bluuebunny/crossref_metadata_2025 huggingface dataset:
Protection of Antigen-Primed Effector T Cells From Glucocorticoid-Induced Apoptosis in Cell Culture and in a Mouse Model of Multiple Sclerosis
Authors: Bier Jasmina , Steiger Sebastian M. , Reichardt Holger M. , Lühder Fred
Published: June 2021

Induction of T cell apoptosis constitutes a major mechanism by which therapeutically administered glucocorticoids (GCs) suppress inflammation and associated clinical symptoms, for instance in multiple sclerosis (MS) patients suffering from an acute relapse. The sensitivity of T cells to GC action depends on their maturation and activation status, but the precise effect of antigen-priming in a pathological setting has not been explored. Here we used transgenic and congenic mouse models to compare GC-induced apoptosis between naïve and antigen-specific effector T cells from mice immunized with a myelin peptide. Antigen-primed effector T cells were protected from the pro-apoptotic activity of the synthetic GC dexamethasone in a dose-dependent manner, which resulted in their accumulation relative to naïve T cellsin vitroandin vivo. Notably, the differential sensitivity of T cells to GC-induced apoptosis correlated with their expression level of the anti-apoptotic proteins Bcl-2 and Bcl-XLand a loss of the mitochondrial membrane potential. Moreover, accumulation of antigen-primed effector T cells following GC treatmentin vitroresulted in an aggravated disease course in an adoptive transfer mouse model of MSin vivo, highlighting the clinical relevance of the observed phenomenon. Collectively, our data indicate that antigen-priming influences the T cells’ sensitivity to therapeutically applied GCs in the context of inflammatory diseases.
Immune Response in Neurological Pathology: Emerging Role of Central and Peripheral Immune Crosstalk
Authors: Passaro Austin P. , Lebos Abraham L. , Yao Yao , Stice Steven L.
Published: June 2021

Neuroinflammation is a key component of neurological disorders and is an important therapeutic target; however, immunotherapies have been largely unsuccessful. In cases where these therapies have succeeded, particularly multiple sclerosis, they have primarily focused on one aspect of the disease and leave room for improvement. More recently, the impact of the peripheral immune system is being recognized, since it has become evident that the central nervous system is not immune-privileged, as once thought. In this review, we highlight key interactions between central and peripheral immune cells in neurological disorders. While traditional approaches have examined these systems separately, the immune responses and processes in neurological disorders consist of substantial crosstalk between cells of the central and peripheral immune systems. Here, we provide an overview of major immune effector cells and the role of the blood-brain barrier in regard to neurological disorders and provide examples of this crosstalk in various disorders, including stroke and traumatic brain injury, multiple sclerosis, neurodegenerative diseases, and brain cancer. Finally, we propose targeting central-peripheral immune interactions as a potential improved therapeutic strategy to overcome failures in clinical translation.
Reversal of the CD8+ T-Cell Exhaustion Induced by Chronic HIV-1 Infection Through Combined Blockade of the Adenosine and PD-1 Pathways
Authors: Li Jing , Huang Hui-Huang , Tu Bo , Zhou Ming-Ju , Hu Wei , Fu Yu-Long , Li Xiao-Yu , Yang Tao , Song Jin-Wen , Fan Xing , Jiao Yan-Mei , Xu Ruo-Nan , Zhang Ji-Yuan , Zhou Chun-Bao , Yuan Jin-Hong , Zhen Cheng , Shi Ming , Wang Fu-Sheng , Zhang Chao
Published: June 2021

Background

Targeting immune checkpoints for HIV treatment potentially provides a double benefit resulting from the ability to restore viral-specific CD8+ T-cell functions and enhance HIV production from reservoir cells. Despite promising pre-clinical data, PD-1 blockade alone in HIV-1-infected patients with advanced cancer has shown limited benefits in controlling HIV, suggesting the need for additional targets beyond PD-1. CD39 and PD-1 are highly co-expressed on CD8+ T cells in HIV-1 infection. However, the characteristics of CD39 and PD-1 dual-positive CD8+ T-cell subsets in chronic HIV-1 infection remain poorly understood.

Methods

This study enrolled 72 HIV-1-infected patients, including 40 treatment naïve and 32 ART patients. A total of 11 healthy individuals were included as controls. Different subsets of CD8+ T cells defined by CD39 and/or PD-1 expression were studied by flow cytometry. The relationships between the frequencies of the different subsets and parameters indicating HIV-1 disease progression were analyzed. Functional (i.e., cytokine secretion, viral inhibition) assays were performed to evaluate the impact of the blockade of adenosine and/or PD-1 signaling on CD8+ T cells.

Results

The proportions of PD-1+, CD39+, and PD-1+CD39+ CD8+ T cells were significantly increased in treatment naïve patients but were partially lowered in patients on antiretroviral therapy. In treatment naïve patients, the proportions of PD-1+CD39+ CD8+ T cells were negatively correlated with CD4+ T-cell counts and the CD4/CD8 ratio, and were positively correlated with viral load. CD39+CD8+ T cells expressed high levels of the A2A adenosine receptor and were more sensitive to 2-chloroadenosine-mediated functional inhibition than their CD39- counterparts. In vitro, a combination of blocking CD39/adenosine and PD-1 signaling showed a synergic effect in restoring CD8+ T-cell function, as evidenced by enhanced abilities to secrete functional cytokines and to kill autologous reservoir cells.

