mikhail , Lahti Leo , Lopes Marta B. , Moreno Victor , Naskinova Irina , Org Elin , Paciência Inês , Papoutsoglou Georgios , Shigdel Rajesh , Stres Blaz , Vilne Baiba , Yousef Malik , Zdravevski Eftim , Tsamardinos Ioannis , Carrillo de Santa Pau Enrique , Claesson Marcus J. , Moreno-Indias Isabel , Truu Jaak
Published: February 2021

The number of microbiome-related studies has notably increased the availability of data on human microbiome composition and function. These studies provide the essential material to deeply explore host-microbiome associations and their relation to the development and progression of various complex diseases. Improved data-analytical tools are needed to exploit all information from these biological datasets, taking into account the peculiarities of microbiome data, i.e., compositional, heterogeneous and sparse nature of these datasets. The possibility of predicting host-phenotypes based on taxonomy-informed feature selection to establish an association between microbiome and predict disease states is beneficial for personalized medicine. In this regard, machine learning (ML) provides new insights into the development of models that can be used to predict outputs, such as classification and prediction in microbiology, infer host phenotypes to predict diseases and use microbial communities to stratify patients by their characterization of state-specific microbial signatures. Here we review the state-of-the-art ML methods and respective software applied in human microbiome studies, performed as part of the COST Action ML4Microbiome activities. This scoping review focuses on the application of ML in microbiome studies related to association and clinical use for diagnostics, prognostics, and therapeutics. Although the data presented here is more related to the bacterial community, many algorithms could be applied in general, regardless of the feature type. This literature and software review covering this broad topic is aligned with the scoping review methodology. The manual identification of data sources has been complemented with: (1) automated publication search through digital libraries of the three major publishers using natural language processing (NLP) Toolkit, and (2) an automated identification of relevant software repositories on GitHub and ranking of the related research papers relying on learning to rank approach.
Direct Detection of Viable but Non-culturable (VBNC) Salmonella in Real Food System by a Rapid and Accurate PMA-CPA Technique
Authors: Ou Aifen , Wang Kan , Ye Yanrui , Chen Ling , Gong Xiangjun , Qian Lu , Liu Junyan
Published: February 2021

Salmonella enterica is a typical foodborne pathogen with multiple toxic effects, including invasiveness, endotoxins, and enterotoxins. Viable but nonculturable (VBNC) is a type of dormant form preserving the vitality of microorganisms, but it cannot be cultured by traditional laboratory techniques. The aim of this study is to develop a propidium monoazide-crossing priming amplification (PMA-CPA) method that can successfully detect S. enterica rapidly with high sensitivity and can identify VBNC cells in food samples. Five primers (4s, 5a, 2a/1s, 2a, and 3a) were specially designed for recognizing the specific invA gene. The specificity of the CPA assay was tested by 20 different bacterial strains, including 2 standard S. enterica and 18 non-S. enterica bacteria strains covering Gram-negative and Gram-positive isolates. Except for the two standard S. enterica ATCC14028 and ATCC29629, all strains showed negative results. Moreover, PMA-CPA can detect the VBNC cells both in pure culture and three types of food samples with significant color change. In conclusion, the PMA-CPA assay was successfully applied on detecting S. enterica in VBNC state from food samples.
Elastic Light Scatter Pattern Analysis for the Expedited Detection of Yersinia Species in Pork Mince: Proof of Concept
Authors: On Stephen L. W. , Zhang Yuwei , Gehring Andrew , Patsekin Valery , Chelikani Venkata , Flint Steve , Wang Haoran , Billington Craig , Fletcher Graham C. , Lindsay James , Robinson J. Paul
Published: February 2021

Isolation of the pathogens Yersinia enterocolitica and Yersinia pseudotuberculosis from foods typically rely on slow (10–21 day) “cold enrichment” protocols before confirmed results are obtained. We describe an approach that yields results in 39 h that combines an alternative enrichment method with culture on a non-selective medium, and subsequent identification of suspect colonies using elastic light scatter (ELS) analysis. A prototype database of ELS profiles from five Yersinia species and six other bacterial genera found in pork mince was established, and used to compare similar profiles of colonies obtained from enrichment cultures from pork mince samples seeded with representative strains of Y. enterocolitica and Y. pseudotuberculosis. The presumptive identification by ELS using computerised or visual analyses of 83/90 colonies in these experiments as the target species was confirmed by partial 16S rDNA sequencing. In addition to seeded cultures, our method recovered two naturally occurring Yersinia strains. Our results indicate that modified enrichment combined with ELS is a promising new approach for expedited detection of foodborne pathogenic yersiniae.
Advances for the Hepatitis A Virus Antigen Production Using a Virus Strain With Codon Frequency Optimization Adjustments in Specific Locations
Authors: Chavarria-Miró Gemma , de Castellarnau Montserrat , Fuentes Cristina , D’Andrea Lucía , Pérez-Rodríguez Francisco-Javier , Beguiristain Nerea , Bosch Albert , Guix Susana , Pintó Rosa M.
Published: February 2021

