bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Core Genes Related to Progression and Prognosis of Hepatocellular Carcinoma and Small-Molecule Drug Predication
Authors: Jiang Nan , Zhang Xinzhuo , Qin Dalian , Yang Jing , Wu Anguo , Wang Long , Sun Yueshan , Li Hong , Shen Xin , Lin Jing , Kantawong Fahsai , Wu Jianming
Published: February 2021

Background

Hepatocellular carcinoma (HCC) is one of the most leading causes of cancer death with a poor prognosis. However, the underlying molecular mechanisms are largely unclear, and effective treatment for it is limited. Using an integrated bioinformatics method, the present study aimed to identify the key candidate prognostic genes that are involved in HCC development and identify small-molecule drugs with treatment potential.

Methods and Results

In this study, by using three expression profile datasets from Gene Expression Omnibus database, 1,704 differentially expressed genes were identified, including 671 upregulated and 1,033 downregulated genes. Then, weighted co-expression network analysis revealed nine modules are related with pathological stage; turquoise module was the most associated module. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway analyses (KEGG) indicated that these genes were enriched in cell division, cell cycle, and metabolic related pathways. Furthermore, by analyzing the turquoise module, 22 genes were identified as hub genes. Based on HCC data from gene expression profiling interactive analysis (GEPIA) database, nine genes associated with progression and prognosis of HCC were screened, including ANLN, BIRC5, BUB1B, CDC20, CDCA5, CDK1, NCAPG, NEK2, and TOP2A. According to the Human Protein Atlas and the Oncomine database, these genes were highly upregulated in HCC tumor samples. Moreover, multivariate Cox regression analysis showed that the risk score based on the gene expression signature of these nine genes was an independent prognostic factor for overall survival and disease-free survival in HCC patients. In addition, the candidate small-molecule drugs for HCC were identified by the CMap database.

Conclusion

In conclusion, the nine key gene signatures related to HCC progression and prognosis were identified and validated. The cell cycle pathway was the core pathway enriched with these key genes. Moreover, several candidate molecule drugs were identified, providing insights into novel therapeutic approaches for HCC.
Capture Sequencing to Explore and Map Rare Casein Variants in Goats
Authors: Rahmatalla Siham A. , Arends Danny , Said Ahmed Ammar , Hassan Lubna M. A. , Krebs Stefan , Reissmann Monika , Brockmann Gudrun A.
Published: February 2021

Genetic variations in the four casein genes CSN1S1, CSN2, CSN1S2, and CSN3 have obtained substantial attention since they affect the milk protein yield, milk composition, cheese processing properties, and digestibility as well as tolerance in human nutrition. Furthermore, milk protein variants are used for breed characterization, biodiversity, and phylogenetic studies. The current study aimed at the identification of casein protein variants in five domestic goat breeds from Sudan (Nubian, Desert, Nilotic, Taggar, and Saanen) and three wild goat species [Capra aegagrus aegagrus (Bezoar ibex), Capra nubiana (Nubian ibex), and Capra ibex (Alpine ibex)]. High-density capture sequencing of 33 goats identified in total 22 non-synonymous and 13 synonymous single nucleotide polymorphisms (SNPs), of which nine non-synonymous and seven synonymous SNPs are new. In the CSN1S1 gene, the new non-synonymous SNP ss7213522403 segregated in Alpine ibex. In the CSN2 gene, the new non-synonymous SNPs ss7213522526, ss7213522558, and ss7213522487 were found exclusively in Nubian and Alpine ibex. In the CSN1S2 gene, the new non-synonymous SNPs ss7213522477, ss7213522549, and ss7213522575 were found in Nubian ibex only. In the CSN3 gene, the non-synonymous SNPs ss7213522604 and ss7213522610 were found in Alpine ibex. The identified DNA sequence variants led to the detection of nine new casein protein variants. New variants were detected for alpha S1 casein in Saanen goats (CSN1S1∗C1), Bezoar ibex (CSN1S1∗J), and Alpine ibex (CSN1S1∗K), for beta and kappa caseins in Alpine ibex (CSN2∗F and CSN3∗X), and for alpha S2 casein in all domesticated and wild goats (CSN1S2∗H), in Nubian and Desert goats (CSN1S2∗I), or in Nubian ibex only (CSN1S2∗J and CSN1S2∗K). The results show that most novel SNPs and protein variants occur in the critically endangered Nubian ibex. This highlights the importance of the preservation of this endangered breed. Furthermore, we suggest validating and further characterizing the new casein protein variants.
Differential Elevation of Inflammation and CD4+ T Cell Activation in Kenyan Female Sex Workers and Non-Sex Workers Using Depot-Medroxyprogesterone Acetate
Authors: Omollo Kenneth , Lajoie Julie , Oyugi Julius , Wessels Jocelyn M. , Mwaengo Dufton , Kimani Joshua , Kaushic Charu , Fowke Keith R.
Published: February 2021

Background

Depot Medroxyprogesterone (DMPA) is one of the most widely used contraceptives in Sub-Saharan Africa where HIV incidence is high. We explored the effect of DMPA on the activation of HIV cellular targets and inflammation as a possible mechanism of increased HIV risk with DMPA use. Since sex work is known to affect the immune system, this study aimed to understand the effect of DMPA on the immune system among sex workers and non-sex worker women.

Methods

Twenty-seven DMPA-using HIV seronegative female sex workers (FSW) and 30 DMPA-using HIV seronegative non-sex worker (SW) women were enrolled in the study. Twenty-four FSWs and 30 non-sex workers who were not using any hormonal contraception (no HC) were recruited as controls. Blood and cervico-vaginal samples were collected from all participants and assayed for T cell activation and proinflammatory cytokines.

