bluuebunny/crossref_metadata_2025 huggingface dataset:
Volatile Organic Compounds Produced by Human Pathogenic Fungi Are Toxic to Drosophila melanogaster
Authors: Almaliki Hadeel S. , Angela Astrid , Goraya Nayab J. , Yin Guohua , Bennett Joan W.
Published: January 2021

Volatile organic compounds (VOCs) are low molecular mass organic compounds that easily evaporate at room temperature. Fungi produce diverse mixtures of VOCs, some of which may contribute to “sick building syndrome,” and which have been shown to be toxigenic in a variety of laboratory bioassays. We hypothesized that VOCs from medically important fungi might be similarly toxigenic and tested strains ofAspergillus fumigatus, Candida albicans, Cryptococcus neoformans, Cryptococcus gattii, andSaccharomyces cerevisiaein aDrosophila melanogastereclosion bioassay. Fungi were grown in a shared microhabitat with third instar larvae ofD. melanogastersuch that there was no physical contact between flies and fungi. As the flies went through metamorphosis, the numbers of larvae, pupae, and adults were counted daily for 15 days. After 8 days, ~80% of controls had eclosed into adults and after 15 days the controls yielded 96–97% eclosion. In contrast, eclosion rates at 8 days were below 70% for flies exposed to VOCs from six differentA. fumigatusstrains; the eclosion rate at 15 days was only 58% for flies exposed to VOCs fromA. fumigatusstrain SRRC 1607. When flies were grown in a shared atmosphere with VOCs fromS. cerevisiae, after 15 days, 82% of flies had eclosed into adults. Exposure to the VOCs from the medically important yeasts Candida albicans, Cryptococcus neoformans, andCryptococcus gattiicaused significant delays in metamorphosis with eclosion rates of 58% forCandida albicans, 44% forCryptococcus neoformans, and 56% forCryptococcus gattii. Using gas chromatography-mass spectrometry, the VOCs from the most toxic and least toxic strains ofA. fumigatuswere assayed. The two most common VOCs produced by both strains were 1-octen-3-ol and isopentyl alcohol; however, these compounds were produced in 10-fold higher concentrations by the more toxic strain. Our research demonstrates that gas phase compounds emitted by fungal pathogens may have been overlooked as contributing to the pathogenicity of medically important fungi and therefore deserve more scrutiny by the medical mycology research community.
Hierarchical Microbial Functions Prediction by Graph Aggregated Embedding
Authors: Hou Yujie , Zhang Xiong , Zhou Qinyan , Hong Wenxing , Wang Ying
Published: January 2021

Matching 16S rRNA gene sequencing data to a metabolic reference database is a meaningful way to predict the metabolic function of bacteria and archaea, bringing greater insight to the working of the microbial community. However, some operational taxonomy units (OTUs) cannot be functionally profiled, especially for microbial communities from non-human samples cultured in defective media. Therefore, we herein report the development of Hierarchical micrObial functions Prediction by graph aggregated Embedding (HOPE), which utilizes co-occurring patterns and nucleotide sequences to predict microbial functions. HOPE integrates topological structures of microbial co-occurrence networks with k-mer compositions of OTU sequences and embeds them into a lower-dimensional continuous latent space, while maximally preserving topological relationships among OTUs. The high imbalance among KEGG Orthology (KO) functions of microbes is recognized in our framework that usually yields poor performance. A hierarchical multitask learning module is used in HOPE to alleviate the challenge brought by the long-tailed distribution among classes. To test the performance of HOPE, we compare it with HOPE-one, HOPE-seq, and GraphSAGE, respectively, in three microbial metagenomic 16s rRNA sequencing datasets, including abalone gut, human gut, and gut of Penaeus monodon. Experiments demonstrate that HOPE outperforms baselines on almost all indexes in all experiments. Furthermore, HOPE reveals significant generalization ability. HOPE's basic idea is suitable for other related scenarios, such as the prediction of gene function based on gene co-expression networks. The source code of HOPE is freely available at https://github.com/adrift00/HOPE.
Moonlighting Proteins Are Important Players in Cancer Immunology
Authors: Adamo Annalisa , Frusteri Cristina , Pallotta Maria Teresa , Pirali Tracey , Sartoris Silvia , Ugel Stefano
Published: January 2021

Plasticity and adaptation to environmental stress are the main features that tumor and immune system share. Except for intrinsic and high-defined properties, cancer and immune cells need to overcome the opponent’s defenses by activating more effective signaling networks, based on common elements such as transcriptional factors, protein-based complexes and receptors. Interestingly, growing evidence point to an increasing number of proteins capable of performing diverse and unpredictable functions. These multifunctional proteins are defined as moonlighting proteins. During cancer progression, several moonlighting proteins are involved in promoting an immunosuppressive microenvironment by reprogramming immune cells to support tumor growth and metastatic spread. Conversely, other moonlighting proteins support tumor antigen presentation and lymphocytes activation, leading to several anti-cancer immunological responses. In this light, moonlighting proteins could be used as promising new potential targets for improving current cancer therapies. In this review, we describe in details 12 unprecedented moonlighting proteins that during cancer progression play a decisive role in guiding cancer-associated immunomodulation by shaping innate or adaptive immune response.
Comparative Proteomics of Ostreid Herpesvirus 1 and Pacific Oyster Interactions With Two Families Exhibiting Contrasted Susceptibility to Viral Infection
Authors: Leprêtre Maxime , Faury Nicole , Segarra Amélie , Claverol Stéphane , Degremont Lionel , Palos-Ladeiro Mélissa , Armengaud Jean , Renault Tristan , Morga Benjamin
Published: January 2021

