bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurophysiological methods of photosensitivity identification in juvenile myoclonic epilepsy (review)
Authors: Petrov K. V. , Shnayder N. A. , Dmitrenko D. V. , Narodova E. A. , Nasyrova R. F.
Published: January 2021

To date, it has been shown that juvenile myoclonic epilepsy (JME) is a common form of genetic (idiopathic) generalized epilepsy. The study of neurophysiological factors that inhibiting and provocating photosensitivity on the electroencephalogram (EEG) in JME expands our understanding of this disease, which is important for diagnosis, treatment and prognosis.

The purposeof this review is to analyze neurophysiological techniques that inhibiting and provocating photosensitivity on EEG in patients with JME.

Materials and methods. We searched for full-text publications in Russian and English over the past two decades in the databases eLibrary, PubMed, Web of Science, OxfordPress, Springer, Clinicalkeys using keywords: juvenile myoclonic epilepsy (JME), diagnostics, neurophysiology, electroencephalography (EEG), eye opening, photostimulation, eye closure sensitivity, photoparoxysmal response (PPR), epilepsy.

Results. Currently, visual triggers such as eye closure, eye closure sensitivity (ECS)/fixation-off sensitivity, other than photosensitivity, are routinely used for EEG in patients with JME, but are rarely scientifically investigated for this pathology. However, it has been shown that ECS is present in 15–25 % of patients with JME. Trigger photostimulation is most effective for detecting photosensitivity in JME compared to intermittent (rhythmic) photostimulation. The frequency of photosensitivity in patients with JME is variable — from 30 % to 54 %. The exact mechanisms of these phenomena are still unknown. It is assumed that ECS and photosensitivity are expressions of hyperexcitability of the occipital cortex in JME.

Conclusion. The analyzed neurophysiological and electroclinical studies indicate positive changes in the diagnosis of JME and changes in our understanding of this disease. The mechanism of ECS and photosensitivity in JME is unknown, which is a reason for future research to clarify their consequences, including their impact on the prognosis of the disease and their role in the development of pharmacoresistance. However, despite the characteristic clinical picture and the progress of modern neurophysiological research methods, the question of the role of photosensitivity in this form of epilepsy remains a problem for practicing neurologists, and the proposed EEG protocols need to be modified and more widely implemented in real clinical practice. Variable light and color patterns in broadcast or video game material with a high rate of image change of high-contrast stimulation (more than 3 repetitions per second) can cause seizures in some patients with JME. This requires changing approaches to the neurophysiological diagnosis of photosensitivity in JME and the use of combined triggers for video EEG monitoring.
Depression and dopamine dysregulation syndrome as risk factor for suicide after deep brain stimulation in Parkinson's disease
Authors: Bril E. V. , Abbasov F. A. , Zimnyakova O. S. , Anikina M. A. , Kesarev D. G.
Published: January 2021

Modern approaches to the management of advanced stages of Parkinson's disease include deep brain stimulation (DBS). Adequate selection of candidates for DBS is a key factor for the effectiveness and safety of this method. Selection criteria are mainly based on data from large multicenter studies. It is known that the use of DBS can be accompanied by the development of side effects, the most common of which is neuropsychiatric disorders. Suicide is an extreme manifestation of neuropsychiatric disorders and a potentially reversible cause of death in patients with Parkinson's disease. Patients with chronic diseases, including neurological diseases, have an increased risk of suicide or suicide attempts. Depression and impulse control disorders following DBS are likely key contributors to suicidal behavior in patients. The authors present a clinical case – an attempt to commit suicide after DBS with the use of levodopa with an analysis of the factors contributing the development of suicidal behavior and an analysis of the management of neuropsychiatric disorders.
Trends in Weight among Undergraduate Students in a Northeast Public University
Authors: Evans Marian A. , Zigmont Victoria A.
Published: January 2021

Objective: Increasing BMI, overweight, and obesity are urgent and grave problems in the US. The goal of this study is to begin to understand trends in overweight and obesity among undergraduate students in the U.S. to assist in informing public health education and health promotion practices. Methods: Data on self-reported weight and height were collected in 2012, 2014, and 2016 from randomly selected college students who were enrolled in a public university in Northeast US. Spearman's Rank Order Test was used to evaluate trends within specific demographic categories. Results: BMI increased for almost all students from 2012-2016. Groups with significant increases in BMI included: males, females, sophomores, and seniors. Conclusions: Results suggest the need for interventions to reduce increases in overweight and obesity that are experienced during college years. College is a critical transitional time when students adopt health behaviors that they continue into adulthood. Increasing BMI in college students indicates a need for additional research to understand the factors that contribute to the increasing trend of overweight and obesity in this population. College is an optimal setting for implementation of effective interventions that can help prevent BMI increases in this population and establish healthy behaviors for the future.
Carbon Nanotube Modified Microelectrode Array for Neural Interface
Authors: Vafaiee Mohaddeseh , Mohammadpour Raheleh , Vossoughi Manouchehr , Asadian Elham , Janahmadi Mahyar , Sasanpour Pezhman
Published: January 2021

