bluuebunny/crossref_metadata_2025 huggingface dataset:
Humanized Mouse Models for the Study of Periodontitis: An Opportunity to Elucidate Unresolved Aspects of Its Immunopathogenesis and Analyze New Immunotherapeutic Strategies
Authors: Rojas Carolina , García Michelle P. , Polanco Alan F. , González-Osuna Luis , Sierra-Cristancho Alfredo , Melgar-Rodríguez Samanta , Cafferata Emilio A. , Vernal Rolando
Published: June 2021

Periodontitis is an oral inflammatory disease in which the polymicrobial synergy and dysbiosis of the subgingival microbiota trigger a deregulated host immune response, that leads to the breakdown of tooth-supporting tissues and finally tooth loss. Periodontitis is characterized by the increased pathogenic activity of T helper type 17 (Th17) lymphocytes and defective immunoregulation mediated by phenotypically unstable T regulatory (Treg), lymphocytes, incapable of resolving the bone-resorbing inflammatory milieu. In this context, the complexity of the immune response orchestrated against the microbial challenge during periodontitis has made the study of its pathogenesis and therapy difficult and limited. Indeed, the ethical limitations that accompany human studies can lead to an insufficient etiopathogenic understanding of the disease and consequently, biased treatment decision-making. Alternatively, animal models allow us to manage these difficulties and give us the opportunity to partially emulate the etiopathogenesis of periodontitis by inoculating periodontopathogenic bacteria or by placing bacteria-accumulating ligatures around the teeth; however, these models still have limited translational application in humans. Accordingly, humanized animal models are able to emulate human-like complex networks of immune responses by engrafting human cells or tissues into specific strains of immunodeficient mice. Their characteristics enable a viable time window for the study of the establishment of a specific human immune response pattern in anin vivosetting and could be exploited for a wider study of the etiopathogenesis and/or treatment of periodontitis. For instance, the antigen-specific response of human dendritic cells against the periodontopathogenPorphyromonas gingivalisfavoring the Th17/Treg response has already been tested in humanized mice models. Hypothetically, the proper emulation of periodontal dysbiosis in a humanized animal could give insights into the subtle molecular characteristics of a human-like local and systemic immune response during periodontitis and support the design of novel immunotherapeutic strategies. Therefore, the aims of this review are: To elucidate how the microbiota-elicited immunopathogenesis of periodontitis can be potentially emulated in humanized mouse models, to highlight their advantages and limitations in comparison with the already available experimental periodontitis non-humanized animal models, and to discuss the potential translational application of using these models for periodontitis immunotherapeutics.
The Early Postnatal Life: A Dynamic Period in Thymic Epithelial Cell Differentiation
Authors: Pinheiro Ruben G. R. , Alves Nuno L.
Published: June 2021

The microenvironments formed by cortical (c) and medullary (m) thymic epithelial cells (TECs) play a non-redundant role in the generation of functionally diverse and self-tolerant T cells. The role of TECs during the first weeks of the murine postnatal life is particularly challenging due to the significant augment in T cell production. Here, we critically review recent studies centered on the timely coordination between the expansion and maturation of TECs during this period and their specialized role in T cell development and selection. We further discuss how aging impacts on the pool of TEC progenitors and maintenance of functionally thymic epithelial microenvironments, and the implications of these chances in the capacity of the thymus to sustain regular thymopoiesis throughout life.
Microglial Morphology Across Distantly Related Species: Phylogenetic, Environmental and Age Influences on Microglia Reactivity and Surveillance States
Authors: Carvalho-Paulo Dario , Bento Torres Neto João , Filho Carlos Santos , de Oliveira Thais Cristina Galdino , de Sousa Aline Andrade , dos Reis Renata Rodrigues , dos Santos Zaire Alves , de Lima Camila Mendes , de Oliveira Marcus Augusto , Said Nivin Mazen , Freitas Sinara Franco , Sosthenes Marcia Consentino Kronka , Gomes Giovanni Freitas , Henrique Ediely Pereira , Pereira Patrick Douglas Côrrea , de Siqueira Lucas Silva , de Melo Mauro André Damasceno , Guerreiro Diniz Cristovam , Magalhães Nara Gyzely de Morais , Diniz José Antonio Picanço , Vasconcelos Pedro Fernando da Costa , Diniz Daniel Guerreiro , Anthony Daniel Clive , Sherry David Francis , Brites Dora , Picanço Diniz Cristovam Wanderley
Published: June 2021

Microglial immunosurveillance of the brain parenchyma to detect local perturbations in homeostasis, in all species, results in the adoption of a spectrum of morphological changes that reflect functional adaptations. Here, we review the contribution of these changes in microglia morphology in distantly related species, in homeostatic and non-homeostatic conditions, with three principal goals (1): to review the phylogenetic influences on the morphological diversity of microglia during homeostasis (2); to explore the impact of homeostatic perturbations (Dengue virus challenge) in distantly related species (Mus musculus and Callithrix penicillata) as a proxy for the differential immune response in small and large brains; and (3) to examine the influences of environmental enrichment and aging on the plasticity of the microglial morphological response following an immunological challenge (neurotropic arbovirus infection). Our findings reveal that the differences in microglia morphology across distantly related species under homeostatic condition cannot be attributed to the phylogenetic origin of the species. However, large and small brains, under similar non-homeostatic conditions, display differential microglial morphological responses, and we argue that age and environment interact to affect the microglia morphology after an immunological challenge; in particular, mice living in an enriched environment exhibit a more efficient immune response to the virus resulting in earlier removal of the virus and earlier return to the homeostatic morphological phenotype of microglia than it is observed in sedentary mice.
Evaluating the Safety of West Nile Virus Immunity During Congenital Zika Virus Infection in Mice
Authors: Acklin Joshua A. , Cattle Javier D. , Moss Arianna S. , Brown Julia A. , Foster Gregory A. , Krysztof David , Stramer Susan L. , Lim Jean K.
Published: June 2021

