bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of Human CD4 T Cells Specific for a C-Peptide/C-Peptide Hybrid Insulin Peptide
Authors: Wiles Timothy A. , Hohenstein Anita , Landry Laurie G. , Dang Mylinh , Powell Roger , Guyer Perrin , James Eddie A. , Nakayama Maki , Haskins Kathryn , Delong Thomas , Baker Rocky L.
Published: May 2021

Hybrid Insulin Peptides (HIPs), which consist of insulin fragments fused to other peptides from β-cell secretory granule proteins, are CD4 T cell autoantigens in type 1 diabetes (T1D). We have studied HIPs and HIP-reactive CD4 T cells extensively in the context of the non-obese diabetic (NOD) mouse model of autoimmune diabetes and have shown that CD4 T cells specific for HIPs are major contributors to disease pathogenesis. Additionally, in the human context, HIP-reactive CD4 T cells can be found in the islets and peripheral blood of T1D patients. Here, we performed an in-depth characterization of the CD4 T cell response to a C-peptide/C-peptide HIP (HIP11) in human T1D. We identified the TCR expressed by the previously-reported HIP11-reactive CD4 T cell clone E2, which was isolated from the peripheral blood of a T1D patient, and determined that it recognizes HIP11 in the context of HLA-DQ2. We also identified a HIP11-specific TCR directly in the islets of a T1D donor and demonstrated that this TCR recognizes a different minimal epitope of HIP11 presented by HLA-DQ8. We generated and tested an HLA-DQ2 tetramer loaded with HIP11 that will enable direct ex vivo interrogation of CD4 T cell responses to HIP11 in human patients and control subjects. Using mass spectrometric analysis, we confirmed that HIP11 is present in human islets. This work represents an important step in characterizing the role of CD4 T cell responses to HIPs in human T1D.
Genetically Engineered Mouse Models Support a Major Role of Immune Checkpoint-Dependent Immunosurveillance Escape in B-Cell Lymphomas
Authors: Lemasson Quentin , Akil Hussein , Feuillard Jean , Vincent-Fabert Christelle
Published: May 2021

These last 20 years, research on immune tumor microenvironment led to identify some critical recurrent mechanisms used in cancer to escape immune response. Through immune checkpoints, which are cell surface molecules involved in the immune system control, it is now established that tumor cells are able to shutdown the immune response. Due to the complexity and heterogeneity of Non Hodgkin B-cell Lymphomas (NHBLs), it is difficult to understand the precise mechanisms of immune escape and to explain the mitigated effect of immune checkpoints blockade for their treatment. Because genetically engineered mouse models are very reliable tools to improve our understanding of molecular mechanisms involved in B-cell transformation and, at the same time, can be useful preclinical models to predict immune response, we reviewed hereafter some of these models that highlight the immune escape mechanisms of NHBLs and open perspectives on future therapies.
Dermatan Sulfate Is a Potential Regulator of IgH via Interactions With Pre-BCR, GTF2I, and BiP ER Complex in Pre-B Lymphoblasts
Authors: Lee Jongmin , Rho Jung-hyun , Roehrl Michael H. , Wang Julia Y.
Published: May 2021

Dermatan sulfate (DS) and autoantigen (autoAg) complexes are capable of stimulating autoreactive CD5+ B1 cells. We examined the activity of DS on CD5+ pre-B lymphoblast NFS-25 cells. CD19, CD5, CD72, PI3K, and Fas possess varying degrees of DS affinity. The three pre-BCR components, Ig heavy chain mu (IgH), VpreB, and lambda 5, display differential DS affinities, with IgH having the strongest affinity. DS attaches to NFS-25 cells, gradually accumulates in the ER, and eventually localizes to the nucleus. DS and IgH co-localize on the cell surface and in the ER. DS associates strongly with 17 ER proteins (e.g., BiP/Grp78, Grp94, Hsp90ab1, Ganab, Vcp, Canx, Kpnb1, Prkcsh, Pdia3), which points to an IgH-associated multiprotein complex in the ER. In addition, DS interacts with nuclear proteins (Ncl, Xrcc6, Prmt5, Eftud2, Supt16h) and Lck. We also discovered that DS binds GTF2I, a required gene transcription factor at theIgHlocus. These findings support DS as a potential regulator of IgH in pre-B cells at protein and gene levels. We propose a (DS•autoAg)-autoBCR dual signal model in which an autoBCR is engaged by both autoAg and DS, and, once internalized, DS recruits a cascade of molecules that may help avert apoptosis and steer autoreactive B cell fate. Through its affinity with autoAgs and its control of IgH, DS emerges as a potential key player in the development of autoreactive B cells and autoimmunity.
Tissue-Resident Memory T Cells in Antifungal Immunity
Authors: LeibundGut-Landmann Salomé
Published: May 2021

Fungi are an integral part of the mammalian microbiota colonizing most if not all mucosal surfaces and the skin. Maintaining stable colonization on these surfaces is critical for preventing fungal dysbiosis and infection, which in some cases can lead to life threatening consequences. The epithelial barriers are protected by T cells and additional controlling immune mechanisms. Noncirculating memory T cells that reside stably in barrier tissues play an important role for host protection from commensals and recurrent pathogens due to their fast response and local activity, which provides them a strategic advantage. So far, only a few specific examples of tissue resident memory T cells (TRMs) that act against fungi have been reported. This review provides an overview of the characteristics and functional attributes of TRMs that have been established based on human and mouse studies with various microbes. It highlights what is currently known about fungi specific TRMs mediating immunosurveillance, how they have been targeted in preclinical vaccination approaches and how they can promote immunopathology, if not controlled. A better appreciation of the host protective and damaging roles of TRMs might accelerate the development of novel tissue specific preventive strategies against fungal infections and fungi-driven immunopathologies.
Sea Ice Reduction During Winter of 2017 Due to Oceanic Heat Supplied by Pacific Water in the Chukchi Sea, West Arctic Ocean
Authors: Wang Yingjie , Liu Na , Zhang Zhanhai
Published: May 2021