Results

Among no HC users, sex workers had lower expression of CD38 and CD69 on blood-derived CD4+ T cells along with lower CD4+CCR5+ cells frequency in the endocervix. Plasma MCP-1, TNFα and IL-17 also had reduced expression in FSW not using HC. Non-sex workers using DMPA had elevated proportions of blood-derived CD4+CD38+, CD4+CD69+ and CD4+HLA-DR+ T cells relative to non-sex workers who were not taking any HC. DMPA-using non-sex workers also had an increased level of plasma interferon gamma (IFN-γ), monokine induced by interferon-γ (MIG) and sCD40L, alongside higher proportion of CD4+CD38+ and CD4+CD69+ T cells at the cervix compared to non-sex workers no-HC controls., Finally, non-sex workers and FSWs using DMPA had similar levels of genital and peripheral CD4+ T cell activation and inflammation.

Conclusion

DMPA increased inflammation and expression of activation markers on potential HIV target cells in non-sex workers. These data show that DMPA is a strong immune modulator and its use counteracts the decreased immune activation associated with sex work. These findings suggest that inflammation and increased HIV target cells in blood and at the genital tract may be mechanisms by which DMPA increases susceptibility to HIV.
Toll-Like Receptors Recognize Intestinal Microbes in Liver Cirrhosis
Authors: Fan Yujing , Li Yunpeng , Chu Yanjie , Liu Jing , Cui Lin , Zhang Dekai
Published: February 2021

Liver cirrhosis is one major cause of mortality in the clinic, and treatment of this disease is an arduous task. The scenario will be even getting worse with increasing alcohol consumption and obesity in the current lifestyle. To date, we have no medicines to cure cirrhosis. Although many etiologies are associated with cirrhosis, abnormal intestinal microbe flora (termed dysbiosis) is a common feature in cirrhosis regardless of the causes. Toll-like receptors (TLRs), one evolutional conserved family of pattern recognition receptors in the innate immune systems, play a central role in maintaining the homeostasis of intestinal microbiota and inducing immune responses by recognizing both commensal and pathogenic microbes. Remarkably, recent studies found that correction of intestinal flora imbalance could change the progress of liver cirrhosis. Therefore, correction of intestinal dysbiosis and targeting TLRs can provide novel and promising strategies in the treatment of liver cirrhosis. Here we summarize the recent advances in the related topics. Investigating the relationship among innate immunity TLRs, intestinal flora disorders, and liver cirrhosis and exploring the underlying regulatory mechanisms will assuredly have a bright future for both basic and clinical research.
Characteristics and Risk Factors of Cytokine Release Syndrome in Chimeric Antigen Receptor T Cell Treatment
Authors: Yan Zhiling , Zhang Huanxin , Cao Jiang , Zhang Cheng , Liu Hui , Huang Hongming , Cheng Hai , Qiao Jianlin , Wang Ying , Wang Yan , Gao Lei , Shi Ming , Sang Wei , Zhu Feng , Li Depeng , Sun Haiying , Wu Qingyun , Qi Yuekun , Li Hujun , Wang Xiangmin , Li Zhenyu , Liu Hong , Zheng Junnian , Qian Wenbin , Zhang Xi , Xu Kailin
Published: February 2021

Clinical trials have confirmed that chimeric antigen receptor (CAR) T cell therapies are revolutionizing approaches for treating several relapsed or refractory hematological tumors. Cytokine release syndrome (CRS) is an adverse event with high incidence during CAR-T treatment. A further understanding of the characteristics and related risk factors of CRS is important for effective management. A total of 142 patients with relapsed or refractory acute lymphocyte leukemia (ALL), lymphoma, or multiple myeloma (MM) received lymphodepletion chemotherapy followed by infusion of CAR-T cells. The characteristics of CRS at different time points after treatment were monitored and risk factors were analyzed. The incidence of CRS for ALL, lymphoma, and multiple myeloma were 82%, 90%, and 90% respectively. Fever was observed on a median of day 3 for ALL, day 1 for lymphoma, and day 8.5 for MM after CAR-T cell infusion, and the duration was different between grade 1–2 CRS and grade 3–5 CRS. Disease types, peak concentration of IL-6, and CRP were associated with CRS. For patients with ALL, numbers of lymphoblast in bone marrow before lymphodepletion, peak concentration of IL-6, and CRP were independent risk factors of CRS. Clinical stage of lymphoma patients and high tumor burden in marrow of MM patients were independent risk factors of CRS. In conclusion, the characteristics and risk factors of CRS in different B-cell hematological tumors are different and should be managed individually during CAR-T cell therapy.
Untangling Local Pro-Inflammatory, Reparative, and Regulatory Damage-Associated Molecular-Patterns (DAMPs) Pathways to Improve Transplant Outcomes
Authors: Dwyer Gaelen K. , Turnquist Hēth R.
Published: February 2021