Carbon nanotubes (CNTs) coatings have been shown over the past few years as a promising material for neural interface applications. In particular, in the field of nerve implants, CNTs have fundamental advantages due to their unique mechanical and electrical properties. In this study, carbon nanotubes multi-electrode arrays (CNT-modified-Au MEAs) were fabricated based on gold multi-electrode arrays (Au-MEAs). The electrochemical impedance spectra of CNT-modified-Au MEA and Au-MEA were compared employing equivalent circuit models. In comparison with Au-MEA (17 Ω), CNT-modified-Au MEA (8 Ω) lowered the overall impedance of the electrode at 1 kHz by 50%. The results showed that CNT-modified-Au MEAs have good properties such as low impedance, high stability and durability, as well as scratch resistance, which makes them appropriate for long-term application in neural interfaces.
Molecular Mechanisms Controlling Lymphatic Endothelial Junction Integrity
Authors: Norden Pieter R. , Kume Tsutomu
Published: January 2021

The lymphatic system is essential for lipid absorption/transport from the digestive system, maintenance of tissue fluid and protein homeostasis, and immune surveillance. Despite recent progress toward understanding the cellular and molecular mechanisms underlying the formation of the lymphatic vascular system, the nature of lymphatic vessel abnormalities and disease in humans is complex and poorly understood. The mature lymphatic vasculature forms a hierarchical network in which lymphatic endothelial cells (LECs) are joined by functionally specialized cell-cell junctions to maintain the integrity of lymphatic vessels. Blind-ended and highly permeable lymphatic capillaries drain interstitial fluid via discontinuous, button-like LEC junctions, whereas collecting lymphatic vessels, surrounded by intact basement membranes and lymphatic smooth muscle cells, have continuous, zipper-like LEC junctions to transport lymph to the blood circulatory system without leakage. In this review, we discuss the recent advances in our understanding of the mechanisms by which lymphatic button- and zipper-like junctions play critical roles in lymphatic permeability and function in a tissue- and organ-specific manner, including lacteals of the small intestine. We also provide current knowledge related to key pathways and factors such as VEGF and RhoA/ROCK signaling that control lymphatic endothelial cell junctional integrity.
Flexible Teaching and Learning Modalities in Undergraduate Science Amid the COVID-19 Pandemic
Authors: Anderton Ryan S. , Vitali Julian , Blackmore Conner , Bakeberg Megan C.
Published: January 2021

Since the first case of the novel coronavirus emerged in late 2019 (COVID-19), it quickly spread beyond China, with reported cases in nearly all countries and territories. As these unprecedented times have resulted in significant social and economic disruption, educational institutions have been forced to implement alternative teaching and learning approaches, including a total transition to online learning. Given the dependence of undergraduate science units and degrees on practical and laboratory activities, students and academics are faced with significant hurdles regarding delivery, learning, and assessment. Therefore, this article considers the impact of COVID-19 and the approaches being utilized to facilitate undergraduate science learning during the evolving pandemic.
Lessons Learned From a Program to Reduce Diabetes Risk Among Low-Income Hispanic Women in a Community Health Clinic
Authors: Lindberg Nangel M. , Vega-López Sonia , LeBlanc Erin S. , Leo Michael C. , Stevens Victor J. , Gille Sara , Arias-Gastelum Mayra , Meenan Richard
Published: January 2021

Background

The Diabetes Prevention Program (DPP) and Look AHEAD studies demonstrated that modest weight loss and increased physical activity can significantly reduce the incidence of diabetes among overweight individuals with prediabetes. However, these studies involved costly interventions, all of which are beyond the reach of most real-world settings serving high-risk, low-income populations. Our project, De Por Vida, implemented a diabetes risk-reduction intervention for Hispanic women in a Federally Qualified Health Center and assessed the program’s efficacy. This report describes the methodology used to develop and implement De Por Vida, the cultural adaptations made, the community–academic partnership formed to carry out this program, and the barriers and challenges encountered through the implementation process.

Methods

Our goal was to translate the DPP and Look AHEAD programs into an intervention to prevent diabetes and reduce diabetes complications among high-risk Hispanic women at a federally qualified health center in Hillsboro, Oregon, where more than half of clinic patients are Spanish-speaking, and nearly all live in poverty. This randomized clinical trial targeted overweight Spanish-speaking women at risk for, or diagnosed with, type 2 diabetes. We developed a 12-month behavioral diabetes risk-reduction intervention that was responsive to the cultural practices of the Hispanic population and that could be implemented in low-income clinical settings. Study planning and implementation involved close collaboration among the clinic leadership, a research team from the Kaiser Permanente Center for Health Research, and Arizona State University.

Discussion

Creating a fully informed partnership between research and clinical institutions is the first step in successful cooperative research projects. The adoption of a bidirectional, rather than a top-down, approach to communication between researchers and health-care providers, and between clinic management and the clinic frontline staff, gave the research study team crucial information about barriers, constraints, and needs that clinic staff experienced in implementing the program. This allowed clinic management and front-line clinic staff to play an active role in study implementation, identifying problem areas, and collaborating in finding practical solutions.

