bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification and Characterization of a Master Transcription Factor of Th1 Cells, T-bet, Within Flounder (Paralichthys olivaceus)
Authors: Tian Hongfei , Xing Jing , Tang Xiaoqian , Chi Heng , Sheng Xiuzhen , Zhan Wenbin
Published: June 2021

T-bet, a T-box family member, is a transcription factor essential for the differentiation of naive CD4+ T cells into Th1 cells that are involved in both innate and adaptive immune responses. In this study, the transcription factor T-bet of flounder (Paralichthys olivaceus) was cloned and characterized, and its expression profile after infection was analyzed. T-bet+ cells were identified in flounder, and the expression and localization of T-bet in T lymphocyte subsets and B lymphocytes were investigated. Finally, the proliferation of T-bet+ cells, T lymphocyte subsets, and B lymphocytes were studied after stimulation with IFN-γ, IL-2, and IL-6, respectively, and the variations of some transcription factors and cytokines in CD4+ T lymphocyte subsets were detected. The results showed that T-bet in flounder consists of 619 aa with a conserved T-box DNA binding domain. T-bet was abundantly expressed in the spleen, head kidney, and heart, and it was significantly upregulated after infection with Vibrio anguillarum, Edwardsiella tarda, and Hirame rhabdovirus, especially in the group of Edwardsiella tarda. A polyclonal antibody against recombinant protein of T-bet was prepared, which specifically recognized the natural T-bet molecule in flounder. T-bet+ cells were found to be distributed in the lymphocytes of peripheral blood, spleen, and head kidney, with the highest proportion in spleen, and the positive signals of T-bet occurred in the cell nucleus. T-bet was also detected in the sorted CD4-1+, CD4-2+, CD8+ T lymphocytes, and IgM+ B lymphocytes. In addition, T-bet+ cells, coordinated with CD4-1+ and CD4-2+ T lymphocytes, were proliferated after stimulation with IFN-γ, IL-2, and IL-6. Especially in sorted CD4-1+ and CD4-2+ T lymphocytes, IFN-γ and IL-2 were able to upregulate the expression of T-bet, forming a positive feedback loop in Th1-type cytokine secretion. These results suggest that T-bet may act as a master transcription factor regulating flounder CD4+ T lymphocytes involved in a Th1-type immune response.
Diversity and Disease: The Effects of Coral Diversity on Prevalence and Impacts of Stony Coral Tissue Loss Disease in Saint Thomas, U.S. Virgin Islands
Authors: Costa Sophia V. , Hibberts Stephanie J. , Olive Danielle A. , Budd Kayla A. , Long Alexys E. , Meiling Sonora S. , Miller Madyson B. , Vaughn Kelsey M. , Carrión Claudia I. , Cohen Maksym B. , Savage Annie E. , Souza Matthew F. , Buckley Lorraine , Grimes Kristin W. , Platenberg Renata , Smith Tyler B. , Blondeau Jeremiah , Brandt Marilyn E.
Published: June 2021

Stony coral tissue loss disease (SCTLD) was first observed in St. Thomas, U.S. Virgin Islands (USVI) in January 2019. This disease affects at least 20 scleractinian coral species; however, it is not well understood how reef diversity affects its spread or its impacts on reef ecosystems. With a large number of susceptible species, SCTLD may not follow the diversity-disease hypothesis, which proposes that high species diversity is negatively correlated with disease prevalence. Instead, SCTLD may have a higher prevalence and a greater impact on reefs with higher coral diversity. To test this, in 2020 we resampled 54 sites around St. Thomas previously surveyed in 2017 or 2019 by the National Oceanic and Atmospheric Administration National Coral Reef Monitoring Program. These sites represented a variety of species diversity values [categorized into poor (<12 spp. rich.) and rich (≥12 spp. rich.)] in multiple disease zones (Endemic: disease present ≥ 9 months; Epidemic: disease present 2–6 months; Control and Emergent: disease present no disease/<2 months). We hypothesized that, contrary to the diversity-disease hypothesis, sites with high species diversity (as measured by species richness or Simpson’s index) would have higher disease prevalence within the epidemic zone, and that high species diversity sites would have a greater impact from disease within the endemic zone. Results indicated a significant positive relationship between disease prevalence and diversity in the epidemic zone, and a similar trend in the endemic zones. Additionally, a negative relationship was seen between pre-outbreak diversity and loss of diversity and coral cover within the endemic zone. This supports the hypothesis that higher diversity predicts greater disease impact and suggests that SCTLD does not follow the diversity-disease hypothesis. Within the epidemic zone, the species with the highest SCTLD prevalence were Dendrogyra cylindrus, Colpophyllia natans, and Meandrina meandrites, while in the endemic zone, Diploria labyrinthiformis, Pseudodiploria strigosa, Montastraea cavernosa, and Siderastrea siderea had the highest SCTLD prevalence. Understanding the relationship between species diversity and SCTLD will help managers predict the most vulnerable reefs, which should be prioritized within the USVI and greater Caribbean region.
Risk Factors of Venous Thromboembolism in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis
Authors: Zhang Hua , Wang Xuehong
Published: June 2021

Background: Patients suffering from chronic inflammatory disorders, such as inflammatory bowel disorder, are at higher risk of developing thromboembolism. The chronic inflammatory nature of inflammatory bowel disease has been identified as a predominant reason for a state of Virchow's triad (i.e., endothelial dysfunction, stasis, and general hypercoagulability), eventually leading to the onset of venous thromboembolism. Recent studies show that certain factors, such as demographics, medication history, and history of surgical intervention may increase thromboembolism risk in patients with inflammatory bowel disease. However, to date, no study has attempted to evaluate the effect of different risk factors associated with the development of venous thromboembolism in inflammatory bowel disease patients.