Over the past few decades, the areal extent of the Arctic sea ice cover has decreased. During the winter of 2017, negative sea ice concentration anomalies occurred mainly in the Chukchi Sea and adjacent seas. The properties of Pacific water through the Bering Strait have changed in recent years. To highlight the role of the Pacific inflow during the 2017 Arctic sea ice retreat, we used mooring measurements and conductivity–temperature–depth (CTD) data to quantify the effect of inflow on sea ice in the Chukchi shelf. In September 2017, the temperature of the Pacific inflow was relatively high compared with the multi-year average, especially in the shelf north of 69°N where the temperature anomaly was generally greater than 1°C. The average heat content of each CTD station in September 2017 ranged from 0.77 to 1.58 GJ m–2, where each station was 0.25 GJ m–2 higher than the multi-year average. In the central shelf of the Chukchi Sea, the temperature of the 25–40 m layer increased after late May, and decreased after mid-September. The Pacific inflow could have provided a large amount of heat to the Chukchi shelf, the accumulated convective heat transported to the surface from September to October was approximately 1.68 × 1018 J and it impacted the sea ice growth conditions.
Eukaryotic Biodiversity and Spatial Patterns in the Clarion-Clipperton Zone and Other Abyssal Regions: Insights From Sediment DNA and RNA Metabarcoding
Authors: Lejzerowicz Franck , Gooday Andrew John , Barrenechea Angeles Inés , Cordier Tristan , Morard Raphaël , Apothéloz-Perret-Gentil Laure , Lins Lidia , Menot Lenaick , Brandt Angelika , Levin Lisa Ann , Martinez Arbizu Pedro , Smith Craig Randall , Pawlowski Jan
Published: May 2021

The abyssal seafloor is a mosaic of highly diverse habitats that represent the least known marine ecosystems on Earth. Some regions enriched in natural resources, such as polymetallic nodules in the Clarion-Clipperton Zone (CCZ), attract much interest because of their huge commercial potential. Since nodule mining will be destructive, baseline data are necessary to measure its impact on benthic communities. Hence, we conducted an environmental DNA and RNA metabarcoding survey of CCZ biodiversity targeting microbial and meiofaunal eukaryotes that are the least known component of the deep-sea benthos. We analyzed two 18S rRNA gene regions targeting eukaryotes with a focus on Foraminifera (37F) and metazoans (V1V2), sequenced from 310 surface-sediment samples from the CCZ and other abyssal regions. Our results confirm huge unknown deep-sea biodiversity. Over 60% of benthic foraminiferal and almost a third of eukaryotic operational taxonomic units (OTUs) could not be assigned to a known taxon. Benthic Foraminifera are more common in CCZ samples than metazoans and dominated by clades that are only known from environmental surveys. The most striking results are the uniqueness of CCZ areas, both datasets being characterized by a high number of OTUs exclusive to the CCZ, as well as greater beta diversity compared to other abyssal regions. The alpha diversity in the CCZ is high and correlated with water depth and terrain complexity. Topography was important at a local scale, with communities at CCZ stations located in depressions more diverse and heterogeneous than those located on slopes. This could result from eDNA accumulation, justifying the interim use of eRNA for more accurate biomonitoring surveys. Our descriptions not only support previous findings and consolidate our general understanding of deep-sea ecosystems, but also provide a data resource inviting further taxon-specific and large-scale modeling studies. We foresee that metabarcoding will be useful for deep-sea biomonitoring efforts to consider the diversity of small taxa, but it must be validated based on ground truthing data or experimental studies.
Insights Into the Microstructure and Dielectric Properties of Cold Sintered NaCa2Mg2V3O12 Based Composites
Authors: Madhuri Rakhi , Narayana Iyer Santha , Ganesanpotti Subodh
Published: May 2021

Cold sintering process (CSP) was successfully employed to fabricate (1 −x) NaCa2Mg2V3O12-xNaCl [abbreviated as (1 −x) NCMVO-xNaCl] microwave dielectric ceramics. (1 −x)NCMVO-xNaCl ceramics prepared at 200°C and at a pressure of 450 MPa had a high relative density of 80–94%. X-ray diffraction (XRD), scanning electron microscope (SEM), energy dispersive X-ray spectroscopy (EDS), and Raman spectroscopy showed that both NCMVO and NaCl phases co-exist in all composite ceramics without forming any secondary phase. Further, dependence of microstructure and dielectric properties on cold sintering temperature and duration were investigated in detail and their optimized values to obtain maximum density of ceramic composites were 200°C and 50 min, respectively. (1 −x)NCMVO-xNaCl (x= 0.4–0.7) composites have relative permittivity (εr) in the range of 6.9–7.4, and a reasonably high microwave quality factor (Q × f) of 5,000 to 13,830 GHz.
Maternal Variables as Determinant of Fetal Growth: Study Protocol on Customized Fetal Growth Charts in Malaysia (GROW-My)
Authors: Za'im Sahul Hameed Muhammad , Sutan Rosnah , Mahdy Zaleha Abdullah , Tamil Azmi Mohd , Sulong Saperi
Published: May 2021