Clinical Trial Registration

www.clinicaltrials.gov, NCT03113916.
Growth Hormone and Neuronal Hemoglobin in the Brain—Roles in Neuroprotection and Neurodegenerative Diseases
Authors: Walser Marion , Svensson Johan , Karlsson Lars , Motalleb Reza , Åberg Maria , Kuhn H Georg , Isgaard Jörgen , Åberg N David
Published: January 2021

In recent years, evidence for hemoglobin (Hb) synthesis in both animal and human brains has been accumulating. While circulating Hb originating from cerebral hemorrhage or other conditions is toxic, there is also substantial production of neuronal Hb, which is influenced by conditions such as ischemia and regulated by growth hormone (GH), insulin-like growth factor-I (IGF-I), and other growth factors. In this review, we discuss the possible functions of circulating and brain Hb, mainly the neuronal form, with respect to the neuroprotective activities of GH and IGF-I against ischemia and neurodegenerative diseases. The molecular pathways that link Hb to the GH/IGF-I system are also reviewed, although the limited number of reports on this topic suggests a need for further studies. In summary, GH and/or IGF-I appear to be significant determinants of systemic and local brain Hb concentrations through mediating responses to oxygen and metabolic demand, as part of the neuroprotective effects exerted by GH and IGF-I. The nature and quantity of the latter deserve further exploration in specific experiments.
Initial Investment in Diversity Is the Efficient Thing to Do for Resilient Forest Landscape Restoration
Authors: Nef Danny P. , Gotor Elisabetta , Wiederkehr Guerra Gabriela , Zumwald Marius , Kettle Chris J.
Published: January 2021

The genetic diversity, quality and suitability of seeds and planting stock is crucial for the short and long-term resilience of restored forest landscapes. However, these genetic aspects are widely neglected during both planning and implementation of restoration. Decisions on seed sourcing during implementation of forest landscape restoration (FLR) initiatives often prioritize short-term cost savings over long-term benefits. Such considerations result in strategies that favor rapid and cheap mass production of homogeneous plants and, thus, quantity over quality, with no regard for genetic diversity. This paper explores in detail the economic cost of improved integration of genetic diversity into restoration projects and tests the assumption that the benefits accruing from better integration of diversity exceed the costs. Using a bottom-up cost model, based on peer reviewed scientific literature, we analyse different FLR cost drivers, integrating genetic quality, in relation to the total costs of a range of tree-based restoration interventions, with a focus on seed sourcing, and tree species selection. The results indicate that the integration of genetic diversity into the management and planning of landscape restoration projects increased the costs incurred at the beginning of FLR interventions, specifically during seed sourcing, and species selection. These additional costs were largely due to the increased effort for the collection of genetically diverse and suitably adapted seed lots. However, despite this initial increase in costs the overall costs of restoration decreased substantially, due to cost savings relating to replacement costs of replanting. Even without these savings, the inclusion of genetic diversity is advisable since the costs involved in the integration of diversity are negligible compared to other restoration costs, such as labor costs related to controlling vegetative competition. We conclude that the expected long-term benefits associated with high genetic diversity far outweigh the costs. It also highlights that investing in genetic diversity as part of FLR is the smart thing to do to ensure cost effective and resilient landscape restoration. Restoration policies need to incentivise consideration of genetic diversity.
Genome-Wide Association for Itraconazole Sensitivity in Non-resistant Clinical Isolates of Aspergillus fumigatus
Authors: Zhao Shu , Ge Wenbo , Watanabe Akira , Fortwendel Jarrod R. , Gibbons John G.
Published: January 2021

Aspergillus fumigatusis a potentially lethal opportunistic pathogen that infects over ~200,000 people and causes ~100,000 deaths per year globally. TreatingA. fumigatusinfections is particularly challenging because of the recent emergence of azole-resistance. The majority of studies focusing on the molecular mechanisms underlying azole resistance have examined azole-resistant isolates. However, isolates that are susceptible to azoles also display variation in their sensitivity, presenting a unique opportunity to identify genes contributing to azole sensitivity. Here, we used genome-wide association (GWA) analysis to identify loci involved in azole sensitivity by analyzing the association between 68,853 SNPs and itraconazole (ITCZ) minimum inhibitory concentration (MIC) in 76 clinical isolates ofA. fumigatusfrom Japan. Population structure analysis suggests the presence of four distinct populations, with ITCZ MICs distributed relatively evenly across populations. We independently conducted GWA when treating ITCZ MIC as a quantitative trait and a binary trait, and identified two SNPs with strong associations in both analyses. These SNPs fell within the coding regions ofAfu2g02220andAfu2g02140. We functionally validatedAfu2g02220by knocking it out using a CRISPR/Cas9 approach, because orthologs of this gene are involved in sterol modification and ITCZ targets the ergosterol biosynthesis pathway. Knockout strains displayed no difference in growth compared to the parent strain in minimal media, yet a minor but consistent inhibition of growth in the presence of 0.15 μg/ml ITCZ. Our results suggest that GWA paired with efficient gene deletion is a powerful and unbiased strategy for identifying the genetic basis of complex traits inA. fumigatus.
RIG-I Has a Role in Immunity Against Haemonchus contortus, a Gastrointestinal Parasite in Ovis aries: A Novel Report
Authors: Banerjee Samiddha , Pal Aruna , Pal Abantika , Mandal Subhas Chandra , Chatterjee Paresh Nath , Chatterjee Jayanta Kumar
Published: January 2021