Massive mortality outbreaks affecting Pacific oysters (Crassostrea gigas) spat/juveniles are often associated with the detection of a herpesvirus called ostreid herpesvirus type 1 (OsHV-1). In this work, experimental infection trials of C. gigas spat with OsHV-1 were conducted using two contrasted Pacific oyster families for their susceptibility to viral infection. Live oysters were sampled at 12, 26, and 144 h post infection (hpi) to analyze host-pathogen interactions using comparative proteomics. Shotgun proteomics allowed the detection of seven viral proteins in infected oysters, some of them with potential immunomodulatoy functions. Viral proteins were mainly detected in susceptible oysters sampled at 26 hpi, which correlates with the mortality and viral load observed in this oyster family. Concerning the Pacific oyster proteome, more than 3,000 proteins were identified and contrasted proteomic responses were observed between infected A- and P-oysters, sampled at different post-injection times. Gene ontology (GO) and KEGG pathway enrichment analysis performed on significantly modulated proteins uncover the main immune processes (such as RNA interference, interferon-like pathway, antioxidant defense) which contribute to the defense and resistance of Pacific oysters to viral infection. In the more susceptible Pacific oysters, results suggest that OsHV-1 manipulate the molecular machinery of host immune response, in particular the autophagy system. This immunomodulation may lead to weakening and consecutively triggering death of Pacific oysters. The identification of several highly modulated and defense-related Pacific oyster proteins from the most resistant oysters supports the crucial role played by the innate immune system against OsHV-1 and the viral infection. Our results confirm the implication of proteins involved in an interferon-like pathway for efficient antiviral defenses and suggest that proteins involved in RNA interference process prevent viral replication in C. gigas. Overall, this study shows the interest of multi-omic approaches applied on groups of animals with differing sensitivities and provides novel insight into the interaction between Pacific oyster and OsHV-1 with key proteins involved in viral infection resistance.
Fine-Tuning Climate Resilience in Marine Socio-Ecological Systems: The Need for Accurate Space-Time Representativeness to Identify Relevant Consequences and Responses
Authors: Saldívar-Lucio Romeo , Trasviña-Castro Armando , Jiddawi Narriman , Chuenpagdee Ratana , Lindström Lars , Jentoft Svein , Fraga Julia , de la Torre-Castro Maricela
Published: January 2021

Climate change triggers a wide mosaic of regional and local responses, often different to the large-scale variability in magnitude and direction. Because of the psychological connections (cognitive and emotional) with the frequency, intensity and age of a climatic event, people may have the capacity to recognize key variations at lower scales, especially those from which they perceive risk. Yet, the anticipatory actions and social engagement to respond or adapt to climate change are difficult to achieve, mostly when there exists a long psychological distance to climatic phenomena. Research about climate change communication provides clues about the relevance of place-based discussion to gauge risk perception and improve response protocols, their design and prioritization. It argues that strategies and actions required to face climate risks may widely differ depending on the scale and accuracy of the local representations displayed during discussions of climate impacts. This work examines how local attributes (from climate to social) operate and control place-specific risks and priorities, by comparing coastal communities in two locations, Cabo Pulmo, Mexico and Zanzibar, Tanzania, which are subject to different climate dynamics. This paper discusses the need to identify relevant climate risks/responses at the local level and how psycho-social factors (e.g., psychological distance, collective memory, and social engagement) may operate positively for building climate resilience. We also illustrate a workflow to increase and enhance collaboration between researchers and local people by promoting dialogue, participation and narratives that rigorously consider the local knowledge.
The Scale, Collections, and Biospecimen Distribution of Grade A Tertiary Hospital Biobanks in China: A National Survey
Authors: Chen Yuanyuan , Sang Chao , Bian Zhouliang , Zhang Yinan , Jiang Erpeng , Zhou Xuexun , Chen Tianlu , Tang Hongming , Wang Congrong
Published: January 2021

Chinese clinical biobanks were built rapidly in grade A tertiary hospitals. However, the general information of biorepositories in China remained largely unknown. The aim of this study was to investigate the size, collections, biospecimens distribution and other characteristics of Chinese biobanks in grade A tertiary hospitals. In 2018, we launched a national survey among biobank leaders to provide a comprehensive understanding of Chinese grade A tertiary hospital biobanks. A total of 70 biobank managers or directors completed an online questionnaire to collect information about the biorepositories. Nearly 20% of biobanks stored over one million specimens, while almost one-third of biobanks stored 50–200,000 specimens. In general, plasma and serum were the specimens most commonly stored. For the use of collections, biospecimens were most commonly applied by internal clinical departments. Further analyses revealed that the large-scale biobanks were characterized by earlier establishment, more types of specimens in storage and distribution compared with small-scale biobanks. Moreover, specimens in large-scale biobanks were more commonly used for basic research (62.86% vs. 34.29%, P = 0.017) and clinical research (57.14% vs. 28.57%, P = 0.016). Large-scale biobanks also had more opportunities to cooperate with domestic research institutes (34.29% vs. 5.71%, P = 0.003). Our survey revealed diversity in collections, distribution and utilization of biospecimens among Chinese grade A tertiary hospital biobanks. Although the biobanks had relatively large collections, the underutilization of stored biospecimens and lack of sharing could hamper clinical and biological research.
Seasonal Changes in Pinus tabuliformis Root-Associated Fungal Microbiota Drive N and P Cycling in Terrestrial Ecosystem
Authors: Wang Hai-Hua , Chu Hong-Long , Dou Qing , Feng Huan , Tang Ming , Zhang Shuo-Xin , Wang Chun-Yan
Published: January 2021