Antibody-dependent enhancement (ADE) is a phenomenon that occurs when cross-reactive antibodies generated from a previous flaviviral infection increase the pathogenesis of a related virus. Zika virus (ZIKV) is the most recent flavivirus introduced to the Western Hemisphere and has become a significant public health threat due to the unanticipated impact on the developing fetus. West Nile virus (WNV) is the primary flavivirus that circulates in North America, and we and others have shown that antibodies against WNV are cross-reactive to ZIKV. Thus, there is concern that WNV immunity could increase the risk of severe ZIKV infection, particularly during pregnancy. In this study, we examined the extent to which WNV antibodies could impact ZIKV pathogenesis in a murine pregnancy model. To test this, we passively transferred WNV antibodies into pregnantStat2-/-mice on E6.5 prior to infection with ZIKV. Evaluation of pregnant dams showed weight loss following ZIKV infection; however, no differences in maternal weights or viral loads in the maternal brain, spleen, or spinal cord were observed in the presence of WNV antibodies. Resorption rates, and other fetal parameters, including fetal and placental size, were similarly unaffected. Further, the presence of WNV antibodies did not significantly alter the viral load or the inflammatory response in the placenta or the fetus in response to ZIKV. Our data suggest that pre-existing WNV immunity may not significantly impact the pathogenesis of ZIKV infection during pregnancy. Our findings are promising for the safety of implementing WNV vaccines in the continental US.
Dental Biofilm Microbiota Dysbiosis Is Associated With the Risk of Acute Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Heidrich Vitor , Bruno Julia S. , Knebel Franciele H. , de Molla Vinícius C. , Miranda-Silva Wanessa , Asprino Paula F. , Tucunduva Luciana , Rocha Vanderson , Novis Yana , Arrais-Rodrigues Celso , Fregnani Eduardo R. , Camargo Anamaria A.
Published: June 2021

Acute graft-versus-host disease (aGVHD) is one of the major causes of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recently, aGVHD onset was linked to intestinal microbiota (IM) dysbiosis. However, other bacterial-rich gastrointestinal sites, such as the mouth, which hosts several distinctive microbiotas, may also impact the risk of GVHD. The dental biofilm microbiota (DBM) is highly diverse and, like the IM, interacts with host cells and modulates immune homeostasis. We characterized changes in the DBM of patients during allo-HSCT and evaluated whether the DBM could be associated with the risk of aGVHD. DBM dysbiosis during allo-HSCT was marked by a gradual loss of bacterial diversity and changes in DBM genera composition, with commensal genera reductions and potentially pathogenic bacteria overgrowths. High Streptococcus and high Corynebacterium relative abundance at preconditioning were associated with a higher risk of aGVHD (67% vs. 33%; HR = 2.89, P = 0.04 and 73% vs. 37%; HR = 2.74, P = 0.04, respectively), while high Veillonella relative abundance was associated with a lower risk of aGVHD (27% vs. 73%; HR = 0.24, P < 0.01). Enterococcus faecalis bloom during allo-HSCT was observed in 17% of allo-HSCT recipients and was associated with a higher risk of aGVHD (100% vs. 40%; HR = 4.07, P < 0.001) and severe aGVHD (60% vs. 12%; HR = 6.82, P = 0.01). To the best of our knowledge, this is the first study demonstrating that DBM dysbiosis is associated with the aGVHD risk after allo-HSCT.
Resistin, a Novel Host Defense Peptide of Innate Immunity
Authors: Li Yanran , Yang Qiyuan , Cai Dongjie , Guo Hongrui , Fang Jing , Cui Hengmin , Gou Liping , Deng Junliang , Wang Zhisheng , Zuo Zhicai
Published: June 2021

Resistin, a cysteine-rich protein, expressed in adipocytes, was initially proposed as a link between obesity and diabetes in mice. In humans, resistin is considered to be a pro-inflammatory molecule expressed in immune cells, which plays a regulatory role in many chronic inflammatory diseases, metabolic diseases, infectious diseases, and cancers. However, increasing evidence shows that resistin functions as a host defense peptide of innate immunity, in terms of its wide-spectrum anti-microbial activity, modulation of immunity, and limitation of microbial product-induced inflammation. To date, the understanding of resistin participating in host defense mechanism is still limited. The review aims to summarize current knowledge about the biological properties, functions, and related mechanisms of resistin in host defense, which provides new insights into the pleiotropic biological function of resistin and yields promising strategies for developing new antimicrobial therapeutic agents.
NLRC5: A Potential Target for Central Nervous System Disorders
Authors: Zhang Lu , Jiao Cui , Liu Lingjuan , Wang Aiping , Tang Li , Ren Yi , Huang Peng , Xu Jie , Mao Dingan , Liu Liqun
Published: June 2021