Retinoic acid inducible gene I (RIG-I) is associated to the DExD/H box RNA helicases. It is a pattern recognition receptor (PRR), playing a crucial role in the system and is a germ line encoded host sensor to perceive pathogen-associated molecular patterns (PAMPs). So far, reports are available for the role of RIG-I in antiviral immunity. This is the first report in which we have documented the role of RIG-I in parasitic immunity. Haemonchus contortus is a deadly parasite affecting the sheep industry, which has a tremendous economic importance, and the parasite is reported to be prevalent in the hot and humid agroclimatic region. We characterize the RIG-I gene in sheep (Ovis aries) and identify the important domains or binding sites with Haemonchus contortus through in silico studies. Differential mRNA expression analysis reveals upregulation of the RIG-I gene in the abomasum of infected sheep compared with that of healthy sheep, further confirming the findings. Thus, it is evident that, in infected sheep, expression of RIG-I is triggered for binding to more pathogens (Haemonchus contortus). Genetically similar studies with humans and other livestock species were conducted to reveal that sheep may be efficiently using a model organism for studying the role of RIG-I in antiparasitic immunity in humans.
Leptospiral Immunoglobulin-Like Domain Proteins: Roles in Virulence and Immunity
Authors: Haake David A. , Matsunaga James
Published: January 2021

The virulence mechanisms required for infection and evasion of immunity by pathogenic Leptospira species remain poorly understood. A number of L. interrogans surface proteins have been discovered, lying at the interface between the pathogen and host. Among these proteins, the functional properties of the Lig (leptospiral immunoglobulin-like domain) proteins have been examined most thoroughly. LigA, LigB, and LigC contain a series of, 13, 12, and 12 closely related domains, respectively, each containing a bacterial immunoglobulin (Big) -like fold. The multidomain region forms a mostly elongated structure that exposes a large surface area. Leptospires wield the Lig proteins to promote interactions with a range of specific host proteins, including those that aid evasion of innate immune mechanisms. These diverse binding events mediate adhesion of L. interrogans to the extracellular matrix, inhibit hemostasis, and inactivate key complement proteins. These interactions may help L. interrogans overcome the physical, hematological, and immunological barriers that would otherwise prevent the spirochete from establishing a systemic infection. Despite significant differences in the affinities of the LigA and LigB proteins for host targets, their functions overlap during lethal infection of hamsters; virulence is lost only when both ligA and ligB transcription is knocked down simultaneously. Lig proteins have been shown to be promising vaccine antigens through evaluation of a variety of different adjuvant strategies. This review serves to summarize current knowledge of Lig protein roles in virulence and immunity and to identify directions needed to better understand the precise functions of the Lig proteins during infection.
G Protein-Coupled Receptor 109A Maintains the Intestinal Integrity and Protects Against ETEC Mucosal Infection by Promoting IgA Secretion
Authors: Gong Yuhong , Jin Xinxin , Yuan Boyu , Lv Yantao , Yan Guangmou , Liu Mingming , Xie Changxin , Liu Juxiong , Tang Yimei , Gao Hongyan , Zhu Yufeng , Huang Yanhua , Wang Wei
Published: January 2021

Several studies have reported an intricate link between the G protein-coupled receptor 109A (GPR109A) and intestinal health. Upon activation, induced by butyric acid and β-hydroxybutyric acid, GPR109A regulates the expression of tight junction proteins, exerts anti-inflammatory effects, and maintains the integrity of the intestinal barrier. However, its function and the mechanism of action in combating the infection caused by exogenous pathogenic microorganisms remain unclear. This study established an animal model of infection by oral enterotoxigenic Escherichia coli (ETEC) gavage to examine the underlying mechanism(s) and protective effects of GPR109A on the intestinal tract. Experimental GPR109A–/–and GPR109A+/+ mice were orally administered with 1 × 109 colony-forming units (CFUs) of ETEC, and changes in body weight were then observed. The colonization and translocation of ETEC in the intestine were detected by the plate counting method. The expression of tight junction proteins and the levels of inflammatory factors and secretory IgA (SIgA) in the intestine were detected by quantitative real-time polymerase chain reaction (q-PCR), western blotting, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry. The results demonstrated that GPR109A–/–mice were more susceptible to ETEC infection, showing more severe inflammatory reactions and intestinal damage. Moreover, the secretion of IgA in the intestinal tract of GPR109A+/+ mice was significantly increased after ETEC infection, whereas the IgA levels in GPR109A–/–mice did not change significantly. We added 5 g/L sodium butyrate to the drinking water of all mice. The GPR109A+/+ mice were protected against ETEC infection and no effect was observed in GPR109A–/–mice. Similarly, sodium butyrate increased the SIgA content in the gut of the GPR109A+/+ mice and no effect was observed in GPR109A–/–mice. In conclusion, activated GPR109A is effective against the colonization and translocation of ETEC in the gut and maintains the integrity of the intestinal barrier, possibly by promoting the secretion of intestinal IgA.
Immunological Insights in Equine Recurrent Uveitis
Authors: Degroote Roxane L. , Deeg Cornelia A.
Published: January 2021

