bluuebunny/crossref_metadata_2025 huggingface dataset:
Gut Microbiome as a Potential Biomarker in Fish: Dietary Exposure to Petroleum Hydrocarbons and Metals, Metabolic Functions and Cytokine Expression in Juvenile Lates calcarifer
Authors: Spilsbury Francis , Foysal Md Javed , Tay Alfred , Gagnon Marthe Monique
Published: July 2022

The gut microbiome of fish contains core taxa whose relative abundances are modulated in response to diet, environmental factors, and exposure to toxicogenic chemicals, influencing the health of the host fish. Recent advances in genomics and metabolomics have suggested the potential of microbiome analysis as a biomarker for exposure to toxicogenic compounds. In this 35-day laboratory study, 16S RNA sequencing and multivariate analysis were used to explore changes in the gut microbiome of juvenile Lates calcarifer exposed to dietary sub-lethal doses of three metals: vanadium (20 mg/kg), nickel (480 mg/kg), and iron (470 mg/kg), and to two oils: bunker C heavy fuel oil (HFO) (1% w/w) and Montara, a typical Australian medium crude oil (ACO) (1% w/w). Diversity of the gut microbiome was significantly reduced compared to negative controls in fish exposed to metals, but not petroleum hydrocarbons. The core taxa in the microbiome of negative control fish comprised phyla Proteobacteria (62%), Firmicutes (7%), Planctomycetes (3%), Actinobacteria (2%), Bacteroidetes (1%), and others (25%). Differences in the relative abundances of bacterial phyla of metal-exposed fish were pronounced, with the microbiome of Ni-, V-, and Fe-exposed fish dominated by Proteobacteria (81%), Firmicutes (68%), and Bacteroidetes (48%), respectively. The genus Photobacterium was enriched proportionally to the concentration of polycyclic aromatic hydrocarbons (PAHs) in oil-exposed fish. The probiotic lactic acid bacterium Lactobacillus was significantly reduced in the microbiota of fish exposed to metals. Transcription of cytokines IL-1, IL-10, and TNF-a was significantly upregulated in fish exposed to metals but unchanged in oil-exposed fish compared to negative controls. However, IL-7 was significantly downregulated in fish exposed to V, Ni, Fe, and HFOs. Fish gut microbiome exhibits distinctive changes in response to specific toxicants and shows potential for use as biomarkers of exposure to V, Ni, Fe, and to PAHs present in crude oil.
Antimicrobial resistance surveillance of Escherichia coli from chickens in the Qinghai Plateau of China
Authors: Tang Biao , Wang Jingge , Zheng Xue , Chang Jiang , Ma Jiangang , Wang Juan , Ji Xiaofeng , Yang Hua , Ding Baoan
Published: July 2022

Antimicrobial resistance (AMR) may lead to worldwide epidemics through human activities and natural transmission, posing a global public safety threat. Colistin resistance mediated by the mcr-1 gene is the most prevalent among animal-derived Escherichia coli, and mcr-1-carrying E. coli have been frequently detected in central-eastern China. However, animal-derived E. coli with AMR and the prevalence of mcr-1 in the Qinghai Plateau have been rarely investigated. Herein, 375 stool samples were collected from 13 poultry farms in Qinghai Province and 346 E. coli strains were isolated, of which eight carried mcr-1. The AMR rates of the E. coli strains to ampicillin, amoxicillin/clavulanic acid, and tetracycline were all above 90%, and the resistance rates to ciprofloxacin, cefotaxime, ceftiofur, and florfenicol were above 70%. Multidrug-resistant strains accounted for 95.66% of the total isolates. Twelve E. coli strains showed colistin resistance, from which a total of 46 AMR genes and 36 virulence factors were identified through whole-genome sequencing. The mcr-1 gene resided on the IncHI2, IncI2-type and IncY-type plasmids, and mcr-1 was located in the nikA-nikB-mcr-1-pap2 gene cassette (three strains) or the pap2-mcr-1-ISApl1 structure (one strain). Completed IncI2-type plasmid pMCR4D31–3 sequence (62,259 bp) revealed that it may cause the horizontal transmission of mcr-1 and may increase the risk of its spread through the food chain. Taken together, the AMR of chicken-derived E. coli in the plateau is of concern, suggesting that it is very necessary for us to strengthen the surveillance in various regions under the background of one health.
Genetic and Functional Characterization of a Conjugative KpVP-2-Type Virulence Plasmid From a Clinical Klebsiella pneumoniae Strain
Authors: Yang Xuemei , Liu Xiaoxuan , Xu Yating , Yang Chen , Chan Edward Wai-Chi , Shum Hoi-ping , Chen Sheng
Published: July 2022

The main mechanism of virulence in Klebsiella pneumoniae is the acquisition of K. pneumoniae virulence plasmids (KpVPs), which include two dominant types, namely, KpVP-1 (carrying iuc1, iro1, rmpA, and rmpA2) and KpVP-2 (carrying iuc2, iro2, and rmpA). Both are non-conjugative and associated with different hypervirulent clones. In contrast to KpVP-1 reported in K1, K2, and other serotypes of K. pneumoniae, KpVP-2 was only reported in K2 strains and rarely characterized. In this study, we identified a conjugative KpVP-2-type virulence plasmid from a clinical hypervirulent K. pneumoniae strain. This plasmid was generated by the integration of conjugative transfer genes into the KpVP-2-type plasmid Kp52.145 II and could be readily conjugated to Escherichia coli strain EC600 and K. pneumoniae strains of various types which are clinically existing, mediating hypervirulence. Furthermore, this kind of conjugative KpVP-2-type virulence plasmid has been disseminated in clinical settings in Hong Kong and other regions of the world. The generation of conjugative virulence plasmid may promote its transmission and explain the evolution of this type of virulence plasmid.
High-fat diet-induced intestinal dysbiosis is associated with the exacerbation of Sjogren’s syndrome
Authors: Zhang Minjie , Liang Yichen , Liu Yanbo , Li Yixuan , Shen Long , Shi Guixiu
Published: July 2022