Detrimental inflammatory responses after solid organ transplantation are initiated when immune cells sense pathogen-associated molecular patterns (PAMPs) and certain damage-associated molecular patterns (DAMPs) released or exposed during transplant-associated processes, such as ischemia/reperfusion injury (IRI), surgical trauma, and recipient conditioning. These inflammatory responses initiate and propagate anti-alloantigen (AlloAg) responses and targeting DAMPs and PAMPs, or the signaling cascades they activate, reduce alloimmunity, and contribute to improved outcomes after allogeneic solid organ transplantation in experimental studies. However, DAMPs have also been implicated in initiating essential anti-inflammatory and reparative functions of specific immune cells, particularly Treg and macrophages. Interestingly, DAMP signaling is also involved in local and systemic homeostasis. Herein, we describe the emerging literature defining how poor outcomes after transplantation may result, not from just an over-abundance of DAMP-driven inflammation, but instead an inadequate presence of a subset of DAMPs or related molecules needed to repair tissue successfully or re-establish tissue homeostasis. Adverse outcomes may also arise when these homeostatic or reparative signals become dysregulated or hijacked by alloreactive immune cells in transplant niches. A complete understanding of the critical pathways controlling tissue repair and homeostasis, and how alloimmune responses or transplant-related processes disrupt these will lead to new immunotherapeutics that can prevent or reverse the tissue pathology leading to lost grafts due to chronic rejection.
Deficiency of Dietary Fiber Modulates Gut Microbiota Composition, Neutrophil Recruitment and Worsens Experimental Colitis
Authors: Shen Sj , Prame Kumar Kathryn , Wen Shu Wen , Shim Raymond , Wanrooy Brooke J. , Stanley Dragana , Moore Robert J. , Van Thi Thu Hao , Robert Remy , Hickey Michael J. , Wong Connie H. Y.
Published: February 2021

Ulcerative colitis is an inflammatory disease of the colon that is associated with colonic neutrophil accumulation. Recent evidence indicates that diet alters the composition of the gut microbiota and influences host–pathogen interactions. Specifically, bacterial fermentation of dietary fiber produces metabolites called short-chain fatty acids (SCFAs), which have been shown to protect against various inflammatory diseases. However, the effect of fiber deficiency on the key initial steps of inflammation, such as leukocyte–endothelial cell interactions, is unknown. Moreover, the impact of fiber deficiency on neutrophil recruitment under basal conditions and during inflammation in vivo is unknown. Herein, we hypothesized that a fiber-deficient diet promotes an inflammatory state in the colon at baseline and predisposes the host to more severe colitis pathology. Mice fed a no-fiber diet for 14 days showed significant changes in the gut microbiota and exhibited increased neutrophil-endothelial interactions in the colonic microvasculature. Although mice fed a no-fiber diet alone did not have observable colitis-associated symptoms, these animals were highly susceptible to low dose (0.5%) dextran sodium sulphate (DSS)-induced model of colitis. Supplementation of the most abundant SCFA, acetate, prevented no-fiber diet-mediated enrichment of colonic neutrophils and colitis pathology. Therefore, dietary fiber, possibly through the actions of acetate, plays an important role in regulating neutrophil recruitment and host protection against inflammatory colonic damage in an experimental model of colitis.
Single Cell RNA-Seq and Machine Learning Reveal Novel Subpopulations in Low-Grade Inflammatory Monocytes With Unique Regulatory Circuits
Authors: Lee Jiyoung , Geng Shuo , Li Song , Li Liwu
Published: February 2021

Subclinical doses of LPS (SD-LPS) are known to cause low-grade inflammatory activation of monocytes, which could lead to inflammatory diseases including atherosclerosis and metabolic syndrome. Sodium 4-phenylbutyrate is a potential therapeutic compound which can reduce the inflammation caused by SD-LPS. To understand the gene regulatory networks of these processes, we have generated scRNA-seq data from mouse monocytes treated with these compounds and identified 11 novel cell clusters. We have developed a machine learning method to integrate scRNA-seq, ATAC-seq, and binding motifs to characterize gene regulatory networks underlying these cell clusters. Using guided regularized random forest and feature selection, our method achieved high performance and outperformed a traditional enrichment-based method in selecting candidate regulatory genes. Our method is particularly efficient in selecting a few candidate genes to explain observed expression pattern. In particular, among 531 candidate TFs, our method achieves an auROC of 0.961 with only 10 motifs. Finally, we found two novel subpopulations of monocyte cells in response to SD-LPS and we confirmed our analysis using independent flow cytometry experiments. Our results suggest that our new machine learning method can select candidate regulatory genes as potential targets for developing new therapeutics against low grade inflammation.
Interferon Regulatory Factor 4 Regulates the Development of Polymorphonuclear Myeloid-Derived Suppressor Cells Through the Transcription of c-Myc in Cancer
Authors: Yang Quan , Xie Hongyan , Li Xing , Feng Yuanfa , Xie Shihao , Qu Jiale , Xie Anqi , Zhu Yiqiang , Zhou Lu , Yang Jinxue , Hu Xiaohao , Wei Haixia , Qiu Huaina , Qin Wenjuan , Huang Jun
Published: February 2021

The accumulation of myeloid-derived suppressor cells (MDSCs) is one of the major obstacles to achieve an appropriate anti-tumor immune response and successful tumor immunotherapy. MDSCs in tumor-bearing hosts are primarily polymorphonuclear (PMN-MDSCs). However, the mechanisms regulating the development of MDSCs remain poorly understood. In this report, we showed that interferon regulatory factor 4 (IRF4) plays a key role in the development of PMN-MDSCs, but not monocytic MDSCs. IRF4 deficiency caused a significant elevation of PMN-MDSCs and enhanced the suppressive activity of PMN-MDSCs, increasing tumor growth and metastasis in mice. Mechanistic studies showed that c-Myc was up-regulated by the IRF4 protein. Over-expression of c-Myc almost abrogated the effects of IRF4 deletion on PMN-MDSCs development. Importantly, the IRF4 expression level was negatively correlated with the PMN-MDSCs frequency and tumor development but positively correlated with c-Myc expression in clinical cancer patients. In summary, this study demonstrated that IRF4 represents a novel regulator of PMN-MDSCs development in cancer, which may have predictive value for tumor progression.
Association Between Vitamin D Exposure and Head and Neck Cancer: A Systematic Review With Meta-Analysis
Authors: Pu Yuting , Zhu Gangcai , Xu Yimin , Zheng Siyuan , Tang Bin , Huang Huimei , Wu Irene X. Y. , Huang Donghai , Liu Yong , Zhang Xin
Published: February 2021

Background

Vitamin D deficiency is a well-described preventable cause of many cancers; the association of vitamin D use with the development of head and neck cancer (HNC) is not clear. We aim to conduct a systematic review of the studies assessing the relation between vitamin D exposure and the prevention and prognosis of the HNC using meta-analysis.

