bluuebunny/crossref_metadata_2025 huggingface dataset:
Answered and Unanswered Questions in Early-Stage Viral Vector Transduction Biology and Innate Primary Cell Toxicity for Ex-Vivo Gene Editing
Authors: Dudek Amanda Mary , Porteus Matthew Hebden
Published: May 2021

Adeno-associated virus is a highly efficient DNA delivery vehicle for genome editing strategies that employ CRISPR/Cas9 and a DNA donor for homology-directed repair. Many groups have used this strategy in development of therapies for blood and immune disorders such as sickle-cell anemia and severe-combined immunodeficiency. However, recent events have called into question the immunogenicity of AAV as a gene therapy vector and the safety profile dictated by the immune response to this vector. The target cells dictating this response and the molecular mechanisms dictating cellular response to AAV are poorly understood. Here, we will investigate the current known AAV capsid and genome interactions with cellular proteins during early stage vector transduction and how these interactions may influence innate cellular responses. We will discuss the current understanding of innate immune activation and DNA damage response to AAV, and the limitations of what is currently known. In particular, we will focus on pathway differences in cell line verses primary cells, with a focus on hematopoietic stem and progenitor cells (HSPCs) in the context of ex-vivo gene editing, and what we can learn from HSPC infection by other parvoviruses. Finally, we will discuss how innate immune and DNA damage response pathway activation in these highly sensitive stem cell populations may impact long-term engraftment and clinical outcomes as these gene-editing strategies move towards the clinic, with the aim to propose pathways relevant for improved hematopoietic stem cell survival and long-term engraftment after AAV-mediated genome editing.
MelLec Exacerbates the Pathogenesis of Aspergillus fumigatus-Induced Allergic Inflammation in Mice
Authors: Tone Kazuya , Stappers Mark H. T. , Hatinguais Remi , Dambuza Ivy M. , Salazar Fabián , Wallace Carol , Yuecel Raif , Morvay Petruta L. , Kuwano Kazuyoshi , Willment Janet A. , Brown Gordon D.
Published: May 2021

Environmental factors, particularly fungi, influence the pathogenesis of allergic airway inflammation, but the mechanisms underlying these effects are still unclear. Melanin is one fungal component which is thought to modulate pulmonary inflammation. We recently identified a novel C-type lectin receptor, MelLec (Clec1a), which recognizes fungal 1,8-dihydroxynaphthalene (DHN)-melanin and is able to regulate inflammatory responses. Here we show that MelLec promotes pulmonary allergic inflammation and drives the development of Th17 T-cells in response to spores of Aspergillus fumigatus. Unexpectedly, we found that MelLec deficiency was protective, with MelLec-/- animals showing normal weight gain and significantly reduced pulmonary inflammation in our allergic model. The lungs of treated MelLec-/- mice displayed significantly reduced inflammatory foci and reduced bronchial wall thickening, which correlated with a reduced cellular influx (particularly neutrophils and inflammatory monocytes) and levels of inflammatory cytokines and chemokines. Notably, fungal burdens were increased in MelLec-/- animals, without apparent adverse effects, and there were no alterations in the survival of these mice. Characterization of the pulmonary T-cell populations, revealed a significant reduction in Th17 cells, and no alterations in Th2, Th1 or Treg cells. Thus, our data reveal that while MelLec is required to control pulmonary fungal burden, the inflammatory responses mediated by this receptor negatively impact the animal welfare in this allergic model.
Sex-Specific Differences of the Inflammatory State in Experimental Autoimmune Myocarditis
Authors: Barcena Maria Luisa , Jeuthe Sarah , Niehues Maximilian H. , Pozdniakova Sofya , Haritonow Natalie , Kühl Anja A. , Messroghli Daniel R. , Regitz-Zagrosek Vera
Published: May 2021