Conclusion

In patients with chronic HIV-1 infection there are increased frequencies of PD-1+, CD39+, and PD-1+CD39+ CD8+ T cells. In treatment naïve patients, the frequencies of PD-1+CD39+ CD8+ T cells are negatively correlated with CD4+ T-cell counts and the CD4/CD8 ratio and positively correlated with viral load. Combined blockade of CD39/adenosine and PD-1 signaling in vitro may exert a synergistic effect in restoring CD8+ T-cell function in HIV-1-infected patients.
Lactylation, a Novel Metabolic Reprogramming Code: Current Status and Prospects
Authors: Chen An-Na , Luo Yan , Yang Yu-Han , Fu Jian-Tao , Geng Xiu-Mei , Shi Jun-Ping , Yang Jin
Published: June 2021

Lactate is an end product of glycolysis. As a critical energy source for mitochondrial respiration, lactate also acts as a precursor of gluconeogenesis and a signaling molecule. We briefly summarize emerging concepts regarding lactate metabolism, such as the lactate shuttle, lactate homeostasis, and lactate-microenvironment interaction. Accumulating evidence indicates that lactate-mediated reprogramming of immune cells and enhancement of cellular plasticity contribute to establishing disease-specific immunity status. However, the mechanisms by which changes in lactate states influence the establishment of diverse functional adaptive states are largely uncharacterized. Posttranslational histone modifications create a code that functions as a key sensor of metabolism and are responsible for transducing metabolic changes into stable gene expression patterns. In this review, we describe the recent advances in a novel lactate-induced histone modification, histone lysine lactylation. These observations support the idea that epigenetic reprogramming-linked lactate input is related to disease state outputs, such as cancer progression and drug resistance.
More Than Effects in Skin: Ultraviolet Radiation-Induced Changes in Immune Cells in Human Blood
Authors: Hart Prue H. , Norval Mary
Published: June 2021

Cells of the skin and circulation are in constant two-way communication. Following exposure of humans to sunlight or to phototherapy, there are alterations in the number, phenotype and function of circulating blood cells. In this review, only data obtained from human studies are considered, with changes induced by UV radiation (UVR) exposure described for phagocytic leukocytes and peripheral blood mononuclear cells plus their component T and B cells, natural killer cells and dendritic cells. These immune modulations illustrate the potential of UVR to have therapeutic effects beyond the skin, and that sunlight exposure is an important environmental influence on human health.
Immunomodulation: Immunoglobulin Preparations Suppress Hyperinflammation in a COVID-19 Model via FcγRIIA and FcαRI
Authors: Bohländer Fabian , Riehl Dennis , Weißmüller Sabrina , Gutscher Marcus , Schüttrumpf Jörg , Faust Stefanie
Published: June 2021

The rapid spread of SARS-CoV-2 has induced a global pandemic. Severe forms of COVID-19 are characterized by dysregulated immune response and “cytokine storm”. The role of IgG and IgM antibodies in COVID-19 pathology is reasonably well studied, whereas IgA is neglected. To improve clinical outcome of patients, immune modulatory drugs appear to be beneficial. Such drugs include intravenous immunoglobulin preparations, which were successfully tested in severe COVID-19 patients. Here we established a versatile in vitro model to study inflammatory as well as anti-inflammatory processes by therapeutic human immunoglobulins. We dissect the inflammatory activation on neutrophil-like HL60 cells, using an immune complex consisting of latex beads coated with spike protein of SARS-CoV-2 and opsonized with specific immunoglobulins from convalescent plasma. Our data clarifies the role of Fc-receptor-dependent phagocytosis via IgA-FcαRI and IgG-FcγR for COVID-19 disease followed by cytokine release. We show that COVID-19 associated inflammation could be reduced by addition of human immunoglobulin preparations (IVIG and trimodulin), while trimodulin elicits stronger immune modulation by more powerful ITAMi signaling. Besides IgG, the IgA component of trimodulin in particular, is of functional relevance for immune modulation in this assay setup, highlighting the need to study IgA mediated immune response.
Long-Term Variability of Piscivorous Fish in China Seas Under Climate Change With Implication for Fisheries Management
Authors: Liu Dan , Tian Yongjun , Ma Shuyang , Li Jianchao , Sun Peng , Ye Zhenjiang , Fu Caihong , Lan Kuowei , Zhou Shijie
Published: June 2021

Due to persistent fishing expansion in the China Seas over the past six decades, fisheries resources have been over-exploited; as a result, exploited fish have become smaller in size and younger in age. Marine piscivorous fish constituted a large portion of Chinese fisheries catch, long-term variability of which has rarely been investigated despite intense fishing pressure and climate change. In this study, we attempt to identify their responses to climate change and fishing activities and to provide scientific basis for sustainable exploitation of these resources. Seven taxa from pelagic to demersal species inhabiting either cold-water or warm-water were selected to represent the piscivorous fish assemblage in the China Seas. Total catch of these piscivorous fish in the China Seas increased during the early 1990s, stabilizing around 1.2 million tons after 1997. Principal component analysis (PCA) showed evident interannual-decadal variabilities in the catch of these fish with step changes around 1985/86 and 1997/98. Individual taxa, however, showed different trends in catches with sharks, rays, and lizardfishes manifesting downward trends while Pacific cod, eels, and hairtail increasing. Common dolphinfish and Japanese-Spanish mackerel increased largely in the 1990s but declined slightly during the 2000s. Although there were temporal overlaps between climate change and fishing variabilities, results of gradient forest analyses indicated that fishing effort imposed the most important influence on piscivorous fish. And among all climate variables explored in this study, sea surface temperature (SST) especially that of the East China Sea, had greatest impacts on variations in piscivorous fish catch, which may have been gradually exacerbated by the continued high fishing intensity. In addition, significant changes were identified in the life history traits in the species we evaluated, such as reduced average body sizes and truncated age compositions, strongly indicating the effect of fishing. We therefore advocate precautionary fishery practices under climate change.
Variability of Microbial Particulate ATP Concentrations in Subeuphotic Microbes Due to Underlying Metabolic Strategies in the South Pacific Ocean
Authors: Lanpher Kaycie B. , Popendorf Kimberly J.
Published: June 2021