In terrestrial ecosystems, mycorrhizal roots play a key role in the cycling of soil carbon (C) and other nutrients. The impact of environmental factors on the mycorrhizal fungal community has been well studied; however, the seasonal variations in the root-associated fungal microbiota affected by environmental changes are less clear. To improve the understanding of how environmental factors shape the fungal microbiota in mycorrhizal roots, seasonal changes in Pinus tabuliformis root-associated fungi were investigated. In the present study, the seasonal dynamics of edaphic properties, soil enzymatic activities, root fungal colonization rates, and root-associated fungal microbiota in P. tabuliformis forests were studied across four seasons during a whole year to reveal their correlations with environmental changes. The results indicate that the soil functions, such as the enzymatic activities related to nitrogen (N) and phosphorus (P) degradation, were varied with the seasonal changes in microclimate factors, resulting in a significant fluctuation of edaphic properties. In addition, the ectomycorrhizal fungal colonization rate in the host pine tree roots increased during warm seasons (summer and autumn), while the fungal colonization rate of dark septate endophyte was declined. Moreover, the present study indicates that the fungal biomass increased in both the pine roots and rhizospheric soils during warm seasons, while the fungal species richness and diversity decreased. While the Basidiomycota and Ascomycota were the two dominant phyla in both root and soil fungal communities, the higher relative abundance of Basidiomycota taxa presented in warm seasons. In addition, the fungal microbial network complexity declined under the higher temperature and humidity conditions. The present study illustrates that the varieties in connectivity between the microbial networks and in functional taxa of root-associated fungal microbiota significantly influence the soil ecosystem functions, especially the N and P cycling.
Shift and Metabolic Potentials of Microbial Eukaryotic Communities Across the Full Depths of the Mariana Trench
Authors: Zhu Xiao-Yu , Liu Jiwen , Xue Chun-Xu , Tian Jiwei , Zhang Xiao-Hua
Published: January 2021

Microbial eukaryotes are widespread and play important roles in marine ecosystems. However, their ecological characteristics in the deep sea (>1,000 m), especially hadal trenches, were largely unknown. Here, we investigated the diversity and metabolic potentials of microbial eukaryotes along the whole water column of the Mariana Trench by metagenomics. Our results showed clear depth-related distribution of microbial eukaryotic community and associated metabolic potentials. Surface seawater was dominated by phototrophic/mixotrophic groups (e.g., Dinoflagellata) and genes involved in biosynthesis (photosynthesis and fatty acid biosynthesis), while deep (bathypelagic and/or hadal) seawaters were enriched with heterotrophic groups (e.g., Bicoecea) and genes related to digestion (lysosomal enzymes and V-type ATPase) and carbohydrate metabolism. Co-occurrence analysis revealed high intra-domain connectivity, indicating that microbial eukaryotic composition was more influenced by microbial eukaryotes themselves than bacteria. Increased abundance of genes associated with unsaturated fatty acid biosynthesis likely plays a role in resisting high hydrostatic pressure. Top1 and hupB genes, responsible for the formation and stabilization of DNA structure, were unique and abundant in the hadal zone and thus may be helpful to stabilize DNA structure in the deep sea. Overall, our results provide insights into the distribution and potential adaptability of microbial eukaryotes in the hadal zone.
Co-dependent and Interdigitated: Dual Quorum Sensing Systems Regulate Conjugative Transfer of the Ti Plasmid and the At Megaplasmid in Agrobacterium tumefaciens 15955
Authors: Barton Ian S. , Eagan Justin L. , Nieves-Otero Priscila A. , Reynolds Ian P. , Platt Thomas G. , Fuqua Clay
Published: January 2021

