bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimizing a Multi-Component Intranasal Entamoeba Histolytica Vaccine Formulation Using a Design of Experiments Strategy
Authors: Abhyankar Mayuresh M. , Orr Mark T. , Kinsey Robert , Sivananthan Sandra , Nafziger Andrew J. , Oakland David N. , Young Mary K. , Farr Laura , Uddin Md Jashim , Leslie Jhansi L. , Burgess Stacey L. , Liang Hong , De Lima Ines , Larson Elise , Guderian Jeffrey A. , Lin Susan , Kahn Aaron , Ghosh Prakash , Reed Sierra , Tomai Mark A. , Pedersen Karl , Petri William A. , Fox Christopher B.
Published: June 2021

Amebiasis is a neglected tropical disease caused by Entamoeba histolytica. Although the disease burden varies geographically, amebiasis is estimated to account for some 55,000 deaths and millions of infections globally per year. Children and travelers are among the groups with the greatest risk of infection. There are currently no licensed vaccines for prevention of amebiasis, although key immune correlates for protection have been proposed from observational studies in humans. We previously described the development of a liposomal adjuvant formulation containing two synthetic TLR ligands (GLA and 3M-052) that enhanced antigen-specific fecal IgA, serum IgG2a, a mixed IFNγ and IL-17A cytokine profile from splenocytes, and protective efficacy following intranasal administration with the LecA antigen. By applying a statistical design of experiments (DOE) and desirability function approach, we now describe the optimization of the dose of each vaccine formulation component (LecA, GLA, 3M-052, and liposome) as well as the excipient composition (acyl chain length and saturation; PEGylated lipid:phospholipid ratio; and presence of antioxidant, tonicity, or viscosity agents) to maximize desired immunogenicity characteristics while maintaining physicochemical stability. This DOE/desirability index approach led to the identification of a lead candidate composition that demonstrated immune response durability and protective efficacy in the mouse model, as well as an assessment of the impact of each active vaccine formulation component on protection. Thus, we demonstrate that both GLA and 3M-052 are required for statistically significant protective efficacy. We also show that immunogenicity and efficacy results differ in female vs male mice, and the differences appear to be at least partly associated with adjuvant formulation composition.
Approach to the Functional Importance of Acropora cervicornis in Outplanting Sites in the Dominican Republic
Authors: Calle-Triviño Johanna , Muñiz-Castillo Aarón Israel , Cortés-Useche Camilo , Morikawa Megan , Sellares-Blasco Rita , Arias-González Jesús Ernesto
Published: June 2021

Coral restoration has been recognized as an increasingly important tool for coral conservation in recent years. In the Caribbean, the endangered staghorn coral, Acropora cervicornis has been studied for restoration for over two decades with most studies focusing on evaluating simple metrics of success such as colony growth and survivorship in both nurseries and outplanted sites. However, for reef restoration to aid in the recovery of ecological function in outplanted sites, there is a need to measure the functional ecology of the impact of outplanting. Here, we present and identify positive ecological processes and ecological functions (such as increased fish biomass, coral cover, and increased in structural complexity) relative to active reef restoration. In the Southeastern Reefs Marine Sanctuary in the Dominican Republic, we monitored the percentage of benthic cover and fish biomass alongside active reef restoration over the period of 12 months in four zones. Subsequently, we developed multidimensional analyses in conjunction with generalized linear models (GLM) and linear models. Our results show there is a remarkable spatial and temporal differentiation favoring greater ecological function in restored areas. We observed the most noticeable patterns of change in the benthos and coral species composition. We found a positive relationship between amounts of outplanted colonies with the total fish biomass for the three outplanted sites. We highlight that Scarus iseri, a parrotfish critical for grazing maintenance, was the species with the greatest benefit. Our results provide evidence of the functional importance of Acropora cervicornis in coral reef active restoration efforts.
Research on the Homogenized Postirradiation Elastoplastic Constitutive Relations for Composite Nuclear Fuels
Authors: Zhang Jing , Zhang Jingyu , Wang Haoyu , Wei Hongyang , Tang Changbing , Lu Chuan , Ding Shurong , Li Yuanming
Published: June 2021

A multi-scale finite element method is developed to simulate the irradiation process and postirradiation uniaxial tensile tests for metal-matrix composite fuels with representative volume elements (RVEs). The simulations of irradiation process are implemented under a wide range of burnup levels, with the irradiation effects on the mechanical constitutive relations of fuel particles and matrix taken into account comprehensively. The simulation results for the macroscopic postirradiation true stress/strain curves are obtained, excluding the irradiation-induced macroscopic deformations. The effects of particle fission density, temperature, and initial particle volume fraction are investigated and analyzed. The research results indicate that 1) a quasi-elastic stage appears during the postirradiation tension, which is mainly induced by the creation of high residual compressive stresses in the particles and matrix after irradiation; 2) with the increase of effective strains, new plastic deformations increase in the particles and matrix to result in the macroscale plastic stage; 3) the macroscale irradiation softening and hardening phenomena appear, which mainly stem from the weakened deformation resistance by the irradiation-induced plastic deformations in the matrix, the enlarged particle volume fraction after irradiation, and the irradiation hardening effects of metal matrix.
Endometriosis and New-Onset Coronary Artery Disease in Taiwan: A Nationwide Population-Based Study
Authors: Wei Chun-Hui , Chang Renin , Wan Yu Hsun , Hung Yao-Min , Wei James Cheng-Chung
Published: June 2021