The available cell-adapted hepatitis A virus (HAV) strains show a very slow replication phenotype hampering the affordable production of antigen. A fast-growing strain characterized by the occurrence of mutations in the internal ribosome entry site (IRES), combined with changes in the codon composition has been selected in our laboratory. A characterization of the IRES activity of this fast-growing strain (HM175-HP; HP) vs. its parental strain (HM175; L0) was assessed in two cell substrates used in vaccine production (MRC-5 and Vero cells) compared with the FRhK-4 cell line in which its selection was performed. The HP-derived IRES was significantly more active than the L0-derived IRES in all cells tested and both IRES were more active in the FRhK-4 cells. The translation efficiency of the HP-derived IRES was also much higher than the L0-derived IRES, particularly, in genes with a HP codon usage background. These results correlated with a higher virus production in a shorter time for the HP strain compared to the L0 strain in any of the three cell lines tested, and of both strains in the FRhK-4 cells compared to Vero and MRC-5 cells. The addition of wortmannin resulted in the increase of infectious viruses and antigen in the supernatant of FRhK-4 infected cells, independently of the strain. Finally, the replication of both strains in a clone of FRhK-4 cells adapted to grow with synthetic sera was optimal and again the HP strain showed higher yields.
CXCL10 is a Tumor Microenvironment and Immune Infiltration Related Prognostic Biomarker in Pancreatic Adenocarcinoma
Authors: Huang Huimin , Zhou Wangxiao , Chen Renpin , Xiang Bingfeng , Zhou Shipeng , Lan Linhua
Published: February 2021

Pancreatic adenocarcinoma (PAAD) is the 10th most common cancer worldwide and the outcomes for patients with the disease remain extremely poor. Precision biomarkers are urgently needed to increase the efficiency of early diagnosis and to improve the prognosis of patients. The tumor microenvironment (TME) and tumor immune infiltration are thought to impact the occurrence, progression, and prognosis of PAAD. Novel biomarkers excavated originating from the TME and immune infiltration may be effective in predicting the prognosis of PAAD patients. In the current study, the ESTIMATE and CIBERSORT algorithms were applied to estimate the division of immune and stromal components and the proportion of tumor-infiltrating immune cells in 182 PAAD cases downloaded from The Cancer Genome Atlas database. Intersection analyses of the Protein-Protein Interaction networks and Cox regression analysis identified the chemokine (CXC-motif) ligand 10 (CXCL10) as a predictive biomarker. We verified that CXCL10 in the TME negatively correlates with prognosis in PAAD and positively correlates with tumor cell differentiation. GSE62452 from the GEO database and cumulative survival analysis were performed to validate CXCL10 expression as an independent prognostic indicator. We also found that memory B cells, regulatory T cells, and macrophages M0 and M1 were correlated with the expression of CXCL10 indicating that expression of CXCL10 influenced the immune activity of the TME. Our data suggest that CXCL10 is beneficial as a prognostic indicator in PAAD patients and highlights the potential for immune targeted therapy in the treatment of PAAD.
Transportin-1: A Nuclear Import Receptor with Moonlighting Functions
Authors: Mboukou Allegra , Rajendra Vinod , Kleinova Renata , Tisné Carine , Jantsch Michael F. , Barraud Pierre
Published: February 2021

Transportin-1 (Trn1), also known as karyopherin-β2 (Kapβ2), is probably the best-characterized nuclear import receptor of the karyopherin-β family after Importin-β, but certain aspects of its functions in cells are still puzzling or are just recently emerging. Since the initial identification of Trn1 as the nuclear import receptor of hnRNP A1 ∼25 years ago, several molecular and structural studies have unveiled and refined our understanding of Trn1-mediated nuclear import. In particular, the understanding at a molecular level of the NLS recognition by Trn1 made a decisive step forward with the identification of a new class of NLSs called PY-NLSs, which constitute the best-characterized substrates of Trn1. Besides PY-NLSs, many Trn1 cargoes harbour NLSs that do not resemble the archetypical PY-NLS, which complicates the global understanding of cargo recognition by Trn1. Although PY-NLS recognition is well established and supported by several structures, the recognition of non-PY-NLSs by Trn1 is far less understood, but recent reports have started to shed light on the recognition of this type of NLSs. Aside from its principal and long-established activity as a nuclear import receptor, Trn1 was shown more recently to moonlight outside nuclear import. Trn1 has for instance been caught in participating in virus uncoating, ciliary transport and in modulating the phase separation properties of aggregation-prone proteins. Here, we focus on the structural and functional aspects of Trn1-mediated nuclear import, as well as on the moonlighting activities of Trn1.
Healthy Aging Alters the Functional Connectivity of Creative Cognition in the Default Mode Network and Cerebellar Network
Authors: Patil Abhishek Uday , Madathil Deepa , Huang Chih-Mao
Published: February 2021