Members of the Rhizobiaceae, often carry multiple secondary replicons in addition to the primary chromosome with compatible repABC-based replication systems. Unlike secondary chromosomes and chromids, repABC-based megaplasmids and plasmids can undergo copy number fluctuations and are capable of conjugative transfer in response to environmental signals. Several Agrobacterium tumefaciens lineages harbor three secondary repABC-based replicons, including a secondary chromosome (often linear), the Ti (tumor-inducing) plasmid and the At megaplasmid. The Ti plasmid is required for virulence and encodes a conjugative transfer (tra) system that is strictly regulated by a subset of plant-tumor released opines and a well-described acyl-homoserine lactone (AHL)-based quorum-sensing mechanism. The At plasmids are generally not required for virulence, but carry genes that enhance rhizosphere survival, and these plasmids are often conjugatively proficient. We report that the At megaplasmid of the octopine-type strain A. tumefaciens 15955 encodes a quorum-controlled conjugation system that directly interacts with the paralogous quorum sensing system on the co-resident Ti plasmid. Both the pAt15955 and pTi15955 plasmids carry homologs of a TraI-type AHL synthase, a TraR-type AHL-responsive transcription activator, and a TraM-type anti-activator. The traI genes from both pTi15955 and pAt15955 can direct production of the inducing AHL (3-octanoyl-L-homoserine lactone) and together contribute to the overall AHL pool. The TraR protein encoded on each plasmid activates AHL-responsive transcription of target tra gene promoters. The pAt15955 TraR can cross-activate tra genes on the Ti plasmid as strongly as its cognate tra genes, whereas the pTi15955 TraR is preferentially biased toward its own tra genes. Putative tra box elements are located upstream of target promoters, and comparing between plasmids, they are in similar locations and share an inverted repeat structure, but have distinct consensus sequences. The two AHL quorum sensing systems have a combinatorial effect on conjugative transfer of both plasmids. Overall, the interactions described here have implications for the horizontal transfer and evolutionary stability of both plasmids and, in a broad sense, are consistent with other repABC systems that often have multiple quorum-sensing controlled secondary replicons.
Considerations for Phage Therapy Against Mycobacterium abscessus
Authors: Senhaji-Kacha Abrar , Esteban Jaime , Garcia-Quintanilla Meritxell
Published: January 2021

There is a global increasing number of Mycobacterium abscessus infections, especially pulmonary infections. Reduced therapeutic options exist against this opportunistic pathogen due to its high intrinsic and acquired levels of antibiotic resistance. Phage therapy is a promising afresh therapy, which uses viruses to lyse bacteria responsible for the infection. Bacteriophages have been recently administered under compassionate use to a 15-year-old patient infected with M. abscessus in combination with antibiotics with excellent results. This mini review highlights different recommendations for future phage administrations such as where to look for new phages, the use of cocktail of mycobacteriophages to broaden phage specificity and to tackle resistance and phage insensitivity due to temperate phages present in bacterial genomes, the combined use of phages and antibiotics to obtain a synergistic effect, the liposomal administration to reach a prolonged effect, intracellular delivery and protection against neutralizing antibodies, and the convenience of using this strategy in patients suffering from cystic fibrosis (CF) since phages are believed to promote immunomodulatory actions and eliminate biofilms.
Functional Analysis and Genome Mining Reveal High Potential of Biocontrol and Plant Growth Promotion in Nodule-Inhabiting Bacteria Within Paenibacillus polymyxa Complex
Authors: Ali Md. Arshad , Lou Yang , Hafeez Rahila , Li Xuqing , Hossain Afsana , Xie Ting , Lin Li , Li Bin , Yin Yanni , Yan Jianli , An Qianli
Published: January 2021

Bacteria belonging to the genus Paenibacillus were frequently isolated from legume nodules. The nodule-inhabiting Paenibacillus as a resource of biocontrol and plant growth-promoting endophytes has rarely been explored. This study explored the nodule-inhabiting Paenibacillus’ antifungal activities and biocontrol potentials against broad-spectrum important phytopathogenic fungi. We collected strains which were isolated from nodules of Robinia pseudoacacia, Dendrolobium triangulare, Ormosia semicastrata, Cicer arietinum, Acacia crassicarpa, or Acacia implexa and belong to P. peoriae, P. kribbensis, P. endophyticus, P. enshidis, P. puldeungensis, P. taichungensis, or closely related to P. kribbensis, or P. anseongense. These nodule-inhabiting Paenibacillus showed diverse antagonistic activities against five phytopathogenic fungi (Fusarium graminearum, Magnaporthe oryzae, Rhizoctonia solani, Sclerotinia sclerotiorum, and Botrytis cinerea). Six strains within the P. polymyxa complex showed broad-spectrum and potent activities against all the five pathogens, and produced multiple hydrolytic enzymes, siderophores, and lipopeptide fusaricidins. Fusaricidins are likely the key antimicrobials responsible for the broad-spectrum antifungal activities. The nodule-inhabiting strains within the P. polymyxa complex were able to epiphytically and endophytically colonize the non-host wheat plants, produce indole acetic acids (IAA), and dissolve calcium phosphate and calcium phytate. P. peoriae strains RP20, RP51, and RP62 could fix N2. P. peoriae RP51 and Paenibacillus sp. RP31, which showed potent plant colonization and plant growth-promotion competence, effectively control fungal infection in planta. Genome mining revealed that all strains (n = 76) within the P. polymyxa complex contain ipdC gene encoding indole-3-pyruvate decarboxylase for biosynthesis of IAA, 96% (n = 73) contain the fus cluster for biosynthesis of fusaricidins, and 43% (n = 33) contain the nif cluster for nitrogen fixation. Together, our study highlights that endophytic strains within the P. polymyxa complex have a high probability to be effective biocontrol agents and biofertilizers and we propose an effective approach to screen strains within the P. polymyxa complex.
Laccase Immobilization Strategies for Application as a Cathode Catalyst in Microbial Fuel Cells for Azo Dye Decolourization
Authors: Mani Priyadharshini , Fidal V. T. , Keshavarz Taj , Chandra T. S. , Kyazze Godfrey
Published: January 2021