Environmental factors are believed to influence the evolution of primary Sjögren’s syndrome (pSS). The aims of this study were to investigate the association of pSS with a high-fat diet (HFD) and to relate HFD-induced gut dysbiosis to pSS exacerbation. Male Wild Type (WT) and IL-14α transgenic mice (IL-14α TG) were fed a standard diet (SD) and HFD for 11 months. We found an increase in the autoantibody level, more severe dry eye, severe dry mouth symptoms, and an earlier presence of systemic features in the IL-14α TG mice treated with HFD. These data suggest that HFD can promote the process of pSS in the IL-14α TG mice. In addition, an HFD leads to a decrease in the richness of gut microbiota of IL-14α TG mice treated with HFD. The abundance of Deferribacterota was significantly enriched in the IL-14α TG mice treated with HFD compared with other groups. Through the mental test between gut microbiota and clinical parameters, we found that HFD-induced dysbiosis gut microbiota were associated with pSS clinical parameters. In conclusion, HFD results in the aggravation of pSS progression, likely due to the increase of potentially pathogenic microorganisms.
Oral administration of branched-chain amino acids ameliorates high-fat diet-induced metabolic-associated fatty liver disease via gut microbiota-associated mechanisms
Authors: Zhang Ranran , Mu Hongna , Li Ziyun , Zeng Jie , Zhou Qi , Li Hongxia , Wang Siming , Li Xianghui , Zhao Xianghui , Sun Liang , Chen Wenxiang , Dong Jun , Yang Ruiyue
Published: July 2022

Branched-chain amino acids (BCAAs), essential amino acids for the human body, are mainly obtained from food. High levels of BCAAs in circulation are considered as potential markers of metabolic-associated fatty liver disease (MAFLD) in humans. However, there are conflicting reports about the effects of supplement of BCAAs on MAFLD, and research on BCAAs and gut microbiota is not comprehensive. Here, C57BL/6J mice were fed with a high-fat diet with or without BCAAs to elucidate the effects of BCAAs on the gut microbiota and metabolic functions in a mouse model of MAFLD. Compared to high-fat diet (HFD) feeding, BCAA supplementation significantly reduced the mouse body weight, ratio of liver/body weight, hepatic lipid accumulation, serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and alanine aminotransferase (ALT), and the expressions of the lipogenesis-related enzymes Fas, Acc, and Scd-1 and increased expressions of the lipolysis-related enzymes Cpt1A and Atgl in the liver. BCAAs supplementation also counteracted HFD-induced elevations in serum BCAAs levels by stimulating the enzymatic activity of BCKDH. Furthermore, BCAAs supplementation markedly improved the gut bacterial diversity and altered the gut microbiota composition and abundances, especially those of genera, in association with MAFLD and BCAAs metabolism. These data suggest that BCAA treatment improves HFD-induced MAFLD through mechanisms involving intestinal microbes.
Rhizosphere soil microbial community and its response to different utilization patterns in the semi-arid alpine grassland of northern Tibet
Authors: Fu Lijiao , Yan Yan , Li Xueqin , Liu Yanling , Lu Xuyang
Published: July 2022

As the link between plants and soils, rhizosphere soil microorganisms play an important role in the element cycle. This study aimed to understand the response of the rhizosphere soil microbial community structure and interaction network to grassland utilization in the alpine steppe of the northern Tibet Plateau. High-throughput sequencing was employed to study the composition, diversity, and species interaction network of rhizosphere soil microbial communities under grazing, mowing, and enclosing treatments. Proteobacteria (47.19%) and Actinobacteria (42.20%) were the dominant bacteria in the rhizosphere soil. There was no significant difference in relative abundance among rhizosphere soil microorganisms at phylum and genus levels, but differences were found in Chlorobi, Ignavibacteriae, and Micromonospora. The alpha diversity index based on Shannon, Chao1, and Simpson indices revealed that except for a significant difference in the Shannon index of the Artemisia nanschanica group, the richness and evenness of rhizosphere soil microbial communities among all groups were similar. Non-metric multidimensional scaling (NMDS) and multi-response permutation procedure (MRPP) analyses showed that the inter-group differences of three plants (Stipa purpurea, Carex moorcroftii, and Artemisia nanschanica) were greater than the differences within the groups; however, only the inter-group difference with the Stipa purpurea group was significant. The microbial interaction network showed that the network complexity of the Artemisia nanschanica group and the enclosing treatment, which were not easily influenced by external factors, were higher than those of the other groups and treatments; this again demonstrated that Proteobacteria and Actinobacteria were the network core microbial species in alpine steppe of the northern Tibet Plateau and were crucial for maintaining stability of the microbial communities. Findings from this study provide a theoretical basis for the restoration of degraded alpine grassland and the development of microbial functions.
Enhancing epitope of PEDV spike protein
Authors: Thavorasak Techit , Chulanetra Monrat , Glab-ampai Kittirat , Mahasongkram Kodchakorn , Sae-lim Nawannaporn , Teeranitayatarn Karsidete , Songserm Thaweesak , Yodsheewan Rungrueang , Nilubol Dachrit , Chaicumpa Wanpen , Sookrung Nitat
Published: July 2022