Adverse perinatal outcomes such as stillbirth, low birth weight and small for gestational age are still reported to be of high prevalence despite advanced healthcare technology and good quality hospital services in Malaysia. The purpose of this study is to create a model to evaluate individualized birth weight customized for maternal characteristics in a Malaysian population. Three phases are involved in designing the customized fetal growth chart (GROW-My). Baseline data is collected from previous pregnancies in the UKM Medical Centre from year 2010 to 2017. Specific maternal attributes were screened for its completeness and validity, namely maternal height and weight at booking, maternal ethnicity and parity, and the baby's birth weight, for all singleton pregnancies. The design and construction of a Malaysian customized fetal growth chart, Growth Related Optimal Weight (GROW-MY) was based on baseline birth data. The customized chart is used in the implementation phase for testing its feasibility, taking into consideration feedback from caregivers and patients before and after implementation. The current study provides staunch information and data regarding the needs and strategies for using maternal variables for estimating birth weight and the risk of being small for gestational age, in order to facilitate screening and appropriate management. With improved diagnosis of fetal growth restriction, medical care and treatment costs can be reduced.
Clinical Significance of Plasma D-Dimer in COVID-19 Mortality
Authors: Li Yayun , Deng Yuhao , Ye Lin , Sun Huiyan , Du Songtao , Huang Huining , Zeng Furong , Chen Xiang , Deng Guangtong
Published: May 2021

It is not clear whether D-dimer can be an independent predictor of coronavirus disease 2019 (COVID-19) mortality, and the cut-off of D-dimer for clinical use remains to be determined. Therefore, a comprehensive analysis is still necessary to illuminate the clinical significance of plasma D-dimer in COVID-19 mortality. We searched PubMed, Embase, Cochrane Library, and Scopus databases until November 2020. STATA software was used for all the statistical analyses. The identifier of systematic review registration was PROSPERO CRD42020220927. A total of 66 studies involving 40,614 COVID-19 patients were included in our meta-analysis. Pooled data showed that patients in high D-dimer group had poor prognosis than those in low D-dimer group [OR = 4.52, 95% CI = (3.61, 5.67), P < 0.001; HR = 2.81, 95% CI = (1.85, 4.27), P < 0.001]. Sensitivity analysis, pooled data based on different effect models and the Duval and Tweedie trim-and-fill method did not change the conclusions. Subgroup analyses stratified by different countries, cutoffs, sample size, study design, and analysis of OR/HR still keep consistent conclusions. D-dimer was identified as an independent predictor for COVID-19 mortality. A series of values including 0.5 μg/ml, 1 μg/ml, and 2 μg/ml could be determined as cutoff of D-dimer for clinic use. Measurement and monitoring of D-dimer might assist clinicians to take immediate medical actions and predict the prognosis of COVID-19.
Urinary Levels of SARS-CoV-2 Nucleocapsid Protein Associate With Risk of AKI and COVID-19 Severity: A Single-Center Observational Study
Authors: Tampe Désirée , Hakroush Samy , Bösherz Mark-Sebastian , Franz Jonas , Hofmann-Winkler Heike , Pöhlmann Stefan , Kluge Stefan , Moerer Onnen , Stadelmann Christine , Ströbel Philipp , Winkler Martin Sebastian , Tampe Björn
Published: May 2021

Background: Acute kidney injury (AKI) is very common in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) disease 2019 (COVID-19) and considered as a risk factor for COVID-19 severity. SARS-CoV-2 renal tropism has been observed in COVID-19 patients, suggesting that direct viral injury of the kidneys may contribute to AKI. We examined 20 adult cases with confirmed SARS-CoV-2 infection requiring ICU supportive care in a single-center prospective observational study and investigated whether urinary markers for viral infection (SARS-CoV-2 N) and shedded cellular membrane proteins (ACE2, TMPRSS2) allow identification of patients at risk for AKI and outcome of COVID-19.

Objectives: The objective of the study was to evaluate whether urinary markers for viral infection (SARS-CoV-2 N) and shedded cellular membrane proteins (ACE2, TMPRSS2) allow identification of patients at risk for AKI and outcome of COVID-19.

Results: Urinary SARS-CoV-2 N measured at ICU admission identified patients at risk for AKI in COVID-19 (HR 5.9, 95% CI 1.4–26, p = 0.0095). In addition, the combination of urinary SARS-CoV-2 N and plasma albumin measurements further improved the association with AKI (HR 11.4, 95% CI 2.7–48, p = 0.0016). Finally, combining urinary SARS-CoV-2 N and plasma albumin measurements associated with the length of ICU supportive care (HR 3.3, 95% CI 1.1–9.9, p = 0.0273) and premature death (HR 7.6, 95% CI 1.3–44, p = 0.0240). In contrast, urinary ACE2 and TMPRSS2 did not correlate with AKI in COVID-19.

Conclusions: In conclusion, urinary SARS-CoV-2 N levels associate with risk for AKI and correlate with COVID-19 severity.
Intrinsic Capacity Assessment by a Mobile Geriatric Team During the Covid-19 Pandemic
Authors: Angioni Davide , Nicolay Camille , Vandergheynst Frédéric , Baré Robin , Cesari Matteo , De Breucker Sandra
Published: May 2021