Horses worldwide suffer from equine recurrent uveitis (ERU), an organ-specific, immune-mediated disease with painful, remitting-relapsing inflammatory attacks alternating with periods of quiescence, which ultimately leads to blindness. In course of disease, both eyes can eventually be affected and since blind horses pose a threat to themselves and their surroundings, these animals have to be killed. Therefore, this disease is highly relevant for veterinary medicine. Additionally, ERU shows strong clinical and pathological resemblance to autoimmune uveitis in man. The exact cause for the onset of ERU is unclear to date. T cells are believed to be the main effector cells in this disease, as they overcome the blood retinal barrier to invade the eye, an organ physiologically devoid of peripheral immune cells. These cells cause severe intraocular inflammation, especially in their primary target, the retina. With every inflammatory episode, retinal degeneration increases until eyesight is completely lost. In ERU, T cells show an activated phenotype, with enhanced deformability and migration ability, which is reflected in the composition of their proteome and downstream interaction pathways even in quiescent stage of disease. Besides the dysregulation of adaptive immune cells, emerging evidence suggests that cells of the innate immune system may also directly contribute to ERU pathogenesis. As investigations in both the target organ and the periphery have rapidly evolved in recent years, giving new insights on pathogenesis-associated processes on cellular and molecular level, this review summarizes latest developments in ERU research.
Minor Clinical Impact of COVID-19 Pandemic on Patients With Primary Immunodeficiency in Israel
Authors: Marcus Nufar , Frizinsky Shirly , Hagin David , Ovadia Adi , Hanna Suhair , Farkash Michael , Maoz-Segal Ramit , Agmon-Levin Nancy , Broides Arnon , Nahum Amit , Rosenberg Elli , Kuperman Amir Asher , Dinur-Schejter Yael , Berkun Yackov , Toker Ori , Goldberg Shmuel , Confino-Cohen Ronit , Scheuerman Oded , Badarneh Basel , Epstein-Rigbi Na‘ama , Etzioni Amos , Dalal Ilan , Somech Raz
Published: January 2021

In the last few months the world has witnessed a global pandemic due to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection causing coronavirus disease 2019 (COVID-19). Obviously, this pandemic affected individuals differently, with a significant impact on populations considered to be at high-risk. One such population, was assumed to be patients with primary genetic defect involving components or pathways of the immune system. While human immunity against COVID-19 is not fully understood, it is, so far, well documented, that both adaptive and innate cells have a critical role in protection against SARS-CoV-2. Here, we aimed to summarize the clinical and laboratory data on primary immunodeficiency (PID) patients in Israel, who were tested positive for SARS-CoV-2, in order to estimate the impact of COVID-19 on such patients. Data was collected from mid-February to end-September. During this time Israel experienced two “waves” of COVID-19 diseases; the first, from mid-February to mid-May and the second from mid-June and still ongoing at the end of data collection. A total of 20 PID patients, aged 4 months to 60 years, were tested positive for SARS-CoV-2, all but one, were detected during the second wave. Fourteen of the patients were on routine monthly IVIG replacement therapy at the time of virus detection. None of the patients displayed severe illness and none required hospitalization; moreover, 7/20 patients were completely asymptomatic. Possible explanations for the minimal clinical impact of COVID-19 pandemic observed in our PID patients include high level of awareness, extra-precautions, and even self-isolation. It is also possible that only specific immune pathways (e.g. type I interferon signaling), may increase the risk for a more severe course of disease and these are not affected in many of the PID patients. In some cases, lack of an immune response actually may be a protective measure against the development of COVID-19 sequelae.
Partial Protection From Lupus-Like Disease by B-Cell Specific Type I Interferon Receptor Deficiency
Authors: Keller Emma J. , Patel Neeva B. , Patt Madeline , Nguyen Jane K. , Jørgensen Trine N.
Published: January 2021

Systemic lupus erythematosus (SLE) is an autoimmune disease that can present with many different permutations of symptom presentation. A large subset of SLE patients have been shown to present with elevated interferon stimulated gene (ISG) expression, and Type I IFNs (IFNαβ) have been shown to drive disease in murine models through global IFNα Receptor (IFNAR) knockouts. However, the disease contribution of distinct immune cell subsets in response to constitutively increased levels of IFNαβ is not fully understood. We utilized a B-cell specific IFNAR knockout (BΔIFNAR) on the B6.Nba2 spontaneous-lupus background to determine the contribution of IFNαβ stimulated B cells in disease. We found that IFNαβ signaling in B cells is driving increased splenomegaly, increased populations of activated B cells, and increased populations of germinal center (GC) B cells, memory B cells, and plasma blasts/cells, but did not affect the development of glomerulonephritis and immune-complex deposition. IFNAR expression by B cells also drove production of anti-chromatin IgG, and anti-dsDNA and -nRNP IgG and IgG2C auto-antibody levels, as well as increased Bcl2 expression, affecting GC B cell survival in B6.Nba2 mice.
Allogeneic CAR Cell Therapy—More Than a Pipe Dream
Authors: Caldwell Kenneth J. , Gottschalk Stephen , Talleur Aimee C.
Published: January 2021

Adoptive cellular immunotherapy using immune cells expressing chimeric antigen receptors (CARs) has shown promise, particularly for the treatment of hematological malignancies. To date, the majority of clinically evaluated CAR cell products have been derived from autologous immune cells. While this strategy can be effective it also imposes several constraints regarding logistics. This includes i) availability of center to perform leukapheresis, ii) necessity for shipment to and from processing centers, and iii) time requirements for product manufacture and clinical release testing. In addition, previous cytotoxic therapies can negatively impact the effector function of autologous immune cells, which may then affect efficacy and/or durability of resultant CAR products. The use of allogeneic CAR cell products generated using cells from healthy donors has the potential to overcome many of these limitations, including through generation of “off the shelf” products. However, allogeneic CAR cell products come with their own challenges, including potential to induce graft-versus-host-disease, as well as risk of immune-mediated rejection by the host. Here we will review promises and challenges of allogeneic CAR immunotherapies, including those being investigated in preclinical models and/or early phase clinical studies.
Inhibition of Biofilm Formation and Related Gene Expression of Listeria monocytogenes in Response to Four Natural Antimicrobial Compounds and Sodium Hypochlorite
Authors: Liu Yunge , Wu Lina , Han Jina , Dong Pengcheng , Luo Xin , Zhang Yimin , Zhu Lixian
Published: January 2021