Objective: To evaluate the risk factors that can influence the incidence of venous thromboembolism in patients with inflammatory bowel disease.

Methods: Academic literature was systematically searched based on the PRISMA guidelines across five databases: Web of Science, EMBASE, CENTRAL, Scopus, and MEDLINE. A random-effect meta-analysis was conducted to evaluate the hazard ratio for the risk factors (i.e., aging, gender, steroid therapy, surgery, and ulcerative colitis) that can influence the incidence of venous thromboembolism in patients with inflammatory bowel disease.

Results: From a total of 963 studies, 18 eligible studies with 1,062,985 (44.59 ± 10.18 years) patients suffering from inflammatory bowel disease were included in the review. A meta-analysis revealed a higher risk of aging (Hazard's ratio: 2.19), steroids (1.87), surgery (1.48), and ulcerative colitis (2.06) on venous thromboembolism in patients with inflammatory bowel disease. We also found that the female gender (0.92) did not increase the incidence of venous thromboembolism in inflammatory bowel disease patients.

Conclusion: The study provides preliminary evidence regarding high risks associated with ulcerative colitis, steroid consumption, and aging for the development of venous thromboembolism in patients with inflammatory bowel disease. The findings from this study may contribute to developing awareness among clinicians, better risk stratification and prevention of venous thromboembolic complications in patients with inflammatory bowel disease.
Novel Highly Divergent SARS-CoV-2 Lineage With the Spike Substitutions L249S and E484K
Authors: Laiton-Donato Katherine , Usme-Ciro Jose A. , Franco-Muñoz Carlos , Álvarez-Díaz Diego A. , Ruiz-Moreno Hector Alejandro , Reales-González Jhonnatan , Prada Diego Andrés , Corchuelo Sheryll , Herrera-Sepúlveda Maria T. , Naizaque Julian , Santamaría Gerardo , Wiesner Magdalena , Walteros Diana Marcela , Ospina Martínez Martha Lucia , Mercado-Reyes Marcela
Published: June 2021

COVID-19 pandemics has led to genetic diversification of SARS-CoV-2 and the appearance of variants with potential impact in transmissibility and viral escape from acquired immunity. We report a new and highly divergent lineage containing 21 distinctive mutations (10 non-synonymous, eight synonymous, and three substitutions in non-coding regions). The amino acid changes L249S and E484K located at the CTD and RBD of the Spike protein could be of special interest due to their potential biological role in the virus-host relationship. Further studies are required for monitoring the epidemiologic impact of this new lineage.
Plant Polysaccharides Modulate Biofilm Formation and Insecticidal Activities of Bacillus thuringiensis Strains
Authors: Li Mengmeng , Shu Changlong , Ke Wang , Li Xiaoxiao , Yu Yiyan , Guan Xiong , Huang Tianpei
Published: June 2021

After the biological pesticide Bacillus thuringiensis (Bt) is applied to the field, it has to remain on the surface of plants to have the insecticidal activities against insect pests. Bt can form biofilms on the surface of vegetable leaves, which were rich in polysaccharides. However, the relationship between polysaccharides of the leaves and the biofilm formation as well as the insecticidal activities of Bt is still unknown. Herein, this study focused on the effects of plant polysaccharides pectin and xylan on biofilm formation and the insecticidal activities of Bt strains. By adding pectin, there were 88 Bt strains with strong biofilm formation, 69 strains with weak biofilm formation, and 13 strains without biofilm formation. When xylan was added, 13 Bt strains formed strong biofilms, 98 strains formed weak biofilms, and 59 strains did not form biofilms. This indicated that two plant polysaccharides, especially pectin, modulate the biofilm formation of Bt strains. The ability of pectin to induce biofilm formation was not related to Bt serotypes. Pectin promoted the biofilms formed by Bt cells in the logarithmic growth phase and lysis phase at the air–liquid interface, while it inhibited the biofilms formed by Bt cells in the sporangial phase at the air–liquid interface. The dosage of pectin was positively correlated with the yield of biofilms formed by Bt cells in the logarithmic growth phase or lysis phase at the solid–liquid interfaces. Pectin did not change the free-living growth and the cell motility of Bt strains. Pectin can improve the biocontrol activities of the spore–insecticidal crystal protein mixture of Bt and BtK commercial insecticides, as well as the biofilms formed by the logarithmic growth phase or lysis phase of Bt cells. Our findings confirmed that plant polysaccharides modulate biofilm formation and insecticidal activities of Bt strains and built a foundation for the construction of biofilm-type Bt biopesticides.
Use of Fourier Transform Infrared Spectroscopy for Monitoring the Shelf Life and Safety of Yogurts Supplemented With a Lactobacillus plantarum Strain With Probiotic Potential
Authors: Papadopoulou Olga S. , Argyri Anthoula A. , Kounani Varvara , Tassou Chrysoula C. , Chorianopoulos Nikos
Published: June 2021