Adenosine triphosphate (ATP) is the primary energy storage molecule in metabolic pathways. It is common in marine studies to use particulate ATP (PATP) concentrations as representative of microbial biomass. However, there is growing evidence from culture studies, models, and transcriptional data that PATP concentration varies across microbes and conditions, thus compromising interpretations in environmental settings. Importantly, there is a lack of open ocean studies assessing variations in PATP concentrations and thus a deficiency of information on the key biogeochemical drivers for variability in microbial PATP independent of biomass. In sampling the U.S. GO-SHIP P06E zonal transect (32.5°S) across the eastern South Pacific, from the subtropical gyre to the upwelling waters off Chile, we conducted the first comprehensive transect survey quantifying PATP. PATP concentrations increased toward the upwelling region of the transect, but varied vertically when normalized against three measures of biomass: particulate phosphorus, microbial abundance, and microbial biovolume. Generally, greater biomass-normalized PATP concentrations were observed below the deep chlorophyll maximum. Subdividing the P06E transect into four biogeochemical regimes highlighted distinct metabolic strategies used by microbes. Between these regimes, we found PATP concentrations were representative of biomass in upper surface waters. However, below the deep chlorophyll maximum we observed higher biomass normalized PATP concentrations that we hypothesize were due to less availability of energy sources in those subeuphotic zone waters and abundances of chemoautotrophs in the microbial community. This finding suggests that stored energy was more important for these deeper microbes.
Screening of Tomato Seed Bacterial Endophytes for Antifungal Activity Reveals Lipopeptide Producing Bacillus siamensis Strain NKIT9 as a Potential Bio-Control Agent
Authors: Sharma Ayushi , Kaushik Nutan , Sharma Abhishek , Bajaj Abhay , Rasane Mandar , Shouche Yogesh S. , Marzouk Takwa , Djébali Naceur
Published: June 2021

The current study investigates the diversity pattern and fungicidal potential of bacterial endophytes isolated from two different organic varieties of tomato plants (V1 and V2). A total of seventy-five bacterial isolates identified by 16S rRNA gene sequencing revealed a majority of genus as Bacillus and one Planococcus, which were grouped into eight different species. The Shannon diversity H’ (1.56), Simpson’s index of diversity (0.93), Magalef’ index (2.23), Evenness (0.96), and Species richness (7) indicated the high endophytic bacterial diversity in the V1 variety of the tomato. Bacterial endophytes isolated from both of the varieties were screened for their antifungal activity against five economically critical fungal pathogens (viz., Botrytis cinerea, Rhizoctonia solani, Fusarium solani, Verticillium lateritium, and Alternaria solani) of tomato crop through dual culture assay. The data revealed B. siamensis strain NKIT9 as the most potent antagonist, significantly (p < 0.05) inhibiting the mycelial growth between 75 to 90% against selected fungal pathogens. High bioactivity of lipopeptide extract of strain NKIT9 was recorded against R. solani with minimum IC50 value of 230 μg/ml. The Ultra Performance Liquid Chromatography-High Definition Mass Spectrometry (UPLC-HDMS) analysis of this lipopeptide extract revealed the presence of Surfactin and Bacillomycin D. Furthermore, in-vitro results showed that the selected bacterial strain significantly minimized the disease incidence in damping-off assay which makes this strain a promising antifungal bio-control agent. Moreover, in the pot experiment the NKIT9 increased the fruit yield by 59.2% compared with the untreated R. solani infested control.
A Homeodomain-Containing Transcriptional Factor PoHtf1 Regulated the Development and Cellulase Expression in Penicillium oxalicum
Authors: Guo Hao , Xu Gen , Wu Ruimei , Li Zhigang , Yan Mengdi , Jia Zhilei , Li Zhonghai , Chen Mei , Bao Xiaoming , Qu Yinbo
Published: June 2021

Homeodomain-containing transcription factors (Htfs) play important roles in animals, fungi, and plants during some developmental processes. Here, a homeodomain-containing transcription factor PoHtf1 was functionally characterized in the cellulase-producing fungi Penicillium oxalicum 114-2. PoHtf1 was shown to participate in colony growth and conidiation through regulating the expression of its downstream transcription factor BrlA, the key regulator of conidiation in P. oxalicum 114-2. Additionally, PoHtf1 inhibited the expression of the major cellulase genes by coordinated regulation of cellulolytic regulators CreA, AmyR, ClrB, and XlnR. Furthermore, transcriptome analysis showed that PoHtf1 participated in the secondary metabolism including the pathway synthesizing conidial yellow pigment. These data show that PoHtf1 mediates the complex transcriptional-regulatory network cascade between developmental processes and cellulolytic gene expression in P. oxalicum 114-2. Our results should assist the development of strategies for the metabolic engineering of mutants for applications in the enzymatic hydrolysis for biochemical production.
Early-Life Intervention Using Exogenous Fecal Microbiota Alleviates Gut Injury and Reduce Inflammation Caused by Weaning Stress in Piglets
Authors: Ma Xin , Zhang Yuchen , Xu Tingting , Qian Mengqi , Yang Zhiren , Zhan Xiuan , Han Xinyan
Published: June 2021