The aim of this study was to assess the efficacy of four natural antimicrobial compounds (cinnamaldehyde, eugenol, resveratrol and thymoquinone) plus a control chemical disinfectant (sodium hypochlorite) in inhibiting biofilm formation by Listeria monocytogenes CMCC54004 (Lm 54004) at a minimum inhibitory concentration (MIC) and sub-MICs. Crystal violet staining assay and microscopic examination were employed to investigate anti-biofilm effects of the evaluated compounds, and a real-time PCR assay was used to investigate the expression of critical genes by Lm 54004 biofilm. The results showed that five antimicrobial compounds inhibited Lm 54004 biofilm formation in a dose dependent way. Specifically, cinnamaldehyde and resveratrol showed better anti-biofilm effects at 1/4 × MIC, while sodium hypochlorite exhibited the lowest inhibitory rates. A swimming assay confirmed that natural compounds at sub-MICs suppressed Lm 54004 motility to a low degree. Supporting these findings, expression analysis showed that all four natural compounds at 1/4 × MIC significantly down-regulated quorum sensing genes (agrA, agrC, and agrD) rather than suppressing the motility- and flagella-associated genes (degU, motB, and flaA). This study revealed that sub-MICs of natural antimicrobial compounds reduced biofilm formation by suppressing the quorum sensing system rather than by inhibiting flagella formation.
Rapid Structural Analysis of a Synthetic Non-canonical Amino Acid by Microcrystal Electron Diffraction
Authors: Gleason Patrick R. , Nannenga Brent L. , Mills Jeremy H.
Published: January 2021

Structural characterization of small molecules is a crucial component of organic synthesis. In this work, we applied microcrystal electron diffraction (MicroED) to analyze the structure of the product of an enzymatic reaction that was intended to produce the unnatural amino acid 2,4-dihydroxyphenylalanine (24DHF). Characterization of our isolated product with nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS) suggested that an isomer of 24DHF had been formed. Microcrystals present in the isolated product were then used to determine its structure to 0.62 Å resolution, which confirmed its identity as 2-amino-2-(2,4-dihydroxyphenyl)propanoic acid (24DHPA). Moreover, the MicroED structural model indicated that both enantiomeric forms of 24DHPA were present in the asymmetric unit. Notably, the entire structure determination process including setup, data collection, and refinement was completed in ~1 h. The MicroED data not only bolstered previous results obtained using NMR and MS but also immediately provided information about the stereoisomers present in the product, which is difficult to achieve using NMR and MS alone. Our results therefore demonstrate that MicroED methods can provide useful structural information on timescales that are similar to many commonly used analytical methods and can be added to the existing suite of small molecule structure determination tools in future studies.
Repetitive Transcranial Magnetic Stimulation for Improving Cognitive Function in Patients With Mild Cognitive Impairment: A Systematic Review
Authors: Jiang Lijuan , Cui Huiru , Zhang Caidi , Cao Xinyi , Gu Nannan , Zhu Yikang , Wang Jijun , Yang Zhi , Li Chunbo
Published: January 2021

Background: Mild cognitive impairment (MCI) is an early stage of Alzheimer's disease. Repetitive transcranial magnetic stimulation (rTMS) has been widely employed in MCI research. However, there is no reliable systematic evidence regarding the effects of rTMS on MCI. The aim of this review was to evaluate the efficacy and safety of rTMS in the treatment of MCI.

Methods: A comprehensive literature search of nine electronic databases was performed to identify articles published in English or Chinese before June 20, 2019. The identified articles were screened, data were extracted, and the methodological quality of the included trials was assessed. The meta-analysis was performed using the RevMan 5.3 software. We used the GRADE approach to rate the quality of the evidence.

Results: Nine studies comprising 369 patients were included. The meta-analysis showed that rTMS may significantly improve global cognitive function (standardized mean difference [SMD] 2.09, 95% confidence interval [CI] 0.94 to 3.24, p = 0.0004, seven studies, n = 296; low-quality evidence) and memory (SMD 0.44, 95% CI 0.16 to 0.72, p = 0.002, six studies, n = 204; moderate-quality evidence). However, there was no significant improvement in executive function and attention (p > 0.05). Subgroup analyses revealed the following: (1) rTMS targeting the left hemisphere significantly enhanced global cognitive function, while rTMS targeting the bilateral hemispheres significantly enhanced global cognitive function and memory; (2) high-frequency rTMS significantly enhanced global cognitive function and memory; and (3) a high number of treatments ≥20 times could improve global cognitive function and memory. There was no significant difference in dropout rate (p > 0.05) between the rTMS and control groups. However, patients who received rTMS had a higher rate of mild adverse effects (risk ratio 2.03, 95% CI 1.16 to 3.52, p = 0.01, seven studies, n = 317; moderate-quality evidence).