Methods

PubMed, EMBASE, Cochrane Library, Web of Science up to 1 January 2021, and reference lists of related studies were searched. We extracted observational studies reporting the association between vitamin D (vitamin D receptor gene polymorphisms, 25-hydroxyvitamin D concentrations, and vitamin D intake) and the outcomes of interest (HNC incidence and HNC mortality) in HNC patients aged 18 or older. Fixed effects models were used to calculate pooled effect sizes and 95% confidence intervals (CIs) by RevMan (version 5.3).

Results

Sixteen studies with a total of 81,908 participants were enrolled in our meta-analysis. Based on the pooled genomic analysis, comparing with participants with the genotypes of Ff + FF or FF, the pooled odds ratio (OR) of participants with the genotype of ff was 0.77 (95% CI: 0.61 to 0.97) and 0.75 (0.58 to 0.97), respectively. A similar trend was noted when comparing tt with Tt + TT or TT, in which OR (95% CI) was 0.70 (0.55 to 0.90) and 0.72 (0.55 to 0.95). No significant association was identified between BsmI polymorphism and HNC. Furthermore, the OR of HNC incidence was 0.77 (0.65 to 0.92) for participants with vitamin D intake over the ones with a regular diet. High concentrations of circulated 25-hydroxyvitamin D (25-OHD) significantly decreased by 32% of HNC incidence (OR (95% CI): 0.68 (0.59 to 0.78)) and increased HNC survival (pooled hazard ratio 1.13, 1.05 to 1.22) during a 4–5 years follow-up. High concentrations of circulating 25-OHD in patients with HNC led to a decreased risk of mortality to 0.75 (0.60 to 0.94) as the follow-up extends to 8–12 years.

Conclusions

Elevated activities of vitamin D by diet intake, genomic polymorphisms, or circulated 25-OHD may protect people from HNC and improve the prognosis of patients with HNC.

Systematic Review Registration

PROSPERO, identifier CRD42020176002 (https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=176002).
Case Report: Dendritic Cells and Macrophages Capture Sperm in Chronically Inflamed Human Epididymis
Authors: Zheng Wenzhong , Zhang Shiqiang , Chen Xiaobao , Jiang Shaoqin , Li Zhihao , Li Mengqiang
Published: February 2021

Chronic inflammation of the male genital tract is thought to be a primary etiological factor of male infertility. The abundance and activation of macrophages and dendritic cells in patients with chronic inflammation of genital tract were closely associated with oligozoospermia and asthenospermia. Chronic epididymitis appears to be more important than seminal vesiculitis or prostatitis due to the direct interaction between spermatozoa and epididymal inflammatory cells. In this study, we present a case report of a 41-year-old male with oligoasthenospermia and chronic epididymitis. Hematoxylin-eosin staining and immunofluorescence analyses showed that antigen presenting cells including macrophages and dendritic cells were found capturing spermatozoa in the lumen of cauda epididymis. To our knowledge, this is the first case report that directly observed dendritic cells capturing spermatozoa in the lumen of an inflamed epididymis. This finding directly explains chronic epididymitis as the possible cause of oligospermia in patients.
Identification of a Novel Serum Proteomic Signature for Primary Sjögren’s Syndrome
Authors: Padern Guillaume , Duflos Claire , Ferreira Rosanna , Assou Said , Guilpain Philippe , Maria Alexandre Thibault Jacques , Goulabchand Radjiv , Galea Pascale , Jurtela Maja , Jorgensen Christian , Pers Yves-Marie
Published: February 2021

Context

Primary Sjögren’s syndrome (pSS) is a complex heterogeneous autoimmune disease (AID) which can mimic rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). Our exploratory study investigated serum biomarkers that may discriminate pSS from RA and SLE.

Methods

Serum concentrations of 63 biomarkers involved in immune cell trafficking, inflammatory response, cellular movement, and cell-to-cell signaling were measured in AID patients, included prospectively into the study at the Montpellier University Hospital. A multivariate analysis by multiple logistic regression was performed, and discriminative power assessed using logistic regression adjusted on significant demographic factors.

Results

Among the 95 patients enrolled, 42 suffered from pSS, 28 from RA, and 25 from SLE. Statistical analysis showed that concentrations of BDNF (OR = 0.493 with 95% CI [0.273–0.891]; p = 0.0193) and I-TAC/CXCL11 (OR = 1.344 with 95% CI [1.027–1.76]; p = 0.0314) can significantly discriminate pSS from RA. Similarly, greater concentrations of sCD163 (OR = 0.803 with 95% CI [0.649–0.994]; p = 0.0436), Fractalkine/CX3CL1 (OR = 0.534 with 95% CI [0.287–0. 991]; p = 0.0466), MCP-1/CCL2 (OR = 0.839 with 95% CI [0.732–0.962]; p = 0.0121), and TNFa (OR = 0.479 with 95% CI [0.247–0.928]; p = 0.0292) were associated with SLE diagnosis compared to pSS. In addition, the combination of low concentrations of BDNF and Fractalkine/CX3CL1 was highly specific for pSS (specificity 96.2%; positive predictive value 80%) compared to RA and SLE, as well as the combination of high concentrations of I-TAC/CXCL11 and low concentrations of sCD163 (specificity 98.1%; positive predictive value 75%).