The current study aimed to explore the performance of a probiotic Lactobacillus strain as an adjunct culture in yogurt production and to assess Fourier transform infrared spectroscopy as a rapid, noninvasive analytical technique to evaluate the quality and the shelf life of yogurt during storage. In this respect, bovine milk (full-fat) was inoculated with the typical yogurt starter culture without (control case) or with the further addition of Lactobacillus plantarum T571 as an adjunct (probiotic case). The milk was also inoculated with a cocktail mixture of three strains of Listeria monocytogenes in two different initial levels of inoculum, and the fermentation process was followed. Accordingly, yogurt samples were stored at 4 and 12°C, and microbiological, physicochemical, molecular, and sensory analyses were performed during storage. Results showed that the lactic acid bacteria exceeded 7 log CFU/g during storage in all samples, where the probiotic samples displayed higher acidity, lower pH, and reduced counts of Lb. monocytogenes in a shorter period than the control ones at both temperatures. Pulsed-field gel electrophoresis verified the presence of the probiotic strain until the end of storage at both temperatures and in adequate amounts, whereas the survival and the distribution of Listeria strains depended on the case. The sensory evaluation showed that the probiotic samples had desirable organoleptic characteristics, similar to the control. Finally, the spectral data collected from the yogurt samples during storage were correlated with microbiological counts and sensory data. Partial least squares and support vector machine regression and classification models were developed to provide quantitative estimations of yogurt microbiological counts and qualitative estimations of their sensory status, respectively, based on Fourier transform infrared fingerprints. The developed models exhibited satisfactory performance, and the acquired results were promising for the rapid estimation of the microbiological counts and sensory status of yogurt.
High Potential for Secondary Metabolite Production of Paracoccus marcusii CP157, Isolated From the Crustacean Cancer pagurus
Authors: Leinberger Janina , Holste Jonas , Bunk Boyke , Freese Heike M. , Spröer Cathrin , Dlugosch Leon , Kück Anna-Carlotta , Schulz Stefan , Brinkhoff Thorsten
Published: June 2021

Secondary metabolites are key components in microbial ecology by mediating interactions between bacteria and their environment, neighboring species or host organisms. Bioactivities can be beneficial for both interaction partners or provide a competitive advantage only for the producer. Colonizers of confined habitats such as biofilms are known as prolific producers of a great number of bioactive secondary metabolites and are a potential source for novel compounds. We investigated the strain Paracoccus marcusii CP157, which originates from the biofilm on the carapace of a shell disease-affected Cancer pagurus specimen, for its potential to produce bioactive secondary metabolites. Its closed genome contains 22 extrachromosomal elements and several gene clusters potentially involved in biosynthesis of bioactive polyketides, bacteriocins, and non-ribosomal peptides. Culture extracts of CP157 showed antagonistic activities against bacteria from different phyla, but also against microalgae and crustacean larvae. Different HPLC-fractions of CP157 culture extracts had antibacterial properties, indicating that several bioactive compounds are produced by CP157. The bioactive extract contains several small, antibacterial compounds that partially withstand elevated temperatures, extreme pH values and exposure to proteolytic enzymes, providing high stability toward environmental conditions in the natural habitat of CP157. Further, screening of 17 Paracoccus spp. revealed that antimicrobial activity, hemolysis and production of N-acyl homoserine lactones are common features within the genus. Taking into account the large habitat diversity and phylogenetic distance of the tested strains, we hypothesize that bioactive secondary metabolites play a central role in the ecology of Paracoccus spp. in their natural environments.
Abundance-Occupancy Relationships Along Taxonomic Ranks Reveal a Consistency of Niche Differentiation in Marine Bacterioplankton With Distinct Lifestyles
Authors: Izabel-Shen Dandan , Höger Anna-Lena , Jürgens Klaus
Published: June 2021

Abundance-occupancy relationships (AORs) are an important determinant of biotic community dynamics and habitat suitability. However, little is known about their role in complex bacterial communities, either within a phylogenetic framework or as a function of niche breadth. Based on data obtained in a field study in the St. Lawrence Estuary, we used 16S rRNA gene sequencing to examine the vertical patterns, strength, and character of AORs for particle-attached and free-living bacterial assemblages. Free-living communities were phylogenetically more diverse than particle-attached communities. The dominant taxa were consistent in terms of their presence/absence but population abundances differed in surface water vs. the cold intermediate layer. Significant, positive AORs characterized all of the surveyed communities across all taxonomic ranks of bacteria, thus demonstrating an ecologically conserved trend for both free-living and particle-attached bacteria. The strength of the AORs was low at the species level but higher at and above the genus level. These results demonstrate that an assessment of the distributions and population densities of finely resolved taxa does not necessarily improve determinations of apparent niche differences in marine bacterioplankton communities at regional scales compared with the information inferred from a broad taxonomic classification.
Translational Attenuation Mechanism of ErmB Induction by Erythromycin Is Dependent on Two Leader Peptides
Authors: Wang Shasha , Jiang Kai , Du Xinyue , Lu Yanli , Liao Lijun , He Zhiying , He Weizhi
Published: June 2021

Ribosome stalling on ermBL at the tenth codon (Asp) is believed to be a major mechanism of ermB induction by erythromycin (Ery). In this study, we demonstrated that the mechanism of ermB induction by Ery depends not only on ermBL expression but also on previously unreported ermBL2 expression. Introducing premature termination codons in ermBL, we proved that translation of the N-terminal region of ermBL is the key component for ermB induced by Ery, whereas translation of the C-terminal region of ermBL did not affect Ery-induced ermB. Mutation of the tenth codon (Asp10) of ermBL with other amino acids showed that the degree of induction in vivo was not completely consistent with the data from the in vitro toe printing assay. Alanine-scanning mutagenesis of ermBL demonstrated that both N-terminal residues (R7-K11) and the latter part of ermBL (K20-K27) are critical for Ery induction of ermB. The frameshifting reporter plasmid showed that a new leader peptide, ermBL2, exists in the ermB regulatory region. Further, introducing premature termination mutation and alanine-scanning mutagenesis of ermBL2 demonstrated that the N-terminus of ermBL2 is essential for induction by Ery. Therefore, the detailed function of ermBL2 requires further study.
Network-Based Expression Analyses and Experimental Verifications Reveal the Involvement of STUB1 in Acute Kidney Injury
Authors: Shi Yanting , Chen Genwen , Teng Jie
Published: June 2021