Nucleotide oligomerization domain-like receptors (NLRs), a class of pattern recognition receptors, participate in the host’s first line of defense against invading pathogenic microorganisms. NLR family caspase recruitment domain containing 5 (NLRC5) is the largest member of the NLR family and has been shown to play an important role in inflammatory processes, angiogenesis, immunity, and apoptosis by regulating the nuclear factor-κB, type I interferon, and inflammasome signaling pathways, as well as the expression of major histocompatibility complex I genes. Recent studies have found that NLRC5 is also associated with neuronal development and central nervous system (CNS) diseases, such as CNS infection, cerebral ischemia/reperfusion injury, glioma, multiple sclerosis, and epilepsy. This review summarizes the research progress in the structure, expression, and biological characteristics of NLRC5 and its relationship with the CNS.
B, N Dual Doped Coral-Like Carbon Framework With Superior Pseudocapacitance and Surface Wettability
Authors: Han Lu , Chen Xu , Zeng Shijie , Liu Jia , Yang Zhongli , Wang Zhiqiang , Li Liang , Wang Haibao , Hou Zhanbin , Xu Min
Published: June 2021

Carbon-based materials are usually considered as conventional electrode materials for supercapacitors (SCs), therefore it is meaningful to enhance supercapacitive capacity and cycling stability via rational surface structure design of carbon-based materials. The bio-inspired coral-like porous carbon structure has attracted much attention recently in that it can offer large surface area for ion accommodation and favor ions-diffusion, promoting its energy storage capacity. Herein, we designed a superiorly hydrophilic B, N dual doped coral-like carbon framework (BN-CCF) and studied its surface wettability via low-field nuclear magnetic resonance relaxation technique. The unique coral-like micro-nano structure and B, N dual doping in carbon framework can enhance its pseudocapacitance and improve surface wettability. Therefore, when used as electrodes of SCs, the BN-CCF displays 457.5 F g−1 at 0.5 A g−1, even when current density increases 20 folds, it still exhibits high capacitance retention of 66.1% and superior cycling stability. The symmetrical SCs assembled by BN-CCF electrodes show a high energy density of 14.92 Wh kg−1 (600 W kg−1). In this work, simple structural regulation with B, N dual doping and surface wettability should be considered as effective strategy to enhance energy storage capacity of carbon-based SCs.
The Enterovirus Theory of Disease Etiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Critical Review
Authors: O'Neal Adam J. , Hanson Maureen R.
Published: June 2021

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multi-system disease whose etiological basis has not been established. Enteroviruses (EVs) as a cause of ME/CFS have sometimes been proposed, as they are known agents of acute respiratory and gastrointestinal infections that may persist in secondary infection sites, including the central nervous system, muscle, and heart. To date, the body of research that has investigated enterovirus infections in relation to ME/CFS supports an increased prevalence of chronic or persistent enteroviral infections in ME/CFS patient cohorts than in healthy individuals. Nevertheless, inconsistent results have fueled a decline in related studies over the past two decades. This review covers the aspects of ME/CFS pathophysiology that are consistent with a chronic enterovirus infection and critically reviews methodologies and approaches used in past EV-related ME/CFS studies. We describe the prior sample types that were interrogated, the methods used and the limitations to the approaches that were chosen. We conclude that there is considerable evidence that prior outbreaks of ME/CFS were caused by one or more enterovirus groups. Furthermore, we find that the methods used in prior studies were inadequate to rule out the presence of chronic enteroviral infections in individuals with ME/CFS. Given the possibility that such infections could be contributing to morbidity and preventing recovery, further studies of appropriate biological samples with the latest molecular methods are urgently needed.
Advection Drives Nitrate Past the Microphytobenthos in Intertidal Sands, Fueling Deeper Denitrification
Authors: Schutte Charles A. , Huanca-Valenzuela Paulina , Lavik Gaute , Marchant Hannah K. , de Beer Dirk
Published: June 2021

Nitrification rates are low in permeable intertidal sand flats such that the water column is the primary source of nitrate to the sediment. During tidal inundation, nitrate is supplied to the pore space by advection rather than diffusion, relieving the microorganisms that reside in the sand from nitrate limitation and supporting higher denitrification rates than those observed under diffusive transport. Sand flats are also home to an abundant community of benthic photosynthetic microorganisms, the microphytobenthos (MPB). Diatoms are an important component of the MPB that can take up and store high concentrations of nitrate within their cells, giving them the potential to alter nitrate availability in the surrounding porewater. We tested whether nitrate uptake by the MPB near the sediment surface decreases its availability to denitrifiers along deeper porewater flow paths. In laboratory experiments, we used NOx (nitrate + nitrite) microbiosensors to confirm that, in the spring, net NOx consumption in the zone of MPB photosynthetic activity was stimulated by light. The maximum potential denitrification rate, measured at high spatial resolution using microsensors with acetylene and nitrate added, occurred below 1.4 cm, much deeper than light-induced NOx uptake (0.13 cm). Therefore, the shallower MPB had the potential to decrease NOx supply to the deeper sediments and limit denitrification. However, when applying a realistic downward advective flow to sediment from our study site, NOx always reached the depths of maximum denitrification potential, regardless of light availability or season. We conclude that during tidal inundation porewater advection overwhelms any influence of shallow NOx uptake by the MPB and drives water column NOx to the depths of maximum denitrification potential.
How Tillage and Crop Rotation Change the Distribution Pattern of Fungi
Authors: Orrù Luigi , Canfora Loredana , Trinchera Alessandra , Migliore Melania , Pennelli Bruno , Marcucci Andrea , Farina Roberta , Pinzari Flavia
Published: June 2021