Endometriosis (EM) with chronic inflammation may accelerate the progression of atherosclerosis. Currently, no large or randomized clinical studies have assessed the incidence of cardiovascular events in patients with endometriosis in Asia to investigate whether incident EM is associated with a higher risk of new-onset coronary artery disease (CAD). In this study of a nationwide cohort in Taiwan, we identified 13,988 patients with newly diagnosed EM from 1 January, 2000, through 31 December, 2012. EM and non-EM groups were matched by propensity score at a ratio of 1:1. Of a total 27,976 participants, 358 developed CAD. The incidence rate in the EM group was higher than that in the non-EM group (1.8 per 1,000 person-years vs. 1.3 per 1,000 person-years) during the follow-up period. The adjusted hazard ratio (aHR) of CAD for the EM group was 1.52 with a 95% confidence interval (1.23–1.87, p < 0.001) after adjusting for demographic characteristics, comorbidities, surgical procedures, frequency of outpatient visits, and medications. Stratified analysis revealed that, among four age groups (20–39, 40–49, 50–54, and above 55 years), the 20–39 years sub-group was associated with a higher risk of CAD (aHR, 1.73; 95% CI, 1.16–2.59, p = 0.008). Several sensitivity analyses were conducted for cross-validation, and it showed consistent positive findings. In conclusion, this cohort study revealed that patients with symptomatic EM in Taiwan were associated with increased risk of subsequent CAD than patients without medical records of EM. Further prospective studies are needed to confirm this causal relationship.
Bacitracin Methylene Disalicylate Improves Intestinal Health by Modulating Its Development and Microbiota in Weaned Rabbits
Authors: Chen Yang , Hu Shuaishuai , Li Jiali , Zhao Bohao , Yang Naisu , Zhou Tong , Liang Shuang , Bai Shaocheng , Wu Xinsheng
Published: June 2021

Intestinal infections are a major cause of morbidity and mortality in humans and agricultural animals, especially newborns and weaned animals. Preventive treatments that help weaned animals maintain homeostasis and balance the hindgut microbial populations are desirable. The present study aimed to explore the impact of bacitracin methylene disalicylate (BMD) on the intestinal health by analyzing the intestinal environment, morphology, expression of peptidoglycan recognition proteins (PGRPs), and flora of weaned rabbits. A total of 300 New Zealand weaned rabbits were randomly divided into the following five treatment groups for a 35-day feed trial: control group (basal diet), bacitracin zinc (BZ) group (50 mg/kg BZ), BMDa group (100 mg/kg BMD), BMDb group (50 mg/kg BMD), and BMDc group (rabbits fed a basal diet supplemented with 25 mg/kg BMD). In each treatment group, 28 rabbits were slaughtered for experimental analysis. The results showed that the supplementation of BMD increased the environmental acidity of the cecum of the weaned rabbits and reduced the ammonia-nitrogen concentration, which was beneficial to the survival of useful bacteria in the intestine. The morphology analysis of the duodenum using hematoxylin and eosin staining revealed that the villus length, villus/crypt ratio, and intestinal wall thickness increased in the BMD group, thereby improving the structure of the duodenum and the absorption capacity of the small intestine. Moreover, real-time polymerase chain reaction test showed that PGRPs (especially PGLYRP-1 and PGLYRP-2) in the intestinal had an antagonistic effect with BMD in the process of inhibiting pathogenic bacteria, resulting in their decreased expression (P < 0.05). Furthermore, through 16S rRNA sequencing in the cecal content, the abundance of the predominant phyla in the BMDa and BZ groups was found to be the closest. The abundance of the genera Lachnospira, Erysipelotrichaceae (p-75-a5), Paraprevotellaceae (YRC22), Mogibacterium, Peptococcaceae (rc4-4), Anaerovibrio, Succinivibrio, and Sphaerochaeta increased in the BMDa and BZ groups (P < 0.05). The relative abundance of Alistipes, Sedimentibacter, and Dorea significantly increased only in the BMDa group (P < 0.05). Conclusively, BMD, as well as microbes, improved the intestinal environment and structure to maintain the intestinal health of weaned rabbits.
Tissue Type: A Crucial Factor Influencing the Fungal Diversity and Communities in Sichuan Pork Bacon
Authors: Zhang Miao , Qiao Haijun , Zhang Weibing , Zhang Zhongming , Wen Pengchen , Zhu Yan
Published: June 2021

This study aimed to the variations of fungal diversity and community structure in different parts of traditional homemade Sichuan pork bacon. A total of seven phyla and 91 fungal genera were identified. Among them, Ascomycota and Basidiomycota were the first and second most abundant phyla in the bacon tissues. In addition, five dominant genera (Aspergillus, Candida, Debaryomyces, Malassezia, and Penicillium) were shared by all bacon tissues. The numbers of OTUs unique to individual groups were 14, 67, and 65 for the muscle tissue, the adipose tissue, and pork skin, respectively. Linear discriminant analysis showed that a total of 31 taxa significantly differed among the groups. Results of redundancy analysis indicated that fat content, protein content, aw, and pH of bacon tissue shaped the bacon fungal communities. Results of network analysis also indicated that tissue type was a crucial factor influencing the fungal interactions in different tissues. This study can lay a foundation for further isolation and identification of fungi in the product and provides a basis for further research of food health in homemade traditional pork bacon.
Microbial Community Succession and Metabolite Changes During Fermentation of BS Sufu, the Fermented Black Soybean Curd by Rhizopus microsporus, Rhizopus oryzae, and Actinomucor elegans
Authors: Yao Di , Xu Lei , Wu Mengna , Wang Xiaoyu , Wang Kun , Li Zhijiang , Zhang Dongjie
Published: June 2021