Creativity is a higher-order neurocognitive process that produces unusual and unique thoughts. Behavioral and neuroimaging studies of younger adults have revealed that creative performance is the product of dynamic and spontaneous processes involving multiple cognitive functions and interactions between large-scale brain networks, including the default mode network (DMN), fronto-parietal executive control network (ECN), and salience network (SN). In this resting-state functional magnetic resonance imaging (rs-fMRI) study, group independent component analysis (group-ICA) and resting state functional connectivity (RSFC) measures were applied to examine whether and how various functional connected networks of the creative brain, particularly the default-executive and cerebro-cerebellar networks, are altered with advancing age. The group-ICA approach identified 11 major brain networks across age groups that reflected age-invariant resting-state networks. Compared with older adults, younger adults exhibited more specific and widespread dorsal network and sensorimotor network connectivity within and between the DMN, fronto-parietal ECN, and visual, auditory, and cerebellar networks associated with creativity. This outcome suggests age-specific changes in the functional connected network, particularly in the default-executive and cerebro-cerebellar networks. Our connectivity data further elucidate the critical roles of the cerebellum and cerebro-cerebellar connectivity in creativity in older adults. Furthermore, our findings provide evidence supporting the default-executive coupling hypothesis of aging and novel insights into the interactions of cerebro-cerebellar networks with creative cognition in older adults, which suggest alterations in the cognitive processes of the creative aging brain.
Long-Term Outcomes of Elderly Brain Arteriovenous Malformations After Different Management Modalities: A Multicenter Retrospective Study
Authors: Chen Yu , Yan Debin , Li Zhipeng , Ma Li , Zhao Yahui , Wang Hao , Ye Xun , Meng Xiangyu , Jin Hengwei , Li Youxiang , Gao Dezhi , Sun Shibin , Liu Ali , Wang Shuo , Chen Xiaolin , Zhao Yuanli
Published: February 2021

Background: More and more elderly patients are being diagnosed with arteriovenous malformation (AVM) in this global aging society, while the treatment strategy remains controversial among these aging population. This study aimed to clarify the long-term outcomes of elderly AVMs after different management modalities.

Methods: The authors retrospectively reviewed 71 elderly AVMs (>60 years) in two tertiary neurosurgery centers between 2011 and 2019. Patients were divided into four groups: conservation, microsurgery, embolization, and stereotactic radiosurgery (SRS). The perioperative complications, short-term and long-term neurological outcomes, obliteration rates, annualized rupture risk, and mortality rates were compared among different management modalities in the ruptured and unruptured subgroups. Kaplan-Meier survival analysis was employed to compare the death-free survival rates among different management modalities. Logistic regression analyses were conducted to calculate the odds ratios (ORs) and 95% confidence intervals (CI) for predictors of long-term unfavorable outcomes (mRS > 2).

Results: A total of 71 elderly AVMs were followed up for an average of 4.2 ± 2.3 years. Fifty-four (76.1%) presented with hemorrhage, and the preoperative annualized rupture risk was 9.4%. Among these patients, 21 cases (29.6%) received conservative treatment, 30 (42.3%) underwent microsurgical resection, 13 (18.3%) received embolization, and 7 (9.9%) underwent SRS. In the prognostic comparison, the short-term and long-term neurological outcomes were similar between conservation and intervention both in the ruptured and unruptured subgroups (ruptured: p = 0.096, p = 0.904, respectively; unruptured: p = 0.568, p = 0.306, respectively). In the ruptured subgroup, the intervention cannot reduce long-term mortality (p = 0.654) despite the significant reduction of subsequent hemorrhage than conservation (p = 0.014), and the main cause of death in the intervention group was treatment-related complications (five of seven, 71.4%). In the logistic regression analysis, higher admission mRS score (OR 3.070, 95% CI 1.559–6.043, p = 0.001) was the independent predictor of long-term unfavorable outcomes (mRS>2) in the intervention group, while complete obliteration (OR 0.146, 95% CI 0.026–0.828, p = 0.030) was the protective factor.

Conclusions: The long-term outcomes of elderly AVMs after different management modalities were similar. Intervention for unruptured elderly AVMs was not recommended. For those ruptured, we should carefully weigh the risk of subsequent hemorrhage and treatment-related complications. Besides, complete obliteration should be pursued once the intervention was initiated.

Clinical Trial Registration:http://www.clinicaltrials.gov. Unique identifier: NCT04136860
Immunoreactivity of Vesicular Glutamate Transporter 2 Corresponds to Cytochrome Oxidase-Rich Subcompartments in the Visual Cortex of Squirrel Monkeys
Authors: Yao Songping , Zhou Qiuying , Li Shuiyu , Takahata Toru
Published: February 2021