Porcine epidemic diarrhea virus (PEDV) is the causative agent of a highly contagious enteric disease of pigs characterized by diarrhea, vomiting, and severe dehydration. PEDV infects pigs of all ages, but neonatal pigs during the first week of life are highly susceptible; the mortality rates among newborn piglets may reach 80–100%. Thus, PEDV is regarded as one of the most devastating pig viruses that cause huge economic damage to pig industries worldwide. Vaccination of sows and gilts at the pre-fertilization or pre-farrowing stage is a good strategy for the protection of suckling piglets against PEDV through the acquisition of the lactating immunity. However, vaccination of the mother pigs for inducing a high level of virus-neutralizing antibodies is complicated with unstandardized immunization protocol and unreliable outcomes. Besides, the vaccine may also induce enhancing antibodies that promote virus entry and replication, so-called antibody-dependent enhancement (ADE), which aggravates the disease upon new virus exposure. Recognition of the virus epitope that induces the production of the enhancing antibodies is an existential necessity for safe and effective PEDV vaccine design. In this study, the enhancing epitope of the PEDV spike (S) protein was revealed for the first time, by using phage display technology and mouse monoclonal antibody (mAbG3) that bound to the PEDV S1 subunit of the S protein and enhanced PEDV entry into permissive Vero cells that lack Fc receptor. The phages displaying mAbG3-bound peptides derived from the phage library by panning with the mAbG3 matched with several regions in the S1-0 sub-domain of the PEDV S1 subunit, indicating that the epitope is discontinuous (conformational). The mAbG3-bound phage sequence also matched with a linear sequence of the S1-BCD sub-domains. Immunological assays verified the phage mimotope results. Although the molecular mechanism of ADE caused by the mAbG3viabinding to the newly identified S1 enhancing epitope awaits investigation, the data obtained from this study are helpful and useful in designing a safe and effective PEDV protein subunit/DNA vaccine devoid of the enhancing epitope.
Antifungal Activity of Endophytic Bacillus K1 Against Botrytis cinerea
Authors: Li Peiqian , Feng Baozhen , Yao Zhen , Wei Bohui , Zhao Yanfei , Shi Shouguo
Published: July 2022

Gray mold caused by Botrytis cinerea is detrimental to plants and fruits. Endophytes have been shown to modify plant disease severity in functional assays. We conducted this study to investigate the endophytic strain Bacillus K1 with excellently antagonistic B. cinerea from the wild grape endosphere. We identified a wild grape endophytic strain K1 with high antifungal activity against B. cinerea both in vitro and in vivo. Combining the phylogenetic results based on 16S rDNA and genome sequencing, K1 was assigned as Bacillus subtilis. The in vitro results displayed that K1 and its volatile substances could significantly inhibit the mycelia growth of B. cinerea. Grape fruit inoculated with Bacillus K1 showed lower gray mold during treatment. The higher levels of defense-related enzymes, including peroxidase, polyphenol oxidase, and phenylalanine ammonia lyase, were induced in grapes after inoculation. Scanning electron microscopy (SEM) suggested that K1 inhibited mycelial growth via bacterial colonization and antibiosis in grapes. The gas chromatography–mass spectrometry analysis identified 33 volatiles in which dibutyl phthalate was the major compound accounting for 74.28%. Dibutyl phthalate demonstrated strong activity in suppressing the mycelia growth of B. cinerea. Genome bioinformatics analysis revealed that the K1 chromosome harbored many known biosynthesis gene clusters encoding subtilosin, bacillaene, bacillibactin, bacilysin, and fengycin. This study provides a potential biological agent to control diseases of post-harvest grape fruit and improves our understanding of the possible biocontrol mechanisms of the Bacillus strain.
Non-structure protein ORF1ab (NSP8) in SARS-CoV-2 contains potential γδT cell epitopes
Authors: Du Boyu , Guo Yang , Li Gang , Zhu Yunhe , Wang Yunfu , Xi Xueyan
Published: July 2022

Upon activation by the pathogen through T-cell receptors (TCRs), γδT cells suppress the pathogenic replication and thus play important roles against viral infections. Targeting SARS-CoV-2 via γδT cells provides alternative therapeutic strategies. However, little is known about the recognition of SARS-CoV-2 antigens by γδT cells. We discovered a specific Vγ9/δ2 CDR3 by analyzing γδT cells derived from the patients infected by SARS-CoV-2. Using a cell model exogenously expressing γδ-TCR established, we further screened the structural motifs within the CDR3 responsible for binding to γδ-TCR. Importantly, these sequences were mapped to NSP8, a non-structural protein in SARS-CoV-2. Our results suggest that NSP8 mediates the recognition by γδT cells and thus could serve as a potential target for vaccines.
Pro-angiogenic New Chloro-Azaphilone Derivatives From the Hadal Trench-Derived Fungus Chaetomium globosum YP-106
Authors: Fan Yaqin , Jiang Chunjiao , Zhang Yan , Ma Zhiheng , Li Peihai , Guo Lizhong , Feng Ting , Zhou Liman , Xu Lili
Published: July 2022