Enzymatic biocathodes have the potential to replace platinum as an expensive catalyst for the oxygen reduction reaction in microbial fuel cells (MFCs). However, enzymes are fragile and prone to loss of activity with time. This could be circumvented by using suitable immobilization techniques to maintain the activity and increase longevity of the enzyme. In the present study, laccase from Trametes versicolor was immobilized using three different approaches, i.e., crosslinking with electropolymerized polyaniline (PANI), entrapment in copper alginate beads (Cu-Alg), and encapsulation in Nafion micelles (Nafion), in the absence of redox mediators. These laccase systems were employed in cathode chambers of MFCs for decolourization of Acid orange 7 (AO7) dye. The biocatalyst in the anode chamber was Shewanella oneidensis MR-1 in each case. The enzyme in the immobilized states was compared with freely suspended enzyme with respect to dye decolourization at the cathode, enzyme activity retention, power production, and reusability. PANI laccase showed the highest stability and activity, producing a power density of 38 ± 1.7 mW m−2 compared to 25.6 ± 2.1 mW m−2 for Nafion laccase, 14.7 ± 1.04 mW m−2 for Cu-Alg laccase, and 28 ± 0.98 mW m−2 for the freely suspended enzyme. There was 81% enzyme activity retained after 1 cycle (5 days) for PANI laccase compared to 69% for Nafion and 61.5% activity for Cu-alginate laccase and 23.8% activity retention for the freely suspended laccase compared to initial activity. The dye decolourization was highest for freely suspended enzyme with over 85% decolourization whereas for PANI it was 75.6%, Nafion 73%, and 81% Cu-alginate systems, respectively. All the immobilized laccase systems were reusable for two more cycles. The current study explores the potential of laccase immobilized biocathode for dye decolourization in a microbial fuel cell.
Physicochemical Characteristics and Microbial Communities in Gochujang, a Traditional Korean Fermented Hot Pepper Paste
Authors: Ryu Jung-A , Kim Eiseul , Kim Mi-Ju , Lee Shinyoung , Yoon Sung-Ran , Ryu Jung-gi , Kim Hae-Yeong
Published: January 2021

Gochujang is a Korean fermented hot pepper paste beneficial to human health by providing various nutrients. In this study, its physicochemical characteristics were identified, and its microbial communities were analyzed by high-throughput sequencing. The interrelationship between physicochemical characteristics and microbial composition was investigated to reveal the properties of gochujang before and after fermentation. After fermentation, all samples showed decreased salt concentration, pH, and reducing sugar content, while the acidity and amino-type nitrogen increased. The water content, salt concentration, amino-type nitrogen, and reducing sugar differed according to the batches of samples. Bacillus, Aerosakkonema, and Enterococcus were identified as the predominant bacterial genera. Furthermore, Aerosakkonema was the most abundant genus before fermentation; however, it was replaced by Bacillus as it decreased after fermentation. For the fungi, Aspergillus dominated before fermentation, whereas Zygosaccharomyces and Millerozyma dominated after fermentation. The high level of amino-type nitrogen in gochujang was related to the relative abundance of B. haynesii/B. licheniformis before fermentation. Additionally, the high abundance of Z. rouxii after fermentation was related to the flavor of gochujang. This comprehensive analysis of the microbial community associated with the physicochemical properties of gochujang could help in understanding the factors affecting the quality of the product.
Metabolic Phenotypes as Potential Biomarkers for Linking Gut Microbiome With Inflammatory Bowel Diseases
Authors: Iablokov Stanislav N. , Klimenko Natalia S. , Efimova Daria A. , Shashkova Tatiana , Novichkov Pavel S. , Rodionov Dmitry A. , Tyakht Alexander V.
Published: January 2021

The gut microbiome is of utmost importance to human health. While a healthy microbiome can be represented by a variety of structures, its functional capacity appears to be more important. Gene content of the community can be assessed by “shotgun” metagenomics, but this approach is still too expensive. High-throughput amplicon-based surveys are a method of choice for large-scale surveys of links between microbiome, diseases, and diet, but the algorithms for predicting functional composition need to be improved to achieve good precision. Here we show how feature engineering based on microbial phenotypes, an advanced method for functional prediction from 16S rRNA sequencing data, improves identification of alterations of the gut microbiome linked to the disease. We processed a large collection of published gut microbial datasets of inflammatory bowel disease (IBD) patients to derive their community phenotype indices (CPI)—high-precision semiquantitative profiles aggregating metabolic potential of the community members based on genome-wide metabolic reconstructions. The list of selected metabolic functions included metabolism of short-chain fatty acids, vitamins, and carbohydrates. The machine-learning approach based on microbial phenotypes allows us to distinguish the microbiome profiles of healthy controls from patients with Crohn's disease and from ones with ulcerative colitis. The classifiers were comparable in quality to conventional taxonomy-based classifiers but provided new findings giving insights into possible mechanisms of pathogenesis. Feature-wise partial dependence plot (PDP) analysis of contribution to the classification result revealed a diversity of patterns. These observations suggest a constructive basis for defining functional homeostasis of the healthy human gut microbiome. The developed features are promising interpretable candidate biomarkers for assessing microbiome contribution to disease risk for the purposes of personalized medicine and clinical trials.
Age-Associated Differences of Modules and Hubs in Brain Functional Networks
Authors: Zhang Yinghui , Wang Yin , Chen Nan , Guo Man , Wang Xiuzhen , Chen Guangcai , Li Yongchao , Yang Lin , Li Shan , Yao Zhijun , Hu Bin
Published: January 2021