Increasing evidence suggests male sex as a potential risk factor for a higher incidence of cardiac fibrosis, stronger cardiac inflammation, and dilated cardiomyopathy (DCM) in human myocarditis. Chronic activation of the immune response in myocarditis may trigger autoimmunity. The experimental autoimmune myocarditis (EAM) model has been well established for the study of autoimmune myocarditis, however the role of sex in this pathology has not been fully explored. In this study, we investigated sex differences in the inflammatory response in the EAM model. We analyzed the cardiac function, as well as the inflammatory stage and fibrosis formation in the heart of EAM male and female rats. 21 days after induction of EAM, male EAM rats showed a decreased ejection fraction, stroke volume and cardiac output, while females did not. A significantly elevated number of infiltrates was detected in myocardium in both sexes, indicating the activation of macrophages following EAM induction. The level of anti-inflammatory macrophages (CD68+ ArgI+) was only significantly increased in female hearts. The expression of Col3A1 and fibrosis formation were more prominent in males. Furthermore, prominent pro-inflammatory factors were increased only in male rats. These findings indicate sex-specific alterations in the inflammatory stage of EAM, with a pro-inflammatory phenotype appearing in males and an anti-inflammatory phenotype in females, which both significantly affect cardiac function in autoimmune myocarditis.
Comparing Coral Colony Surveys From In-Water Observations and Structure-From-Motion Imagery Shows Low Methodological Bias
Authors: Couch Courtney S. , Oliver Thomas A. , Suka Rhonda , Lamirand Mia , Asbury Mollie , Amir Corinne , Vargas-Ángel Bernardo , Winston Morgan , Huntington Brittany , Lichowski Frances , Halperin Ariel , Gray Andrew , Garriques Joao , Samson Jennifer
Published: May 2021

As the threats to coral reefs mount, scientists and managers are looking for innovative ways to increase the scope, scale, and efficiency of coral reef monitoring. Monitoring changes in coral communities and demographic features provides key information about ecosystem function and resilience of reefs. While most monitoring programs continue to rely on in-water visual survey methods, scientists are exploring 3D imaging technologies such as photogrammetry, also known as Structure-from-Motion (SfM), to enhance precision of monitoring, increase logistical efficiency in the field, and generate a permanent record of the reef. Here, we quantitatively compare data generated from in-water surveys to SfM-derived metrics for assessing coral demography, bleaching, and diversity in the main Hawaiian Islands as part of NOAA’s National Coral Reef Monitoring Program. Our objectives were to compare between-method error to within-method error, test for bias between methods, and identify strengths and weaknesses of both methods. Colony density, average colony diameter, average partial mortality, prevalence of bleaching, species richness, and species diversity were recorded using both methods within the same survey areas. For all metrics, the magnitude of between-method error was comparable to the within-method error for the in-water method and between method error was significantly higher than within-method error for SfM for one of the seven metrics. Our results also reveal that a majority of the metrics do not vary significantly between methods, nor did we observe a significant interaction between method and habitat type or method and depth. Exceptions include estimates of partial mortality, bleaching prevalence, and Porites juvenile density–though differences between methods are generally small. Our study also highlights that SfM offers a unique opportunity to more rigorously quantify and mitigate inter-observer error by providing observers unlimited “bottom time” and the opportunity to work together to resolve difficult annotations. However, the necessary investment in equipment and expertise does present substantial up-front costs, and the time associated with curating imagery, photogrammetric modeling, and manual image annotation can reduce the timeliness of data reporting. SfM provides a powerful tool to reimagine how we study and manage coral reefs, and this study provides the first quantified methodological comparison to validate the transition from standard in-water methods to SfM survey methods for estimates of coral colony-level surveys.
Fabrication of Polylactic Acid/β-Tricalcium Phosphate FDM 3D Printing Fiber to Enhance Osteoblastic-Like Cell Performance
Authors: Salamanca Eisner , Tsao Ting-Chia , Hseuh Hao-Wen , Wu Yi-Fan , Choy Cheuk-Sing , Lin Chin-Kai , Pan Yu-Hwa , Teng Nai-Chia , Huang Mao-Chuan , Lin Shang-Ming , Chang Wei-Jen
Published: May 2021