Massive sequencing of fungal communities showed that climatic factors, followed by edaphic and spatial variables, are feasible predictors of fungal richness and community composition. This study, based on a long-term field experiment with tillage and no-tillage management since 1995 and with a crop rotation introduced in 2009, confirmed that tillage practices shape soil properties and impact soil fungal communities. Results highlighted higher biodiversity of saprotrophic fungi in soil sites with low disturbance and an inverse correlation between the biodiversity of ectomycorrhizal and saprotrophic fungi. We speculated how their mutual exclusion could be due to a substrate-mediated niche partitioning or by space segregation. Moreover, where the soil was ploughed, the species were evenly distributed. There was higher spatial variability in the absence of ploughing, with fungal taxa distributed according to a small-scale pattern, corresponding to micro-niches that probably remained undisturbed and heterogeneously distributed. Many differentially represented OTUs in all the conditions investigated were unidentified species or OTUs matching at high taxa level (i.e., phylum, class, order). Among the fungi with key roles in all the investigated conditions, there were several yeast species known to have pronounced endemism in soil and are also largely unidentified. In addition to yeasts, other fungal species emerged as either indicator of a kind of management or as strongly associated with a specific condition. Plant residues played a substantial role in defining the assortment of species.
Role of Vaginal Microbiota Dysbiosis in Gynecological Diseases and the Potential Interventions
Authors: Han Yiwen , Liu Zhaoxia , Chen Tingtao
Published: June 2021

Vaginal microbiota dysbiosis, characterized by the loss ofLactobacillusdominance and increase of microbial diversity, is closely related to gynecological diseases; thus, intervention on microbiota composition is significant and promising in the treatment of gynecological diseases. Currently, antibiotics and/or probiotics are the mainstay of treatment, which show favorable therapeutic effects but also bring problems such as drug resistance and high recurrence. In this review, we discuss the role of vaginal microbiota dysbiosis in various gynecological infectious and non-infectious diseases, as well as the current and potential interventions.
Diverse Roles of TgMIC1/4/6 in the Toxoplasma Infection
Authors: Zhu Jinjin , Wang Yang , Cao Yuanyuan , Shen Jilong , Yu Li
Published: June 2021

Toxoplasma gondii microneme is a specialized secretory organelle that discharges its contents at the apical tip of this apicomplexan parasite in a sequential and regulated manner. Increasing number of studies on microneme proteins (MICs) have shown them as a predominant and important role in host cell attachment, invasion, motility and pathogenesis. In this review, we summarize the research advances in one of the most important MICs complexes, TgMIC1/4/6, which will contribute to improve the understanding of the molecular mechanism of T. gondii infection and provide a theoretical basis for the effective control against T. gondii.
Molecular Characterization and Survive Abilities of Salmonella Heidelberg Strains of Poultry Origin in Brazil
Authors: Melo Roberta T. , Galvão Newton N. , Guidotti-Takeuchi Micaela , Peres Phelipe A. B. M. , Fonseca Belchiolina B. , Profeta Rodrigo , Azevedo Vasco A. C. , Monteiro Guilherme P. , Brenig Bertram , Rossi Daise A.
Published: June 2021

The aim of the study was to evaluate the genotypic and phenotypic characteristics of 20 strains of S. Heidelberg (SH) isolated from broilers produced in southern Brazil. The similarity and presence of genetic determinants linked to virulence, antimicrobial resistance, biofilm formation, and in silico-predicted metabolic interactions revealed this serovar as a threat to public health. The presence of the ompC, invA, sodC, avrA, lpfA, and agfA genes was detected in 100% of the strains and the luxS gene in 70% of them. None of the strains carries the blaSHV, mcr-1, qnrA, qnrB, and qnrS genes. All strains showed a multidrug-resistant profile to at least three non-β-lactam drugs, which include colistin, sulfamethoxazole, and tetracycline. Resistance to penicillin, ceftriaxone (90%), meropenem (25%), and cefoxitin (25%) were associated with the presence of blaCTX–M and blaCMY–2 genes. Biofilm formation reached a mature stage at 25 and 37°C, especially with chicken juice (CJ) addition. The sodium hypochlorite 1% was the least efficient in controlling the sessile cells. Genomic analysis of two strains identified more than 100 virulence genes and the presence of resistance to 24 classes of antibiotics correlated to phenotypic tests. Protein-protein interaction (PPI) prediction shows two metabolic pathways correlation with biofilm formation. Virulence, resistance, and biofilm determinants must be constant monitoring in SH, due to the possibility of occurring infections extremely difficult to cure and due risk of the maintenance of the bacterium in production environments.
Highly Efficient CRISPR-Mediated Base Editing in Sinorhizobium meliloti
Authors: Wang Longxiang , Xiao Yuan , Wei Xiaowei , Pan Jimin , Duanmu Deqiang
Published: June 2021