Conclusion

Our study highlights biomarkers potentially involved in pSS, RA, and SLE pathophysiology that could be useful for developing a pSS-specific diagnostic tool.
Tantalum Nanoparticles Reinforced PCL Scaffolds Using Direct 3D Printing for Bone Tissue Engineering
Authors: Xiong Zixuan , Liu Wenbin , Qian Hu , Lei Ting , He Xi , Hu Yihe , Lei Pengfei
Published: February 2021

Polycarbonate (PCL) has been widely used in tissue engineering, but its hydrophobicity and low biological activity limit its further promotion and application. By adding nanoparticles, the hydrophilicity and biological activity of PCL can be improved. In this study, different amounts of Ta (1–10%wt) were added to PCL, and then their mechanical and biological properties were studiedin vitro. XRD found that 5%Ta-PCL has the highest crystallinity. At the same time, cell experiments CCK8, cell adhesion, osteogenic differentiation, and osteogenesis related gene expression showed that Ta can enhance the mechanical and biological properties of PCL, while 5% Ta-PCL showed the best mechanical and biological properties. This composite of tantalum and PCL could have a clinical potential for orthopedic implants.
Depth Profile of Nitrifying Archaeal and Bacterial Communities in the Remote Oligotrophic Waters of the North Pacific
Authors: Semedo Miguel , Lopes Eva , Baptista Mafalda S. , Oller-Ruiz Ainhoa , Gilabert Javier , Tomasino Maria Paola , Magalhães Catarina
Published: February 2021

Nitrification is a vital ecosystem function in the open ocean that regenerates inorganic nitrogen and promotes primary production. Recent studies have shown that the ecology and physiology of nitrifying organisms is more complex than previously postulated. The distribution of these organisms in the remote oligotrophic ocean and their interactions with the physicochemical environment are relatively understudied. In this work, we aimed to evaluate the depth profile of nitrifying archaea and bacteria in the Eastern North Pacific Subtropical Front, an area with limited biological surveys but with intense trophic transferences and physicochemical gradients. Furthermore, we investigated the dominant physicochemical and biological relationships within and between ammonia-oxidizing archaea (AOA), ammonia-oxidizing bacteria (AOB), and nitrite-oxidizing bacteria (NOB) as well as with the overall prokaryotic community. We used a 16S rRNA gene sequencing approach to identify and characterize the nitrifying groups within the first 500 m of the water column and to analyze their abiotic and biotic interactions. The water column was characterized mainly by two contrasting environments, warm O2-rich surface waters with low dissolved inorganic nitrogen (DIN) and a cold O2-deficient mesopelagic layer with high concentrations of nitrate (NO3–). Thaumarcheotal AOA and bacterial NOB were highly abundant below the deep chlorophyll maximum (DCM) and in the mesopelagic. In the mesopelagic, AOA and NOB represented up to 25 and 3% of the total prokaryotic community, respectively. Interestingly, the AOA community in the mesopelagic was dominated by unclassified genera that may constitute a novel group of AOA highly adapted to the conditions observed at those depths. Several of these unclassified amplicon sequence variants (ASVs) were positively correlated with NO3– concentrations and negatively correlated with temperature and O2, whereas known thaumarcheotal genera exhibited the opposite behavior. Additionally, we found a large network of positive interactions within and between putative nitrifying ASVs and other prokaryotic groups, including 13230 significant correlations and 23 sub-communities of AOA, AOB, NOB, irrespective of their taxonomic classification. This study provides new insights into our understanding of the roles that AOA may play in recycling inorganic nitrogen in the oligotrophic ocean, with potential consequences to primary production in these remote ecosystems.
Albumin Alters the Conformational Ensemble of Amyloid-β by Promiscuous Interactions: Implications for Amyloid Inhibition
Authors: Xie Huisi , Guo Cong
Published: February 2021

Human serum albumin (HSA) is a key endogenous inhibitor of amyloid-β (Αβ) aggregation. In vitro HSA inhibits Aβ fibrillization and targets multiple species along the aggregation pathway including monomers, oligomers, and protofibrils. Amyloid inhibition by HSA has both pathological implications and therapeutic potential, but the underlying molecular mechanism remains elusive. As a first step towards addressing this complex question, we studied the interactions of an Aβ42 monomer with HSA by molecular dynamics simulations. To adequately sample the conformational space, we adapted the replica exchange with solute tempering (REST2) method to selectively heat the Aβ42 peptide in the absence and presence of HSA. Aβ42 binds to multiple sites on HSA with a preference to domain III and adopts various conformations that all differ from the free state. The β-sheet abundances of H14-E22 and A30-M33 regions are significantly reduced by HSA, so are the β-sheet lengths. HSA shifts the conformational ensemble towards more disordered states and alters the β-sheet association patterns. In particular, the frequent association of Q15-V24 and N27-V36 regions into β-hairpin which is critical for aggregation is impeded. HSA primarily interacts with the latter β-region and the N-terminal charged residues. They form promiscuous interactions characterized by salt bridges at the edge of the peptide-protein interface and hydrophobic cores at the center. Consequently, intrapeptide interactions crucial for β-sheet formation are disrupted. Our work builds the bridge between the modification of Aβ conformational ensemble and amyloid inhibition by HSA. It also illustrates the potential of the REST2 method in studying interactions between intrinsically disordered peptides and globular proteins.
Enhanced Autolysosomal Function Ameliorates the Inflammatory Response Mediated by the NLRP3 Inflammasome in Alzheimer’s Disease
Authors: Zhou Wen , Xiao Deng , Zhao Yueyang , Tan Botao , Long Zhimin , Yu Lehua , He Guiqiong
Published: February 2021