Five new chloro-azaphilones, chaetofanixins A–E (1–5), and five known analogs (6–10) were isolated and identified from the hadal trench-derived fungus Chaetomium globosum YP-106. The structure of chaetofanixin E (5) is unique and interesting, bearing a highly rigid 6/6/5/3/5 penta-cyclic ring system, which is first encountered in natural products. The structures of these compounds, including absolute configurations, were determined based on the spectroscopic analysis, electronic circular dichroism (ECD) calculations, and analysis of biogenetic origins. Compounds 1–7 significantly promoted angiogenesis in a dose-dependent manner, and thus, these compounds might be used as promising molecules for the development of natural cardiovascular disease agents.
Characterization and Fitness Cost of Tn7100, a Novel Integrative and Conjugative Element Conferring Multidrug Resistance in Haemophilus influenzae
Authors: Johannessen Helene , Anthonisen Inger Lill , Zecic Nermin , Hegstad Kristin , Ranheim Trond Egil , Skaare Dagfinn
Published: July 2022

A multidrug-resistant (MDR) strain of Haemophilus influenzae, Hi-228, with phenotypic resistance toward ampicillin, cefotaxime, chloramphenicol, gentamicin, and azithromycin, was isolated in Oslo, Norway. The strain was part of a clonal outbreak (2016–2017) comprising five ST143 strains with identical resistotypes. Hi-228 carries a novel integrative and conjugative element (ICE), Tn7100, contributing to this remarkable and previously unreported MDR profile. Tn7100 contains the following resistance genes: blaTEM−1B, catA2, aac(6′)-Im, aph(2″)-Ib, mef (E), and mel. The latter four are previously unreported or rarely reported in H. influenzae. In this study, we investigated the genetic environment, mechanisms of transfer, impact on phenotypic susceptibility, and fitness cost of this ICE. We found that Tn7100 has an overall structure similar to the previously described ICE Tn6686, with blaTEM−1B and catA2 carried by Tn3 and Tn10, respectively. The major difference between Tn7100 and Tn6686 is that Tn7100 lacks tet(B) but carries the resistance gene pairs aac(6′)-Im and aph(2″)-Ib and mef (E) and mel. The gene pairs are located on the novel transposable elements Tn7470 and Tn7471, which have high sequence identities to a plasmid in Enterobacterales and an ICE in streptococcal species, respectively. Tn7100 does circularize and is transferable, however, at a low frequency. Head-to-head competition experiments showed that uptake of Tn7100 reduces bacterial fitness. Our study shows that MDR strains are capable of clonal spread and that the H. influenzae supragenome comprises an increasingly wide range of transferable resistance genes, with evidence of transfer from unrelated genera. The findings offer a glimpse into the genome dynamics of H. influenzae, highlighting the importance of rational antibiotic usage to contain antimicrobial resistance and the emergence of MDR strains in this important pathogen.
Mechanism of dielectric barrier discharge plasma technology to improve the quantity of short-chain fatty acids in anaerobic fermentation of waste active sludge
Authors: Wang Jie , Liu Xingguo , He Jinling , Cheng Guofeng , Xu Junli , Lu Ming , Shangguan Yuyi , Zhang Ai
Published: July 2022

The mechanism of improving the anaerobic fermentation performance of waste active sludge by using dielectric barrier discharge (DBD) plasma pretreatment technology was investigated. The maximum accumulation of short-chain fatty acids (SCFAs) was observed on the 7th day of anaerobic fermentation when the DBD power was 76.50 W, which was 1726.70 mg COD/L, 1.50 times of the control group. The ratio of acetic acid in DBD group was 9.30% higher than that in the control. Further mechanism research indicated that DBD pretreatment can destroy the structure of extracellular polymer substances and release organic substances such as protein and polysaccharide. The dissolved organic matter analysis indicated that the DBD technique could increase the release of biodegradable organics (eg., tyrosine proteins, soluble microbial by-products), thus accelerate the biotransformation of organic substance. Bacterial community structure analysis showed that the increase in the abundance of Firmicutes and Bacteroidetes and the decrease in the abundance of Proteobacteria in DBD group were beneficial to the accumulation of SCFAs. Besides, further archaeal analysis indicated that the decrease of Methanosaeta sp. and Methanosarcina sp. abundance in the DBD group facilitate acetic acid accumulation. This study demonstrated that the DBD technique can be used as an effective and potential pretreatment method to improve sludge anaerobic fermentation performance.
Glucose Deprivation Induced by Acarbose and Oncolytic Newcastle Disease Virus Promote Metabolic Oxidative Stress and Cell Death in a Breast Cancer Model
Authors: Obaid Qayssar A. , Al-Shammari Ahmed Majeed , Khudair Khalisa K.
Published: July 2022