Fecal microbiota transplantation (FMT) could shape the structure of intestinal microbiota in animals. This study was conducted to explore the changes that happen in the structure and function of microbiota caused by weaning stress, and whether early-life FMT could alleviate weaning stress through modifying intestinal microbiota in weaned piglets. Diarrheal (D) and healthy (H) weaned piglets were observed, and in the same farm, a total of nine litters newborn piglets were randomly allocated to three groups: sucking normally (S), weaned at 21 d (W), and early-life FMT + weaned at 21 d (FW). The results demonstrated that differences of fecal microbiota existed in group D and H. Early-life FMT significantly decreased diarrhea incidence of weaned piglets. Intestinal morphology and integrity were improved in the FW group. Both ZO-1 and occludin (tight junction proteins) of jejunum were greatly enhanced, while the zonulin expression was significantly down-regulated through early-life FMT. The expression of IL-6 and TNF-α (intestinal mucosal inflammatory cytokines) were down-regulated, while IL-10 (anti-inflammatory cytokines) was up-regulated by early-life FMT. In addition, early-life FMT increased the variety of the intestinal microbial population and the relative amounts of some beneficial bacteria such as Spirochaetes, Akkermansia, and Alistipes. Functional alteration of the intestinal microbiota revealed that lipid biosynthesis and aminoacyl-tRNA biosynthesis were enriched in the FW group. These findings suggested that alteration of the microbiota network caused by weaning stress induced diarrhea, and early-life FMT alleviated weaning stress in piglets, which was characterized by decreased diarrhea incidence, improved intestinal morphology, reduced intestinal inflammation, and modified intestinal bacterial composition and function.
Comparative Analysis of the IclR-Family of Bacterial Transcription Factors and Their DNA-Binding Motifs: Structure, Positioning, Co-Evolution, Regulon Content
Authors: Suvorova Inna A. , Gelfand Mikhail S.
Published: June 2021

The IclR-family is a large group of transcription factors (TFs) regulating various biological processes in diverse bacteria. Using comparative genomics techniques, we have identified binding motifs of IclR-family TFs, reconstructed regulons and analyzed their content, finding co-occurrences between the regulated COGs (clusters of orthologous genes), useful for future functional characterizations of TFs and their regulated genes. We describe two main types of IclR-family motifs, similar in sequence but different in the arrangement of the half-sites (boxes), with GKTYCRYW3–4RYGRAMC and TGRAACAN1–2TGTTYCA consensuses, and also predict that TFs in 32 orthologous groups have binding sites comprised of three boxes with alternating direction, which implies two possible alternative modes of dimerization of TFs. We identified trends in site positioning relative to the translational gene start, and show that TFs in 94 orthologous groups bind tandem sites with 18–22 nucleotides between their centers. We predict protein–DNA contacts via the correlation analysis of nucleotides in binding sites and amino acids of the DNA-binding domain of TFs, and show that the majority of interacting positions and predicted contacts are similar for both types of motifs and conform well both to available experimental data and to general protein–DNA interaction trends.
Characterization of a Hyaluronic Acid Utilization Locus and Identification of Two Hyaluronate Lyases in a Marine Bacterium Vibrio alginolyticus LWW-9
Authors: Wang Xiaoyi , Wei Ziwei , Wu Hao , Li Yujiao , Han Feng , Yu Wengong
Published: June 2021

Hyaluronic acid (HA) is a negatively charged and linear polysaccharide existing in the tissues and body fluids of all vertebrates. Some pathogenic bacteria target hyaluronic acid for adhesion and/or infection to host cells. Vibrio alginolyticus is an opportunistic pathogen related to infections of humans and marine animals, and the hyaluronic acid-degrading potential of Vibrio spp. has been well-demonstrated. However, little is known about how Vibrio spp. utilize hyaluronic acid. In this study, a marine bacterium V. alginolyticus LWW-9 capable of degrading hyaluronic acid has been isolated. Genetic and bioinformatic analysis showed that V. alginolyticus LWW-9 harbors a gene cluster involved in the degradation, transport, and metabolism of hyaluronic acid. Two novel PL8 family hyaluronate lyases, VaHly8A and VaHly8B, are the key enzymes for the degradation of hyaluronic acid. VaHly8A and VaHly8B have distinct biochemical properties, reflecting the adaptation of the strain to the changing parameters of the aquatic habitats and hosts. Based on genomic and functional analysis, we propose a model for the complete degradation of hyaluronic acid by V. alginolyticus LWW-9. Overall, our study expands our knowledge of the HA utilization paradigm within the Proteobacteria, and the two novel hyaluronate lyases are excellent candidates for industrial applications.
Unexpected Gating Behaviour of an Engineered Potassium Channel Kir
Authors: Fagnen Charline , Bannwarth Ludovic , Zuniga Dania , Oubella Iman , De Zorzi Rita , Forest Eric , Scala Rosa , Guilbault Samuel , Bendahhou Saïd , Perahia David , Vénien-Bryan Catherine
Published: June 2021