BS Sufu is a fermented food that is made by mixed black soybeans and soybeans. Microbial communities and metabolites play an important role for the final product. We characterized microbial diversity of BS Sufu during fermentation by high-throughput DNA sequencing. Meanwhile, volatile compounds were investigated by solid-phase microextraction (SPME) coupled with gas chromatography–mass spectrometry (GC-MS). The results showed that bacterial diversity was higher than that of fungi in BS Sufu. We found the existence of bacterial and fungal core communities, including Enterococcus, Enterobacter, Rhizopus, and Monascus. Network analysis indicated that bacterial and fungal communities maintain positive and negative interactions, which are important to shape the resident microbial communities in Sufu. In addition, 17 free amino acids (FAAs) were detected at the post-fermentation stage, and umami amino acid mainly contributed to taste of BS Sufu. Furtherly, a total of 79 volatile constituents in BS Sufu, including nine alcohols, 31 esters, and four aldehydes, form synergistically the unique odor of Sufu. Additionally, the correlations between microbiota and metabolites were analyzed. Our results suggested that these microbial taxa and metabolites contribute to the taste and flavor of BS Sufu. This study provided information for analysis of BS Sufu at different fermentation periods in terms of the microbial diversity and metabolites, and this information was important to understand the properties of mixed soybeans Sufu.
Outbreaks of Root Rot Disease in Different Aged American Ginseng Plants Are Associated With Field Microbial Dynamics
Authors: Ji Li , Nasir Fahad , Tian Lei , Chang Jingjing , Sun Yu , Zhang Jianfeng , Li Xiujun , Tian Chunjie
Published: June 2021

American ginseng (Panax quinquefoliumL.) is a perennial plant that is cultivated for medicinal purposes. Unfortunately, outbreaks of root rot disease in American ginseng (AG) reduce yields and result in serious economic losses. Information on the dynamics of soil microbial communities associated with healthy and diseased AG of different ages is limited. The present study explored the differences in field soil microbial community structure, composition, interaction, and their predictive functions associated with healthy and diseased AG at different growth ages. Changes in soil physicochemical properties were also examined to determine the possible reasons for disease outbreaks. Results revealed that in different growth years, the genera of soil-borne pathogens, such asAlternaria,Botrytis,Cladosporium,Sarocladium, andFusarium, were increased in diseased AG soil samples in comparison with those in the healthy AG soil samples. In contrast, the abundance of some key and potentially beneficial microbes, such asBacillus,Chaetomium,Dyella,Kaistobacter,Paenibacillus,Penicillium, andTrichoderma, was decreased. Additionally, as AG plants age, the relative abundance of symbiotic fungi tended to decrease, while the relative abundance of potential plant pathogenic fungi gradually increased. Various soil properties, such as available phosphorus, the ratio of total nitrogen to total phosphorus (N/P), and pH, were significantly (P< 0.05) associated with microbial community composition. Our findings provide a scientific basis for understanding the relationship among the root rot disease outbreaks in American ginseng as well as their corresponding soil microbial communities and soil physicochemical properties.
A Master Regulator BrpR Coordinates the Expression of Multiple Loci for Robust Biofilm and Rugose Colony Development in Vibrio vulnificus
Authors: Hwang Seung-Ho , Im Hanhyeok , Choi Sang Ho
Published: June 2021

Vibrio vulnificus, a fulminating human pathogen, forms biofilms to enhance its survival in nature and pathogenicity during host infection. BrpR is the transcriptional regulator governing robust biofilm and rugose colony formation in V. vulnificus, but little is known about both the direct regulon of BrpR and the role of BrpR in regulation of downstream genes. In this study, transcript analyses revealed that BrpR is highly expressed and thus strongly regulates the downstream gene in the stationary and elevated cyclic di-GMP conditions. Transcriptome analyses discovered the genes, whose expression is affected by BrpR but not by the downstream regulator BrpT. Two unnamed adjacent genes (VV2_1626-1627) were newly identified among the BrpR regulon and designated as brpL and brpG in this study. Genetic analyses showed that the deletion of brpL and brpG impairs the biofilm and rugose colony formation, indicating that brpLG plays a crucial role in the development of BrpR-regulated biofilm phenotypes. Comparison of the colony morphology and exopolysaccharide (EPS) production suggested that although the genetic location and regulation of brpLG are distinct from the brp locus, brpABCDFHIJK (VV2_1574-1582), brpLG is also responsible for the robust EPS production together with the brp locus genes. Electrophoretic mobility shift assays and DNase I protection assays demonstrated that BrpR regulates the expression of downstream genes in distinct loci by directly binding to their upstream regions, revealing a palindromic binding sequence. Altogether, this study suggests that BrpR is a master regulator coordinating the expression of multiple loci responsible for EPS production and thus, contributing to the robust biofilm and rugose colony formation of V. vulnificus.
Roseobacters in a Sea of Poly- and Paraphyly: Whole Genome-Based Taxonomy of the Family Rhodobacteraceae and the Proposal for the Split of the “Roseobacter Clade” Into a Novel Family, Roseobacteraceae fam. nov.
Authors: Liang Kevin Y. H. , Orata Fabini D. , Boucher Yann F. , Case Rebecca J.
Published: June 2021