Cancer cells are distinguished by enhanced glucose uptake and an aerobic glycolysis pathway in which its products support metabolic demands for cancer cell growth and proliferation. Inhibition of aerobic glycolysis is a smart therapeutic approach to target the progression of the cancer cell. We employed acarbose (ACA), a particular alpha-glucosidase inhibitor, to induce glucose deprivation combined with oncolytic Newcastle disease virus (NDV) to enhance antitumor activity. In this work, we used a mouse model of breast cancer with mammary adenocarcinoma tumor cells (AN3) that were treated with ACA, NDV, and a combination of both. The study included antitumor efficacy, relative body weight, glucose level, hexokinase (HK-1) level by ELISA, glycolysis product (pyruvate), total ATP, oxidative stress (ROS and reduced glutathione), and apoptosis by immunohistochemistry. The results showed significant antitumor efficacy against breast cancer after treatment with combination therapy. Antitumor efficacy was accompanied by a reduction in body weight and glucose level, HK-1 downregulation, inhibition of glycolysis products (pyruvate), total ATP, induction of oxidative stress (increase ROS and decrease reduced glutathione), and apoptotic cell death. The findings propose a novel anti–breast cancer combination involving the suppression of glycolysis, glucose deprivation, oxidative stress, and apoptosis, which can be translated clinically.
The permeation of potassium ions through the lipid scrambling path of the membrane protein nhTMEM16
Authors: Cheng Xiaolu , Khelashvili George , Weinstein Harel
Published: July 2022

The TMEM16 family of transmembrane proteins includes Ca2+-activated phospholipid scramblases (PLS) that can also function as non-selective ion channels. Extensive structural and functional studies have established that a membrane-exposed hydrophilic groove in TMEM16 PLS can serve as a translocation pathway for lipids. However, it is still unclear how the TMEM16 PLS conduct ions. A “protein-delimited pore” model suggests that ions are translocated through a narrow opening of the groove region, which is not sufficiently wide to allow lipid movement, whereas a “proteolipidic pore” model envisions ions and lipids translocating through an open conformation of the groove. We investigated the dynamic path of potassium ion (K+) translocation that occurs when an open groove state of nhTMEM16 is obtained from long atomistic molecular dynamics (MD) simulations, and calculated the free energy profile of the ion movement through the groove with umbrella sampling methodology. The free energy profile identifies effects of specific interactions along the K+ permeation path. The same calculations were performed to investigate ion permeation through a groove closed to lipid permeation in the nhTMEM16 L302A mutant which exhibits a stable conformation of the groove that does not permit lipid scrambling. Our results identify structural and energy parameters that enable K+ permeation, and suggest that the presence of lipids in the nhTMEM16 groove observed in the simulations during scrambling or in/out diffusion, affect the efficiency of K+ permeation to various extents.
Redesigning Enzymes for Biocatalysis: Exploiting Structural Understanding for Improved Selectivity
Authors: Ding Yaoyu , Perez-Ortiz Gustavo , Peate Jessica , Barry Sarah M.
Published: July 2022

The discovery of new enzymes, alongside the push to make chemical processes more sustainable, has resulted in increased industrial interest in the use of biocatalytic processes to produce high-value and chiral precursor chemicals. Huge strides in protein engineering methodology and in silico tools have facilitated significant progress in the discovery and production of enzymes for biocatalytic processes. However, there are significant gaps in our knowledge of the relationship between enzyme structure and function. This has demonstrated the need for improved computational methods to model mechanisms and understand structure dynamics. Here, we explore efforts to rationally modify enzymes toward changing aspects of their catalyzed chemistry. We highlight examples of enzymes where links between enzyme function and structure have been made, thus enabling rational changes to the enzyme structure to give predictable chemical outcomes. We look at future directions the field could take and the technologies that will enable it.
MetastaSite: Predicting metastasis to different sites using deep learning with gene expression data
Authors: Albaradei Somayah , Albaradei Abdurhman , Alsaedi Asim , Uludag Mahmut , Thafar Maha A. , Gojobori Takashi , Essack Magbubah , Gao Xin
Published: July 2022

Deep learning has massive potential in predicting phenotype from different omics profiles. However, deep neural networks are viewed as black boxes, providing predictions without explanation. Therefore, the requirements for these models to become interpretable are increasing, especially in the medical field. Here we propose a computational framework that takes the gene expression profile of any primary cancer sample and predicts whether patients’ samples are primary (localized) or metastasized to the brain, bone, lung, or liver based on deep learning architecture. Specifically, we first constructed an AutoEncoder framework to learn the non-linear relationship between genes, and then DeepLIFT was applied to calculate genes’ importance scores. Next, to mine the top essential genes that can distinguish the primary and metastasized tumors, we iteratively added ten top-ranked genes based upon their importance score to train a DNN model. Then we trained a final multi-class DNN that uses the output from the previous part as an input and predicts whether samples are primary or metastasized to the brain, bone, lung, or liver. The prediction performances ranged from AUC of 0.93–0.82. We further designed the model’s workflow to provide a second functionality beyond metastasis site prediction, i.e., to identify the biological functions that the DL model uses to perform the prediction. To our knowledge, this is the first multi-class DNN model developed for the generic prediction of metastasis to various sites.
Linking Brain Age Gap to Mental and Physical Health in the Berlin Aging Study II
Authors: Jawinski Philippe , Markett Sebastian , Drewelies Johanna , Düzel Sandra , Demuth Ilja , Steinhagen-Thiessen Elisabeth , Wagner Gert G. , Gerstorf Denis , Lindenberger Ulman , Gaser Christian , Kühn Simone
Published: July 2022