Conclusions: rTMS appears to improve global cognitive function and memory in patients with MCI and may have good acceptability and mild adverse effects. Nevertheless, these results should be interpreted cautiously due to the relatively small number of trials, particularly for low-frequency rTMS.
What Is the “Optimal” Target Mismatch Criteria for Acute Ischemic Stroke?
Authors: Chen Chushuang , Parsons Mark W. , Levi Christopher R. , Spratt Neil J. , Lin Longting , Kleinig Timothy , Butcher Kenneth , Cheng Xin , Dong Qiang , O'Brien Billy , Avivi Richard I. , Krause Martin , Sylaja P. N. , Choi Philip , Bhuta Sandeep , Yin Congguo , Yang Jianhong , Wang Peng , Qiu Weiwen , Bivard Andrew
Published: January 2021

We aimed to compare Perfusion Imaging Mismatch (PIM) and Clinical Core Mismatch (CCM) criteria in ischemic stroke patients to identify the effect of these criteria on selected patient population characteristics and clinical outcomes. Patients from the INternational Stroke Perfusion Imaging REgistry (INSPIRE) who received reperfusion therapy, had pre-treatment multimodal CT, 24-h imaging, and 3 month outcomes were analyzed. Patients were divided into 3 cohorts: endovascular thrombectomy (EVT), intravenous thrombolysis alone with large vessel occlusion (IVT-LVO), and intravenous thrombolysis alone without LVO (IVT-nonLVO). Patients were classified using 6 separate mismatch criteria: PIM-using 3 different measures to define the perfusion deficit (Delay Time, Tmax, or Mean Transit Time); or CCM-mismatch between age-adjusted National Institutes of Health Stroke Scale and CT Perfusion core, defined as relative cerebral blood flow <30% within the perfusion deficit defined in three ways (as above). We assessed the eligibility rate for each mismatch criterion and its ability to identify patients likely to respond to treatment. There were 994 patients eligible for this study. PIM with delay time (PIM-DT) had the highest inclusion rate for both EVT (82.7%) and IVT-LVO (79.5%) cohorts. In PIM positive patients who received EVT, recanalization was strongly associated with achieving an excellent outcome at 90-days (e.g., PIM-DT: mRS 0-1, adjusted OR 4.27, P = 0.005), whereas there was no such association between reperfusion and an excellent outcome with any of the CCM criteria (all p > 0.05). Notably, in IVT-LVO cohort, 58.2% of the PIM-DT positive patients achieved an excellent outcome compared with 31.0% in non-mismatch patients following successful recanalization (P = 0.006).

Conclusion: PIM-DT was the optimal mismatch criterion in large vessel occlusion patients, combining a high eligibility rate with better clinical response to reperfusion. No mismatch criterion was useful to identify patients who are most likely response to reperfusion in non-large vessel occlusion patients.
The European Reference Network for Rare Neurological Diseases
Authors: Reinhard Carola , Bachoud-Lévi Anne-Catherine , Bäumer Tobias , Bertini Enrico , Brunelle Alicia , Buizer Annemieke I. , Federico Antonio , Gasser Thomas , Groeschel Samuel , Hermanns Sanja , Klockgether Thomas , Krägeloh-Mann Ingeborg , Landwehrmeyer G. Bernhard , Leber Isabelle , Macaya Alfons , Mariotti Caterina , Meissner Wassilios G. , Molnar Maria Judit , Nonnekes Jorik , Ortigoza Escobar Juan Dario , Pérez Dueñas Belen , Renna Linton Lori , Schöls Ludger , Schuele Rebecca , Tijssen Marina A. J. , Vandenberghe Rik , Volkmer Anna , Wolf Nicole I. , Graessner Holm
Published: January 2021

While rare diseases (RDs) are by definition of low prevalence, the total number of patients suffering from an RD is high, and the majority of them have neurologic manifestations, involving central, peripheral nerve, and muscle. In 2017, 24 European Reference Networks (ERNs), each focusing on a specific group of rare or low-prevalence complex diseases, were formed to improve the care for patients with an RD. One major aim is to have “the knowledge travel instead of the patient,” which has been put into practice by the implementation of the Clinical Patient Management System (CPMS) that enables clinicians to perform pan-European virtual consultations. The European Reference Network for Rare Neurological Diseases (ERN-RND) provides an infrastructure for knowledge sharing and care coordination for patients affected by a rare neurological disease (RND) involving the most common central nervous system pathological conditions. It covers the following disease groups: (i) Cerebellar Ataxias and Hereditary Spastic Paraplegias; (ii) Huntington's disease and Other Choreas; (iii) Frontotemporal dementia; (iv) Dystonia, (non-epileptic) paroxysmal disorders, and Neurodegeneration with Brain Iron Accumulation; (v) Leukoencephalopathies; and (vi) Atypical Parkinsonian Syndromes. At the moment, it unites 32 expert centers and 10 affiliated partners in 21 European countries, as well as patient representatives, but will soon cover nearly all countries of the European Union as a result of the ongoing expansion process. Disease expert groups developed and consented on diagnostic flowcharts and disease scales to assess the different aspects of RNDs. ERN-RND has started to discuss diagnostically unclear patients in the CPMS, is one of four ERNs that serve as foundation of Solve-RD, and has established an RND training and education program. The network will facilitate trial readiness through the establishment of an ERN-RND registry with a minimal data of all patients seen at the ERN-RND centers, thus providing a unique overview of existing genotype-based cohorts. The overall aim of the ERNs is to improve access for patients with RDs to quality diagnosis, care, and treatment. Based on this objective, ERNs are monitored by the European Commission on a regular basis to provide transparency and reassurance to the RD community and the general public.
Methamphetamine Inhibits Long-Term Memory Acquisition and Synaptic Plasticity by Evoking Endoplasmic Reticulum Stress
Authors: Chen Guang , Wei Xiaoning , Xu Xiang , Yu Gang , Yong Zheng , Su Ruibin , Tao Luyang
Published: January 2021