Rhizobia are widespread gram-negative soil bacteria and indispensable symbiotic partners of leguminous plants that facilitate the most highly efficient biological nitrogen fixation in nature. Although genetic studies in Sinorhizobium meliloti have advanced our understanding of symbiotic nitrogen fixation (SNF), the current methods used for genetic manipulations in Sinorhizobium meliloti are time-consuming and labor-intensive. In this study, we report the development of a few precise gene modification tools that utilize the CRISPR/Cas9 system and various deaminases. By fusing the Cas9 nickase to an adenine deaminase, we developed an adenine base editor (ABE) system that facilitated adenine-to-guanine transitions at one-nucleotide resolution without forming double-strand breaks (DSB). We also engineered a cytidine base editor (CBE) and a guanine base editor (GBE) that catalyze cytidine-to-thymine substitutions and cytidine-to-guanine transversions, respectively, by replacing adenine deaminase with cytidine deaminase and other auxiliary enzymes. All of these base editors are amenable to the assembly of multiple synthetic guide RNA (sgRNA) cassettes using Golden Gate Assembly to simultaneously achieve multigene mutations or disruptions. These CRISPR-mediated base editing tools will accelerate the functional genomics study and genome manipulation of rhizobia.
Taxonomy and Molecular Phylogeny of Two New Species of Prostomatean Ciliates With Establishment of Foissnerophrys gen. n. (Alveolata, Ciliophora)
Authors: Jiang Limin , Zhuang Wenbao , El-Serehy Hamed A. , Al-Farraj Saleh A. , Warren Alan , Hu Xiaozhong
Published: June 2021

Prostomatean ciliates play important roles in the flow of material and energy in aquatic microbial food webs, and thus have attracted wide attention for over a century. Their taxonomy and systematics are, however, still poorly understood because of their relatively few taxonomically informative morphological characters. In this study, two new prostomateans, Lagynus binucleatus sp. n. and Foissnerophrys alveolata gen. n., sp. n., collected from a freshwater pool and the intertidal zone of a sandy beach, respectively, in Qingdao, China, are investigated using living observation, protargol staining, and SSU rRNA gene sequencing methods. The genus Lagynus is redefined, and the new species L. binucleatus sp. n. is established based on significant morphological differences with similar forms. Furthermore, a new genus, Foissnerophrys gen. n., is established based on a combination of morphological and molecular data with F. alveaolata sp. n. the type species by monotypy. The identities of intracellular prokaryotes of these two new species are discussed based on fluorescence in situ hybridization (FISH) data and newly obtained 16S rRNA gene sequences.
Single-Target Regulators Constitute the Minority Group of Transcription Factors in Escherichia coli K-12
Authors: Shimada Tomohiro , Ogasawara Hiroshi , Kobayashi Ikki , Kobayashi Naoki , Ishihama Akira
Published: June 2021

The identification of regulatory targets of all transcription factors (TFs) is critical for understanding the entire network of genome regulation. A total of approximately 300 TFs exist in the model prokaryote Escherichia coli K-12, but the identification of whole sets of their direct targets is impossible with use of in vivo approaches. For this end, the most direct and quick approach is to identify the TF-binding sites in vitro on the genome. We then developed and utilized the gSELEX screening system in vitro for identification of more than 150 E. coli TF-binding sites along the E. coli genome. Based on the number of predicted regulatory targets, we classified E. coli K-12 TFs into four groups, altogether forming a hierarchy ranging from a single-target TF (ST-TF) to local TFs, global TFs, and nucleoid-associated TFs controlling as many as 1,000 targets. Using the collection of purified TFs and a library of genome DNA segments from a single and the same E. coli K-12, we identified here a total of 11 novel ST-TFs, CsqR, CusR, HprR, NorR, PepA, PutA, QseA, RspR, UvrY, ZraR, and YqhC. The regulation of single-target promoters was analyzed in details for the hitherto uncharacterized QseA and RspR. In most cases, the ST-TF gene and its regulatory target genes are adjacently located on the E. coli K-12 genome, implying their simultaneous transfer in the course of genome evolution. The newly identified 11 ST-TFs and the total of 13 hitherto identified altogether constitute the minority group of TFs in E. coli K-12.
Genomic and Phenotypic Characterization of Chloracidobacterium Isolates Provides Evidence for Multiple Species
Authors: Saini Mohit Kumar , Sebastian Aswathy , Shirotori Yoshiki , Soulier Nathan T. , Garcia Costas Amaya M. , Drautz-Moses Daniela I. , Schuster Stephan C. , Albert Istvan , Haruta Shin , Hanada Satoshi , Thiel Vera , Tank Marcus , Bryant Donald A.
Published: June 2021