Acute kidney injury (AKI) is a severe and frequently observed condition associated with high morbidity and mortality. The molecular mechanisms underlying AKI have not been elucidated due to the complexity of the pathophysiological processes. Thus, we investigated the key biological molecules contributing to AKI based on the transcriptome profile. We analyzed the RNA sequencing data from 39 native human renal biopsy samples and 9 reference nephrectomies from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) and Gene Ontology (GO) analysis revealed that various GO terms were dysregulated in AKI. Gene set enrichment analysis (GSEA) highlighted dysregulated pathways, including “DNA replication,” “chemokine signaling pathway,” and “metabolic pathways.” Furthermore, the protein-to-protein interaction (PPI) networks of the DEGs were constructed, and the hub genes were identified using Cytoscape. Moreover, weighted gene co-expression network analysis (WGCNA) was performed to validate the DEGs in AKI-related modules. Subsequently, the upregulated hub genes STUB1, SOCS1, and VHL were validated as upregulated in human AKI and a mouse cisplatin-induced AKI model. Moreover, the biological functions of STUB1 were investigated in renal tubular epithelial cells. Cisplatin treatment increased STUB1 expression in a dose-dependent manner at both the mRNA and protein levels. Knockdown of STUB1 by siRNA increased the expression of proapoptotic Bax and cleaved caspase-3 while decreasing antiapoptotic Bcl-2. In addition, silencing STUB1 increased the apoptosis of HK-2 cells and the proinflammatory cytokine production of IL6, TNFα, and IL1β induced by cisplatin. These results indicated that STUB1 may contribute to the initiation and progression of AKI by inducing renal tubular epithelial cell apoptosis and renal inflammation.
TRPV4 is a Prognostic Biomarker that Correlates with the Immunosuppressive Microenvironment and Chemoresistance of Anti-Cancer Drugs
Authors: Wang Kai , Feng Xingjun , Zheng Lingzhi , Chai Zeying , Yu Junhui , You Xinxin , Li Xiaodan , Cheng Xiaodong
Published: June 2021

Background: Transient receptor potential cation channel subfamily V member 4 (TRPV4) has been reported to regulate tumor progression in many tumor types. However, its association with the tumor immune microenvironment remains unclear.

Methods: TRPV4 expression was assessed using data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) database. The clinical features and prognostic roles of TRPV4 were assessed using TCGA cohort. Gene set enrichment analysis (GSEA) of TRPV4 was conducted using the R package clusterProfiler. We analyzed the association between TRPV4 and immune cell infiltration scores of TCGA samples downloaded from published articles and the TIMER2 database. The IC50 values of 192 anti-cancer drugs were downloaded from the Genomics of Drug Sensitivity in Cancer (GDSC) database and the correlation analysis was performed.

Results: TRPV4 was highly expressed and associated with worse overall survival (OS), disease-specific survival (DSS), disease-free interval (DFI), and progression-free interval (PFI) in colon adenocarcinoma (COAD) and ovarian cancer. Furthermore, TRPV4 expression was closely associated with immune regulation-related pathways. Moreover, tumor-associated macrophage (TAM) infiltration levels were positively correlated with TRPV4 expression in TCGA pan-cancer samples. Immunosuppressive genes such as PD-L1, PD-1, CTLA4, LAG3, TIGIT, TGFB1, and TGFBR1 were positively correlated with TRPV4 expression in most tumors. In addition, patients with high expression of TRPV4 might be resistant to the treatment of Cisplatin and Oxaliplatin.

Conclusion: Our results suggest that TRPV4 is an oncogene and a prognostic marker in COAD and ovarian cancer. High TRPV4 expression is associated with tumor immunosuppressive status and may contribute to TAM infiltration based on TCGA data from pan-cancer samples. Patients with high expression of TRPV4 might be resistant to the treatment of Cisplatin and Oxaliplatin.
Mutational Landscape of Pirin and Elucidation of the Impact of Most Detrimental Missense Variants That Accelerate the Breast Cancer Pathways: A Computational Modelling Study
Authors: Suleman Muhammad , Tahir ul Qamar Muhammad , Saleem Shoaib , Ahmad Sajjad , Ali Syed Shujait , Khan Haji , Akbar Fazal , Khan Wajid , Alblihy Adel , Alrumaihi Faris , Waseem Muhammad , Allemailem Khaled S.
Published: June 2021

Pirin (PIR) protein is highly conserved in both prokaryotic and eukaryotic organisms. Recently, it has been identified that PIR positively regulates breast cancer cell proliferation, xenograft tumor formation, and metastasis, through an enforced transition of G1/S phase of the cell cycle by upregulation of E2F1 expression at the transcriptional level. Keeping in view the importance of PIR in many crucial cellular processes in humans, we used a variety of computational tools to identify non-synonymous single-nucleotide polymorphisms (SNPs) in the PIR gene that are highly deleterious for the structure and function of PIR protein. Out of 173 SNPs identified in the protein, 119 are non-synonymous, and by consensus, 24 mutations were confirmed to be deleterious in nature. Mutations such as V257A, I28T, and I264S were unveiled as highly destabilizing due to a significant stability fold change on the protein structure. This observation was further established through molecular dynamics (MD) simulation that demonstrated the role of the mutation in protein structure destability and affecting its internal dynamics. The findings of this study are believed to open doors to investigate the biological relevance of the mutations and drugability potential of the protein.
Analysis of Age-Related White Matter Microstructures Based on Diffusion Tensor Imaging
Authors: Ouyang Yahui , Cui Dong , Yuan Zilong , Liu Zhipeng , Jiao Qing , Yin Tao , Qiu Jianfeng
Published: June 2021