In the autumn of 2020, the second wave of the COVID-19 pandemic hit Europe. In this context, because of the insufficient number of beds in geriatric COVID units, non-geriatric wards were confronted with a significant number of admissions of geriatric patients. In this perspective article, we describe the role of a mobile geriatric team in the framework of the COVID-19 pandemic and specifically how it assisted other specialists in the management of hospitalized geriatric patients by implementing a new approach: the systematic assessment and optimization of Intrinsic Capacity functions. For each patient, assessed by this consultative team, an individualized care plan, including an anticipated end-of-life decision-making process, was established. Intensity of care was most often not stated by considering chronological age but rather the comorbidity burden, the frailty status, and the patient's wishes. Further studies are needed to determine if this mobile geriatric team approach was beneficial in terms of mortality, length of stay, or functional, psychological, and cognitive outcomes in COVID-19 geriatric patients.
Global REnal Involvement of CORonavirus Disease 2019 (RECORD): A Systematic Review and Meta-Analysis of Incidence, Risk Factors, and Clinical Outcomes
Authors: Chan Kam Wa , Yu Kam Yan , Lee Pak Wing , Lai Kar Neng , Tang Sydney Chi-Wai
Published: May 2021

Introduction: The quantitative effect of underlying non-communicable diseases on acute kidney injury (AKI) incidence and the factors affecting the odds of death among coronavirus disease 2019 (COVID-19) AKI patients were unclear at population level. This study aimed to assess the association between AKI, mortality, underlying non-communicable diseases, and clinical risk factors.

Methods: A systematic search of six databases was performed from January 1, 2020, until October 5, 2020. Peer-reviewed observational studies containing quantitative data on risk factors and incidence of renal manifestations of COVID-19 were included. Location, institution, and time period were matched to avoid duplicated data source. Incidence, prevalence, and odds ratio of outcomes were extracted and pooled by random-effects meta-analysis. History of renal replacement therapy (RRT) and age group were stratified for analysis. Univariable meta-regression models were built using AKI incidence as dependent variable, with underlying comorbidities and clinical presentations at admission as independent variables.

Results: Global incidence rates of AKI and RRT in COVID-19 patients were 20.40% [95% confidence interval (CI) = 12.07–28.74] and 2.97% (95% CI = 1.91–4.04), respectively, among patients without RRT history. Patients who developed AKI during hospitalization were associated with 8 times (pooled OR = 9.03, 95% CI = 5.45–14.94) and 16.6 times (pooled OR = 17.58, 95% CI = 10.51–29.38) increased odds of death or being critical. At population level, each percentage increase in the underlying prevalence of diabetes, hypertension, chronic kidney disease, and tumor history was associated with 0.82% (95% CI = 0.40–1.24), 0.48% (95% CI = 0.18–0.78), 0.99% (95% CI = 0.18–1.79), and 2.85% (95% CI = 0.93–4.76) increased incidence of AKI across different settings, respectively. Although patients who had a kidney transplant presented with a higher incidence of AKI and RRT, their odds of mortality was lower. A positive trend of increased odds of death among AKI patients against the interval between symptom onset and hospital admission was observed.

Conclusion: Underlying prevalence of non-communicable diseases partly explained the heterogeneity in the AKI incidence at population level. Delay in admission after symptom onset could be associated with higher mortality among patients who developed AKI and warrants further research.
Function-Oriented Graphene Quantum Dots Probe for Single Cell in situ Sorting of Active Microorganisms in Environmental Samples
Authors: Luo Yeshen , Liu Fei , Song Jianhua , Luo Qian , Yang Yonggang , Mei Chengfang , Xu Meiying , Liao Bing
Published: May 2021

Functional microorganisms play a vital role in removing environmental pollutants because of their diverse metabolic capability. Herein, a function-oriented fluorescence resonance energy transfer (FRET)-based graphene quantum dots (GQDs-M) probe was developed for the specific identification and accurate sorting of azo-degrading functional bacteria in the original location of environmental samples for large-scale culturing. First, nitrogen-doped GQDs (GQDs-N) were synthesized using a bottom-up strategy. Then, a GQDs-M probe was synthesized based on bonding FRET-based GQDs-N to an azo dye, methyl red, and the quenched fluorescence was recovered upon cleavage of the azo bond. Bioimaging confirmed the specific recognition capability of GQDs-M upon incubation with the target bacteria or environmental samples. It is suggested that the estimation of environmental functional microbial populations based on bioimaging will be a new method for rapid preliminary assessment of environmental pollution levels. In combination with a visual single-cell sorter, the target bacteria in the environmental samples could be intuitively screened at the single-cell level in 17 bacterial strains, including the positive control Shewanella decolorationis S12, and were isolated from environmental samples. All of these showed an azo degradation function, indicating the high accuracy of the single-cell sorting strategy using the GQDs-M. Furthermore, among the bacteria isolated, two strains of Bacillus pacificus and Bacillus wiedmannii showed double and triple degradation efficiency for methyl red compared to the positive control (strain S12). This strategy will have good application prospects for finding new species or high-activity species of specific functional bacteria.
Modular Molecular Weaponry Plays a Key Role in Competition Within an Environmental Vibrio cholerae Population
Authors: Hussain Nora A. S. , Kirchberger Paul C. , Case Rebecca J. , Boucher Yann F.
Published: May 2021

The type VI secretion system (T6SS) operons ofVibrio choleraecontain extraordinarily diverse arrays of toxic effector and cognate immunity genes, which are thought to play an important role in the environmental lifestyle and adaptation of this human pathogen. Through the T6SS, proteinaceous “spears” tipped with antibacterial effectors are injected into adjacent cells, killing those not possessing immunity proteins to these effectors. Here, we investigate the T6SS-mediated dynamics of bacterial competition within a single environmental population ofV. cholerae. We show that numerous members of a North AmericanV. choleraepopulation possess strain-specific repertoires of cytotoxic T6SS effector and immunity genes. Using pairwise competition assays, we demonstrate that the vast majority of T6SS-mediated duels end in stalemates between strains with different T6SS repertoires. However, horizontally acquired effector and immunity genes can significantly alter the outcome of these competitions. Frequently observed horizontal gene transfer events can both increase or reduce competition between distantly related strains by homogenizing or diversifying the T6SS repertoire. Our results also suggest temperature-dependent outcomes in T6SS competition, with environmental isolates faring better against a pathogenic strain under native conditions than under those resembling a host-associated environment. Taken altogether, these interactions produce density-dependent fitness effects and a constant T6SS-mediated arms race in individualV. choleraepopulations, which could ultimately preserve intraspecies diversity. Since T6SSs are widespread, we expect within-population diversity in T6SS repertoires and the resulting competitive dynamics to be a common theme in bacterial species harboring this machinery.
Positioning Diverse Type IV Structures and Functions Within Class 1 CRISPR-Cas Systems
Authors: Taylor Hannah N. , Laderman Eric , Armbrust Matt , Hallmark Thomson , Keiser Dylan , Bondy-Denomy Joseph , Jackson Ryan N.
Published: May 2021