Guided-bone regeneration (GBR) is increasingly using three-dimensional (3D) printing by fused deposition modeling (FDM) to build the filaments used for treatment. Polylactic acid (PLA) and beta-tricalcium phosphate (β-TCP) are widely used as base materials in 3D printing, necessitating that they are studied together in the context of GBR treatment. This study sought to test and compare the properties and efficacy of different ratios of β-TCP and PLA used to make the 3D-printed filament material to find the most effective combination of materials for GBR treatment. Several ratios of PLA to β-TCP were tested, including PLA/β-TCP ratios of 95%/5% (PLA-5), 90%/10% (PLA-10), 85%/15% (PLA-15), and 80%/20% (PLA-20), and quantitative real-time polymerase chain reaction (qPCR) in vitro testing was done to characterize the material. After adding β-TCP to PLA, mechanical testing indicated that tensile and elongation strengths decreased, hardness was retained, and cell proliferation was promoted. The effect of PLA and β-TCP on increasing alkaline phosphatase (ALP) activity was significantly greater in a ratio of 10% β-TCP/90% PLA at 5 days (p < 0.05) than in any other ratios tested. This is supported by results from qPCR testing, which showed early osteoblast-like differentiation of DLX5, RUNX2, OPG, OC, and collagen type 1 (COL-1) expression levels similar to cells cultured on PLA-10. Our results demonstrated that 3D printing of filaments produced in a ratio of 90% PLA to 10% β-TCP was more effective for GBR than that of filaments produced only using PLA.
Enhanced Electrical Properties of Lead-Free Piezoelectric KNLN-BZ-BNT Ceramics With the Modification of Sm3+ Ions
Authors: Quan Yi , Wang Lingyan , Ren Wei , Zhao Jinyan , Zhuang Jian , Zheng Kun , Wang Zhe , Karaki Tomoaki , Jiang Zhishui , Wen Li
Published: May 2021

Environment-friendly lead-free piezoelectric ceramics with great properties and high thermal stability are desired in the industry. In this work, the Sm3+-modified lead-free 0.915(K0.45Na0.5Li0.05)NbO3–0.075BaZrO3–0.01(Bi0.5Na0.5)TiO3 (KNLN-BZ-BNT) ceramics are prepared. The piezoelectric properties are improved with the introduction of Sm3+, and the optimal properties (d33 = 325 pC/N and d33* = 384 pm/V) are achieved in the ceramic modified with 0.3 mol% Sm3+ ions. Meanwhile, this sample shows good thermal stability such that the values of d33* decreased less than 20% when the temperature raised from 30 to 180oC. These results show the Sm3+-modified KNLN-BZ-BNT ceramics are good for further applications even under high temperature.
Interplay Between Microbiota, Toll-Like Receptors and Cytokines for the Maintenance of Epithelial Barrier Integrity
Authors: Semin Iaroslav , Ninnemann Justus , Bondareva Marina , Gimaev Ilia , Kruglov Andrey A.
Published: May 2021

The intestinal tract is densely populated by microbiota consisting of various commensal microorganisms that are instrumental for the healthy state of the living organism. Such commensals generate various molecules that can be recognized by the Toll-like receptors of the immune system leading to the inflammation marked by strong upregulation of various proinflammatory cytokines, such as TNF, IL-6, and IL-1β. To prevent excessive inflammation, a single layer of constantly renewing, highly proliferating epithelial cells (IEC) provides proper segregation of such microorganisms from the body cavities. There are various triggers which facilitate the disturbance of the epithelial barrier which often leads to inflammation. However, the nature and duration of the stress may determine the state of the epithelial cells and their responses to cytokines. Here we discuss the role of the microbiota-TLR-cytokine axis in the maintenance of the epithelial tissue integrity. In particular, we highlight discrepancies in the function of TLR and cytokines in IEC barrier during acute or chronic inflammation and we suggest that intervention strategies should be applied based on the type of inflammation.
A Mixed Methods Process Evaluation of a Clustered-Randomized Controlled Trial to Determine the Effects of Community-Based Dietary Sodium Reduction in Rural China
Authors: Chu Hongling , Zhang Jing , Fetters Michael D. , Niu Wenyi , Li Huijuan , Li Nicole , Yan Lijing L. , Wang Yanfang , Wu Yangfeng
Published: May 2021

Purpose:A clustered-randomized controlled trial was conducted to determine the effects of a sodium reduction program in 120 rural villages in Northern China. This mixed-methods process evaluation was used to investigate the implementation and to evaluate the feasibility of the complex intervention to translate the findings from clinical study to the real world.