In this study, we investigated the dynamics and functional characteristics of the KirBac3.1 S129R, a mutated bacterial potassium channel for which the inner pore-lining helix (TM2) was engineered so that the bundle crossing is trapped in an open conformation. The structure of this channel has been previously determined at high atomic resolution. We explored the dynamical characteristics of this open state channel using an in silico method MDeNM that combines molecular dynamics simulations and normal modes. We captured the global and local motions at the mutation level and compared these data with HDX-MS experiments. MDeNM provided also an estimation of the probability of the different opening states that are in agreement with our electrophysiological experiments. In the S129R mutant, the Arg129 mutation releases the two constriction points in the channel that existed in the wild type but interestingly creates another restriction point.
Task-Related c-Fos Expression in the Posterior Parietal Cortex During the “Rubber Tail Task” Is Diminished in Ca2+-Dependent Activator Protein for Secretion 2 (Caps2)-Knockout Mice
Authors: Wada Makoto , Takano Kouji , Ide Masakazu , Sano Yoshitake , Shinoda Yo , Furuichi Teiichi , Kansaku Kenji
Published: June 2021

Rubber hand illusion (RHI), a kind of body ownership illusion, is sometimes atypical in individuals with autism spectrum disorder; however, the brain regions associated with the illusion are still unclear. We previously reported that mice responded as if their own tails were being touched when rubber tails were grasped following synchronous stroking to rubber tails and their tails (a “rubber tail illusion”, RTI), which is a task based on the human RHI; furthermore, we reported that the RTI response was diminished inCa2+-dependent activator protein for secretion 2-knockout (Caps2-KO) mice that exhibit autistic-like phenotypes. Importance of the posterior parietal cortex in the formation of illusory perception has previously been reported in human imaging studies. However, the local neural circuits and cell properties associated with this process are not clear. Therefore, we aimed to elucidate the neural basis of the RTI response and its impairment by investigating the c-Fos expression in both wild-type (WT) andCaps2-KO mice during the task since the c-Fos expression occurred soon after the neural activation. Immediately following the delivery of the synchronous stroking to both rubber tails and actual tails, the mice were perfused. Subsequently, whole brains were cryo-sectioned, and each section was immunostained with anti-c-Fos antibody; finally, c-Fos positive cell densities among the groups were compared. The c-Fos expression in the posterior parietal cortex was significantly lower in theCaps2-KO mice than in the WT mice. Additionally, we compared the c-Fos expression in the WT mice between synchronous and asynchronous conditions and found that the c-Fos-positive cell densities were significantly higher in the claustrum and primary somatosensory cortex of the WT mice exposed to the synchronous condition than those exposed to the asynchronous condition. Hence, the results suggest that decreased c-Fos expression in the posterior parietal cortex may be related to impaired multisensory integrations inCaps2-KO mice.
Towards Clinically Relevant Oculomotor Biomarkers in Early Schizophrenia
Authors: Athanasopoulos Fotios , Saprikis Orionas-Vasilis , Margeli Myrto , Klein Christoph , Smyrnis Nikolaos
Published: June 2021

In recent years, psychiatric research has focused on the evaluation and implementation of biomarkers in the clinical praxis. Oculomotor function deviances are among the most consistent and replicable cognitive deficits in schizophrenia and have been suggested as viable candidates for biomarkers. In this narrative review, we focus on oculomotor function in first-episode psychosis, recent onset schizophrenia as well as individuals at high risk for developing psychosis. We critically discuss the evidence for the possible utilization of oculomotor function measures as diagnostic, susceptibility, predictive, monitoring, and prognostic biomarkers for these conditions. Based on the current state of research we conclude that there are not sufficient data to unequivocally support the use of oculomotor function measures as biomarkers in schizophrenia.
Involvement of Mast Cells in the Pathophysiology of Pain
Authors: Mai Lijia , Liu Qing , Huang Fang , He Hongwen , Fan Wenguo
Published: June 2021

Mast cells (MCs) are immune cells and are widely distributed throughout the body. MCs are not only classically viewed as effector cells of some allergic diseases but also participate in host defense, innate and acquired immunity, homeostatic responses, and immunoregulation. Mounting evidence indicates that activation of MCs releasing numerous vasoactive and inflammatory mediators has effects on the nervous system and has been involved in different pain conditions. Here, we review the latest advances made about the implication of MCs in pain. Possible cellular and molecular mechanisms regarding the crosstalk between MC and the nervous system in the initiation and maintenance of pain are also discussed.
The Complement of Projection Neurons Activated Determines the Type of Feeding Motor Program in Aplysia
Authors: Evans Colin G. , Barry Michael A. , Jing Jian , Perkins Matthew H. , Weiss Klaudiusz R. , Cropper Elizabeth C.
Published: June 2021