Cytochrome oxidase (CO) histochemistry has been used to reveal the cytoarchitecture of the primate brain, including blobs/puffs/patches in the striate cortex (V1), and thick, thin and pale stripes in the middle layer of the secondary visual cortex (V2). It has been suggested that CO activity is coupled with the spiking activity of neurons, implying that neurons in these CO-rich subcompartments are more active than surrounding regions. However, we have discussed possibility that CO histochemistry represents the distribution of thalamo-cortical afferent terminals that generally use vesicular glutamate transporter 2 (VGLUT2) as their main glutamate transporter, and not the activity of cortical neurons. In this study, we systematically compared the labeling patterns observed between CO histochemistry and immunohistochemistry (IHC) for VGLUT2 from the system to microarchitecture levels in the visual cortex of squirrel monkeys. The two staining patterns bore striking similarities at all levels of the visual cortex, including the honeycomb structure of V1 layer 3Bβ (Brodmann's layer 4A), the patchy architecture in the deep layers of V1, the superficial blobs of V1, and the V2 stripes. The microarchitecture was more evident in VGLUT2 IHC, as expected. VGLUT2 protein expression that produced specific IHC labeling is thought to originate from the thalamus since the lateral geniculate nucleus (LGN) and the pulvinar complex both show high expression levels of VGLUT2 mRNA, but cortical neurons do not. These observations support our theory that the subcompartments revealed by CO histochemistry represent the distribution of thalamo-cortical afferent terminals in the primate visual cortex.
Emerging Perspectives on Dipeptide Repeat Proteins in C9ORF72 ALS/FTD
Authors: Schmitz Alexander , Pinheiro Marques João , Oertig Irina , Maharjan Niran , Saxena Smita
Published: February 2021

The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a hexanucleotide expansion in the chromosome 9 open reading frame 72 gene (C9ORF72). This hexanucleotide expansion consists of GGGGCC (G4C2) repeats that have been implicated to lead to three main modes of disease pathology: loss of function of the C9ORF72 protein, the generation of RNA foci, and the production of dipeptide repeat proteins (DPRs) through repeat-associated non-AUG (RAN) translation. Five different DPRs are currently known to be formed: glycine–alanine (GA) and glycine–arginine (GR) from the sense strand, proline–alanine (PA), and proline–arginine (PR) from the antisense strand, and glycine–proline (GP) from both strands. The exact contribution of each DPR to disease pathology is currently under intense scrutiny and is still poorly understood. However, recent advances in both neuropathological and cellular studies have provided us with clues enabling us to better understand the effect of individual DPRs on disease pathogenesis. In this review, we compile the current knowledge of specific DPR involvement on disease development and highlight recent advances, such as the impact of arginine-rich DPRs on nucleolar protein quality control, the correlation of poly-GR with neurodegeneration, and the possible involvement of chimeric DPR species. Further, we discuss recent findings regarding the mechanisms of RAN translation, its modulators, and other promising therapeutic options.
Indoleamine-2,3-Dioxygenase 1 Deficiency Suppresses Seizures in Epilepsy
Authors: Deng Ning , Hu Jiao , Hong Yu , Ding Yuewen , Xiong Yifan , Wu Zhiyong , Xie Wei
Published: February 2021

Background: Indoleamine-2,3-dioxygenase 1 (IDO1) is the initial and rate-limiting enzyme in the metabolism of tryptophan (TRP) to kynurenine (KYN). IDO1-dependent neurotoxic KYN metabolism plays a crucial role in the pathogenesis of many neurodegenerative disorders. However, the function of IDO1 in epilepsy is still unclear.

Objective: In this study, we investigated whether IDO1 deficiency could affect epilepsy in a lithium-pilocarpine-induced model.

Methods: Patients with epilepsy and controls were enrolled. Male C57BL/6 mice and IDO1 knockout (KO, IDO1−/−) mice were subjected to intraperitoneal injection of lithium and pilocarpine to induce epilepsy. The levels of IDO1 and concentrations of TRP and KYN in patients with epilepsy and epileptic mice were evaluated by enzyme-linked immunosorbent assay (ELISA) and liquid chromatography-mass spectrometry (LC-MS), respectively. Then, behavioral phenotypes related to epileptic seizures and neuronal damage were compared between KO and wild-type (WT) mice with lithium-pilocarpine-induced epilepsy. To explore the underlying pathways involved in the effects of IDO1 deficiency, the concentrations of kynurenic acid (KYNA) and quinolinic acid (QUIN), glial cell activation, the levels of major pro-inflammatory cytokines, and antioxidant enzyme activity were measured by LC-MS, immunohistochemistry, and ELISA.

Results: In this study, IDO1 levels and the KYN/TRP ratio in the sera and cerebrospinal fluid (CSF) were increased in patients with epilepsy. Also, IDO1 levels, the KYN/TRP ratio, and the levels of pro-inflammatory cytokines in the sera and hippocampi were increased in mice during the acute phase and chronic phase after status epilepticus (SE). Furthermore, IDO1 was localized in microglial cells in epileptic mice. IDO1 deficiency delayed SE onset and attenuated the frequency, duration, and severity of spontaneous recurrent seizures (SRSs). Moreover, IDO1 deficiency improved neuronal survival. Additionally, IDO1−/− epileptic mice showed progressive declines in QUIN production, glial cell activation and pro-inflammatory cytokines levels, and enhanced antioxidant enzyme activity.