Methods:A convergent mixed-methods process evaluation design was used in this study. Quantitative data were collected from activity logs and routine study records. Qualitative data were collected from 53 project stakeholders and 45 villagers from 10 intervention villages. Thematic analysis of qualitative interviews facilitated integration with the descriptive quantitative data analysis based on theory-informed domains of fidelity, delivery, reach, receipt, and contextual factors of intervention from a process evaluation framework.

Results:The intervention was implemented with high fidelity, delivery, reach, and receipt. A total of 5,450 sheets of posters, 31,400 calendars, and 78,000 sheets of stickers were delivered as planned, and 11 promotion activities were conducted in each village. Contextual factors hindering full uptake of the intervention included preference for salty taste, higher cost of low-sodium salt, and low education levels of villagers. Other contextual factors, positive policy support, administrative support, and staff enthusiasm were the facilitators for implementation.

Conclusions:This multifaceted intervention was implemented well and effectively in rural China. This process evaluation has indicated that conducting health education interventions in rural areas requires policy and administrative support, enthusiastic staff, easy-to-understand health education materials and activities, and key persons, but tempered expectations as behavior change requires time. This project demonstrates the feasibility and benefits of using mixed-methods process evaluation in large-scale studies.
Vitrectomy With Silicone Oil Tamponade and Without Internal Limiting Membrane Peeling for the Treatment of Myopic Foveoschisis With High Risk of Macular Hole Development
Authors: Yao Yuou , Qu Jinfeng , Shi Xuan , Hu Jie , Hou Jing , Miao Heng , Cheng Yong , Zhao Mingwei
Published: May 2021

Purpose: To explore the efficiency and safety of the surgical procedure of pars plana vitrectomy (PPV) with silicone oil (SO) tamponade and without internal limiting membrane (ILM) peeling for myopic foveoschisis (MF) eyes with high risk of macular hole formation.

Methods: Three eyes (three patients) with MF and foveal detachment were enrolled into the study. Comprehensive preoperative ophthalmological assessments, including best corrected visual acuity (BCVA) and spectral-domain optical coherence tomography (SD-OCT) were performed on the eyes. Central foveal thickness (CFT) and thickness of continuous neurosensory retina at foveola were measured. All patients underwent PPV followed by SO tamponade and without ILM peeling. SO was removed when MF and retinal detachment were resolved. Patients were followed up postoperative at month 1, 3, 6, and 12.

Results: All the three eyes achieved complete resolution of MF and foveal reattachment with an average SO tamponade period of 11.67 ± 0.58 months. The average CFT at 6 months was 91 ± 27.5 μm, hence reduced significantly from baseline at 365.3 ± 137.85 μm (P = 0.037). There was no postoperative macular hole formation despite the average preoperative sensory retina thickness of 58 ± 20.07 μm. Mean BCVA was improved from logMAR 1.43 ± 0.75 to logMAR 0.8 ± 0.75 on the last follow-up. Manageable SO-related complications were reported, including SO emulsification, ocular hypertension, and cataract.

Conclusion: Vitrectomy with SO tamponade and without ILM peeling as an optional surgical protocol to treat MF is effective and safe, especially for MF eyes vulnerable to macular hole formation.
Lower Urinary Tract Symptoms and Sexual Dysfunction in Male: A Systematic Review and Meta-Analysis
Authors: Song Guoda , Wang Min , Chen Bingliang , Long Gongwei , Li Hao , Li Rui , Liu Zhuo , Wei Chao , Wang Tao , Wang Shaogang , Liu Jihong , Zhang Yucong , Liu Xiaming
Published: May 2021

Background: An association between lower urinary tract symptoms (LUTS) and risk of sexual dysfunction in male remains controversial in recent decades.

Materials and Methods: PubMed and Web of Science were searched up to October 28, 2020, for articles reporting the prevalence of sexual dysfunction in men with LUTS. The main outcomes were results from sexual dysfunction assessments. Pooled odds ratio (OR) and weighted mean difference (WMD) with 95% confidence interval (CI) were calculated. The quality assessment of the included studies was performed by using The Newcastle-Ottawa Scale (NOS) or JBI Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI).