Chloracidobacterium is the first and until now the sole genus in the phylum Acidobacteriota (formerly Acidobacteria) whose members perform chlorophyll-dependent phototrophy (i.e., chlorophototrophy). An axenic isolate of Chloracidobacterium thermophilum (strain BT) was previously obtained by using the inferred genome sequence from an enrichment culture and diel metatranscriptomic profiling analyses in situ to direct adjustments to the growth medium and incubation conditions, and thereby a defined growth medium for Chloracidobacterium thermophilum was developed. These advances allowed eight additional strains of Chloracidobacterium spp. to be isolated from microbial mat samples collected from Mushroom Spring, Yellowstone National Park, United States, at temperatures of 41, 52, and 60°C; an axenic strain was also isolated from Rupite hot spring in Bulgaria. All isolates are obligately photoheterotrophic, microaerophilic, non-motile, thermophilic, rod-shaped bacteria. Chloracidobacterium spp. synthesize multiple types of (bacterio-)chlorophylls and have type-1 reaction centers like those of green sulfur bacteria. Light harvesting is accomplished by the bacteriochlorophyll a-binding, Fenna-Matthews-Olson protein and chlorosomes containing bacteriochlorophyll c. Their genomes are approximately 3.7 Mbp in size and comprise two circular chromosomes with sizes of approximately 2.7 Mbp and 1.0 Mbp. Comparative genomic studies and phenotypic properties indicate that the nine isolates represent three species within the genus Chloracidobacterium. In addition to C. thermophilum, the microbial mats at Mushroom Spring contain a second species, tentatively named Chloracidobacterium aggregatum, which grows as aggregates in liquid cultures. The Bulgarian isolate, tentatively named Chloracidobacterium validum, will be proposed as the type species of the genus, Chloracidobacterium. Additionally, Chloracidobacterium will be proposed as the type genus of a new family, Chloracidobacteriaceae, within the order Blastocatellales, the class Blastocatellia, and the phylum Acidobacteriota.
Aggregation is a Context-Dependent Constraint on Protein Evolution
Authors: Monti Michele , Armaos Alexandros , Fantini Marco , Pastore Annalisa , Tartaglia Gian Gaetano
Published: June 2021

Solubility is a requirement for many cellular processes. Loss of solubility and aggregation can lead to the partial or complete abrogation of protein function. Thus, understanding the relationship between protein evolution and aggregation is an important goal. Here, we analysed two deep mutational scanning experiments to investigate the role of protein aggregation in molecular evolution. In one data set, mutants of a protein involved in RNA biogenesis and processing, human TAR DNA binding protein 43 (TDP-43), were expressed in S. cerevisiae. In the other data set, mutants of a bacterial enzyme that controls resistance to penicillins and cephalosporins, TEM-1 beta-lactamase, were expressed in E. coli under the selective pressure of an antibiotic treatment. We found that aggregation differentiates the effects of mutations in the two different cellular contexts. Specifically, aggregation was found to be associated with increased cell fitness in the case of TDP-43 mutations, as it protects the host from aberrant interactions. By contrast, in the case of TEM-1 beta-lactamase mutations, aggregation is linked to a decreased cell fitness due to inactivation of protein function. Our study shows that aggregation is an important context-dependent constraint of molecular evolution and opens up new avenues to investigate the role of aggregation in the cell.
Niacin Enhancement for Parkinson’s Disease: An Effectiveness Trial
Authors: Chong Raymond , Wakade Chandramohan , Seamon Marissa , Giri Banabihari , Morgan John , Purohit Sharad
Published: June 2021

We previously reported that individuals with Parkinson’s disease (PD) present with lower vitamin B3 levels compared to controls. It may be related to carbidopa interaction, defective tryptophan metabolism, and stresses of night sleep disorder. Vitamin B3 is the energy source for all cells by producing NAD+ and NADP+ in redox reactions of oxidative phosphorylation. Thus, some symptoms of PD such as fatigue, sleep dysfunction, and mood changes may be related to the deficiency of vitamin B3. Here, we conducted an effectiveness trial to determine the effect of 12 months of low-dose niacin (a vitamin B3 derivative) enhancement in PD individuals. An average of 9 ± 6-point improvement in the Unified Parkinson’s Disease Rating Scale (UPDRS) III (motor) score was observed after 12 months of daily niacin compared to the expected decline in score (effect size = 0.78, 95% CI = 7–11). Additionally, secondary outcome measures improved. Notably, handwriting size increased, fatigue perception decreased, mood improved, frontal beta rhythm during quiet stance increased, and stance postural sway amplitude and range of acceleration decreased. Set shifting, however, as measured by the Trail Making-B test, worsened from 66 to 96 s. Other measures did not change after 12 months, but it is not clear whether this represents a positive benefit of the vitamin. For example, while the quality of night sleep remained the same, there was a trend towards a decrease in the frequency of awakening episodes. These results suggest that niacin enhancement has the potential to maintain or improve quality of life in PD and slow disease progression.
RETRACTED: ADVIAN: Alzheimer's Disease VGG-Inspired Attention Network Based on Convolutional Block Attention Module and Multiple Way Data Augmentation
Authors: Wang Shui-Hua , Zhou Qinghua , Yang Ming , Zhang Yu-Dong
Published: June 2021

Aim: Alzheimer's disease is a neurodegenerative disease that causes 60–70% of all cases of dementia. This study is to provide a novel method that can identify AD more accurately.

Methods: We first propose a VGG-inspired network (VIN) as the backbone network and investigate the use of attention mechanisms. We proposed an Alzheimer's Disease VGG-Inspired Attention Network (ADVIAN), where we integrate convolutional block attention modules on a VIN backbone. Also, 18-way data augmentation is proposed to avoid overfitting. Ten runs of 10-fold cross-validation are carried out to report the unbiased performance.

Results: The sensitivity and specificity reach 97.65 ± 1.36 and 97.86 ± 1.55, respectively. Its precision and accuracy are 97.87 ± 1.53 and 97.76 ± 1.13, respectively. The F1 score, MCC, and FMI are obtained as 97.75 ± 1.13, 95.53 ± 2.27, and 97.76 ± 1.13, respectively. The AUC is 0.9852.