The pathogenesis of Alzheimer’s disease (AD) involves activation of many NLRP3 inflammatory bodies, which may be related to amyloid β peptide and aggregation of misfolded proteins. Autophagy is an important regulator of inflammatory bodies. However, autophagy shows dynamic changes in the development of AD, and its role in inflammation remains controversial. In this study, the key link between autophagic disorders and the NLRP3 inflammasome in AD was investigated. APP/PS1 double transgenic mice and C57 mice with Aβ25–35 injected into the lateral ventricle were used as two animal models of AD. Immunofluorescence staining and Western blot analysis showed that NLRP3 inflammasome-related proteins and inflammatory cytokines, such as IL-1α, IL-1β, IL-6, IL-12, and TNF-α, were increased and microglia were activated in the brains of both AD animal models. Endogenous overexpression of the APPswe gene and exogenous addition of Aβ25–35 increased the expression of NLRP3 inflammasome-related proteins, while exogenous Aβ25–35 intervention more significantly activated inflammation. Furthermore, LC3 was increased in the AD animal and cell models, and the level of Lamp1 decreased. After overexpression of the primary regulator of lysosomal biogenesis, TFEB, the lysosome protein Lamp1 was increased, and LC3 and inflammatory protein expression were decreased. These results suggest that the NLRP3 inflammasome-mediated inflammatory response is activated in AD animal and cell models, which may be related to the decline in autolysosome function. Overexpression of the TFEB protein can reduce the inflammatory response by improving autolysosome function in AD model cells.
NEUBOrg: Artificially Induced Pluripotent Stem Cell-Derived Brain Organoid to Model and Study Genetics of Alzheimer’s Disease Progression
Authors: Esmail Sally , Danter Wayne R.
Published: February 2021

Alzheimer’s disease (AD) is the most common type of neurodegenerative diseases. There are over 44 million people living with the disease worldwide. While there are currently no effective treatments for AD, induced pluripotent stem cell-derived brain organoids have the potential to provide a better understanding of Alzheimer’s pathogenesis. Nevertheless, developing brain organoid models is expensive, time consuming and often does not reflect disease progression. Using accurate and inexpensive computer simulations of human brain organoids can overcome the current limitations. Induced whole brain organoids (aiWBO) will greatly expand our ability to model AD and can guide wet lab research. In this study, we have successfully developed and validated artificially induced a whole brain organoid platform (NEUBOrg) using our previously validated machine learning platform, DeepNEU (v6.1). Using NEUBorg platform, we have generated aiWBO simulations of AD and provided a novel approach to test genetic risk factors associated with AD progression and pathogenesis.
Emerging Roles of Extracellular Vesicles in the Central Nervous System: Physiology, Pathology, and Therapeutic Perspectives
Authors: Gassama Yadaly , Favereaux Alexandre
Published: February 2021

Extracellular vesicles or EVs are secreted by most, if not all, eukaryote cell types and recaptured by neighboring or distant cells. Their cargo, composed of a vast diversity of proteins, lipids, and nucleic acids, supports the EVs’ inter-cellular communication. The role of EVs in many cellular processes is now well documented both in physiological and pathological conditions. In this review, we focus on the role of EVs in the central nervous system (CNS) in physiological as well as pathological conditions such as neurodegenerative diseases or brain cancers. We also discuss the future of EVs in clinical research, in particular, their value as biomarkers as well as innovative therapeutic agents. While an increasing number of studies reveal EV research as a promising field, progress in the standardization of protocols and innovation in analysis as well as in research tools is needed to make a breakthrough in our understanding of their impact in the pathophysiology of the brain.
Eros, Beauty, and Phon-Aesthetic Judgements of Language Sound. We Like It Flat and Fast, but Not Melodious. Comparing Phonetic and Acoustic Features of 16 European Languages
Authors: Kogan Vita V. , Reiterer Susanne M.
Published: February 2021

This article concerns sound aesthetic preferences for European foreign languages. We investigated the phonetic-acoustic dimension of the linguistic aesthetic pleasure to describe the “music” found in European languages. The Romance languages, French, Italian, and Spanish, take a lead when people talk about melodious language – the music-like effects in the language (a.k.a., phonetic chill). On the other end of the melodiousness spectrum are German and Arabic that are often considered sounding harsh and un-attractive. Despite the public interest, limited research has been conducted on the topic of phonaesthetics, i.e., the subfield of phonetics that is concerned with the aesthetic properties of speech sounds (Crystal, 2008). Our goal is to fill the existing research gap by identifying the acoustic features that drive the auditory perception of language sound beauty. What is so music-like in the language that makes people say “it is music in my ears”? We had 45 central European participants listening to 16 auditorily presented European languages and rating each language in terms of 22 binary characteristics (e.g., beautiful – ugly and funny – boring) plus indicating their language familiarities, L2 backgrounds, speaker voice liking, demographics, and musicality levels. Findings revealed that all factors in complex interplay explain a certain percentage of variance: familiarity and expertise in foreign languages, speaker voice characteristics, phonetic complexity, musical acoustic properties, and finally musical expertise of the listener. The most important discovery was the trade-off between speech tempo and so-called linguistic melody (pitch variance): the faster the language, the flatter/more atonal it is in terms of the pitch (speech melody), making it highly appealing acoustically (sounding beautiful and sexy), but not so melodious in a “musical” sense.
Stable Anatomy Detection in Multimodal Imaging Through Sparse Group Regularization: A Comparative Study of Iron Accumulation in the Aging Brain
Authors: Pietrosanu Matthew , Zhang Li , Seres Peter , Elkady Ahmed , Wilman Alan H. , Kong Linglong , Cobzas Dana
Published: February 2021