Methamphetamine (MA), an illicit drug abused worldwide, leads to cognitive impairment and memory loss. However, the detailed mechanisms of MA-induced neurologic impairment are still unclear. The present study aimed to investigate the mechanisms of MA-induced inhibition of memory acquisition from the perspective of endoplasmic reticulum (ER) stress. ER stress, caused by the accumulation of wrongly folded proteins in the ER, is important for new protein synthesis, which further influence the formation of long-term memory. A subacute MA poisoning model of mice was established and several behavioral experiments were performed, including elevated plus maze, Morris water maze, electro-stimulus Y-maze, and novel object recognition tasks. The present results suggested that 4 days exposure to MA induced significant memory loss. Whereas, this damage to memory formation could be protected when mice were pre-treated with ER stress inhibitor, tauroursodeoxycholic acid (TUDCA). The results of Western blotting showed that subacute exposure to MA increased the expression levels of ER stress marker proteins, such as binding immunoglobulin protein, phosphorylated eukaryotic translation initiation factor 2α, cyclic AMP-dependent transcription factor (ATF)-4, ATF-6, and CCAAT-enhancer binding protein homologous protein. Meanwhile, the enhanced expression levels of these proteins were reversed by TUDCA, indicating that MA administration induced memory loss by evoking ER stress in the hippocampus. We also found that MA inhibited the induction of long-term potentiation (LTP) in the hippocampus. Nevertheless, LTP could be induced when mice were pre-treated with TUDCA. In conclusion, MA inhibited long-term memory acquisition and synaptic plasticity via ER stress.
Downregulation of miR-146b-3p Inhibits Proliferation and Migration and Modulates the Expression and Location of Sodium/Iodide Symporter in Dedifferentiated Thyroid Cancer by Potentially Targeting MUC20
Authors: Hou Shasha , Xie Xiaorui , Zhao Jing , Wu Cailan , Li Ning , Meng Zhaowei , Cai Chunquan , Tan Jian
Published: January 2021

The dedifferentiation of differentiated thyroid cancer (DTC) is a challenging problem for radioactive iodine (131I) treatment, also known as radioiodine refractory differentiated thyroid cancer (RAIR-DTC). The purpose of this study was to further explore the mechanism of the redifferentiation of dedifferentiated thyroid cancer. Ineffective and effective groups of 131I therapy were analyzed and compared in both our clinical and TCGA samples. Whole-exome sequencing, mutation analysis, transcriptome analysis, and in vitro functional experiments were conducted. FLG, FRG1, MUC6, MUC20, and PRUNE2 were overlapping mutation genes between our clinical cases, and the TCGA cases only appeared in the ineffective group. The expression of miR-146b-3p target MUC20 was explored. The expression levels of miR-146b-3p and MUC20 were significantly increased, and the inhibition of miR-146b-3p expression significantly inhibited proliferation and migration, promoted apoptosis, regulated the expression and location of thyroid differentiation-related genes, and sodium/iodide symporter (NIS) in dedifferentiated thyroid cancer cells (WRO). Thus, miR-146b-3p potentially targets MUC20 participation in the formation of DTC dedifferentiation, resulting in resistance to 131I and the loss of the iodine uptake ability of DTC cancer foci, promoting refractory differentiated thyroid cancer. miR-146b-3p may be a potentially therapeutic target for the reapplication of 131I therapy in dedifferentiated thyroid cancer patients.
Staging for Breast Cancer With Internal Mammary Lymph Nodes Metastasis: Utility of Incorporating Biologic Factors
Authors: Lian Chen-Lu , Zhang Hai-Yan , Wang Jun , Lei Jian , Hua Li , Chen Yong-Xiong , Wu San-Gang
Published: January 2021

Purpose

To validate the 8th edition of the American Joint Committee on Cancer (AJCC) pathological prognostic staging system for breast cancer patients with internal mammary lymph nodes (IMN) metastasis (N3b disease, stage IIIC in 7th AJCC anatomical staging).

Methods

Breast cancer patients with IMN metastasis diagnosed between 2010 and 2014 were retrieved from the Surveillance, Epidemiology, and End Results program. Chi-squared test, Log-rank test, Kaplan-Meier method, and Cox proportional hazard analysis were applied to statistical analysis.

Results

We included 678 patients with N3b disease in this study. Overall, 68.4% of patients were downstaged to IIIA and IIIB diseases from the 7th anatomical staging to 8th pathological prognostic staging. The new pathological prognostic staging system had better discriminatory value on prognosis prediction among IMN-metastasized breast cancer patients, with a 5-year breast cancer-specific survival (BCSS) of 92.7, 77.4, and 66.0% in stage IIIA, IIIB, and IIIC diseases, respectively (P<0.0001), and the 5-year overall survival (OS) rates was 85.9, 72.1, and 58.7%, respectively (P<0.0001). The results of the multivariate prognostic analysis showed that the new pathological prognostic staging was the independent prognosis related to BCSS and OS, the 8th AJCC pathological prognostic stages showed worse BCSS and OS with gradually increased hazard ratios.

Conclusion

The 8th AJCC pathological prognostic staging system offers more refined prognostic stratification to IMN-metastasized breast cancer patients and endorses its use in routine clinical practice for this specific subgroup of breast cancer.