The family Rhodobacteraceae consists of alphaproteobacteria that are metabolically, phenotypically, and ecologically diverse. It includes the roseobacter clade, an informal designation, representing one of the most abundant groups of marine bacteria. The rapid pace of discovery of novel roseobacters in the last three decades meant that the best practice for taxonomic classification, a polyphasic approach utilizing phenotypic, genotypic, and phylogenetic characteristics, was not always followed. Early efforts for classification relied heavily on 16S rRNA gene sequence similarity and resulted in numerous taxonomic inconsistencies, with several poly- and paraphyletic genera within this family. Next-generation sequencing technologies have allowed whole-genome sequences to be obtained for most type strains, making a revision of their taxonomy possible. In this study, we performed whole-genome phylogenetic and genotypic analyses combined with a meta-analysis of phenotypic data to review taxonomic classifications of 331 type strains (under 119 genera) within the Rhodobacteraceae family. Representatives of the roseobacter clade not only have different environmental adaptions from other Rhodobacteraceae isolates but were also found to be distinct based on genomic, phylogenetic, and in silico-predicted phenotypic data. As such, we propose to move this group of bacteria into a new family, Roseobacteraceae fam. nov. In total, reclassifications resulted to 327 species and 128 genera, suggesting that misidentification is more problematic at the genus than species level. By resolving taxonomic inconsistencies of type strains within this family, we have established a set of coherent criteria based on whole-genome-based analyses that will help guide future taxonomic efforts and prevent the propagation of errors.
A Case of Intragenic Recombination Dramatically Impacting the Phage WO Genetic Diversity in Gall Wasps
Authors: Zhu Dao-Hong , Su Cheng-Yuan , Yang Xiao-Hui , Abe Yoshihisa
Published: June 2021

The phage WO was characterized in Wolbachia, a strictly intracellular bacterium causing several reproductive alterations in its arthropod hosts. This study aimed to screen the presence of Wolbachia and phage WO in 15 gall wasp species from six provinces of southern China to investigate their diversity and prevalence patterns. A high incidence of Wolbachia infection was determined in the gall wasp species, with an infection rate of 86.7% (13/15). Moreover, seven species had double or multiple infections. All Wolbachia-infected gall wasp species were found to harbor phage WO. The gall wasp species infected with a single Wolbachia strain were found to harbor a single phage WO type. On the contrary, almost all species with double or multiple Wolbachia infections harbored a high level of phage WO diversity (ranging from three to 27 types). Six horizontal transfer events of phage WO in Wolbachia were found to be associated with gall wasps, which shared identical orf7 sequences among their respective accomplices. The transfer potentially took place through gall inducers and associated inquilines infected with or without Wolbachia. Furthermore, 10 putative recombination events were identified from Andricus hakonensis and Andricus sp2, which harbored multiple phage WO types, suggesting that intragenic recombination was the important evolutionary force, which effectively promoted the high level of phage WO diversity associated with gall wasps.
In vitro Characterization of Fitness and Convalescent Antibody Neutralization of SARS-CoV-2 Cluster 5 Variant Emerging in Mink at Danish Farms
Authors: Lassaunière Ria , Fonager Jannik , Rasmussen Morten , Frische Anders , Polacek Charlotta , Rasmussen Thomas Bruun , Lohse Louise , Belsham Graham J. , Underwood Alexander , Winckelmann Anni Assing , Bollerup Signe , Bukh Jens , Weis Nina , Sækmose Susanne Gjørup , Aagaard Bitten , Alfaro-Núñez Alonzo , Mølbak Kåre , Bøtner Anette , Fomsgaard Anders
Published: June 2021

In addition to humans, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can transmit to animals that include hamsters, cats, dogs, mink, ferrets, tigers, lions, cynomolgus macaques, rhesus macaques, and treeshrew. Among these, mink are particularly susceptible. Indeed, 10 countries in Europe and North America reported SARS-CoV-2 infection among mink on fur farms. In Denmark, SARS-CoV-2 spread rapidly among mink farms and spilled-over back into humans, acquiring mutations/deletions with unknown consequences for virulence and antigenicity. Here we describe a mink-associated SARS-CoV-2 variant (Cluster 5) characterized by 11 amino acid substitutions and four amino acid deletions relative to Wuhan-Hu-1. Temporal virus titration, together with genomic and subgenomic viral RNA quantitation, demonstrated a modest in vitro fitness attenuation of the Cluster 5 virus in the Vero-E6 cell line. Potential alterations in antigenicity conferred by amino acid changes in the spike protein that include three substitutions (Y453F, I692V, and M1229I) and a loss of two amino acid residues 69 and 70 (ΔH69/V70), were evaluated in a virus microneutralization assay. Compared to a reference strain, the Cluster 5 variant showed reduced neutralization in a proportion of convalescent human COVID-19 samples. The findings underscore the need for active surveillance SARS-CoV-2 infection and virus evolution in susceptible animal hosts.
Circular RNA TLK1 Promotes Sepsis-Associated Acute Kidney Injury by Regulating Inflammation and Oxidative Stress Through miR-106a-5p/HMGB1 Axis
Authors: Xu Hai-Ping , Ma Xiao-Ying , Yang Chen
Published: June 2021