Multiple projection neurons are often activated to initiate behavior. A question that then arises is, what is the unique functional role of each neuron activated? We address this issue in the feeding system ofAplysia. Previous experiments identified a projection neuron [cerebral buccal interneuron 2 (CBI-2)] that can trigger ingestive motor programs but only after it is repeatedly stimulated, i.e., initial programs are poorly defined. As CBI-2 stimulation continues, programs become progressively more ingestive (repetition priming occurs). This priming results, at least in part, from persistent actions of peptide cotransmitters released from CBI-2. We now show that in some preparations repetition priming does not occur. There is no clear seasonal effect; priming and non-priming preparations are encountered throughout the year. CBI-2 is electrically coupled to a second projection neuron, cerebral buccal interneuron 3 (CBI-3). In preparations in which priming does not occur, we show that ingestive activity is generated when CBI-2 and CBI-3 are coactivated. Programs are immediately ingestive, i.e., priming is not necessary, and a persistent state is not induced. Our data suggest that dynamic changes in the configuration of activity can vary and be determined by the complement of projection neurons that trigger activity.
Genomic Investigation of Infantile and Childhood Epileptic Encephalopathies in Kazakhstan: An Urgent Priority
Authors: Jaxybayeva Altynshash , Nauryzbayeva Alissa , Khamzina Assem , Takhanova Meruert , Abilhadirova Assel , Rybalko Anastasia , Jamanbekova Kymbat
Published: June 2021

Objectives: Infantile and childhood epileptic encephalopathies are a group of severe epilepsies that begin within the first year of life and often portend increased morbidity. Many of them are genetically determined. The medical strategy for their management depends on the genetic cause. There are no facilities for genetic testing of children in Kazakhstan but we have a collection of data with already defined genes responsible for clinical presentations.

Methods: We analyzed children with epileptic encephalopathies that began in the first 3 years of life and were accompanied by a delay/arrest of intellectual development, in the absence of structural changes in the brain. Such patients were recommended to undergo genetic testing using epileptic genetic panels in laboratories in different countries.

Results: We observed 350 infants with clinical presentation of epileptic encephalopathies. 4.3% of them followed our recommendations and underwent genetic testing privately. In total 12/15 children became eligible for targeted treatment, 3/15 were likely to have non-epileptic stereotypies/movements, 2/15 were unlikely to respond to any therapy and all had a high chance of intellectual disability, behavioral and social communication disorders.

Conclusion: The genetic results of 15/350 (4.3% of patients) have demonstrated the potential and enormous impact from gene panel analysis in management of epileptic encephalopathy. Availability of genetic testing within the country will improve management of children with genetic epilepsies and help to create a local database of pathogenic variants.
Inhouse Bridging Thrombolysis Is Associated With Improved Functional Outcome in Patients With Large Vessel Occlusion Stroke: Findings From the German Stroke Registry
Authors: Maier Ilko L. , Leha Andreas , Badr Mostafa , Allam Ibrahim , Bähr Mathias , Jamous Ala , Hesse Amelie , Psychogios Marios-Nikos , Behme Daniel , Liman Jan
Published: June 2021

Background: Endovascular treatment (EVT) for large vessel occlusion stroke (LVOS) is highly effective. To date, it remains controversial if intravenous thrombolysis (IVT) prior to EVT is superior compared with EVT alone. The aim of our study was to specifically address the question, whether bridging IVT directly prior to EVT has additional positive effects on reperfusion times, successful reperfusion, and functional outcomes compared with EVT alone.

Methods: Patients with LVOS in the anterior circulation eligible for EVT with and without prior IVT and direct admission to endovascular centers (mothership) were included in this multicentric, retrospective study. Patient data was derived from the German Stroke Registry (an open, multicenter, and prospective observational study). Outcome parameters included groin-to-reperfusion time, successful reperfusion [defined as a Thrombolysis in Cerebral Infarction (TICI) scale 2b-3], change in National Institute of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), and mortality at 90 days.

Results: Of the 881 included mothership patients with anterior circulation LVOS, 486 (55.2%) received bridging therapy with i.v.-rtPA prior to EVT, and 395 (44.8%) received EVT alone. Adjusted, multivariate linear mixed effect models revealed no difference in groin-to-reperfusion time between the groups (48 ± 36 vs. 49 ± 34 min; p = 0.299). Rates of successful reperfusion (TICI ≥ 2b) were higher in patients with bridging IVT (fixed effects estimate 0.410, 95% CI, 0.070; 0.750, p = 0.018). There was a trend toward a higher improvement in the NIHSS during hospitalization [ΔNIHSS: bridging-IVT group 8 (IQR, 9.8) vs. 4 (IQR 11) points in the EVT alone group; fixed effects estimate 1.370, 95% CI, −0.490; 3.240, p = 0.149]. mRS at 90 days follow-up was lower in the bridging IVT group [3 (IQR, 4) vs. 4 (IQR, 4); fixed effects estimate −0.350, 95% CI, −0.680; −0.010, p = 0.041]. There was a non-significantly lower 90 day mortality in the bridging IVT group compared with the EVT alone group (22.4% vs. 33.6%; fixed effects estimate 0.980, 95% CI −0.610; 2.580, p = 0.351). Rates of any intracerebral hemorrhage did not differ between both groups (4.1% vs. 3.8%, p = 0.864).