Healthy aging is usually accompanied by changes in the functional modular organization of the human brain, which may result in the decline of cognition and underlying brain dysfunction. However, the relationship between age-related brain functional modular structure differences and cognition remain debatable. In this study, we investigated the age-associated differences of modules and hubs from young, middle and old age groups, using resting-state fMRI data from a large cross-sectional adulthood sample. We first divided the subjects into three age groups and constructed an individual-level network for each subject. Subsequently, a module-guided group-level network construction method was applied to form a weighted network for each group from which functional modules were detected. The intra- and inter-modular connectivities were observed negatively correlated with age. According to the detected modules, we found the number of connector hubs in the young group was more than middle-age and old group, while the quantity of provincial hubs in middle-age group was discovered more than other two groups. Further ROI-wise analysis shows that different hubs have distinct age-associated trajectories of intra- and inter-modular connections, which suggests the different types of topological role transitions in functional networks across age groups. Our results indicated an inverse association between functional segregation/integration with age, which demonstrated age-associated differences in communication effeciency. This study provides a new perspective and useful information to better understand the normal aging of brain networks.
Microvascular Alterations in Alzheimer's Disease
Authors: Steinman Joe , Sun Hong-Shuo , Feng Zhong-Ping
Published: January 2021

Alzheimer's disease (AD) is a neurodegenerative disorder associated with continual decline in cognition and ability to perform routine functions such as remembering familiar places or understanding speech. For decades, amyloid beta (Aβ) was viewed as the driver of AD, triggering neurodegenerative processes such as inflammation and formation of neurofibrillary tangles (NFTs). This approach has not yielded therapeutics that cure the disease or significant improvements in long-term cognition through removal of plaques and Aβ oligomers. Some researchers propose alternate mechanisms that drive AD or act in conjunction with amyloid to promote neurodegeneration. This review summarizes the status of AD research and examines research directions including and beyond Aβ, such as tau, inflammation, and protein clearance mechanisms. The effect of aging on microvasculature is highlighted, including its contribution to reduced blood flow that impairs cognition. Microvascular alterations observed in AD are outlined, emphasizing imaging studies of capillary malfunction. The review concludes with a discussion of two therapies to protect tissue without directly targeting Aβ for removal: (1) administration of growth factors to promote vascular recovery in AD; (2) inhibiting activity of a calcium-permeable ion channels to reduce microglial activation and restore cerebral vascular function.
Neurophysiological Changes in the First Year After Cell Transplantation in Sub-acute Complete Paraplegia
Authors: Santamaria Andrea J. , Benavides Francisco D. , Saraiva Pedro M. , Anderson Kimberly D. , Khan Aisha , Levi Allan D. , Dietrich W. Dalton , Guest James D.
Published: January 2021

Neurophysiological testing can provide quantitative information about motor, sensory, and autonomic system connectivity following spinal cord injury (SCI). The clinical examination may be insufficiently sensitive and specific to reveal evolving changes in neural circuits after severe injury. Neurophysiologic data may provide otherwise imperceptible circuit information that has rarely been acquired in biologics clinical trials in SCI. We reported a Phase 1 study of autologous purified Schwann cell suspension transplantation into the injury epicenter of participants with complete subacute thoracic SCI, observing no clinical improvements. Here, we report longitudinal electrophysiological assessments conducted during the trial. Six participants underwent neurophysiology screening pre-transplantation with three post-transplantation neurophysiological assessments, focused on the thoracoabdominal region and lower limbs, including MEPs, SSEPs, voluntarily triggered EMG, and changes in GSR. We found several notable signals not detectable by clinical exam. In all six participants, thoracoabdominal motor connectivity was detected below the clinically assigned neurological level defined by sensory preservation. Additionally, small voluntary activations of leg and foot muscles or positive lower extremity MEPs were detected in all participants. Voluntary EMG was most sensitive to detect leg motor function. The recorded MEP amplitudes and latencies indicated a more caudal thoracic level above which amplitude recovery over time was observed. In contrast, further below, amplitudes showed less improvement, and latencies were increased. Intercostal spasms observed with EMG may also indicate this thoracic “motor level.” Galvanic skin testing revealed autonomic dysfunction in the hands above the injury levels. As an open-label study, we can establish no clear link between these observations and cell transplantation. This neurophysiological characterization may be of value to detect therapeutic effects in future controlled studies.
Etiological Approach to Understanding Recanalization Failure in Intracranial Large Vessel Occlusion and Thrombectomy: Close to Embolism but Distant From Atherosclerosis
Authors: Lee Seong-Joon , Park So Young , Hong Ji Man , Choi Jin Wook , Kang Dong-Hun , Kim Yong-Won , Kim Yong-Sun , Hong Jeong-Ho , Kim Chang-Hyun , Yoo Joonsang , Nogueira Raul G. , Hwang Yang-Ha , Sohn Sung-Il , Lee Jin Soo
Published: January 2021

Introduction: In patients with intracranial large vessel occlusion (LVO) who undergo endovascular treatment (EVT), recanalization failure may be related to intracranial atherosclerotic stenosis (ICAS). We evaluated whether the risk factors of recanalization failure could possibly be a marker of ICAS among various types of LVO.