Conclusions: IDO1 deletion suppressed seizures and alleviated neuronal damage by reducing the IDO1-dependent production of neurotoxic metabolites, which finally inhibited glial cell activation and pro-inflammatory cytokine production and improved antioxidant enzyme activity. Our study demonstrates that IDO1 may be involved in the pathogenesis of epilepsy and has the potential to be a therapeutic target for epilepsy treatment.
Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) as a Novel Regulator of Early Astroglial Differentiation
Authors: Romeo Ramona , Boden-El Mourabit Damian , Scheller Anja , Mark Melanie D. , Faissner Andreas
Published: February 2021

Astrocytes are the most abundant cell type within the central nervous system (CNS) with various functions. Furthermore, astrocytes show a regional and developmental heterogeneity traceable with specific markers. In this study, the influence of the low-density lipoprotein receptor-related protein 1 (LRP1) on astrocytic maturation within the hippocampus was analyzed during development. Previous studies mostly focused on the involvement of LRP1 in the neuronal compartment, where the deletion caused hyperactivity and motor dysfunctions in knockout animals. However, the influence of LRP1 on glia cells is less intensively investigated. Therefore, we used a newly generated mouse model, where LRP1 is specifically deleted from GLAST-positive astrocytes co-localized with the expression of the reporter tdTomato to visualize recombination and knockout events in vivo. The influence of LRP1 on the maturation of hippocampal astrocytes was assessed with immunohistochemical stainings against stage-specific markers as well as on mRNA level with RT-PCR analysis. The examination revealed that the knockout induction caused a significantly decreased number of mature astrocytes at an early developmental timepoint compared to control animals. Additionally, the delayed maturation of astrocytes also caused a reduced activity of neurons within the hippocampus. As previous studies showed that the glial specification and maturation of astrocytes is dependent on the signaling cascades Ras/Raf/MEK/Erk and PI3K/Akt, the phosphorylation of the signaling molecules Erk1/2 and Akt was analyzed. The hippocampal tissue of LRP1-deficient animals at P21 showed a significantly decreased amount of activated Erk in comparison to control tissue leading to the conclusion that the activation of this signaling cascade is dependent on LRP1 in astrocytes, which in turn is necessary for proper maturation of astrocytes. Our results showed that the deletion of LRP1 at an early developmental timepoint caused a delayed maturation of astrocytes in the hippocampus based on an altered activation of the Ras/Raf/MEK/Erk signaling pathway. However, with ongoing development these effects were compensated and the number of mature astrocytes was comparable as well as the activity of neurons. Therefore, LRP1 acts as an early regulator of the differentiation and maturation of astrocytes within the hippocampus.
Neurologic Care of COVID-19 in Children
Authors: Boronat Susana
Published: February 2021

Most children with SARS-CoV-2 infection have relatively mild clinical symptoms without fever or pneumonia, although severe cases with multiple-organ failure have been reported. Neurological symptoms, which have been mainly reported in adults, are very rare in children. This article will review 2 different aspects of neurological involvement related to this infection in children. In the first part, we will review the neurological abnormalities reported in children caused by this viral infection. Adults frequently report muscle pain, headache, anosmia, dysgeusia, and occasionally more severe central or peripheral nervous system damage. Neurological involvement seems infrequent in children, although some cases have been reported. In the second part, we will discuss the COVID-19 pandemic impact on the healthcare system of some countries, causing collateral damage to general pediatric care and in particular to those children affected with chronic diseases, mainly neurological conditions, including autism, intellectual disability, attention deficit and hyperactivity disorder (ADHD), neuromuscular disorders, cerebral palsy, and epilepsy, and patients needing neurosurgical procedures.
Prediabetes Is Associated With Brain Hypometabolism and Cognitive Decline in a Sex-Dependent Manner: A Longitudinal Study of Nondemented Older Adults
Authors: Sundermann Erin E. , Thomas Kelsey R. , Bangen Katherine J. , Weigand Alexandra J. , Eppig Joel S. , Edmonds Emily C. , Wong Christina G. , Bondi Mark W. , Delano-Wood Lisa
Published: February 2021

Although type 2 diabetes is a well-known risk factor for Alzheimer's disease (AD), little is known about how its precursor—prediabetes—impacts neuropsychological function and brain health. Thus, we examined the relationship between prediabetes and AD-related biological and cognitive/clinical markers in a well-characterized sample drawn from the Alzheimer's Disease Neuroimaging Initiative. Additionally, because women show higher rates of AD and generally more atherogenic lipid profiles than men, particularly in the context of diabetes, we examined whether sex moderates any observed associations. The total sample of 911 nondemented and non-diabetic participants [normal control = 540; mild cognitive impairment (MCI) = 371] included 391 prediabetic (fasting blood glucose: 100–125 mg/dL) and 520 normoglycemic individuals (age range: 55–91). Linear mixed effects models, adjusted for demographics and vascular and AD risk factors, examined the independent and interactive effects of prediabetes and sex on 2–6 year trajectories of FDG-PET measured cerebral metabolic glucose rate (CMRglu), hippocampal/intracranial volume ratio (HV/IV), cerebrospinal fluid phosphorylated tau-181/amyloid-β1−42 ratio (p-tau181/Aβ1−42), cognitive function (executive function, language, and episodic memory) and the development of dementia. Analyses were repeated in the MCI subsample. In the total sample, prediabetic status had an adverse effect on CMRglu across time regardless of sex, whereas prediabetes had an adverse effect on executive function across time in women only. Within the MCI subsample, prediabetic status was associated with lower CMRglu and poorer executive function and language performance across time within women, whereas these associations were not seen within men. In the total sample and MCI subsample, prediabetes did not relate to HV/IV, p-tau181/Aβ1−42, memory function or dementia risk regardless of sex; however, among incident dementia cases, prediabetic status related to earlier age of dementia onset in women but not in men. Results suggest that prediabetes may affect cognition through altered brain metabolism, and that women may be more vulnerable to the negative effects of glucose intolerance.
Inhibition of Colony Stimulating Factor 1 Receptor Suppresses Neuroinflammation and Neonatal Hypoxic-Ischemic Brain Injury
Authors: Zhang Bohao , Ran Yunwei , Wu Siting , Zhang Fang , Huang Huachen , Zhu Changlian , Zhang Shusheng , Zhang Xiaoan
Published: February 2021