Type IV CRISPR systems encode CRISPR associated (Cas)-like proteins that combine with small RNAs to form multi-subunit ribonucleoprotein complexes. However, the lack of Cas nucleases, integrases, and other genetic features commonly observed in most CRISPR systems has made it difficult to predict type IV mechanisms of action and biological function. Here we summarize recent bioinformatic and experimental advancements that collectively provide the first glimpses into the function of specific type IV subtypes. We also provide a bioinformatic and structural analysis of type IV-specific proteins within the context of multi-subunit (class 1) CRISPR systems, informing future studies aimed at elucidating the function of these cryptic systems.
Nucleolar Phosphoprotein NPM1 Interacts With Porcine Circovirus Type 3 Cap Protein and Facilitates Viral Replication
Authors: Song Jiangwei , Hou Lei , Wang Dan , Wei Li , Zhu Shanshan , Wang Jing , Quan Rong , Jiang Haijun , Shi Ruihan , Liu Jue
Published: May 2021

Porcine circovirus type 3 (PCV3) is a recently discovered virus with potentially significant implications on the global swine industry. PCV3 replication involves the entry of the viral capsid (Cap) protein with nucleolar localization signals into the nucleus. Using liquid chromatography-mass spectrometry analysis, nucleolar phosphoprotein NPM1 was identified as one of the cellular proteins bound to PCV3 Cap. Co-immunoprecipitation demonstrated that PCV3 Cap interacts directly with NPM1, where the region binding with NPM1 is mapped to amino acid residues 1–38 of Cap. Upon co-transfection, the expression of Cap protein promoted the redistribution of NPM1, which translocated from the nucleus to the cytoplasm and colocalized with Cap in cultured PK15 cells. NPM1 expression was upregulated and translocated from the nucleus to the cytoplasm in PCV3-infected cells, upon siRNA-mediated depletion, or upon treatment with NPM1 inhibitor in PK15 cells with impaired PCV3 replication, as evidenced by decreased levels of viral DNA synthesis and protein expression. By contrast, the replication of PCV3 was enhanced in stably NPM1-expressing cells via a lentivirus-delivered system. Taken together, these findings indicate that NPM1 interacts with PCV3 Cap and plays a crucial role in PCV3 replication.
Human Gastric Cancer Stem Cell (GCSC) Markers Are Prognostic Factors Correlated With Immune Infiltration of Gastric Cancer
Authors: Lin Tong , Peng Wenya , Mai Peipei , Zhang E. , Peng Lisheng
Published: May 2021

The prognosis of patients with gastric cancer (GC) is still unsatisfying. Numerous markers of gastric cancer stem cells (GCSCs) have been identified and were thought to be related to cancer aggressiveness. However, the roles of GCSC markers in GC patients’ prognosis and immune infiltration remain unknown. Expression of GCSC markers was analyzed using Oncomine and Gene Expression Profiling Interactive Analysis (GEPIA). Their associations with clinicopathological parameters were analyzed using UALCAN and LinkedOmics. Alternations and protein expression of GCSC markers were analyzed by cBioPortal and the Human Protein Atlas databases, respectively. The prognostic significance of GCSC markers was evaluated using Kaplan-Meier plotter. Correlations between the expression of GCSC markers and immune infiltration along with biomarkers of tumor-infiltrating immune cells (TIICs) were assessed combined Tumor Immune Estimation Resource and GEPIA. GeneMANIA was used to discover the interactive genes of GCSC markers, and enrichment analysis was performed using Database for Annotation, Visualization, and Integrated Discovery server. We identified six GCSC markers significantly up-expressed in GC, compared with normal stomach tissues. Among them, the overexpression of ICAM1, THY1, and CXCR4 significantly indicated adverse, while EPCAM indicated beneficial clinicopathological features of GC patients. The up-regulation of CXCR4 showed unfavorable prognostic significance, whereas EPCAM and TFRC showed the opposite. The six GCSC markers were all correlated with the infiltration and activation of distinct TIICs. Especially, ICAM1, THY1, and CXCR4 showed strongly positive correlations with tumor-associated macrophages. Besides, chemokine, Toll-like receptor, NF-kappa B, and HIF-1 signaling pathways might be involved in the regulation of GCSC markers on cancer development. This study proposed that GCSC markers might be promising targets of GC treatment to weaken cancer stem-like properties and strengthen anticancer immunity.
Protein Docking Model Evaluation by Graph Neural Networks
Authors: Wang Xiao , Flannery Sean T. , Kihara Daisuke
Published: May 2021