Multimodal neuroimaging provides a rich source of data for identifying brain regions associated with disease progression and aging. However, present studies still typically analyze modalities separately or aggregate voxel-wise measurements and analyses to the structural level, thus reducing statistical power. As a central example, previous works have used two quantitative MRI parameters—R2* and quantitative susceptibility (QS)—to study changes in iron associated with aging in healthy and multiple sclerosis subjects, but failed to simultaneously account for both. In this article, we propose a unified framework that combines information from multiple imaging modalities and regularizes estimates for increased interpretability, generalizability, and stability. Our work focuses on joint region detection problems where overlap between effect supports across modalities is encouraged but not strictly enforced. To achieve this, we combine L1 (lasso), total variation (TV), and L2 group lasso penalties. While the TV penalty encourages geometric regularization by controlling estimate variability and support boundary geometry, the group lasso penalty accounts for similarities in the support between imaging modalities. We address the computational difficulty in this regularization scheme with an alternating direction method of multipliers (ADMM) optimizer. In a neuroimaging application, we compare our method against independent sparse and joint sparse models using a dataset of R2* and QS maps derived from MRI scans of 113 healthy controls: our method produces clinically-interpretable regions where specific iron changes are associated with healthy aging. Together with results across multiple simulation studies, we conclude that our approach identifies regions that are more strongly associated with the variable of interest (e.g., age), more accurate, and more stable with respect to training data variability. This work makes progress toward a stable and interpretable multimodal imaging analysis framework for studying disease-related changes in brain structure and can be extended for classification and disease prediction tasks.
Validation of Computer-Adaptive Contrast Sensitivity as a Tool to Assess Visual Impairment in Multiple Sclerosis Patients
Authors: Rosenkranz Sina C. , Kaulen Barbara , Zimmermann Hanna G. , Bittner Ava K. , Dorr Michael , Stellmann Jan-Patrick
Published: February 2021

Background

Impairment of visual function is one of the major symptoms of people with multiple sclerosis (pwMS). A multitude of disease effects including inflammation and neurodegeneration lead to structural impairment in the visual system. However, the gold standard of disability quantification, the expanded disability status scale (EDSS), relies on visual assessment charts. A more comprehensive assessment of visual function is the full contrast sensitivity function (CSF), but most tools are time consuming and not feasible in clinical routine. The quantitative CSF (qCSF) test is a computerized test to assess the full CSF. We have already shown a better correlation with visual quality of life (QoL) than for classical high and low contrast charts in multiple sclerosis (MS).

Objective

To study the precision, test duration, and repeatability of the qCSF in pwMS. In order to evaluate the discrimination ability, we compared the data of pwMS to healthy controls.

Methods

We recruited two independent cohorts of MS patients. Within the precision cohort (n = 54), we analyzed the benefit of running 50 instead of 25 qCSF trials. The repeatability cohort (n = 44) was assessed by high contrast vision charts and qCSF assessments twice and we computed repeatability metrics. For the discrimination ability we used the data from all pwMS without any previous optic neuritis and compared the area under the log CSF (AULCSF) to an age-matched healthy control data set.

Results

We identified 25 trials of the qCSF algorithm as a sufficient amount for a precise estimate of the CSF. The median test duration for one eye was 185 s (range 129–373 s). The AULCSF had better test–retest repeatability (Mean Average Precision, MAP) than visual acuity measured by standard high contrast visual acuity charts or CSF acuity measured with the qCSF (0.18 vs. 0.11 and 0.17, respectively). Even better repeatability (MAP = 0.19) was demonstrated by a CSF-derived feature that was inspired by low-contrast acuity charts, i.e., the highest spatial frequency at 25% contrast. When compared to healthy controls, the MS patients showed reduced CSF (average AULCSF 1.21 vs. 1.42, p < 0.01).

Conclusion

High precision, usability, repeatability, and discrimination support the qCSF as a tool to assess contrast vision in pwMS.
Bio-Inspired Architectures Substantially Reduce the Memory Requirements of Neural Network Models
Authors: Dalgaty Thomas , Miller John P. , Vianello Elisa , Casas Jérôme
Published: February 2021

We propose a neural network model for the jumping escape response behavior observed in the cricket cercal sensory system. This sensory system processes low-intensity air currents in the animal's immediate environment generated by predators, competitors, and mates. Our model is inspired by decades of physiological and anatomical studies. We compare the performance of our model with a model derived through a universal approximation, or a generic deep learning, approach, and demonstrate that, to achieve the same performance, these models required between one and two orders of magnitude more parameters. Furthermore, since the architecture of the bio-inspired model is defined by a set of logical relations between neurons, we find that the model is open to interpretation and can be understood. This work demonstrates the potential of incorporating bio-inspired architectural motifs, which have evolved in animal nervous systems, into memory efficient neural network models.
Nuclear Factor Erythroid 2-Related Factor 2 Activation Might Mitigate Clinical Symptoms in Friedreich’s Ataxia: Clues of an “Out-Brain Origin” of the Disease From a Family Study
Authors: Petrillo Sara , Santoro Massimo , La Rosa Piergiorgio , Perna Alessia , Gallo Maria Giovanna , Bertini Enrico Silvio , Silvestri Gabriella , Piemonte Fiorella
Published: February 2021