Hypoxic-ischemic (HI) brain injury is a major cause of neonatal death or lifetime disability without widely accepted effective pharmacological treatments. It has been shown that the survival of microglia requires colony-stimulating factor 1 receptor (CSF1R) signaling and microglia participate in neonatal HI brain injury. We therefore hypothesize that microglia depletion during a HI insult period could reduce immature brain injury. In this study, CD1 mouse pups were treated with a CSF1R inhibitor (PLX3397, 25 mg/kg/daily) or a vehicle from postnatal day 4 to day 11 (P4–11), and over 90% of total brain microglia were deleted at P9. Unilateral hemisphere HI injury was induced at P9 by permanently ligating the left common carotid arteries and exposing the pups to 10% oxygen for 30 min to produce moderate left hemisphere injury. We found that the PLX3397 treatment reduced HI brain injury by 46.4%, as evaluated by the percentage of brain infarction at 48 h after HI. Furthermore, CSF1R inhibition suppressed the infiltration of neutrophils (69.7% reduction, p = 0.038), macrophages (77.4% reduction, p = 0.009), and T cells (72.9% reduction, p = 0.008) to the brain, the production of cytokines and chemokines (such as CCL12, CCL6, CCL21, CCL22, CCL19, IL7, CD14, and WISP-1), and reduced neuronal apoptosis as indicated by active caspase-3 labeled cells at 48 h after HI (615.20 ± 156.84/mm2 vs. 1,205.00 ± 99.15/mm2, p = 0.013). Our results suggest that CSF1R inhibition suppresses neuroinflammation and neonatal brain injury after acute cerebral hypoxia-ischemia in neonatal mice.
Neuroprotective Treatment of Postanoxic Encephalopathy: A Review of Clinical Evidence
Authors: Nutma Sjoukje , le Feber Joost , Hofmeijer Jeannette
Published: February 2021

Postanoxic encephalopathy is the key determinant of death or disability after successful cardiopulmonary resuscitation. Animal studies have provided proof-of-principle evidence of efficacy of divergent classes of neuroprotective treatments to promote brain recovery. However, apart from targeted temperature management (TTM), neuroprotective treatments are not included in current care of patients with postanoxic encephalopathy after cardiac arrest. We aimed to review the clinical evidence of efficacy of neuroprotective strategies to improve recovery of comatose patients after cardiac arrest and to propose future directions. We performed a systematic search of the literature to identify prospective, comparative clinical trials on interventions to improve neurological outcome of comatose patients after cardiac arrest. We included 53 studies on 21 interventions. None showed unequivocal benefit. TTM at 33 or 36°C and adrenaline (epinephrine) are studied most, followed by xenon, erythropoietin, and calcium antagonists. Lack of efficacy is associated with heterogeneity of patient groups and limited specificity of outcome measures. Ongoing and future trials will benefit from systematic collection of measures of baseline encephalopathy and sufficiently powered predefined subgroup analyses. Outcome measurement should include comprehensive neuropsychological follow-up, to show treatment effects that are not detectable by gross measures of functional recovery. To enhance translation from animal models to patients, studies under experimental conditions should adhere to strict methodological and publication guidelines.
Sleep Duration and the Risk of Metabolic Syndrome in Adults: A Systematic Review and Meta-Analysis
Authors: Hua Jianian , Jiang Hezi , Wang Hui , Fang Qi
Published: February 2021

Objective: Epidemiological studies have reported inconsistent findings for the association between sleep duration and metabolic syndrome. We aimed to clarify the effects of short and long sleep durations on metabolic syndrome in adults by performing a meta-analysis.

Methods: Adopting random-effects models, this study analyzed the effects of short and long sleep durations based on data from prospective cohort studies and cross-sectional studies retrieved from four electronic databases from inception to May 2020.

Results: We collected data from 235,895 participants included in nine prospective cohort studies and 340,492 participants included in 27 cross-sectional studies. In cohort studies, short sleep duration was associated with an increased risk of metabolic syndrome (RR, 1.15; 95% CI, 1.05–1.25, I2 = 63.1%, P < 0.001) compared with normal sleep duration. While long sleep duration was not associated with new-onset metabolic syndrome (RR, 1.02, 0.85–1.18, I2 = 38.0%, P = 0.491). In cross-sectional studies, both short (OR, 1.06, 95% CI, 1.01–1.11, I2 = 66.5%, P < 0.001) and long (OR, 1.11, 95% CI, 1.04–1.17, I2 = 73.8%, P < 0.001) sleep durations were associated with a high prevalence of metabolic syndrome.