From a biological perspective, humans differ in the speed they age, and this may manifest in both mental and physical health disparities. The discrepancy between an individual’s biological and chronological age of the brain (“brain age gap”) can be assessed by applying machine learning techniques to Magnetic Resonance Imaging (MRI) data. Here, we examined the links between brain age gap and a broad range of cognitive, affective, socioeconomic, lifestyle, and physical health variables in up to 335 adults of the Berlin Aging Study II. Brain age gap was assessed using a validated prediction model that we previously trained on MRI scans of 32,634 UK Biobank individuals. Our statistical analyses revealed overall stronger evidence for a link between higher brain age gap and less favorable health characteristics than expected under the null hypothesis of no effect, with 80% of the tested associations showing hypothesis-consistent effect directions and 23% reaching nominal significance. The most compelling support was observed for a cluster covering both cognitive performance variables (episodic memory, working memory, fluid intelligence, digit symbol substitution test) and socioeconomic variables (years of education and household income). Furthermore, we observed higher brain age gap to be associated with heavy episodic drinking, higher blood pressure, and higher blood glucose. In sum, our results point toward multifaceted links between brain age gap and human health. Understanding differences in biological brain aging may therefore have broad implications for future informed interventions to preserve mental and physical health in old age.
An individualized functional magnetic resonance imaging protocol to assess semantic congruency effects on episodic memory in an aging multilingual population
Authors: Perquin Magali , Viswanathan Shivakumar , Vaillant Michel , Risius Okka , Huiart Laetitia , Schmit Jean-Claude , Diederich Nico J. , Fink Gereon R. , Kukolja Juraj
Published: July 2022

The cognitive stimulation induced by multilingualism may slow down age-related memory impairment. However, a suitable neuroscientific framework to assess the influence of multilingualism on age-related memory processes is missing. We propose an experimental paradigm that assesses the effects of semantic congruency on episodic memory using functional magnetic resonance imaging (fMRI). To this end, we modified the picture-word interference (PWI) task to be suitable for the assessment of older multilingual subjects undergoing fMRI. In particular, stimulus materials were prepared in multiple languages (French, German, Luxembourgish, English) and closely matched in semantic properties, thus enabling participants to perform the experiment in a language of their choice. This paradigm was validated in a group (n = 62) of healthy, older participants (over 64 years) who were multilingual, all practicing three or more languages. Consistent with the engagement of semantic congruency processes, we found that the encoding and recognition of semantically related vs. unrelated picture-word pairs evoked robust differences in behavior and the neural activity of parietal-temporal networks. These effects were negligibly modulated by the language used to perform the task. Based on this validation in a multilingual population, we conclude that the proposed paradigm will allow future studies to evaluate whether multilingualism aptitude engages neural systems in a manner that protects long-term memory from aging-related decline.
β-secretase inhibition prevents structural spine plasticity deficits in AppNL-G-F mice
Authors: Blume Tanja , Filser Severin , Sgobio Carmelo , Peters Finn , Neumann Ulf , Shimshek Derya , Saito Takashi , Saido Takaomi C. , Brendel Matthias , Herms Jochen
Published: July 2022

All clinical BACE1-inhibitor trials for the treatment of Alzheimer's Disease (AD) have failed due to insufficient efficacy or side effects like worsening of cognitive symptoms. However, the scientific evidence to date suggests that BACE1-inhibition could be an effective preventative measure if applied prior to the accumulation of amyloid-beta (Aβ)-peptide and resultant impairment of synaptic function. Preclinical studies have associated BACE1-inhibition-induced cognitive deficits with decreased dendritic spine density. Therefore, we investigated dose-dependent effects of BACE1-inhibition on hippocampal dendritic spine dynamics in an APP knock-in mouse line for the first time. We conducted in vivo two-photon microscopy in the stratum oriens layer of hippocampal CA1 neurons in 3.5-month-old AppNL-G-FGFP-M mice over 6 weeks to monitor the effect of potential preventive treatment with a high and low dose of the BACE1-inhibitor NB-360 on dendritic spine dynamics. Structural spine plasticity was severely impaired in untreated AppNL-G-FGFP-M mice, although spines were not yet showing signs of degeneration. Prolonged high-dose BACE1-inhibition significantly enhanced spine formation, improving spine dynamics in the AD mouse model. We conclude that in an early AD stage characterized by low Aβ-accumulation and no irreversible spine loss, BACE1-inhibition could hold the progressive synapse loss and cognitive decline by improving structural spine dynamics.
Inhibition of Rac1 in ventral hippocampal excitatory neurons improves social recognition memory and synaptic plasticity
Authors: Zhang Haiwang , Ben Zablah Youssif , Zhang Haorui , Liu An , Gugustea Radu , Lee Dongju , Luo Xiao , Meng Yanghong , Li Song , Zhou Changxi , Xin Tao , Jia Zhengping
Published: July 2022

Rac1 is critically involved in the regulation of the actin cytoskeleton, neuronal structure, synaptic plasticity, and memory. Rac1 overactivation is reported in human patients and animal models of Alzheimer’s disease (AD) and contributes to their spatial memory deficits, but whether Rac1 dysregulation is also important in other forms of memory deficits is unknown. In addition, the cell types and synaptic mechanisms involved remain unclear. In this study, we used local injections of AAV virus containing a dominant-negative (DN) Rac1 under the control of CaMKIIα promoter and found that the reduction of Rac1 hyperactivity in ventral hippocampal excitatory neurons improves social recognition memory in APP/PS1 mice. Expression of DN Rac1 also improves long-term potentiation, a key synaptic mechanism for memory formation. Our results suggest that overactivation of Rac1 in hippocampal excitatory neurons contributes to social memory deficits in APP/PS1 mice and that manipulating Rac1 activity may provide a potential therapeutic strategy to treat social deficits in AD.
The Influence of Vicarious Fear-Learning in “Infecting” Reactive Action Inhibition
Authors: Battaglia Simone , Cardellicchio Pasquale , Di Fazio Chiara , Nazzi Claudio , Fracasso Alessio , Borgomaneri Sara
Published: July 2022