Population aging has become a serious social problem. Accordingly, many researches are focusing on changes in brains of the elderly. In this study, we used multiple parameters to analyze age-related changes in white matter fibers. A sample cohort of 58 individuals was divided into young and middle-age groups and tract-based spatial statistics (TBSS) were used to analyze the differences in fractional anisotropy (FA), mean diffusion (MD), axial diffusion (AD), and radial diffusion (RD) between the two groups. Deterministic fiber tracking was used to investigate the correlation between fiber number and fiber length with age. The TBSS analysis revealed significant differences in FA, MD, AD, and RD in multiple white matter fibers between the two groups. In the middle-age group FA and AD were lower than in young people, whereas the MD and RD values were higher. Deterministic fiber tracking showed that the fiber length of some fibers correlated positively with age. These fibers were observed in the splenium of corpus callosum (SCC), the posterior limb of internal capsule (PLIC), the right posterior corona radiata (PCR_R), the anterior corona radiata (ACR), the left posterior thalamic radiation (include optic radiation; PTR_L), and the left superior longitudinal fasciculus (SLF_L), among others. The results showed that the SCC, PLIC, PCR_R, ACR, PTR_L, and SLF_L significantly differed between young and middle-age people. Therefore, we believe that these fibers could be used as image markers of age-related white matter changes.
Normal and Abnormal Sharp Wave Ripples in the Hippocampal-Entorhinal Cortex System: Implications for Memory Consolidation, Alzheimer's Disease, and Temporal Lobe Epilepsy
Authors: Zhen Zhi-Hang , Guo Mo-Ran , Li He-Ming , Guo Ou-Yang , Zhen Jun-Li , Fu Jian , Tan Guo-Jun
Published: June 2021

The appearance of hippocampal sharp wave ripples (SWRs) is an electrophysiological biomarker for episodic memory encoding and behavioral planning. Disturbed SWRs are considered a sign of neural network dysfunction that may provide insights into the structural connectivity changes associated with cognitive impairment in early-stage Alzheimer's disease (AD) and temporal lobe epilepsy (TLE). SWRs originating from hippocampus have been extensively studied during spatial navigation in rodents, and more recent studies have investigated SWRs in the hippocampal-entorhinal cortex (HPC-EC) system during a variety of other memory-guided behaviors. Understanding how SWR disruption impairs memory function, especially episodic memory, could aid in the development of more efficacious therapeutics for AD and TLE. In this review, we first provide an overview of the reciprocal association between AD and TLE, and then focus on the functions of HPC-EC system SWRs in episodic memory consolidation. It is posited that these waveforms reflect rapid network interactions among excitatory projection neurons and local interneurons and that these waves may contribute to synaptic plasticity underlying memory consolidation. Further, SWRs appear altered or ectopic in AD and TLE. These waveforms may thus provide clues to understanding disease pathogenesis and may even serve as biomarkers for early-stage disease progression and treatment response.
Monocyte to High-Density Lipoprotein Ratio Is Associated With Early Neurological Deterioration in Acute Isolated Pontine Infarction
Authors: Bi Xinwei , Liu Xiaoqian , Cheng Jiaqi
Published: June 2021

Objectives: The monocyte to high-density lipoprotein ratio (MHR) has been considered to be a novel inflammatory marker of atherosclerotic cardiovascular disease. However, its role in the acute phase of acute isolated pontine infarctions remains elusive. We explored whether an association existed between elevated MHR levels and early neurological deterioration (END) in patients with isolated pontine infarction.

Methods: Data from 212 patients with acute isolated pontine infarction were retrospectively analyzed. We examined the MHR in quartiles of increasing levels to evaluate for possible threshold effects. END was defined as an elevation in the total National Institutes of Health Stroke Scale (NIHSS) score ≥2 or an increase in NIHSS score ≥1 in motor power within the first week after symptom onset. Patients were divided into an END group and a non-END group. The association of MHR on END following pontine infarction was examined by logistic regression models after adjusting for age, NIHSS at admission, basilar artery stenosis, history of hypertension or hyperlipidemia or stroke, infarct size, fasting blood glucose, and paramedian pontine infarction.

Results: The mean MHR was 0.44 ± 0.22. A total of 58 (27.36%) patients were diagnosed with END. END occurred within the first 48 h after hospitalization in 38 patients (65.52%). After adjusting for confounding and risk factors, the multivariate logistic regression analysis showed NIHSS at admission [odds ratio (OR), 1.228; 95% confidence interval (CI), 1.036–1.456], basilar artery stenosis (OR, 2.843; 95% CI, 1.205–6.727), and fasting blood glucose (OR, 1.296; 95% CI, 1.004–1.672) were independently associated with END. The odds ratio of END increased as the quartile level of MHR increased, with the lowest quartile used as the reference value. Compared to the first quartile of MHR, the third and fourth quartiles were associated with 4.847-fold (95% CI, 1.532–15.336) and 5.824-fold (95% CI, 1.845–18.385) higher odds of END in multivariate analysis.