Friedreich’s ataxia (FRDA) is the most frequent autosomal recessive ataxia in western countries, with a mean age of onset at 10–15 years. Patients manifest progressive cerebellar and sensory ataxia, dysarthria, lower limb pyramidal weakness, and other systemic manifestations. Previously, we described a family displaying two expanded GAA alleles not only in the proband affected by late-onset FRDA but also in the two asymptomatic family members: the mother and the younger sister. Both of them showed a significant reduction of frataxin levels, without any disease manifestation. Here, we analyzed if a protective mechanism might contribute to modulate the phenotype in this family. We particularly focused on the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), the first line of antioxidant defense in cells, and on the glutathione (GSH) system, an index of reactive oxygen species (ROS) detoxification ability. Our findings show a great reactivity of the GSH system to the frataxin deficiency, particularly in the asymptomatic mother, where the genes of GSH synthesis [glutamate–cysteine ligase (GCL)] and GSSG detoxification [GSH S-reductase (GSR)] were highly responsive. The GSR was activated even in the asymptomatic sister and in the proband, reflecting the need of buffering the GSSG increase. Furthermore, and contrasting the NRF2 expression documented in FRDA tissues, NRF2 was highly activated in the mother and in the younger sister, while it was constitutively low in the proband. This suggests that, also under frataxin depletion, the endogenous stimulation of NRF2 in asymptomatic FRDA subjects may contribute to protect against the progressive oxidative damage, helping to prevent the onset of neurological symptoms and highlighting an “out-brain origin” of the disease.
Scale-Free Analysis of Intraoperative ECoG During Awake Craniotomy for Glioma
Authors: Ghinda Diana Cristina , Lambert Ben , Lu Junfeng , Jiang Ning , Tsai Eve , Sachs Adam , Wu Jin-Song , Northoff Georg
Published: February 2021

Background

Electrocorticography (ECoG) has been utilized in many epilepsy cases however, the use of this technique for evaluating electrophysiological changes within tumoral zones is spare. Nonetheless, epileptic activities seem to arise from the neocortex surrounding the gliomas suggesting a link between epileptogenesis and glioma cell infiltration in the peritumoral area. The purpose of this study was to implement novel scale-free measures to assess how cortical physiology is altered by the presence of an invasive brain tumor.

Methods

Twelve patients undergoing an awake craniotomy for resection of a supratentorial glioma were included. ECoG data over the main tumor and the exposed surroundings was acquired intra-operatively just prior to tumor resection. Six of the patients presented with seizures and had data acquired both in the awake and anesthetic state. The corresponding anatomical location of each electrode in relation to the macroscopically-detectable tumor was recorded using the neuronavigation system based on structural anatomical images obtained pre-operatively. The electrodes were classified into tumoral, healthy or peritumoral based on the macroscopically detectable tumoral tissue from the pre-operative structural MRI.

Results

The electrodes overlying the tumoral tissue revealed higher power law exponent (PLE) values across tumoral area compared to the surrounding tissues. The difference between the awake and anesthetic states was significant in the tumoral and healthy tissue (p < 0.05) but not in the peritumoral tissue. The absence of a significant PLE reduction in the peritumoral tissue from the anesthetic to the awake state could be considered as an index of the presence or absence of infiltration of tumor cells into the peritumoral tissue.

Conclusions

The current study portrays for the first time distinct power law exponent features in the tumoral tissue, which could provide a potential novel electrophysiological marker in the future. The distinct features seen in the peritumoral tissue of gliomas seem to indicate the area where both the onset of epileptiform activity and the tumor infiltration take place.
The Impact of Programmed Death-Ligand 1 Expression on the Prognosis of Early Stage Resected Non-Small Cell Lung Cancer: A Meta-Analysis of Literatures
Authors: Shi Tao , Zhu Shuai , Guo Hengjuan , Li Xiongfei , Zhao Shikang , Wang Yanye , Lei Xi , Huang Dingzhi , Peng Ling , Li Ziming , Xu Song
Published: February 2021

Introduction

Previous studies have demonstrated that programmed cell death-ligand 1 (PD-L1) serves as biomarker for poor prognosis and survival in advanced-stage non-small cell lung cancer (NSCLC) patients. However, the merit of PD-L1 expression to predict the prognosis of early stage NSCLC patients who underwent complete resection remains controversial. In the present study, we performed a meta-analysis to investigate the relationship between PD-L1 expression and prognosis in patients with early stage resected NSCLC.

Methods

Electronic databases, including PubMed, EMBASE, and the Cochrane Library, were searched until July 23 2020 for studies evaluating the expression of PD-L1 and the prognosis of resected NSCLCs. Hazard ratios (HRs) with 95% confidence intervals (CIs) of overall survival (OS) and disease-free survival (DFS) were pooled and analyzed. Heterogeneity and publication bias analyses were also assessed.

Results

A total of 15 studies involving 3,790 patients were considered in the present meta-analysis. The pooled HR indicated that PD-L1 expression related to a much shorter DFS (HR = 1.56, 95% CI: 1.18–2.05, p < 0.01), as well a significantly worse OS (HR = 1.68, 95% CI: 1.29–2.18, p < 0.01). Furthermore, our analysis indicated that PD-L1 expression was significantly associated with gender (male vs. female: OR = 1.27, 95% CI:1.01–1.59, p = 0.038), histology (ADC vs. SCC: OR = 0.54, 95% CI:0.38–0.77, p = 0.001), TNM stage (I vs. II–III: OR = 0.45, 95% CI:0.34–0.60, p = 0.000), smoking status (Yes vs No: OR = 1.43, 95% CI:1.14–1.80, p = 0.002) and lymph node metastasis (N+ vs N−: OR = 1.97, 95% CI:1.26–3.08, p = 0.003).

Conclusions

The results of this meta-analysis suggest that PD-L1 expression predicts an unfavorable prognosis in early stage resected NSCLCs. The role of personalized anti-PD-L1/PD-1 immunotherapy in the adjuvant settings of resected NSCLC warrants further investigation.