Conclusion: The proposed ADVIAN gives better results than 11 state-of-the-art methods. Besides, experimental results demonstrate the effectiveness of 18-way data augmentation.
Rest Is Required to Learn an Appetitively-Reinforced Operant Task in Drosophila
Authors: Wiggin Timothy D. , Hsiao Yungyi , Liu Jeffrey B. , Huber Robert , Griffith Leslie C.
Published: June 2021

Maladaptive operant conditioning contributes to development of neuropsychiatric disorders. Candidate genes have been identified that contribute to this maladaptive plasticity, but the neural basis of operant conditioning in genetic model organisms remains poorly understood. The fruit flyDrosophila melanogasteris a versatile genetic model organism that readily forms operant associations with punishment stimuli. However, operant conditioning with a food reward has not been demonstrated in flies, limiting the types of neural circuits that can be studied. Here we present the first sucrose-reinforced operant conditioning paradigm for flies. In the paradigm, flies walk along a Y-shaped track with reward locations at the terminus of each hallway. When flies turn in the reinforced direction at the center of the track, they receive a sucrose reward at the end of the hallway. Only flies that rest early in training learn the reward contingency normally. Flies rewarded independently of their behavior do not form a learned association but have the same amount of rest as trained flies, showing that rest is not driven by learning. Optogenetically-induced sleep does not promote learning, indicating that sleep itself is not sufficient for learning the operant task. We validated the sensitivity of this assay to detect the effect of genetic manipulations by testing the classic learning mutantdunce. Dunceflies are learning-impaired in the Y-Track task, indicating a likely role for cAMP in the operant coincidence detector. This novel training paradigm will provide valuable insight into the molecular mechanisms of disease and the link between sleep and learning.
Social Housing Leads to Increased Ethanol Intake in Male Mice Housed in Environmentally Enriched Cages
Authors: Fulenwider Hannah D. , Robins Meridith T. , Caruso Maya A. , Ryabinin Andrey E.
Published: June 2021

An individual's social environment affects alcohol intake. However, the complex interactions between social context and alcohol intake remain understudied in preclinical models. In the present study, we sought to characterize the effects of social housing on voluntary ethanol intake in male C567BL/6J mice using a continuous access two-bottle choice model. This was accomplished using HM2 cages, which allow for the continuous monitoring of individuals' fluid intake through radiofrequency tracking while they remain undisturbed in a group setting. These cages are moderately environmentally enriched compared to standard shoebox cages. By analyzing the levels of voluntary ethanol intake between socially- and individually-housed mice in HM2 cages, we were able to parse apart the effects of environmental enrichment vs. social enrichment. We found that while intake levels were overall lower than those observed when animals are singly housed in standard shoebox cages, socially-housed males consumed significantly more ethanol compared to individually-housed mice, suggesting that while environmental enrichment attenuates ethanol intake, social enrichment may, in fact, potentiate it. This effect was not specific for alcohol, however, in that ethanol preference did not differ as a product of social context. We also found that the total number of non-consummatory channel entries were consistently higher in individually-housed mice. Additionally, a single corticotropin releasing factor receptor 1 antagonist treatment significantly decreased both water and ethanol intake in socially- and individually-housed mice up to 3 h post-treatment, though the effect on water intake was longer lasting. This treatment also significantly decreased the number of non-consummatory channel entries in individually-housed mice, but not in socially-housed mice, suggesting that increased channel visits may be a stress-related behavior. Lastly, we examined blood ethanol concentrations and FosB immunoreactivity to characterize the physiological responses to ethanol intake in socially- and individually-housed mice. The number of FosB-positive cells in the centrally-projecting Edinger-Westphal nucleus and nucleus accumbens shell positively correlated with average baseline ethanol intake in individually-housed mice, but not in socially-housed mice. Overall, we found that social, but not environmental, enrichment can increase ethanol intake in male C57BL/6J mice. Future studies need to test this phenomenon in female mice and assess the generalizability of this finding.
New-Onset Postoperative Seizures in Patients With Diffuse Gliomas: A Risk Assessment Analysis
Authors: Li Lianwang , Li Guanzhang , Fang Shengyu , Zhang Kenan , Huang Ruoyu , Wang Yinyan , Zhang Chuanbao , Li Yiming , Zhang Wei , Zhang Zhong , Jin Qiang , Zhou Dabiao , Fan Xing , Jiang Tao
Published: June 2021

Background: Glioma-related epilepsy (GRE) is the most common presenting sign of patients with diffuse glioma. According to clinical experience, new-onset postoperative seizures can be observed even in patients without preoperative GRE. The current study mainly aimed to explore the risk factors of new-onset postoperative seizures in those patients. In addition, the prognostic value of new-onset postoperative seizures was also discussed.

Methods: Data of 313 patients without GRE were retrospectively reviewed. Chi-square test or Fisher's exact test were first performed to compare categorical variables between patients with new-onset postoperative seizures and those without. Subsequently, binary logistic regression analysis was conduct to further assess risk factors of new-onset postoperative seizures. Kaplan-Meier and Cox analysis were used to investigate the prognostic value of new-onset postoperative seizures for progression-free survival (PFS) and overall survival (OS).