Conclusions: Elevated MHR levels may be valuable as a biomarker of END in patients with isolated pontine infarction. The elevated MHR was independently associated with END in isolated pontine infarction.
Polyphenol-Mediated Gut Microbiota Modulation: Toward Prebiotics and Further
Authors: Rodríguez-Daza Maria Carolina , Pulido-Mateos Elena C. , Lupien-Meilleur Joseph , Guyonnet Denis , Desjardins Yves , Roy Denis
Published: June 2021

The genome of gut microbes encodes a collection of enzymes whose metabolic functions contribute to the bioavailability and bioactivity of unabsorbed (poly)phenols. Datasets from high throughput sequencing, metabolome measurements, and other omics have expanded the understanding of the different modes of actions by which (poly)phenols modulate the microbiome conferring health benefits to the host. Progress have been made to identify direct prebiotic effects of (poly)phenols; albeit up to date, these compounds are not recognized as prebiotics sensu stricto. Interestingly, certain probiotics strains have an enzymatic repertoire, such as tannase, α-L-rhamnosidase, and phenolic acid reductase, involved in the transformation of different (poly)phenols into bioactive phenolic metabolites. In vivo studies have demonstrated that these (poly)phenol-transforming bacteria thrive when provided with phenolic substrates. However, other taxonomically distinct gut symbionts of which a phenolic-metabolizing activity has not been demonstrated are still significantly promoted by (poly)phenols. This is the case of Akkermansia muciniphila, a so-called antiobesity bacterium, which responds positively to (poly)phenols and may be partially responsible for the health benefits formerly attributed to these molecules. We surmise that (poly)phenols broad antimicrobial action free ecological niches occupied by competing bacteria, thereby allowing the bloom of beneficial gut bacteria. This review explores the capacity of (poly)phenols to promote beneficial gut bacteria through their direct and collaborative bacterial utilization and their inhibitory action on potential pathogenic species. We propose the term duplibiotic, to describe an unabsorbed substrate modulating the gut microbiota by both antimicrobial and prebiotic modes of action. (Poly)phenol duplibiotic effect could participate in blunting metabolic disturbance and gut dysbiosis, positioning these compounds as dietary strategies with therapeutic potential.
Nonsmoking and Nondrinking Oral Squamous Cell Carcinoma Patients: A Different Entity
Authors: Yang Zhan , Du Wei , Zhang Xu , Chen Defeng , Fang Qigen , He Yuezhong , Yang Yang , Li Ding , Fan Jie
Published: June 2021

Objective

Our goal was to analyze the demographic and pathologic characteristics as well as prognosis in nonsmoking and nondrinking (NSND) oral squamous cell carcinoma (SCC) patients compared with typical oral SCC patients.

Patients and Methods

A total of 353 patients were retrospectively enrolled and divided into two groups: the NSND group and the current smoking/current drinking (CSCD) group. Demographic, pathologic, and molecular data were compared between the two groups. The main research endpoints were locoregional control (LRC) and disease-specific survival (DSS).

Results

In the NSND group, 16.3%, 41.9%, and 53.5% of patients were aged no more than 40 years, were female, and had an educational background of high school or above compared to 3.7%, 6.0%, and 38.2% of patients in the CSCD group, respectively. A total of 15.1% of the NSND patients had SCC of the lower gingiva and floor of the mouth, which was lower than the 35.6% of patients in the CSCD group. CSCD patients were likely to have an advanced disease stage (48.7% vs 32.5%, p=0.042) and poorly differentiated cancer (26.6% vs 16.3%, p=0.042). The NSND patients had a mean Ki-67 index of 24.5%, which was lower than the mean of 35.7% in the CSCD patients. The two groups had no HPV infection and similar p16 expression (4.7% vs 10.1%, p=0.132), but there was higher expression of p53 (38.6% vs 17.4%, p<0.001) and p63 (59.9% vs 29.1%, p<0.001) in the CSCD group. The 5-year LRC rates for NSND patients and CSCD patients were 48% and 38%, respectively, and the difference was significant (p=0.048). The 5-year DSS rates for NSND patients and CSCD patients were 56% and 39%, respectively, and the difference was significant (p=0.047). Further, a Cox model confirmed the independence of smoking and drinking status for affecting LRC and DSS.

Conclusion

NSND oral SCC patients are a different entity. HPV infection has a limited role in carcinogenesis in NSND patients, and p16 expression is associated with worse locoregional control.
Development and Validation of Prognostic Nomograms Based on Gross Tumor Volume and Cervical Nodal Volume for Nasopharyngeal Carcinoma Patients With Concurrent Chemoradiotherapy
Authors: Zhang Cui-Dai , Li Mei , Hong Ying-Ji , Cai Ze-Man , Huang Kai-Chun , Lin Zhi-Xiong , Yang Zhi-Ning
Published: June 2021

Purpose

Our study aimed to establish and validate prognostic nomograms based on gross tumor volume (GTV) and cervical nodal volume (CNV) for nasopharyngeal carcinoma (NPC) patients treated with two cycles of concurrent chemoradiotherapy (CCRT).

Methods

From 2012 to 2015, 620 eligible patients who received radical treatment at the Cancer Hospital of Shantou University Medical College were recruited for a nomogram study. Variables were determined in a training set of 463 patients from 2012 to 2014 by X-tile analysis, univariate and multivariate Cox proportional hazard analyses, and the least absolute shrinkage and selection operator (LASSO). Another cohort of 157 patients in 2015 was validated with bootstrap resampling. The concordance index (C-index) and calibration curves were applied to assess its predictive discriminative and accuracy ability, while decision curve analysis (DCA), X-tile analysis and Kaplan–Meier curve for clinical application.