Since the dawn of cognitive neuroscience, emotions have been recognized to impact on several executive processes, such as action inhibition. However, the complex interplay between emotional stimuli and action control is not yet fully understood. One way to measure inhibitory control is the stop-signal task (SST), which estimates the ability to cancel outright an action to the presentation of a stop signal by means of the stop-signal reaction times (SSRTs). Impaired as well as facilitated action control has been found when faced with intrinsic emotional stimuli as stop signals in SSTs. Here, we aimed at investigating more deeply the power of negative stimuli to influence our action control, testing the hypothesis that a previously neutral stimulus [i.e., the image of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)], which has been conditioned through vicarious fear learning, has the same impact on reactive action inhibition performance as an intrinsically negative stimulus (i.e., a fearful face or body). Action control capabilities were tested in 90 participants by means of a SST, in which the stop signals were represented by different negative stimuli. Results showed that the SARS-CoV-2 image enhanced the ability to suppress an ongoing action similarly to observing fearful facial expressions or fearful body postures. Interestingly, we found that this effect was predicted by impulsivity traits: for example, the less self-control the participants had, the less they showed emotional facilitation for inhibitory performance. These results demonstrated that vicarious fear learning has a critical impact on cognitive abilities, making a neutral image as threatening as phylogenetically innate negative stimuli and able to impact on our behavioral control.
The potential role of DNA methylation as preventive treatment target of epileptogenesis
Authors: Berger Toni Christoph , Taubøll Erik , Heuser Kjell
Published: July 2022

Pharmacological therapy of epilepsy has so far been limited to symptomatic treatment aimed at neuronal targets, with the result of an unchanged high proportion of patients lacking seizure control. The dissection of the intricate pathological mechanisms that transform normal brain matter to a focus for epileptic seizures—the process of epileptogenesis—could yield targets for novel treatment strategies preventing the development or progression of epilepsy. While many pathological features of epileptogenesis have been identified, obvious shortcomings in drug development are now believed to be based on the lack of knowledge of molecular upstream mechanisms, such as DNA methylation (DNAm), and as well as a failure to recognize glial cell involvement in epileptogenesis. This article highlights the potential role of DNAm and related gene expression (GE) as a treatment target in epileptogenesis.
Advances in Potential Cerebrospinal Fluid Biomarkers for Autoimmune Encephalitis: A Review
Authors: Zhang Shuyu , Mao Chengyuan , Li Xinwei , Miao Wang , Teng Junfang
Published: July 2022

Autoimmune encephalitis (AE) is a severe inflammatory disease of the brain. Patients with AE demonstrate amnesia, seizures, and psychosis. Recent studies have identified numerous associated autoantibodies (e.g., against NMDA receptors (NMDARs), LGI1, etc.) involved in the pathogenesis of AE, and the levels of diagnosis and treatment are thus improved dramatically. However, there are drawbacks of clinical diagnosis and treatment based solely on antibody levels, and thus the application of additional biomarkers is urgently needed. Considering the important role of immune mechanisms in AE development, we summarize the relevant research progress in identifying cerebrospinal fluid (CSF) biomarkers with a focus on cytokines/chemokines, demyelination, and nerve damage.
Quantitative Evaluation of a Cross-Sectional Area of the Fetal Straight Sinus by Magnetic Resonance Imaging and Its Clinical Value
Authors: Fu Shi-Jia , Xu Jing-Bo , Liu Xin , Cao Yi-Min , Yi Ze-Xi , Zhou Li-Xia
Published: July 2022

Objective

The intracranial venous system plays an important role in ensuring blood circulation and a stable blood supply to the fetal brain. In the present study, a cross-sectional area of the fetal straight sinus was quantitatively evaluated by fetal magnetic resonance imaging (MRI) to explore the method's clinical value.

Methods

The clinical and MRI data of 126 normal fetuses in mid-to-late stage pregnancies were retrospectively analyzed. The “dominant” sequence of the fetal straight sinus was selected, and the cross-sectional area of the lumen was measured at each gestational age to obtain the normal range at different ages and to analyze the developmental pattern and characteristics of the fetal straight sinus.

Results

There were statistically significant differences in the cross-sectional area of the fetal straight sinus among different gestational ages (P < 0.05). The cross-sectional area of the fetal straight sinus was positively correlated with gestational age (coefficient of determination = 0.6892, P < 0.05). That is, the cross-sectional area of the fetal straight sinus grew with increasing gestational age, and the regression equation was y = 0.27 x – 2.14 (P < 0.05). Additionally, there were five fetuses with cerebral venous abnormalities, including four with heart failure and one with venous sinus thrombosis.