Sepsis is an inflammatory disorder and leads to severe acute kidney injury (AKI). Circular RNAs (circRNAs) have been identified as a critical type of regulatory noncoding RNAs (ncRNAs) that present the important functions in various diseases. In this study, we identified a novel circRNA circTLK1 in the regulation of sepsis-induced AKI. We observed that circTLK1 expression was elevated in the cecal ligation and puncture (CLP) rat model compared with that in the control rats. The urine levels of neutrophil gelatinase–associated lipocalin (NGAL) and kidney injury molecule-1 (Kim-1) and the serum levels of creatinine (sCr) and blood urea nitrogen (BUN) were increased by the CLP treatment in the rats but were blocked by the circTLK1 shRNA. The circTLK1 shRNA reduced the CLP-induced kidney injury in the rats. The circTLK1 knockdown repressed oxidation stress, inflammation, and apoptosis in the sepsis-related AKI rat model. Moreover, lipopolysaccharide (LPS) treatment increased the production of TNF-α, IL-1β, and IL-6 in the HK-2 cells, while the circTLK1 shRNA could attenuate the enhancement in the cells. Bax and cleaved caspase-3 expression was upregulated, but Bcl-2 expression was downregulated by the LPS in the HK-2 cells, in which circTLK1 depletion reversed this effect in the cells. The depletion of circTLK1 attenuated the LPS-induced apoptosis in the HK-2 cells. CircTLK1 enhanced HMGB1 expression by sponging miR-106a-5p in the HK-2 cells, and miR-106a-5p and HMGB1 were involved in circTLK1-meidated injury of LPS-treated cells. Therefore, we concluded that circTLK1 contributed to sepsis-associated AKI by regulating inflammation and oxidative stress through the miR-106a-5p/HMGB1 axis. CircTLK1 and miR-106a-5p may be employed as the potential targets for the treatment of AKI.
Selective Regional Loss of Cortical Synapses Lacking Presynaptic Mitochondria in the 5xFAD Mouse Model
Authors: Seo Na-young , Kim Gyu Hyun , Noh Jeong Eun , Shin Ji Won , Lee Chan Hee , Lee Kea Joo
Published: June 2021

Synaptic loss in Alzheimer's disease (AD) is strongly correlated with cognitive impairment. Accumulating evidence indicates that amyloid pathology leads to synaptic degeneration and mitochondrial damage in AD. However, it remains unclear whether synapses and presynaptic mitochondria are differentially affected in various cortical regions of the AD brain at the ultrastructural level. Using serial block-face scanning electron microscopy, we assessed synaptic structures in the medial prefrontal cortex (mPFC) and primary visual cortex (V1) of the 5xFAD mouse model of AD. At 6 months of age, 5xFAD mice exhibited significantly elevated levels of amyloid deposition in layer 2/3 of the mPFC but not V1. Accordingly, three-dimensional reconstruction of synaptic connectivity revealed a significant reduction in excitatory synaptic density in layer 2 of the mPFC, but not V1, of male transgenic mice. Notably, the density of synapses lacking presynaptic mitochondria was selectively decreased in the mPFC of 5xFAD mice, with no change in the density of mitochondria-containing synapses. Further classification of spines into shape categories confirmed a preferential loss of thin spines whose presynaptic boutons were largely devoid of mitochondria in the 5xFAD mPFC. Furthermore, the number of mitochondria per bouton in spared mitochondria-containing boutons was reduced in the mPFC, but not V1, of 5xFAD mice. Collectively, these results highlight region-specific vulnerability of cortical synapses to amyloid deposition and suggest that the presence of presynaptic mitochondria may affect synaptic degeneration in AD.
Endothelial Senescence and Chronic Fatigue Syndrome, a COVID-19 Based Hypothesis
Authors: Sfera Adonis , Osorio Carolina , Zapata Martín del Campo Carlos M. , Pereida Shaniah , Maurer Steve , Maldonado Jose Campo , Kozlakidis Zisis
Published: June 2021

Myalgic encephalomyelitis/chronic fatigue syndrome is a serious illness of unknown etiology, characterized by debilitating exhaustion, memory impairment, pain and sleep abnormalities. Viral infections are believed to initiate the pathogenesis of this syndrome although the definite proof remains elusive. With the unfolding of COVID-19 pandemic, the interest in this condition has resurfaced as excessive tiredness, a major complaint of patients infected with the SARS-CoV-2 virus, often lingers for a long time, resulting in disability, and poor life quality. In a previous article, we hypothesized that COVID-19-upregulated angiotensin II triggered premature endothelial cell senescence, disrupting the intestinal and blood brain barriers. Here, we hypothesize further that post-viral sequelae, including myalgic encephalomyelitis/chronic fatigue syndrome, are promoted by the gut microbes or toxin translocation from the gastrointestinal tract into other tissues, including the brain. This model is supported by the SARS-CoV-2 interaction with host proteins and bacterial lipopolysaccharide. Conversely, targeting microbial translocation and cellular senescence may ameliorate the symptoms of this disabling illness.
Functional Genomics of Axons and Synapses to Understand Neurodegenerative Diseases
Authors: Di Paolo Andres , Garat Joaquin , Eastman Guillermo , Farias Joaquina , Dajas-Bailador Federico , Smircich Pablo , Sotelo-Silveira José Roberto
Published: June 2021