Results: A total of 24 full-manuscript papers met the inclusion criteria. The pooled OR for 21 studies suggested that patients with severer LUTS had a higher risk of sexual dysfunction (OR = 3.31, 95% CI: 2.43 to 4.49, p < 0.001, I2 = 90%). A significant decrease in scores of assessment tools for sexual dysfunction was observed in the patients with higher severity of LUTS compared with those patients with lower severity (WMD = −5.49, 95%CI: −7.25 to −3.27, P < 0.001, I2 = 96%). Similar outcomes were also found in subgroup analyses. In a detailed analysis of specific sexual function domains, the severity of LUTS was associated with erectile dysfunction, intercourse satisfaction, and overall satisfaction, except for sexual desire.

Conclusion: The study demonstrates an association between exposure of lower urinary tract symptoms and risk of sexual dysfunction in male. Assessment of sexual function is necessary for patients with lower urinary tract symptoms.

Systematic Review Registration:http://www.crd.york.ac.uk/prospero, identifier: CRD42020208747.
Association of Preadmission Statin Use and Mortality in Critically Ill Patients: A Meta-Analysis of Cohort Studies
Authors: Yu Shao-shuo , Jin Jian , Yao Ren-qi , Wang Bo-li , Hu Lun-yang , Wu Guo-sheng , Sun Yu
Published: May 2021

Background: A large number of studies have been conducted to determine whether there is an association between preadmission statin use and improvement in outcomes following critical illness, but the conclusions are quite inconsistent. Therefore, this meta-analysis aims to include the present relevant PSM researches to examine the association of preadmission use of statins with the mortality of critically ill patients.

Methods: The PubMed, Web of Science, Embase electronic databases, and printed resources were searched for English articles published before March 6, 2020 on the association between preadmission statin use and mortality in critically ill patients. The included articles were analyzed in RevMan 5.3. The Newcastle-Ottawa Scale (NOS) was used to conduct quality evaluation, and random/fixed effects modeling was used to calculate the pooled ORs and 95% CIs. We also conducted subgroup analysis by outcome indicators (30-, 90-day, hospital mortality).

Results: All six PSM observational studies were assessed as having a low risk of bias according to the NOS. For primary outcome—overall mortality, the pooled OR (preadmission statins use vs. no use) across the six included studies was 0.86 (95% CI, 0.76–0.97; P = 0.02). For secondary outcome—use of mechanical ventilation, the pooled OR was 0.94 (95% CI, 0.91–0.97; P = 0.0005). The corresponding pooled ORs were 0.67 (95% CI, 0.43–1.05; P = 0.08), 0.91 (95% CI, 0.83–1.01; P = 0.07), and 0.86 (95% CI, 0.83–0.89; P < 0.00001) for 30-, 90-day, and hospital mortality, respectively.

Conclusions: Preadmission statin use is associated with beneficial outcomes in critical ill patients, indicating a lower short-term mortality, less use of mechanical ventilation, and an improvement in hospital survival. Further high-quality original studies or more scientific methods are needed to draw a definitive conclusion.
Microbial Glycoside Hydrolases in the First Year of Life: An Analysis Review on Their Presence and Importance in Infant Gut
Authors: Ioannou Athanasia , Knol Jan , Belzer Clara
Published: May 2021

The first year of life is a crucial period during which the composition and functionality of the gut microbiota develop to stabilize and resemble that of adults. Throughout this process, the gut microbiota has been found to contribute to the maturation of the immune system, in gastrointestinal physiology, in cognitive advancement and in metabolic regulation. Breastfeeding, the “golden standard of infant nutrition,” is a cornerstone during this period, not only for its direct effect but also due to its indirect effect through the modulation of gut microbiota. Human milk is known to contain indigestible carbohydrates, termed human milk oligosaccharides (HMOs), that are utilized by intestinal microorganisms. Bacteria that degrade HMOs likeBifidobacterium longumsubsp.infantis,Bifidobacterium bifidum, andBifidobacterium brevedominate the infant gut microbiota during breastfeeding. A number of carbohydrate active enzymes have been found and identified in the infant gut, thus supporting the hypothesis that these bacteria are able to degrade HMOs. It is suggested that via resource-sharing and cross-feeding, the initial utilization of HMOs drives the interplay within the intestinal microbial communities. This is of pronounced importance since these communities promote healthy development and some of their species also persist in the adult microbiome. The emerging production and accessibility to metagenomic data make it increasingly possible to unravel the metabolic capacity of entire ecosystems. Such insights can increase understanding of how the gut microbiota in infants is assembled and makes it a possible target to support healthy growth. In this manuscript, we discuss the co-occurrence and function of carbohydrate active enzymes relevant to HMO utilization in the first year of life, based on publicly available metagenomic data. We compare the enzyme profiles of breastfed children throughout the first year of life to those of formula-fed infants.
Diversity of the Tellurite Resistance Gene Operon in Escherichia coli
Authors: Nguyen Thi Thu Huong , Kikuchi Taisei , Tokunaga Tadaaki , Iyoda Sunao , Iguchi Atsushi
Published: May 2021