Conclusions: Only a short sleep duration was associated with an increased risk of metabolic syndrome. Future studies should address whether the association is casual and modifiable.
Characterizing the Action-Observation Network Through Functional Near-Infrared Spectroscopy: A Review
Authors: Condy Emma E. , Miguel Helga O. , Millerhagen John , Harrison Doug , Khaksari Kosar , Fox Nathan , Gandjbakhche Amir
Published: February 2021

Functional near-infrared spectroscopy (fNIRS) is a neuroimaging technique that has undergone tremendous growth over the last decade due to methodological advantages over other measures of brain activation. The action-observation network (AON), a system of brain structures proposed to have “mirroring” abilities (e.g., active when an individual completes an action or when they observe another complete that action), has been studied in humans through neural measures such as fMRI and electroencephalogram (EEG); however, limitations of these methods are problematic for AON paradigms. For this reason, fNIRS is proposed as a solution to investigating the AON in humans. The present review article briefly summarizes previous neural findings in the AON and examines the state of AON research using fNIRS in adults. A total of 14 fNIRS articles are discussed, paying particular attention to methodological choices and considerations while summarizing the general findings to aid in developing better protocols to study the AON through fNIRS. Additionally, future directions of this work are discussed, specifically in relation to researching AON development and potential multimodal imaging applications.
Intraoperative Brain Mapping by Cortico-Cortical Evoked Potential
Authors: Yamao Yukihiro , Matsumoto Riki , Kikuchi Takayuki , Yoshida Kazumichi , Kunieda Takeharu , Miyamoto Susumu
Published: February 2021

To preserve postoperative brain function, it is important for neurosurgeons to fully understand the brain's structure, vasculature, and function. Intraoperative high-frequency electrical stimulation during awake craniotomy is the gold standard for mapping the function of the cortices and white matter; however, this method can only map the “focal” functions and cannot monitor large-scale cortical networks in real-time. Recently, an in vivo electrophysiological method using cortico-cortical evoked potentials (CCEPs) induced by single-pulse electrical cortical stimulation has been developed in an extraoperative setting. By using the CCEP connectivity pattern intraoperatively, mapping and real-time monitoring of the dorsal language pathway is available. This intraoperative CCEP method also allows for mapping of the frontal aslant tract, another language pathway, and detection of connectivity between the primary and supplementary motor areas in the frontal lobe network. Intraoperative CCEP mapping has also demonstrated connectivity between the frontal and temporal lobes, likely via the ventral language pathway. Establishing intraoperative electrophysiological monitoring is clinically useful for preserving brain function, even under general anesthesia. This CCEP technique demonstrates potential clinical applications for mapping and monitoring large-scale cortical networks.
Constructing Brain Connectivity Model Using Causal Network Reconstruction Approach
Authors: Saetia Supat , Yoshimura Natsue , Koike Yasuharu
Published: February 2021

Studying brain function is a challenging task. In the past, we could only study brain anatomical structures post-mortem, or infer brain functions from clinical data of patients with a brain injury. Nowadays technology, such as functional magnetic resonance imaging (fMRI), enable non-invasive brain activity observation. Several approaches have been proposed to interpret brain activity data. The brain connectivity model is a graphical tool that represents the interaction between brain regions, during certain states. It depicts how a brain region cause changes to other parts of the brain, which can be implied as information flow. This model can be used to help interpret how the brain works. There are several mathematical frameworks that can be used to infer the connectivity model from brain activity signals. Granger causality is one such approach and is one of the first that has been applied to brain activity data. However, due to the concept of the framework, such as the use of pairwise correlation, combined with the limitation of brain activity data such as low temporal resolution in case of fMRI signal, makes the interpretation of the connectivity difficult. We therefore propose the application of the Tigramite causal discovery framework on fMRI data. The Tigramite framework uses measures such as causal effect to analyze causal relations in the system. This enables the framework to identify both direct and indirect pathways or connectivities. In this paper, we applied the framework to the Human Connectome Project motor task-fMRI dataset. We then present the results and discuss how the framework improves interpretability of the connectivity model. We hope that this framework will help us understand more complex brain functions such as memory, consciousness, or the resting-state of the brain, in the future.
A Novel SOD1 Intermediate Oligomer, Role of Free Thiols and Disulfide Exchange
Authors: Koo Bon-Kyung , Munroe William , Gralla Edith B. , Valentine Joan Selverstone , Whitelegge Julian P.
Published: February 2021