Functional genomics studies through transcriptomics, translatomics and proteomics have become increasingly important tools to understand the molecular basis of biological systems in the last decade. In most cases, when these approaches are applied to the nervous system, they are centered in cell bodies or somatodendritic compartments, as these are easier to isolate and, at least in vitro, contain most of the mRNA and proteins present in all neuronal compartments. However, key functional processes and many neuronal disorders are initiated by changes occurring far away from cell bodies, particularly in axons (axopathologies) and synapses (synaptopathies). Both neuronal compartments contain specific RNAs and proteins, which are known to vary depending on their anatomical distribution, developmental stage and function, and thus form the complex network of molecular pathways required for neuron connectivity. Modifications in these components due to metabolic, environmental, and/or genetic issues could trigger or exacerbate a neuronal disease. For this reason, detailed profiling and functional understanding of the precise changes in these compartments may thus yield new insights into the still intractable molecular basis of most neuronal disorders. In the case of synaptic dysfunctions or synaptopathies, they contribute to dozens of diseases in the human brain including neurodevelopmental (i.e., autism, Down syndrome, and epilepsy) as well as neurodegenerative disorders (i.e., Alzheimer’s and Parkinson’s diseases). Histological, biochemical, cellular, and general molecular biology techniques have been key in understanding these pathologies. Now, the growing number of omics approaches can add significant extra information at a high and wide resolution level and, used effectively, can lead to novel and insightful interpretations of the biological processes at play. This review describes current approaches that use transcriptomics, translatomics and proteomic related methods to analyze the axon and presynaptic elements, focusing on the relationship that axon and synapses have with neurodegenerative diseases.
Validation of Two Kinetic Assays for the Quantification of Endotoxin in Human Serum
Authors: Barro Christian , Paul Anu , Saleh Fermisk , Chitnis Tanuja , Weiner Howard L.
Published: June 2021

Background: There is an emerging evidence of the role of the microbiome in neurological diseases. Endotoxin is a component of gram-negative bacteria and thought to be one of the possible signals between the gut microbiota and the immune system. Previous studies explored the blood levels of endotoxin using an endpoint chromogenic assay.

Methods: We validated and compared the analytical performance of two kinetic assays for the quantification of endotoxin in serum: (1) the Limulus Amebocyte Lysate (LAL) Kinetic-QCL assay and (2) the turbidimetric LAL Pyrogent-5000 assay. We used the best-performing validated assay to measure the endotoxin level in 20 patients with multiple sclerosis (MS) and eight healthy controls.

Results: The Pyrogent-5000 and QCL assay achieved similar performance in regard to spike recovery and linear dilution; however, the Pyrogent-5000 had a better signal to noise in the calibrator curve. By using the Pyrogent-5000 assay, we found that serum samples from MS patients and healthy controls have a similar level of endotoxin; hence, we did not find evidence to support a penetration of endotoxin in the blood of MS patients. Our findings do not exclude a role of endotoxin in mediating signals from the gut microbiota in MS patients directly at the gut–blood barrier where numerous antigen-presenting cells are actively sensing metabolites and bacterial products.
A Systematic Review of Neuromodulation Treatment Effects on Suicidality
Authors: Kucuker Mehmet Utku , Almorsy Ammar G. , Sonmez Ayse Irem , Ligezka Anna N. , Doruk Camsari Deniz , Lewis Charles P. , Croarkin Paul E.
Published: June 2021

Introduction: Neuromodulation is an important group of therapeutic modalities for neuropsychiatric disorders. Prior studies have focused on efficacy and adverse events associated with neuromodulation. Less is known regarding the influence of neuromodulation treatments on suicidality. This systematic review sought to examine the effects of various neuromodulation techniques on suicidality.

Methods: A systematic review of the literature from 1940 to 2020 following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline was conducted. Any reported suicide-related outcome, including suicidal ideation, suicide intent, suicide attempt, completed suicide in reports were considered as a putative measure of treatment effect on suicidality.

Results: The review identified 129 relevant studies. An exploratory analysis of a randomized controlled trial comparing the effects of sertraline and transcranial direct-current stimulation (tDCS) for treating depression reported a decrease in suicidal ideation favoring tDCS vs. placebo and tDCS combined with sertraline vs. placebo. Several studies reported an association between repetitive transcranial magnetic stimulation and improvements in suicidal ideation. In 12 of the studies, suicidality was the primary outcome, ten of which showed a significant improvement in suicidal ideation. Electroconvulsive therapy (ECT) and magnetic seizure therapy was also shown to be associated with lower suicidal ideation and completed suicide rates. There were 11 studies which suicidality was the primary outcome and seven of these showed an improvement in suicidal ideation or suicide intent and fewer suicide attempts or completed suicides in patients treated with ECT. There was limited literature focused on the potential protective effect of vagal nerve stimulation with respect to suicidal ideation. Data were mixed regarding the potential effects of deep brain stimulation on suicidality.

Conclusions: Future prospective studies of neuromodulation that focus on the primary outcome of suicidality are urgently needed.

Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=125599, identifier: CRD42019125599.
Sensory-Induced Human LTP-Like Synaptic Plasticity – Using Visual Evoked Potentials to Explore the Relation Between LTP-Like Synaptic Plasticity and Visual Perceptual Learning
Authors: Lengali Lilly , Hippe Johannes , Hatlestad-Hall Christoffer , Rygvold Trine Waage , Sneve Markus Handal , Andersson Stein
Published: June 2021

Objective

Stimulus-selective response modulation (SRM) of sensory evoked potentials represents a well-established non-invasive index of long-term potentiation-like (LTP-like) synaptic plasticity in the human sensory cortices. Although our understanding of the mechanisms underlying stimulus-SRM has increased over the past two decades, it remains unclear how this form of LTP-like synaptic plasticity is related to other basic learning mechanisms, such as perceptual learning. The aim of the current study was twofold; firstly, we aimed to corroborate former stimulus-SRM studies, demonstrating modulation of visual evoked potential (VEP) components following high-frequency visual stimulation. Secondly, we aimed to investigate the association between the magnitudes of LTP-like plasticity and visual perceptual learning (VPL).

Methods

42 healthy adults participated in the study. EEG data was recorded during a standard high-frequency stimulus-SRM paradigm. Amplitude values were measured from the peaks of visual components C1, P1, and N1. Embedded in the same experimental session, the VPL task required the participants to discriminate between a masked checkerboard pattern and a visual “noise” stimulus before, during and after the stimulus-SRM probes.

Results

We demonstrated significant amplitude modulations of VEPs components C1 and N1 from baseline to both post-stimulation probes. In the VPL task, we observed a significant change in the average threshold levels from the first to the second round. No significant association between the magnitudes of LTP-like plasticity and performance on the VPL task was evident.

Conclusion

To the extent of our knowledge, this study is the first to examine the relationship between the visual stimulus-RM phenomenon and VPL in humans. In accordance with previous studies, we demonstrated robust amplitude modulations of the C1 and N1 components of the VEP waveform. However, we did not observe any significant correlations between modulation magnitude of VEP components and VPL task performance, suggesting that these phenomena rely on separate learning mechanisms implemented by different neural mechanisms.
Arpra: An Arbitrary Precision Range Analysis Library
Authors: Turner James Paul , Nowotny Thomas
Published: June 2021

Motivated by the challenge of investigating the reproducibility of spiking neural network simulations, we have developed the Arpra library: an open source C library for arbitrary precision range analysis based on the mixed Interval Arithmetic (IA)/Affine Arithmetic (AA) method. Arpra builds on this method by implementing a novel mixed trimmed IA/AA, in which the error terms of AA ranges are minimised using information from IA ranges. Overhead rounding error is minimised by computing intermediate values as extended precision variables using the MPFR library. This optimisation is most useful in cases where the ratio of overhead error to range width is high. Three novel affine term reduction strategies improve memory efficiency by merging affine terms of lesser significance. We also investigate the viability of using mixed trimmed IA/AA and other AA methods for studying reproducibility in unstable spiking neural network simulations.
T2-Weighted Whole-Brain Intracranial Vessel Wall Imaging at 3 Tesla With Cerebrospinal Fluid Suppression
Authors: Zhang Lei , Zhu Yanjie , Qi Yulong , Wan Liwen , Ren Lijie , Zhu Yi , Zhang Na , Liang Dong , Li Ye , Zheng Hairong , Liu Xin
Published: June 2021

Background

T2-weighted (T2w) intracranial vessel wall imaging (IVWI) provides good contrast to differentiate intracranial vasculopathies and discriminate various important plaque components. However, the strong cerebrospinal fluid (CSF) signal in T2w images interferes with depicting the intracranial vessel wall. In this study, we propose a T2-prepared sequence for whole-brain IVWI at 3T with CSF suppression.

Methods

A preparation module that combines T2 preparation and inversion recovery (T2IR) was used to suppress the CSF signal and was incorporated into the commercial three-dimensional (3D) turbo spin echo sequence-Sampling Perfection with Application optimized Contrast using different flip angle Evolution (SPACE). This new technique (hereafter called T2IR-SPACE) was evaluated on nine healthy volunteers and compared with two other commonly used 3D T2-weighted sequences: T2w-SPACE and FLAIR-SPACE (FLAIR: fluid-attenuated inversion recovery). The signal-to-noise ratios (SNRs) of the vessel wall (VW) and CSF and contrast-to-noise ratios (CNRs) between them were measured and compared among these three T2-weighted sequences. Subjective wall visualization of the three T2-weighted sequences was scored blindly and independently by two radiologists using a four-point scale followed by inter-rater reproducibility analysis. A pilot study of four stroke patients was performed to preliminarily evaluate the diagnostic value of this new sequence, which was compared with two conventional T2-weighted sequences.

Results

T2IR-SPACE had the highest CNR (11.01 ± 6.75) compared with FLAIR-SPACE (4.49 ± 3.15; p < 0.001) and T2w-SPACE (−56.16 ± 18.58; p < 0.001). The subjective wall visualization score of T2IR-SPACE was higher than those of FLAIR-SPACE and T2w-SPACE (T2IR-SPACE: 2.35 ± 0.59; FLAIR-SPACE: 0.52 ± 0.54; T2w-SPACE: 1.67 ± 0.58); the two radiologists’ scores showed excellent agreement (ICC = 0.883).