Methods: From a multicenter registry, patients with middle cerebral artery M1 segment occlusions who underwent thrombectomy within 24 h were included. Based on the on-procedure and post-procedure angiographic findings, patients were classified into embolic, ICAS-related, tandem occlusion, and recanalization failure groups. Recanalization failure was defined if the occluded vessel could not be recanalized by stent retrieval, contact aspiration, or local lytics treatment. Risk factors, imaging markers, and EVT methods were compared between groups.

Results: Among 326 patients, 214 were classified as embolism, 76 as ICAS, 16 as tandem, and 20 as recanalization failure. The group with recanalization failure showed higher scores on the National Institutes of Health Stroke Scale (NIHSS) (median, 16.0 vs. 14.5 vs. 14.0 vs. 17.0, p = 0.097), frequent atrial fibrillation (59.3 vs. 18.4 vs. 0 vs. 40.0% p < 0.001), and elevation in erythrocyte sedimentation rate (ESR) (14.5 ± 15.7 vs. 15.0 ± 14.1 vs. 21.2 ± 19.5 vs. 36.0 ± 32.9, p < 0.001) among the groups. The rate of computed tomography angiography-based truncal-type occlusion in recanalization failure group was not as high as that in the ICAS group (8.1 vs. 37.5 vs. 0 vs. 16.7%, p < 0.001). Balloon guide catheters (BGC) were less frequently utilized in the recanalization failure group as compared to their use in the other groups (72.0 vs. 72.4 vs. 62.5 vs. 30.0%, p = 0.001). In the multivariable analysis, initial higher NIHSS [odds ratio (OR), 1.11 95% confidence interval (CI), 1.01–1.22 p = 0.027], higher ESR (OR, 1.03 CI, 1.01–1.05 p = 0.006), and non-use of BGCs (OR, 3.41 CI, 1.14–10.17 p = 0.028) were associated with recanalization failure. In M1 occlusions, the predominant mechanism of recanalization failure was presumed to be embolic in 80% and due to ICAS in 20%.

Conclusion: The analysis of recanalization failures does not suggest an underlying predominant ICAS mechanism. Sufficient utilization of thrombectomy devices and procedures may improve the rates of recanalization.
Pragmatic Profiles of Toddlers With Autism Spectrum Disorder at the Onset of Speech
Authors: Oren Alona , Dromi Esther , Goldberg Sheila , Mimouni-Bloch Aviva
Published: January 2021

Using speech to communicate pragmatic functions is challenging among individuals with Autism Spectrum Disorder (ASD). Given the role language plays in developing everyday skills, we traced the unique pragmatic profile of early words, seeking comparison to typically developing (TD) toddlers at similar lexical stages. Twenty-four mother-toddler dyads participated (9 ASD and 15 TD). Dyads were video recorded when toddlers reached a productive lexicon of 40–70 words. These recordings were captured three times during naturalistic interaction and at two consecutive visits with a 2-month interval. Seven thousand three hundred seventy-six productions were analyzed and classified into four communicative intentions (Declaratives, Requests, Objections, and Non-Communicative speech). ASD toddlers were delayed in the emergence of words compared to TD toddlers, with a greater within-group variability (median 28 months, IQR 24.5–35, median 17 months, IQR 17–18, respectively,p< 0.001). In both groups, the most common communicative intention was Declarative. However, the percentage of Declaratives was higher among TD toddlers across visits compared to ASD toddlers. In both groups, most productions were directed toward the communicative partner, but ASD toddlers used Non-Communicative speech more often than TD peers. Non-Communicative speech gradually decreased over time. We conclude that while TD toddlers begin to talk with an already-established knowledge of the main communicative functions of words, ASD toddlers seem to have only a partial understanding and gradually improve communicative use as they expand their lexicon. These findings bear theoretical and practical implications for early intervention in ASD. We suggest that communicative profiles are affected by individual characteristics and by the interaction style.
Impaired Ganglion Cell Function Objectively Assessed by the Photopic Negative Response in Affected and Asymptomatic Members From Brazilian Families With Leber's Hereditary Optic Neuropathy
Authors: Botelho Gabriel Izan Santos , Salomão Solange Rios , Tengan Célia Harumi , Karanjia Rustum , Moura Felipo Victor , Rocha Daniel Martins , Silva Paula Baptista Eliseo da , Fernandes Arthur Gustavo , Watanabe Sung Eun Song , Sacai Paula Yuri , Belfort Rubens , Carelli Valerio , Sadun Alfredo Arrigo , Berezovsky Adriana
Published: January 2021

Purpose: The photopic negative response (PhNR) is an electrophysiological method that provides retinal ganglion cell function assessment using full-field stimulation that does not require clear optics or refractive correction. The purpose of this study was to assess ganglion cell function by PhNR in affected and asymptomatic carriers from Brazilian families with LHON.