Results

Independent prognostic variables for overall survival (OS) were age, GTV, CNV, cranial nerve, positive cervical lymph node laterality below the caudal border of cricoid cartilage (LNBC), and were selected for the nomogram. Optimal prognostic factors including Karnofsky performance status (KPS), age, GTV, CNV, LNBC were incorporated in the nomogram for progression-free survival (PFS). In the training set, the C-index of our nomograms for OS and PFS were 0.755 (95% CI, 0.704 to 0.807) and 0.698 (95% CI, 0.652 to 0.744). The calibration curve showed good agreement between nomogram-predicted and actual survival. DCA indicated that our nomograms were of clinical benefit.

Conclusion

Our nomograms are capable of effective prognostic prediction for patients with NPC.
Simple Quantitative Sensory Testing Reveals Paradoxical Co-existence of Hypoesthesia and Hyperalgesia in Diabetes
Authors: Hansen Line Elise Møller , Fjelsted Camilla Ann , Olesen Søren Schou , Phillips Anna Evans , Faghih Mahya , Wegeberg Anne-Marie , Drewes Asbjørn Mohr , Brock Christina
Published: June 2021

Background: Diabetic neuropathy is characterized by the paradoxical co-existence of hypo- and hyperalgesia to sensory stimuli. The literature shows consistently sensory differences between healthy and participants with diabetes. We hypothesized that due to differences in pathophysiology, advanced quantitative sensory testing (QST) might reveal sensory discrepancies between type 1 (T1D) and type 2 diabetes (T2D). Furthermore, we investigated whether vibration detection thresholds (VDT) were associated with sensory response.

Method: Fifty-six adults with T1D [43 years (28–58)], 99 adults with T2D [65 years (57–71)], and 122 healthy individuals [51 years (34–64)] were included. VDT, pressure pain detection thresholds (pPDT) and tolerance (pPTT), tonic cold pain (hand-immersion in iced water), and central pain mechanisms (temporal summation and conditioned pain modulation) were tested and compared between T1D and T2D. VDT was categorized into normal (< 18 V), intermediary (18–25 V), or high (> 25 V).

Results: In comparison to healthy, analysis adjusted for age, BMI, and gender revealed hypoalgesia to tibial (pPDT): p = 0.01, hyperalgesia to tonic cold pain: p < 0.01, and diminished temporal summation (arm: p < 0.01; abdomen: p < 0.01). In comparison to participants with T2D, participants with T1D were hypoalgesic to tibial pPDT: p < 0.01 and pPTT: p < 0.01, and lower VDT: p = 0.02. VDT was not associated with QST responses.

Conclusion: Participants with T1D were more hypoalgesic to bone pPDT and pPTT independent of lower VDT, indicating neuronal health toward normalization. Improved understanding of differentiated sensory profiles in T1D and T2D may identify improved clinical endpoints in future trials.
X-Linked Agammaglobulinemia Presenting as Neutropenia: Case Report and an Overview of Literature
Authors: Lanlokun Mosopefoluwa , Borden Amanda , Nieves Daime , Walter Jolan E. , Albright Deborah
Published: June 2021

X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency caused by mutations in the Bruton Tyrosine Kinase (BTK) gene. Marked neutropenia can be the initial abnormal laboratory finding in patients with XLA who are presenting with their first illness. The two cases presented herein support early consideration of evaluation for primary humoral immune deficiency in previously healthy male patients under the age of 12 months who present with neutropenia in the setting of infection shortly after passively acquired maternal antibody has sufficiently waned. Initial consideration of XLA (or other humoral immune deficiencies) in this particular population of young male neutropenic patients may afford the opportunity to avoid bone marrow biopsy in otherwise stable cases with similar presentations.
Combination of the Herbs Radix Rehmanniae and Cornus Officinalis Mitigated Testicular Damage From Diabetes Mellitus by Enhancing Glycolysis via the AGEs/RAGE/HIF-1α Axis
Authors: Chen Yuping , Chen Jing , Shu Anmei , Liu Liping , Wu Qin , Wu Juansong , Song Siyuan , Fan Weiping , Zhu Yihui , Xu Huiqin , Sun Jihu , Yang Liucai
Published: June 2021

Radix Rehmanniae and Cornus Officinalis (RR-CO) have been widely used as “nourishing Yin and tonifying kidney” herb pairs for the treatment of diabetes mellitus (DM) and its complications in traditional Chinese medicine (TCM). Based on the theory of “kidney governing reproduction” in TCM, the aim of this study was to investigate the therapeutic effects of RR-CO on DM-induced reproduction damage through regulating testicular glycolysis. Moreover, the regulation of AGEs/RAGE/HIF-1α axis on the testicular glycolysis process has also been studied. Spontaneous DM model KK-Ay mice were used to investigate the protective effect of RR, CO, RR-CO on DM-induced reproductive disturbances. RR, CO, RR-CO improved DM-induced renal and testicular morphology damages. Moreover, the impaired spermatogenesis, germ cell apoptosis and motility in testis induced upon DM were also attenuated by RR, CO or RR-CO, accompanied by an increased level of glycolysis metabolomics such as l-lactate, d-Fructose 1,6-bisphosphate, etc. Meanwhile, glucose membrane transporters (GLUT1, GLUT3), monocarboxylate transporter 4 (MCT4) expression, lactate dehydrogenase (LDH) activity, HIF-1α were upregulated by RR, CO and RR-CO treatment compared with the model group, whereas AGE level and RAGE expression were decreased with the drug administration. The RR-CO group was associated with superior protective effects in comparison to RR, CO use only. Aminoguanidine (Ami) and FPS-ZM1, the AGEs and RAGE inhibitors, were used as a tool drug to study the mechanism, showing different degrees of protection against DM-induced reproductive damage. This work preliminarily sheds light on the herb pair RR-CO exhibited favorable effects against DM-induced reproductive disturbances through enhancing testicular glycolysis, which might be mediated by AGEs/RAGE/HIF-1α axis.
Ultrasound Microbubble–Facilitated Inner Ear Delivery of Gold Nanoparticles Involves Transient Disruption of the Tight Junction Barrier in the Round Window Membrane
Authors: Lin Yi-Chun , Shih Cheng-Ping , Chen Hsin-Chien , Chou Ying-Liang , Sytwu Huey-Kang , Fang Mei-Cho , Lin Yuan-Yung , Kuo Chao-Yin , Su Hsiao-Han , Hung Chia-Lien , Chen Hang-Kang , Wang Chih-Hung
Published: June 2021