Conclusion

Quantitative measurement of a cross-sectional area of the fetal straight sinus by MRI enhanced understanding of the anatomical features and developmental pattern of fetal cerebral veins and provided a reference for the clinical diagnosis of related diseases and investigation concerning pathogenesis.
Reduced Metabotropic Glutamate Receptor Type 5 Availability in the Epileptogenic Hippocampus: An in vitro Study
Authors: Zimmermann Maria , Minuzzi Luciano , Aliaga Aliaga Arturo , Guiot Marie-Christine , Hall Jeffery A. , Soucy Jean-Paul , Massarweh Gassan , El Mestikawy Salah , Rosa-Neto Pedro , Kobayashi Eliane
Published: July 2022

Abnormalities in the expression of metabotropic glutamate receptor type 5 (mGluR5) have been observed in the hippocampus of patients with drug-resistant mesial Temporal Lobe Epilepsy (mTLE). Ex-vivo studies in mTLE hippocampal surgical specimens have shown increased mGluR5 immunoreactivity, while in vivo whole brain imaging using positron emission tomography (PET) demonstrated reduced hippocampal mGluR5 availability. To further understand mGluR5 abnormalities in mTLE, we performed a saturation autoradiography study with [3H]ABP688 (a negative mGluR5 allosteric modulator). We aimed to evaluate receptor density (Bmax) and dissociation constants (KD) in hippocampal mTLE surgical specimens and in non-epilepsy hippocampi from necropsy controls. mTLE specimens showed a 43.4% reduction in receptor density compared to control hippocampi, which was independent of age, sex and KD (multiple linear regression analysis). There was no significant difference in KD between the groups, which suggests that the decreased mGluR5 availability found in vivo with PET cannot be attributed to reduced affinity between ligand and binding site. The present study supports that changes within the epileptogenic tissue include mGluR5 internalization or conformational changes that reduce [3H]ABP688 binding, as previously suggested in mTLE patients studied in vivo.
Serotonergic drug repurposing in multiple sclerosis: A new possibility for disease-modifying therapy
Authors: Melnikov Mikhail , Kasatkin Dmitriy , Lopatina Anna , Spirin Nikolay , Boyko Alexey , Pashenkov Mikhail
Published: July 2022

Investigation of neuroimmune interactions is one of the most developing areas in the study of multiple sclerosis pathogenesis. Recent evidence suggests the possibility of modulating neuroinflammation by targeting biogenic amine receptors. It has been shown that selective serotonin reuptake inhibitor fluoxetine modulates innate and adaptive immune system cells' function and can reduce experimental autoimmune encephalomyelitis and multiple sclerosis severity. This brief report discusses the immune mechanisms underlying the multiple sclerosis pathogenesis and the influence of fluoxetine on them. The retrospective data on the impact of fluoxetine treatment on the course of multiple sclerosis are also presented. The results of this and other studies suggest that fluoxetine could be considered an additional therapy to the standard first-line disease-modifying treatment for relapsing–remitting multiple sclerosis.
The clinical correlation between Alzheimer's disease and epilepsy
Authors: Zhang Dandan , Chen Siyuan , Xu Shoucheng , Wu Jing , Zhuang Yuansu , Cao Wei , Chen Xiaopeng , Li Xuezhong
Published: July 2022

Alzheimer's disease and epilepsy are common nervous system diseases in older adults, and their incidence rates tend to increase with age. Patients with mild cognitive impairment and Alzheimer's disease are more prone to have seizures. In patients older than 65 years, neurodegenerative conditions accounted for ~10% of all late-onset epilepsy cases, most of which are Alzheimer's disease. Epilepsy and seizure can occur in the early and late stages of Alzheimer's disease, leading to functional deterioration and behavioral alterations. Seizures promote amyloid-β and tau deposits, leading to neurodegenerative processes. Thus, there is a bi-directional association between Alzheimer's disease and epilepsy. Epilepsy is a risk factor for Alzheimer's disease and, in turn, Alzheimer's disease is an independent risk factor for developing epilepsy in old age. Many studies have evaluated the shared pathogenesis and clinical relevance of Alzheimer's disease and epilepsy. In this review, we discuss the clinical associations between Alzheimer's disease and epilepsy, including their incidence, clinical features, and electroencephalogram abnormalities. Clinical studies of the two disorders in recent years are summarized, and new antiepileptic drugs used for treating Alzheimer's disease are reviewed.
Whole genomic approach in mutation discovery of infantile spasms patients
Authors: Lee Seungbok , Jang Sesong , Kim Jong-Il , Chae Jong Hee , Kim Ki Joong , Lim Byung Chan
Published: July 2022

Infantile spasms (IS) are a clinically and genetically heterogeneous group of epilepsy disorders in early infancy. The genetic backgrounds of IS have been gradually unraveled along with the increased application of next-generation sequencing (NGS). However, to date, only selected genomic regions have been sequenced using a targeted approach in most cases of IS, and the genetic etiologies of the majority of patients remain unknown. We conducted a proof-of-concept study using whole-genome sequencing (WGS) for the genetic diagnosis of IS. We included 16 patients with IS for this study, and WGS was applied as a first-tier test for genetic diagnosis. In total, we sequenced the whole genomes of 28 participants, including the genomes of six patients, which were sequenced with those of their parents. Among variants identified, we focused on those located in epilepsy or seizure-associated genes. We used two different methods to call relevant large deletions from WGS results. We found pathogenic or likely pathogenic variants in four patients (25.0%); a de novo variant in HDAC4, compound heterozygous variants in GRM7, and heterozygous variants in CACNA1E and KMT2E. We also selected two more candidate variants in SOX5 and SHROOM4 intronic regions. Although there are currently several difficulties in applying WGS for genetic diagnosis, especially in clinical interpretation of non-coding variants, we believe that developing sequencing technologies would overcome these hurdles in the near future. Considering the vast genetic heterogeneity and the substantial portion of patients with unknown etiologies, further studies using whole genomic approaches are necessary for patients with IS.