Methods: Individuals either under suspicion or previously diagnosed with LHON and their family members were invited to participate in this cross-sectional study. Screening for the most frequent LHON mtDNA mutations was performed. Visual acuity, color discrimination, visual fields, pattern-reversal visual evoked potentials (PRVEP), full-field electroretinography and PhNR were tested. A control group of healthy subjects was included. Full-field ERG PhNR were recorded using red (640 nm) flashes at 1 cd.s/m2, on blue (470 nm) rod saturating background. PhNR amplitude (μV) was measured using baseline-to-trough (BT). Optical coherence tomography scans of both the retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) were measured. PhNR amplitudes among affected, carriers and controls were compared by Kruskal-Wallis test followed by post-hoc Dunn test. The associations between PhNR amplitude and OCT parameters were analyzed by Spearman rank correlation.

Results: Participants were 24 LHON affected patients (23 males, mean age=30.5 ± 11.4 yrs) from 19 families with the following genotype: m.11778G>A [N = 15 (62%), 14 males]; m.14484T>C [N = 5 (21%), all males] and m.3460G>A [N = 4 (17%), all males] and 14 carriers [13 females, mean age: 43.2 ± 13.3 yrs; m.11778G>A (N = 11); m.3460G>A (N = 2) and m.14484T>C (N = 1)]. Controls were eight females and seven males (mean age: 32.6 ± 11.5 yrs). PhNR amplitudes were significantly reduced (p = 0.0001) in LHON affected (−5.96 ± 3.37 μV) compared to carriers (−16.53 ± 3.40 μV) and controls (−23.91 ± 4.83; p < 0.0001) and in carriers compared to controls (p = 0.01). A significant negative correlation was found between PhNR amplitude and total macular ganglion cell thickness (r = −0.62, p < 0.05). Severe abnormalities in color discrimination, visual fields and PRVEPs were found in affected and subclinical abnormalities in carriers.

Conclusions: In this cohort of Brazilian families with LHON the photopic negative response was severely reduced in affected patients and mildly reduced in asymptomatic carriers suggesting possible subclinical abnormalities in the latter. These findings were similar among pathogenic mutations.
Transmembrane Collagens in Neuromuscular Development and Disorders
Authors: Wakabayashi Tomoko
Published: January 2021

Neuromuscular development is a multistep process and involves interactions among various extracellular and transmembrane molecules that facilitate the precise targeting of motor axons to synaptogenic regions of the target muscle. Collagenous proteins with transmembrane domains have recently emerged as molecules that play essential roles in multiple aspects of neuromuscular formation. Membrane-associated collagens with interrupted triple helices (MACITs) are classified as an unconventional subtype of the collagen superfamily and have been implicated in cell adhesion in a variety of tissues, including the neuromuscular system. Collagen XXV, the latest member of the MACITs, plays an essential role in motor axon growth within the developing muscle. In humans, loss-of-function mutations of collagen XXV result in developmental ocular motor disorders. In contrast, collagen XIII contributes to the formation and maintenance of neuromuscular junctions (NMJs), and disruption of its function leads to the congenital myasthenic syndrome. Transmembrane collagens are conserved not only in mammals but also in organisms such as C. elegans, where a single MACIT, COL-99, has been documented to function in motor innervation. Furthermore, in C. elegans, a collagen-like transmembrane protein, UNC-122, is implicated in the structural and functional integrity of the NMJ. This review article summarizes recent advances in understanding the roles of transmembrane collagens and underlying molecular mechanisms in multiple aspects of neuromuscular development and disorders.
Protective Effect of Lemon Peel Polyphenols on Oxidative Stress-Induced Damage to Human Keratinocyte HaCaT Cells Through Activation of the Nrf2/HO-1 Signaling Pathway
Authors: Gao Xi , Xu Diru , Zhang Xinyue , Zhao Hengguang
Published: January 2021

Lemon peel can be used as traditional Chinese medicine. Flavonoids are the most important components in lemon peel, which can be developed as natural medicine without side effects. This study investigated the protective effect of lemon peel polyphenols (LPP) on human keratinocyte HaCaT cells under oxidative stress. The active components of LPP were determined by high performance liquid chromatography. The abilities of LPP to scavenge DPPH and ABTS+ free radicals were studied for detection of antioxidation in vitro. Cell survival rates were determined by MTT assay. The antioxidant enzyme activity and antioxidant index of cells were determined using kit. The mRNA and protein expression of cells were determined by qPCR and western blot. The ability of LPP to scavenge DPPH and ABTS+ free radicals were stronger than those of vitamin C (Vc) at the same concentration. As expected, compared with the normal group of cells, the model group had decreased cell survival, increased lactate dehydrogenase (LDH), decreased levels of superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH), and increased malondialdehyde (MDA) content. qPCR and western blot results indicated that the expression of Bcl-2-related X protein (Bax), caspases-3, erythroid-derived nuclear factor 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) were decreased and the expression of B-cell lymphoma-2 (Bcl-2) was increased in the model group, compared with the normal group. LPP treatment improved cell survival rate, reduced intracellular LDH and MDA levels, increased intracellular SOD, CAT, GSH levels, down-regulated Bax, caspases-3, Nrf2, HO-1 expression, and up-regulated Bcl-2 expression. Component analyses found that LPP contains gallic acid, neochlorogenic acid, (+)-catechin, caffeic acid, (−)-Catechin gallate, isochlorogenic acid A, rosmarinic acid, and protocatechuic acid. LPP was found to regulate the Nrf2/HO-1 signaling pathway through 8 active substances to protect HaCaT cells against oxidative stress in vitro.