Physical interactions of proteins play key functional roles in many important cellular processes. To understand molecular mechanisms of such functions, it is crucial to determine the structure of protein complexes. To complement experimental approaches, which usually take a considerable amount of time and resources, various computational methods have been developed for predicting the structures of protein complexes. In computational modeling, one of the challenges is to identify near-native structures from a large pool of generated models. Here, we developed a deep learning–based approach named Graph Neural Network–based DOcking decoy eValuation scorE (GNN-DOVE). To evaluate a protein docking model, GNN-DOVE extracts the interface area and represents it as a graph. The chemical properties of atoms and the inter-atom distances are used as features of nodes and edges in the graph, respectively. GNN-DOVE was trained, validated, and tested on docking models in the Dockground database and further tested on a combined dataset of Dockground and ZDOCK benchmark as well as a CAPRI scoring dataset. GNN-DOVE performed better than existing methods, including DOVE, which is our previous development that uses a convolutional neural network on voxelized structure models.
3D Structural View of Pathogen Recognition by Mammalian Lectin Receptors
Authors: Manabe Noriyoshi , Yamaguchi Yoshiki
Published: May 2021

Humans and other mammals resist exogenous pathogens by recognizing them as non-self. How do they do this? The answer lies in the recognition by mammalian lectin receptors of glycans usually found on the surface of pathogens and whose chemical structure is species-specific. Some glycan components, such as galactofuranose, only occur in microbes, and is the principal means by which mammalian lectin receptors recognize non-self. Several lectins may function together as pattern recognition receptors to survey the infecting pathogen before the adaptive immune system is invoked. Most lectins have primary and secondary monosaccharide-binding sites which together determine the specificity of a receptor toward microbial glycans. There may also be a hydrophobic groove alongside the sugar binding sites that increases specificity. Another elaboration is through oligomerization of lectin domains with defined spacing and arrangement that creates high-affinity binding towards multiply-presented glycans on microbes. Microbe-specific polysaccharides may arise through unique sugar linkages. Specificity can come from mammalian receptors possessing a shallow binding site and binding only internal disaccharide units, as in the recognition of mannan by Dectin-2. The accumulation of 3D structural information on lectins receptors has allowed the recognition modes of microbe glycans to be classified into several groupings. This review is an introduction to our current knowledge on the mechanisms of pathogen recognition by representative mammalian lectin receptors.
Odor Recognition Memory in Parkinson's Disease: A Systematic Review
Authors: Eek Tom , Larsson Maria , Dizdar Nil
Published: May 2021

Olfactory impairment is a central non-motor symptom in Parkinson's disease (PD). Previous studies have demonstrated that olfactory dysfunction is associated with mental illness and impaired cognition. The frequently investigated olfactory functions are odor detection, discrimination, and identification. However, few studies have focused on odor recognition memory (ORM). ORM tasks involves episodic memory which therefore can facilitate the detection of dementia among patients with PD and consequently adjust their treatment. Thus, the aim of this systematic review is to summarize the existing research on ORM in PD. Databases and reference lists were used for data collection. Studies were included in the review if they met the eligibility criteria derived from the PICOS-framework. Quality evaluation of the studies was based on the STROBE-statement. Six studies with small samples were included in the analysis which demonstrated the scarce research on the subject. The studies targeting ORM were heterogenous and involved two main tasks: odor recognition and odor matching. The synthesis of the data demonstrated that PD patients performed significantly lower than controls on both tasks, especially on odor matching task. Only the odor recognition task exhibited a difference between patients with PD vs. Alzheimer's disease (AD). PD patients performed significantly better than AD patients. The findings based on the available limited data support the notion that odor recognition task can be of importance in identifying Parkinson's disease dementia (PDD). To investigate this hypothesis, future research needs to include larger samples of PD, PDD and AD patients executing the same odor recognition task.
Cornel Iridoid Glycoside Protects Against STAT1-Dependent Synapse and Memory Deficits by Increasing N-Methyl-D-aspartate Receptor Expression in a Tau Transgenic Mice
Authors: Ma Denglei , Huang Rui , Guo Kaiwen , Zhao Zirun , Wei Weipeng , Gu Lihong , Li Lin , Zhang Lan
Published: May 2021

P301S transgenic mice are an animal model of tauopathy and Alzheimer’s disease (AD), exhibiting tau pathology and synaptic dysfunction. Cornel iridoid glycoside (CIG) is an active ingredient extracted from Cornus officinalis, a traditional Chinese herb. In the present study, the purpose was to investigate the effects and mechanisms of CIG on tau pathology and synaptic dysfunction using P301S transgenic mice. The results showed that intragastric administration of CIG for 3.5 months improved cognitive impairments and the survival rate of P301S mice. Electrophysiological recordings and transmission electron microscopy study showed that CIG improved synaptic plasticity and increased the ultrastructure and number of synapse. Moreover, CIG increased the expression levels of N-methyl-D-aspartate receptors (NMDAR) subunits GluN1, GluN2A, and GluN2B, and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) subunit GluA1. We inferred that the major mechanism of CIG involving in the regulation of synaptic dysfunctions was inhibiting the activation of Janus kinase-2 (JAK2)/signal transducer and activator of transcription 1 (STAT1) signaling pathway and alleviating STAT1-induced suppression of NMDAR expressions. Based on our findings, we thought CIG might be a promising candidate for the therapy of tauopathy such as AD.
Overexpressed NaV1.7 Channels Confer Hyperexcitability to in vitro Trigeminal Sensory Neurons of CaV2.1 Mutant Hemiplegic Migraine Mice
Authors: Mehboob Riffat , Marchenkova Anna , van den Maagdenberg Arn M. J. M. , Nistri Andrea
Published: May 2021