Wild-type human SOD1 forms a highly conserved intra-molecular disulfide bond between C57-C146, and in its native state is greatly stabilized by binding one copper and one zinc atom per monomer rendering the protein dimeric. Loss of copper extinguishes dismutase activity and destabilizes the protein, increasing accessibility of the disulfide with monomerization accompanying disulfide reduction. A further pair of free thiols exist at C6 and C111 distant from metal binding sites, raising the question of their function. Here we investigate their role in misfolding of SOD1 along a pathway that leads to formation of amyloid fibrils. We present the seeding reaction of a mutant SOD1 lacking free sulfhydryl groups (AS-SOD1) to exclude variables caused by these free cysteines. Completely reduced fibril seeds decreasing the kinetic barrier to cleave the highly conserved intramolecular disulfide bond, and accelerating SOD1 reduction and initiation of fibrillation. Presence or absence of the pair of free thiols affects kinetics of fibrillation. Previously, we showed full maturation with both Cu and Zn prevents this behavior while lack of Cu renders sensitivity to fibrillation, with presence of the native disulfide bond modulating this propensity much more strongly than presence of Zn or dimerization. Here we further investigate the role of reduction of the native C57-C146 disulfide bond in fibrillation of wild-type hSOD1, firstly through removal of free thiols by paired mutations C6A, C111S (AS-SOD1), and secondly in seeded fibrillation reactions modulated by reductant tris (2-carboxyethyl) phosphine (TCEP). Fibrillation of AS-SOD1 was dependent upon disulfide reduction and showed classic lag and exponential growth phases compared with wild-type hSOD1 whose fibrillation trajectories were typically somewhat perturbed. Electron microscopy showed that AS-SOD1 formed classic fibrils while wild-type fibrillation reactions showed the presence of smaller “sausage-like” oligomers in addition to fibrils, highlighting the potential for mixed disulfides involving C6/C111 to disrupt efficient fibrillation. Seeding by addition of sonicated fibrils lowered the TCEP concentration needed for fibrillation in both wild-type and AS-SOD1 providing evidence for template-driven structural disturbance that elevated susceptibility to reduction and thus propensity to fibrillate.
Region-Specific Effects of 10-Hz Transcranial Alternate Current Stimulation Over the Left Posterior Parietal Cortex and Primary Somatosensory Area on Tactile Two-Point Discrimination Threshold
Authors: Yokota Hirotake , Otsuru Naofumi , Saito Kei , Kojima Sho , Miyaguchi Shota , Inukai Yasuto , Nagasaka Kazuaki , Onishi Hideaki
Published: February 2021

Changes in α-band cortical oscillatory activity (8–13 Hz) affect perception; however, how these changes in the left posterior parietal cortex (PPC) and primary somatosensory cortex (S1), which play different roles in determining the two-point discrimination (TPD) threshold, affect TPD threshold remains unelucidated. Therefore, to determine TPD threshold, we aimed to investigate the function of the left PPC and S1 by applying α-band transcranial alternating current stimulation (α-tACS; 10 Hz). TPD threshold was examined at the pad of the right index finger, contralateral to the stimulation site, in 17 healthy adults using a custom-made, computer-controlled, two-point tactile stimulation device, with random application of either active or sham α-tACS over the left PPC (Experiment 1) and left S1 (Experiment 2). Then, 50% TPD threshold was obtained in the active and sham conditions via logistic regression analysis. Afterward, we compared the difference between the active and sham conditions at 50% TPD threshold in each region and found that α-tACS reduced TPD threshold when applied over the left PPC (P= 0.010); however, its effect was insignificant when applied over the left S1 (P= 0.74). Moreover, a comparison of the change in 50% TPD threshold among the regions revealed that α-tACS applied over the left PPC significantly reduced TPD threshold compared with that applied over the left S1 (P= 0.003). Although we did not reveal the actual changes in cortical activity induced by α-tACS, this is the first empirical evidence that α-tACS applied over the left PPC and left S1 exerts region-specific effects on determining TPD threshold assessed in the contralateral index finger pad by stimulation.
Low-Latency Spiking Neural Networks Using Pre-Charged Membrane Potential and Delayed Evaluation
Authors: Hwang Sungmin , Chang Jeesoo , Oh Min-Hye , Min Kyung Kyu , Jang Taejin , Park Kyungchul , Yu Junsu , Lee Jong-Ho , Park Byung-Gook
Published: February 2021

Spiking neural networks (SNNs) have attracted many researchers’ interests due to its biological plausibility and event-driven characteristic. In particular, recently, many studies on high-performance SNNs comparable to the conventional analog-valued neural networks (ANNs) have been reported by converting weights trained from ANNs into SNNs. However, unlike ANNs, SNNs have an inherent latency that is required to reach the best performance because of differences in operations of neuron. In SNNs, not only spatial integration but also temporal integration exists, and the information is encoded by spike trains rather than values in ANNs. Therefore, it takes time to achieve a steady-state of the performance in SNNs. The latency is worse in deep networks and required to be reduced for the practical applications. In this work, we propose a pre-charged membrane potential (PCMP) for the latency reduction in SNN. A variety of neural network applications (e.g., classification, autoencoder using MNIST and CIFAR-10 datasets) are trained and converted to SNNs to demonstrate the effect of the proposed approach. The latency of SNNs is successfully reduced without accuracy loss. In addition, we propose a delayed evaluation method (DE), by which the errors during the initial transient are discarded. The error spikes occurring in the initial transient is removed byDE, resulting in the further latency reduction.DEcan be used in combination withPCMPfor further latency reduction. Finally, we also show the advantages of the proposed methods in improving the number of spikes required to reach a steady-state of the performance in SNNs for energy-efficient computing.