Conclusions: This study provides evidence that bridging IVT might improve rates of successful reperfusion and long-term functional outcome in mothership patients with anterior circulation LVOS eligible for EVT.
Anti-Neurofascin 155 Antibody-Positive Chronic Inflammatory Demyelinating Polyneuropathy/Combined Central and Peripheral Demyelination: Strategies for Diagnosis and Treatment Based on the Disease Mechanism
Authors: Kira Jun-ichi
Published: June 2021

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated demyelinating disease of the peripheral nervous system (PNS). A small number of CIDP patients harbors autoantibodies against nodal/paranodal proteins, such as neurofascin 155 (NF155), contactin 1, and contactin-associated protein 1. In most cases, the predominant immunoglobulin (IgG) subclass is IgG4. Node/paranode antibody-positive CIDP demonstrates distinct features compared with antibody-negative CIDP, including a poor response to intravenous immunoglobulin. The neuropathology of biopsied sural nerve shows Schwann cell terminal loop detachment from axons without macrophage infiltration or inflammation. This is partly attributable to IgG4, which blocks protein–protein interactions without inducing inflammation. Anti-NF155 antibody-positive (NF155+) CIDP is unique because of the high frequency of subclinical demyelinating lesions in the central nervous system (CNS). This is probably because NF155 coexists in the PNS and CNS. Such cases showing demyelinating lesions in both the CNS and PNS are now termed combined central and peripheral demyelination (CCPD). NF155+ CIDP/CCPD commonly presents hypertrophy of spinal nerve roots and cranial nerves, such as trigeminal and oculomotor nerves, and extremely high levels of cerebrospinal fluid (CSF) protein, which indicates nerve root inflammation. In the CSF, the CXCL8/IL8, IL13, TNFα, CCL11/eotaxin, CCL2/MCP1, and IFNγ levels are significantly higher and the IL1β, IL1ra, and GCSF levels are significantly lower in NF155+ CIDP than in non-inflammatory neurological diseases. Even compared with anti-NF155 antibody-negative (NF155−) CIDP, the CXCL8/IL8 and IL13 levels are significantly higher and the IL1β and IL1ra levels are significantly lower than those in NF155+ CIDP. Canonical discriminant analysis revealed NF155+ and NF155− CIDP to be separable with IL4, IL10, and IL13, the three most significant discriminators, all of which are required for IgG4 class switching. Therefore, upregulation of both Th2 and Th1 cytokines and downregulation of macrophage-related cytokines are characteristic of NF155+ CIDP, which explains spinal root inflammation and the lack of macrophage infiltration in the sural nerves. All Japanese patients with NF155+ CIDP/CCPD have one of two specific human leukocyte antigen (HLA) haplotypes, which results in a significantly higher prevalence of HLA-DRB1*15:01-DQB1*06:02 compared with healthy Japanese controls. This indicates an involvement of specific HLA class II molecules and relevant T cells in addition to IgG4 anti-NF155 antibodies in the mechanism underlying IgG4 NF155+ CIDP/CCPD.
Altered Relationship Between Heart Rate Variability and fMRI-Based Functional Connectivity in People With Epilepsy
Authors: Kassinopoulos Michalis , Harper Ronald M. , Guye Maxime , Lemieux Louis , Diehl Beate
Published: June 2021

Background: Disruptions in central autonomic processes in people with epilepsy have been studied through evaluation of heart rate variability (HRV). Decreased HRV appears in epilepsy compared to healthy controls, suggesting a shift in autonomic balance toward sympathetic dominance; recent studies have associated HRV changes with seizure severity and outcome of interventions. However, the processes underlying these autonomic changes remain unclear. We examined the nature of these changes by assessing alterations in whole-brain functional connectivity, and relating those alterations to HRV.

Methods: We examined regional brain activity and functional organization in 28 drug-resistant epilepsy patients and 16 healthy controls using resting-state functional magnetic resonance imaging (fMRI). We employed an HRV state-dependent functional connectivity (FC) framework with low and high HRV states derived from the following four cardiac-related variables: 1. RR interval, 2. root mean square of successive differences (RMSSD), 4. low-frequency HRV (0.04–0.15 Hz; LF-HRV) and high-frequency HRV (0.15–0.40 Hz; HF-HRV). The effect of group (epilepsy vs. controls), HRV state (low vs. high) and the interactions of group and state were assessed using a mixed analysis of variance (ANOVA). We assessed FC within and between 7 large-scale functional networks consisting of cortical regions and 4 subcortical networks, the amygdala, hippocampus, basal ganglia and thalamus networks.

Results: Consistent with previous studies, decreased RR interval (increased heart rate) and decreased HF-HRV appeared in people with epilepsy compared to healthy controls. For both groups, fluctuations in heart rate were positively correlated with BOLD activity in bilateral thalamus and regions of the cerebellum, and negatively correlated with BOLD activity in the insula, putamen, superior temporal gyrus and inferior frontal gyrus. Connectivity strength in patients between right thalamus and ventral attention network (mainly insula) increased in the high LF-HRV state compared to low LF-HRV; the opposite trend appeared in healthy controls. A similar pattern emerged for connectivity between the thalamus and basal ganglia.