Trigeminal sensory neurons of transgenic knock-in (KI) mice expressing the R192Q missense mutation in the α1A subunit of neuronal voltage-gated CaV2.1 Ca2+ channels, which leads to familial hemiplegic migraine type 1 (FHM1) in patients, exhibit a hyperexcitability phenotype. Here, we show that the expression of NaV1.7 channels, linked to pain states, is upregulated in KI primary cultures of trigeminal ganglia (TG), as shown by increased expression of its α1 subunit. In the majority of TG neurons, NaV1.7 channels are co-expressed with ATP-gated P2X3 receptors (P2X3R), which are important nociceptive sensors. Reversing the trigeminal phenotype with selective CaV2.1 channel inhibitor ω-agatoxin IVA inhibited NaV1.7 overexpression. Functionally, KI neurons revealed a TTX-sensitive inward current of larger amplitude that was partially inhibited by selective NaV1.7 blocker Tp1a. Under current-clamp condition, Tp1a raised the spike threshold of both wild-type (WT) and KI neurons with decreased firing rate in KI cells. NaV1.7 activator OD1 accelerated firing in WT and KI neurons, a phenomenon blocked by Tp1a. Enhanced expression and function of NaV1.7 channels in KI TG neurons resulted in higher excitability and facilitated nociceptive signaling. Co-expression of NaV1.7 channels and P2X3Rs in TGs may explain how hypersensitivity to local stimuli can be relevant to migraine.
MiR-30c-5p/ATG5 Axis Regulates the Progression of Parkinson’s Disease
Authors: Zhang Li , Chen Xiufen , Chang Mingxiu , Jiao Boning
Published: May 2021

Serum miR-30c-5p correlates with Parkinson’s disease (PD), yet its role has not been illustrated. This research analyzed the function of miR-30c-5p in PD. The behavioral evaluation was performed on MPTP-treated PD mice transfected with miR-30c-5p agomiR, antagomiR, siATG5, or 3-MA (an autophagy inhibitor). Oxidative stress-related factors, miR-30c-5p, and apoptosis- and autophagy-associated proteins in brain tissues or cells were determined by molecular experiments. Tyrosine hydroxylase (TH) and dopamine metabolic markers were detected using immunofluorescence and Diode Array Detector (DAD), respectively. Effects of miR-30c-5p and its target gene Autophagy-related gene (ATG) 5 protein (ATG5) on MPP+-treated SH-SY5Y cells were determined through a series of molecular experiments. MiR-30c-5p was upregulated but ATG5 was downregulated in PD mice. MiR-30c-5p antagomiR attenuated the decrease of ATG5 in PD mice. MiR-30c-5p antagomiR partly alleviated the behavioral symptoms and inhibited the increases of malondialdehyde (MDA), catalase (CAT), and SOD in PD mice. The levels of Bcl-2, dopamine, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), TH, and LC3 II were downregulated in PD mice, while Bax, cleaved caspase-3, P62, and LC3 I were upregulated. However, miR-30c-5p antagomiR partly reversed the levels of these factors in PD mice. 3-MA could block the effects of miR-30c-5p antagomiR on PD mice. MiR-30c-5p antagomiR attenuated apoptosis and induced autophagy in brain tissues of MPTP-treated mice by targeting ATG5. In vitro assay results also showed that silence of ATG5 reduced the protective effect of miR-30c-5p downregulation on the cells. MiR-30c-5p regulates the progression of Parkinson’s disease through attenuating ATG5-inhibited apoptosis and -induced autophagy.
The Prognostic Value of the Acute Phase Systemic Immune–Inflammation Index in Patients With Intracerebral Hemorrhage
Authors: Li Yunke , Wen Dingke , Cui Wenyao , Chen Yuqi , Zhang Fazhen , Yuan Maolin , Xiao Han , Li Hao , Ma Lu , Hu Xin , You Chao
Published: May 2021

Background and Purpose: The systemic immune–inflammation index (SII) is a novel prognostic index in various diseases. We evaluated the predictive value of SII in patients with intracerebral hemorrhage (ICH).

Methods: Patients with primary spontaneous ICH were enrolled. SII was constructed based on peripheral platelet (P), neutrophil (N), and lymphocyte (L) and defined as P*N/L. In addition to admission testing, acute phase SII was collected to analyze the potential dynamic change. Poor outcome was defined as modified Rankin Scale of more than 3 at 90 days.

Results: We included 291 patients; 98 (34%) achieved favorable functional outcomes. Day-1 SII was higher and was more related to poor outcome than was admission SII. Median time of day-1 SII was 29 h from onset. Day-1 SII had an OR in outcome (mRS >3) 1.74 (95% CI = 1.03–3.00, p = 0.04). The binary cutoff point of SII calculated using the area under the curve (AUC) method was 1,700 × 109/L, AUC 0.699 (95% CI = 0.627–0.774) (sensitivity 53.3%, specificity 77.3%) (OR = 2.36, 95% CI = 1.09–5.26, p = 0.03).

Conclusions: SII, especially day-1 SII, was highly associated with 90-day functional outcome in patients with ICH and could be used to predict outcomes.
Evaluation of the Degree of Agreement of Four Methods for Diagnosing Diabetic Autonomic Neuropathy
Authors: Peng Yu , Liu Ying-shan , Wu Min-yi , Chen Chu-na , Li Chu-qiao , Jiang An-qi , Li Chong-xin , Wang Yao , Tian Ge , Pan Su-yue , Xu Ling-ling
Published: May 2021

Background: There are many methods to diagnose diabetic autonomic neuropathy (DAN); however, often, the various methods do not provide consistent results. Even the two methods recommended by the American Diabetes Association (ADA) guidelines, Ewing's test and heart rate variability (HRV), sometimes give conflicting results. The purpose of this study was to evaluate the degree of agreement of the results of the Composite Autonomic Symptom Score 31 (COMPASS-31), skin sympathetic reaction (SSR) test, Ewing's test, and HRV in diagnosing DAN.