Conclusion

The T2IR preparation module markedly suppressed the CSF signal without much SNR loss of the other tissues (i.e., vessel wall, white matter, and gray matter) compared with the IR pulse. Our results suggest that T2IR-SPACE is a potential alternative T2-weighted sequence for assessing intracranial vascular diseases.
Moderate Ethanol Pre-treatment Mitigates ICH-Induced Injury via ER Stress Modulation in Rats
Authors: Lin Peter Bor-Chian , Wang Po-Kai , Pang Cheng-Yoong , Hu Wei-Fen , Tsai Andy Po-Yi , Oblak Adrian L. , Liew Hock-Kean
Published: June 2021

Intracerebral hemorrhage (ICH) is a life-threatening type of stroke that disrupts the normal neurological function of the brain. Clinical studies have reported a non-linear J-shaped association between alcohol consumption levels and the occurrence of cerebral stroke. Specifically, alcohol intoxication increases stroke incidence, while moderate alcohol pre-conditioning decreases stroke frequency and improves outcomes. Although alcohol pre-consumption is likely a crucial player in ICH, the underlying mechanism remains unclear. We performed 1-h alcohol pre-conditioning followed by ICH induction in Sprague-Dawley (SD) rats to investigate the role of alcohol pre-conditioning in ICH. Interestingly, behavioral test analysis found that ethanol intoxication (3 g/kg) aggravated ICH-induced neurological deficits, but moderate ethanol pre-conditioning (0.75 g/kg) ameliorated ICH-induced neurological deficits by reducing the oxidative stress and proinflammatory cytokines release. Moreover, we found that moderate ethanol pretreatment improved the striatal endoplasmic reticulum (ER) homeostasis by increasing the chaperone protein expression and reducing oxidative stress and apoptosis caused by ICH. Our findings show that the mechanism regulated by moderate ethanol pre-conditioning might be beneficial for ICH, indicating the importance of ER homeostasis, oxidative stress, and differential cytokines release in ICH.
Gluten-Free Labeling Is Misused Frequently in Foods Marketed in Northwestern Mexico
Authors: Calderón de la Barca Ana M. , Luna-Alcocer Valeria , Valenzuela-Miranda José R. , Mejía-León Maria E.
Published: June 2021

Background: Patients with celiac disease (CD) require a gluten-free (GF) diet, including industrialized products containing ≤ 20 mg gluten/kg. The market status of GF food products is almost unknown in Mexico. Therefore, we studied the GF-labeled products on the northwestern Mexican market and analyzed their gluten content.

Methods: We searched for GF type of foods in three different supermarkets of each chain in Mexicali Baja California and Hermosillo Sonora and corroborated the price, origin, and GF certification of each item using internet sites. We quantified the gluten in the foods using the sandwich R5-enzyme-linked immunosorbent assay (ELISA) and detected their immune-reactivity for IgA from patients with CD.

Results: The study included >263 different GF-labeled foodstuffs, and 55% of them were made in Mexico. The Mexican items were principally flours, sausages, bread and bakery, milk-type products, and tortillas, while pasta, snacks, and breakfast cereals were mainly imported. The cost ratio of GF products to the conventional mean was 3.5, ranging principally from 1 to 13. The most common GF-labeled foods were flours and pasta (34), cookies and snacks (32), breakfast cereals, sausages, and milk-type products (18–20). Although 36% of the products were certified, 17.4% of the analyzed samples contained >20 mg gluten/kg, mainly the non-certified ones and those made in Mexico. IgA from patients with CD reacted in vitro against gluten proteins from the contaminated GF-labeled products.

Conclusion: The accessibility of GF products in the northwestern Mexican market is wide; however, such products are expensive, and some could be risky for patients with CD because they contain gluten, which is recognized by the immune systems of these patients.
Modulation of Tumor Microenvironment to Enhance Radiotherapy Efficacy in Esophageal Squamous Cell Carcinoma by Inhibiting Carbonic Anhydrase IX
Authors: Xu Pengqin , Zhang Yu , Ge Fanghong , Zhang Fuming , He Xia , Gao Xingya
Published: June 2021

The radiotherapy outcomes of patients with advanced esophageal squamous cell carcinoma (ESCC) remain poor due to hypoxia. Carbonic anhydrase IX (CAIX) is a membrane-associated enzyme that induces hypoxia, extracellular acidity, and upregulation of hypoxia-related factors in tumor microenvironment, thereby promoting tumor metastasis. CAIX is upregulated in ESCC tissues compared to normal surrounding tissues. In the current study, we aimed to investigate the effect of CAIX inhibition on the modulation of tumor microenvironment and radiotherapy efficacy in ESCC. Higher CAIX expression was correlated with poorer progression-free survival in ESCC patients. Then, the ethyl N-(4-methylphenyl) sulfonylcarbamate (S4) was used to inhibit CAIX expression in ESCC cells and mice xenografts. The pretreatment of ESCC cells with S4 significantly downregulated CAIX expression, decreased intracellular pH, reduced cell viability, resulting in decreased oxygen consumption and more sensitive response to X-ray irradiation. In mice inoculated with ESCC cells, the combination of X-ray irradiation with S4 further improved survival, delayed tumor growth, decreased hypoxia level, exaggerated DNA damage, and increased apoptosis compared with the groups treated solely with S4 or radiotherapy. In conclusion, our study showed that the inhibition of CAIX by S4 treatment altered hypoxic tumor micro-environment, exaggerated DNA damage, increased apoptosis, and thus enhanced radiotherapy efficacy in ESCC. These findings provided a potential therapeutic strategy for patients with resistant ESCC.