Results: Patients with low-grade tumors (p = 0.006), isocitrate dehydrogenase 1 (IDH1) mutation (p = 0.040) or low Ki-67 expression (p = 0.005) showed a higher incidence of new-onset postoperative seizures. IDH1 mutation was identified as the only independent predictor for new-onset postoperative seizures (OR, 2.075; 95% CI, 1.051–4.098; p = 0.035). Additionally, new-onset postoperative seizure occurrence was demonstrated as an independent predicter of prolonged OS (OR, 0.574; 95% CI, 0.335–0.983; p = 0.043), while younger age, gross total resection, low-grade and IDH1 mutation were independently correlated with prolonged OS and PFS.

Conclusions: IDH1 mutation is an independent predictor for new-onset postoperative seizures in patients without preoperative GRE. Moreover, new-onset postoperative seizures can independently predict prolonged OS in those patients. The results of the current study can contribute to improving the individualized management of diffuse glioma.
Using the Flexor Reflex in a Chronic Stroke Patient for Gait Improvement: A Case Report
Authors: Salzmann Christian , Sehle Aida , Liepert Joachim
Published: June 2021

The flexor reflex or withdrawal reflex can be elicited by electrical stimulation of the sole of the foot, which serves as a reflex to protect the stimulated limb against tissue damage and consists of flexion movements in the hip, knee, and ankle joint. Triggering this reflex might improve walking abilities in hemiparetic patients. We report the first case of a chronic stroke patient with the most severe impairment of walking. She was examined with and without flexor reflex activation by the Incedo® system. Tests included a 10-m walk and a 2-min walk at baseline, after 3 weeks of training with the Incedo® system and after a follow-up 3 weeks later. Moreover, a kinematic gait analysis was done before and after the training period. At baseline, activation of the flexor reflex induced an improved gait velocity. After the training period, the patient walked twice as fast compared with baseline. Her gait velocity without Incedo® was faster than the gait velocity with Incedo® at baseline. Examination at follow-up indicated that the improvements remained almost unchanged. The kinematic analysis showed an improved stride length and gait velocity during flexor reflex activation. Initially, the foot was elevated higher above the ground during flexor reflex activation. In conclusion, this first case report of a chronic stroke patient demonstrates that flexor reflex activation is feasible and improves gait parameters despite severe impairment of walking abilities.
Key Intrinsic Connectivity Networks for Individual Identification With Siamese Long Short-Term Memory
Authors: Park Yeong-Hun , Shin Seong A. , Kim Seonggyu , Lee Jong-Min
Published: June 2021

In functional magnetic resonance imaging (fMRI) analysis, many studies have been conducted on inter-subject variability as well as intra-subject reproducibility. These studies indicate that fMRI could have unique characteristics for individuals. In this study, we hypothesized that the dynamic information during 1 min of fMRI was unique and repetitive enough for each subject, so we applied long short-term memory (LSTM) using initial time points of dynamic resting-state fMRI for individual identification. Siamese network is used to obtain robust individual identification performance without additional learning on a new dataset. In particular, by adding a new structure called region of interest–wise average pooling (RAP), individual identification performance could be improved, and key intrinsic connectivity networks (ICNs) for individual identification were also identified. The average performance of individual identification was 97.88% using the test dataset in eightfold cross-validation analysis. Through the visualization of features learned by Siamese LSTM with RAP, ICNs spanning the parietal region were observed as the key ICNs in identifying individuals. These results suggest the key ICNs in fMRI could represent individual uniqueness.
COVID-19: Sleep, Circadian Rhythms and Immunity – Repurposing Drugs and Chronotherapeutics for SARS-CoV-2
Authors: Giri Allan , Srinivasan Ashokkumar , Sundar Isaac Kirubakaran
Published: June 2021

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has affected nearly 28 million people in the United States and has caused more than five hundred thousand deaths as of February 21, 2021. As the novel coronavirus continues to take its toll in the United States and all across the globe, particularly among the elderly (>65 years), clinicians and translational researchers are taking a closer look at the nexus of sleep, circadian rhythms and immunity that may contribute toward a more severe coronavirus disease-19 (COVID-19). SARS-CoV-2-induced multi-organ failure affects both central and peripheral organs, causing increased mortality in the elderly. However, whether differences in sleep, circadian rhythms, and immunity between older and younger individuals contribute to the age-related differences in systemic dysregulation of target organs observed in SARS-CoV-2 infection remain largely unknown. Current literature demonstrates the emerging role of sleep, circadian rhythms, and immunity in the development of chronic pulmonary diseases and respiratory infections in human and mouse models. The exact mechanism underlying acute respiratory distress syndrome (ARDS) and other cardiopulmonary complications in elderly patients in combination with associated comorbidities remain unclear. Nevertheless, understanding the critical role of sleep, circadian clock dysfunction in target organs, and immune status of patients with SARS-CoV-2 may provide novel insights into possible therapies. Chronotherapy is an emerging concept that is gaining attention in sleep medicine. Accumulating evidence suggests that nearly half of all physiological functions follow a strict daily rhythm. However, healthcare professionals rarely take implementing timed-administration of drugs into consideration. In this review, we summarize recent findings directly relating to the contributing roles of sleep, circadian rhythms and immune response in modulating infectious disease processes, and integrate chronotherapy in the discussion of the potential drugs that can be repurposed to improve the treatment and management of COVID-19.