Methods: Patients with type 2 diabetes were recruited and each received the COMPASS-31, SSR, Ewing's test, and HRV for the diagnosis of DAN. Patients were categorized as DAN(+) and DAN(–) by each of the tests. Kappa consistency tests were used to evaluate the agreement of diagnosing DAN between any two methods. Spearman's correlation test was used to evaluate the correlations of the severity of DAN between any two methods. Receiver operating characteristic (ROC) analyses were used to evaluate the diagnostic value and the cutoff value of each method.

Results: A total of 126 type 2 diabetic patients were included in the study. The percentages of DAN(+) results by HRV, Ewing's test, COMPASS-31, and SSR were 61, 40, 35, and 33%, respectively. COMPASS-31 and Ewing's test had the best agreement for diagnosing DAN (κ = 0.512, p < 0.001). COMPASS-31 and Ewing's test also had the best correlation with respect to the severity of DAN (r = 0.587, p < 0.001). Ewing's test and COMPASS-31 had relatively good diagnostic values (AUC = 0.703 and 0.630, respectively) in the ROC analyses.

Conclusions: COMPASS-31 and Ewing's test exhibit good diagnostic consistency and severity correlation for the diagnosis of DAN. Either test is suitable for the diagnosis of DAN and treatment follow-up.
Risk Factors and Imaging Mechanisms of Fatigue After Mild Ischemic Stroke: An Exploratory Study From a Single Chinese Center
Authors: Zhang Xiaoxiao , Fang Hongjuan , Ma Ding , Duan Yunyun , Wang Zhaozhao , Zhang Ning , Wang Chunxue
Published: May 2021

Objective: To explore the biochemical risk factors and imaging mechanisms of post fatigue after mild ischemic stroke among a Chinese population.

Methods: Forty consecutive patients with mild ischemic stroke within onset of 14 ± 2 days were enrolled between March and June 2018. The clinical information, scale data, biomarkers in peripheral venous blood, and imaging data during hospitalization and follow-up period were collected.

Results: Patient age (range 34–78) was positively correlated with the prevalence of fatigue (p = 0.009). Both blood norepinephrine and serotonin levels during hospitalization were negatively correlated to the prevalence of post-stroke fatigue (model 1 p = 0.009 and model 2 P = 0.043, respectively). Infarct of right cerebral hemisphere is positively correlated with the occurrence of fatigue after mild ischemic stroke (p = 0.020). Compared to non-fatigue patients, amplitude of low-frequency fluctuation (ALFF) was lower in several areas of brain in stroke patients with fatigue, including the right orbital inferior frontal, right inner orbital frontal, right frontal, right triangular frontal inferior, right anterior and lateral cingulate, and right medial frontal gyruses. Analysis of the difference in functional connectivity between the fatigue and non-fatigue groups found no cluster.

Conclusions: Frontal lobe-related neural pathways may play an essential role in the regulation of fatigue after mild ischemic stroke. Abnormal neural circuits may reduce the levels of neurotransmitters such as serotonin and norepinephrine and lead to post-stroke fatigue.
Thirty-Day and One-Year Outcomes of Endovascular Treatments for Severe Atherosclerotic Stenosis of Intracranial ICA: Results From a Single Center
Authors: Shen Shengli , Wang Yingjin , He Xudong , Ma Ning , Gao Feng , Song Ligang , Sun Xuan , Liu Lian , Miao Zhongrong , Duan Hongzhou , Mo Dapeng
Published: May 2021

Background: Endovascular treatment for intracranial atherosclerotic stenosis (ICAS) has been developed. However, the intracranial internal carotid artery (ICA) presents a particular challenge due to the location and tortuous route, and the outcomes of endovascular treatment in patients with stenosis of the intracranial ICA still have not been reported. This article retrospectively investigated the 30-day and 1-year outcomes of tailored endovascular treatment for patients with severe intracranial ICA stenosis from a single center.

Methods: Between June 2014 and December 2017, 96 consecutive patients with severe atherosclerotic stenosis (70–99%) of the intracranial ICA were managed with endovascular treatment in Beijing Tiantan Hospital. Three different kinds of treatments [angioplasty with balloon dilatation alone (BD group), balloon-mounted stent (BMS group), and self-expanding stent (SES group)] were performed according to the characteristics of the lesions. The primary endpoints included any stroke or death within 30 days and ipsilateral ischemic stroke afterwards within 1 year. Secondary endpoints included the revascularization success rate (residual stenosis <30%) and the restenosis rate (stenosis ≥ 50%) within 1 year.

Results: The 30-day death rate was 0, and the stroke rate of all patients was 7.3% (7/96). The stroke rate was higher in the BD group (15.8%) and SES group (9.8%) than in the BMS group (0%) (p = 0.047). Thirteen (13.5%) patients suffered at least one onset of ischemic stroke in the ipsilateral ICA territory within 1 year, and there was no significant difference among the three groups (p = 0.165). The overall revascularization success rate was 93.8%, and the revascularization success rate was significantly higher in the SES group (100%) than in the BD group (78.9%) (p = 0.006). The restenosis rate of all patients within 12 months was 20.8%, and there was no significant difference among the three groups. Patients with Mori type C target lesions were more likely to suffer stroke within 30 days (25%) and restenosis within 1 year (31.3%).

Conclusions: Both the 30-day and 1-year outcomes of tailored endovascular treatments seemed to be acceptable in the treatment of symptomatic atherosclerotic stenosis of the intracranial ICA. However, this needs to be confirmed by further investigation, preferably in large multicenter randomized controlled clinical trials.