Conclusion: The findings suggest that resting connectivity patterns between the thalamus and other structures underlying HRV expression are modified in people with drug-resistant epilepsy compared to healthy controls.
Gait Analysis in Progressive Supranuclear Palsy Phenotypes
Authors: Picillo Marina , Ricciardi Carlo , Tepedino Maria Francesca , Abate Filomena , Cuoco Sofia , Carotenuto Immacolata , Erro Roberto , Ricciardelli Gianluca , Russo Michela , Cesarelli Mario , Barone Paolo , Amboni Marianna
Published: June 2021

The objective of the present study was to describe gait parameters of progressive supranuclear palsy (PSP) phenotypes at early stage verifying the ability of gait analysis in discriminating between disease phenotypes and between the other variant syndromes of PSP (vPSP) and Parkinson's disease (PD). Nineteen PSP (10 PSP-Richardson's syndrome, five PSP-parkinsonism, and four PSP-progressive gait freezing) and nine PD patients performed gait analysis in single and dual tasks. Although phenotypes showed similar demographic and clinical variables, Richardson's syndrome presented worse cognitive functions. Gait analysis demonstrated worse parameters in Richardson's syndrome compared with the vPSP. The overall diagnostic accuracy of the statistical model during dual task was almost 90%. The correlation analysis showed a significant relationship between gait parameters and visuo-spatial, praxic, and attention abilities in PSP-Richardson's syndrome only. vPSP presented worse gait parameters than PD. Richardson's syndrome presents greater gait dynamic instability since the earliest stages than other phenotypes. Computerized gait analysis can differentiate between PSP phenotypes and between vPSP and PD.
Advantage of Handwriting Over Typing on Learning Words: Evidence From an N400 Event-Related Potential Index
Authors: Ihara Aya S. , Nakajima Kae , Kake Akiyuki , Ishimaru Kizuku , Osugi Kiyoyuki , Naruse Yasushi
Published: June 2021

The growing implementation of digital education comes with an increased need to understand the impact of digital tools on learning. Previous behavioral studies have shown that handwriting on paper is more effective for learning than typing on a keyboard. However, the impact of writing with a digital pen on a tablet remains to be clarified. In the present study, we compared learning by handwriting with an ink pen on paper, handwriting with a digital pen on a tablet, and typing on a keyboard. Behavioral and electroencephalographic indices were measured immediately after learning with each writing tool. The moods of the subjects during the training were also assessed. The participants were divided according to their use of digital pen in their everyday lives, allowing us to take into account the effect of the familiarity with the digital pen on the learning process (familiar group vs. unfamiliar group). We performed an EEG experiment applying a repetition priming paradigm. In each trial, a learned foreign language word (prime word) and a mother tongue word (target word) were consecutively presented. The target word was either semantically identical to the prime word (repetitive condition) or different (non-repetitive condition). We assumed that a larger priming effect on N400 reflects larger learning progress. The familiar group showed a greater N400 priming effect for words learned with the digital or ink pen than those learned with the keyboard. The unfamiliar group showed the greater N400 priming effect for words learned with the ink pen compared with words learned by typing. In addition, positive mood during learning was significantly higher during handwriting than during typing, regardless of the groups. On the other hand, the behavioral indices were not influenced by the writing tool. These results suggest that the movements involved in handwriting allow a greater memorization of new words. The advantage of handwriting over typing might also be caused by a more positive mood during learning. Finally, our results show that handwriting with a digital pen and tablet can increase the ability to learn compared with keyboard typing once the individuals are accustomed to it.
Globus Pallidus Internus Deep Brain Stimulation for Dystonic Opisthotonus in Adult-Onset Dystonia: A Personalized Approach
Authors: Tambirajoo Kantharuby , Furlanetti Luciano , Samuel Michael , Ashkan Keyoumars
Published: June 2021

Introduction

Dystonic opisthotonus is defined as a backward arching of the neck and trunk, which ranges in severity from mild backward jerks to life-threatening prolonged severe muscular spasms. It can be associated with generalized dystonic syndromes or, rarely, present as a form of axial truncal dystonia. The etiologies vary from idiopathic, genetic, tardive, hereditary-degenerative, or associated with parkinsonism. We report clinical cases of dystonic opisthotonus associated with adult-onset dystonic syndromes, that benefitted from globus pallidus internus (GPi) deep brain stimulation (DBS).

Methods

Clinical data from patients with dystonic syndromes who underwent comprehensive medical review, multidisciplinary assessment, and tailored medical and neurosurgical managements were prospectively analyzed. Quantification of dystonia severity pre- and postoperatively was performed using the Burke-Fahn-Marsden Dystonia Rating Scale and quantification of overall pain severity was performed using the Visual Analog Scale.

Results

Three male patients, with age of onset of the dystonic symptoms ranging from 32 to 51 years old, were included. Tardive dystonia, adult-onset dystonia-parkinsonism and adult-onset idiopathic axial dystonia were the etiologies identified. Clinical investigation and management were tailored according to the complexity of the individual presentations. Although they shared common clinical features of adult-onset dystonia, disabling dystonic opisthotonus, refractory to medical management, was the main indication for GPi-DBS in all patients presented. The severity of axial dystonia ranged from disturbance of daily function to life-threatening truncal distortion. All three patients underwent bilateral GPi DBS at a mean age of 52 years (range 48–55 years), after mean duration of symptoms prior to DBS of 10.7 years (range 4–16 years). All patients showed a rapid and sustained clinical improvement of their symptoms, notably of the dystonic opisthotonos, at postoperative follow-up ranging from 20 to 175 months. In some, the ability to resume activities of daily living and reintegration into the society was remarkable.

Conclusion

Adult-onset dystonic syndromes predominantly presenting with dystonic opisthotonus are relatively rare. The specific nature of dystonic opisthotonus remains a treatment challenge, and thorough investigation of this highly disabling condition with varying etiologies is often necessary. Although patients may be refractory to medical management and botulinum toxin injection, Globus pallidus stimulation timed and tailored provided symptomatic control in this cohort and may be considered in other carefully selected cases.