The application of ultrasound microbubbles (USMBs) enhances the permeability of the round window membrane (RWM) and improves drug delivery to the inner ear. In this study, we investigated the efficiency of USMB-aided delivery of chitosan-coated gold nanoparticles (CS-AuNPs) and the mechanism of USMB-mediated enhancement of RMW permeability. We exposed mouse inner ears to USMBs at an intensity of 2 W/cm2 and then filled the tympanic bulla with CS-AuNPs or fluorescein isothiocyanate-decorated CS-AuNPs (FITC-CS-AuNPs). The membrane uptake of FITC-CS-AuNPs and their depth of permeation into the three-layer structure of the RWM, with or without prior USMB treatment, were visualized by z-stack confocal laser scanning microscopy. Ultrastructural changes in the RWM due to USMB-mediated cavitation appeared as sunburn-like peeling and various degrees of depression in the RWM surface, with pore-like openings forming in the outer epithelium. This disruption of the outer epithelium was paralleled by a transient reduction in tight junction (TJ)-associated protein levels in the RWM and an enhanced delivery of FITC-CS-AuNPs into the RWM. Without prior USMB exposure, the treatment with CS-AuNPs also caused a noticeable reduction in TJ proteins of the RWM. Our findings indicated that the combined treatment with USMBs and CS-AuNPs represents a promising and efficient drug and gene delivery vehicle for a trans-RWM approach for inner ear therapy. The outer epithelial layer of the RWM plays a decisive role in controlling the transmembrane transport of substances such as CS-AuNPs following the administration of USMBs. Most importantly, the enhanced permeation of AuNPs involved the transient disruption of the TJ-created paracellular barrier in the outer epithelium of the RWM.
The Direction of Arrival Location Deception Model Counter Duel Baseline Phase Interferometer Based on Frequency Diverse Array
Authors: Ge Jiaang , Xie Junwei , Chen Chushu , Wang Bo
Published: June 2021

With the emergence and development of the passive localization, the radiation source is more visible for the location system which endangers their survival. Therefore, there is an urgent demand for the radio frequency (RF) stealth technology. An effective method to realize RF stealth is location deception, therefore, for the passive localization system, this paper proposes a direction of arrival (DOA) location deception method using the frequency diverse array (FDA) against the dual baseline phase interferometer. Since the direction-finding of the dual baseline phase interferometer is based on the received signal with fixed frequency, the FDA signal has a deception effect on the interferometer owing to the introduction of the small frequency increment. Considering the influence of the frequency increment sequence on the deception effect, we derive the optimizations of the DOA location deception via the average location deviation for the sampling time in the case of no noise and noise, respectively. Besides, considering the time dependency of the beam, we investigate the average SNR (ASNR) and the corresponding CRLB to verify the proposed method. Numerical examples and simulations show that the proposed method can counter the interferometer by realizing location deception.
Genome-Wide DNA Methylation Changes Associated With High-Altitude Acclimatization During an Everest Base Camp Trek
Authors: Childebayeva Ainash , Harman Taylor , Weinstein Julien , Day Trevor , Brutsaert Tom D. , Bigham Abigail W.
Published: June 2021

The individual physiological response to high-altitude hypoxia involves both genetic and non-genetic factors, including epigenetic modifications. Epigenetic changes in hypoxia factor pathway (HIF) genes are associated with high-altitude acclimatization. However, genome-wide epigenetic changes that are associated with short-term hypoxia exposure remain largely unknown. We collected a series of DNA samples from 15 participants of European ancestry trekking to Everest Base Camp to identify DNA methylation changes associated with incremental altitude ascent. We determined genome-wide DNA methylation levels using the Illumina MethylationEPIC chip comparing two altitudes: baseline 1,400 m (day 0) and elevation 4,240 m (day 7). The results of our epigenome-wide association study revealed 2,873 significant differentially methylated positions (DMPs) and 361 significant differentially methylated regions (DMRs), including significant positions and regions in hypoxia inducible factor (HIF) and the renin–angiotensin system (RAS) pathways. Our pathway enrichment analysis identified 95 significant pathways including regulation of glycolytic process (GO:0006110), regulation of hematopoietic stem cell differentiation (GO:1902036), and regulation of angiogenesis (GO:0045765). Lastly, we identified an association between theACEgene insertion/deletion (I/D) polymorphism and oxygen saturation, as well as averageACEmethylation. These findings shed light on the genes and pathways experiencing the most epigenetic change associated with short-term exposure to hypoxia.