Tellurite is highly toxic to most bacteria owing to its strong oxidative ability. However, some bacteria demonstrate tellurite resistance. In particular, some Escherichia coli strains, including Shiga toxin-producing E. coli O157:H7, are known to be resistant to tellurite. This resistance is involved in ter operon, which is usually located on a prophage-like element of the chromosome. The characteristics of the ter operon have been investigated mainly by genome analysis of pathogenic E. coli; however, the distribution and structural characteristics of the ter operon in other E. coli are almost unknown. To clarify these points, we examined 106 E. coli strains carrying the ter operon from various animals. The draft genomes of 34 representative strains revealed that ter operons were clearly classified into four subtypes, ter-type 1–4, at the nucleotide sequence level. Complete genomic sequences revealed that operons belonging to three ter-types (1, 3, and 4) were located on the prophage-like elements on the chromosome, whereas the ter-type 2 operon was located on the IncHI2 plasmid. The positions of the tRNASer, tRNAMet, and tRNAPhe indicated the insertion sites of elements carrying the ter operons. Using the PCR method developed in this study, 106 strains were classified as type 1 (n = 66), 2 (n = 13), 3 (n = 8), and 4 (n = 17), and two strains carried both types 1 and 2. Furthermore, significant differences in the minimum inhibitory concentration (MIC) of tellurite were observed between strains carrying ter-type 4 and the others (p < 0.05). The ter-type was also closely related to the isolation source, with types 2 and 4 associated with chickens and deer, respectively. This study provided new insights related not only to genetic characteristics of the ter operons, but also to phenotypic and ecological characteristics that may be related to the diversity of the operon.
Cytosine Base Editor-Mediated Multiplex Genome Editing to Accelerate Discovery of Novel Antibiotics in Bacillus subtilis and Paenibacillus polymyxa
Authors: Kim Man Su , Kim Ha-Rim , Jeong Da-Eun , Choi Soo-Keun
Published: May 2021

Genome-based identification of new antibiotics is emerging as an alternative to traditional methods. However, uncovering hidden antibiotics under the background of known antibiotics remains a challenge. To over this problem using a quick and effective genetic approach, we developed a multiplex genome editing system using a cytosine base editor (CBE). The CBE system achieved simultaneous double, triple, quadruple, and quintuple gene editing with efficiencies of 100, 100, 83, and 75%, respectively, as well as the 100% editing efficiency of single targets in Bacillus subtilis. Whole-genome sequencing of the edited strains showed that they had an average of 8.5 off-target single-nucleotide variants at gRNA-independent positions. The CBE system was used to simultaneously knockout five known antibiotic biosynthetic gene clusters to leave only an uncharacterized polyketide biosynthetic gene cluster in Paenibacillus polymyxa E681. The polyketide showed antimicrobial activities against gram-positive bacteria, but not gram-negative bacteria and fungi. Therefore, our findings suggested that the CBE system might serve as a powerful tool for multiplex genome editing and greatly accelerating the unraveling of hidden antibiotics in Bacillus and Paenibacillus species.
Plasma Microbial Cell-Free DNA Sequencing Technology for the Diagnosis of Sepsis in the ICU
Authors: Wang Lili , Guo Wenzheng , Shen Hui , Guo Jian , Wen Donghua , Yu Yuetian , Wu Wenjuan
Published: May 2021

Sepsis is a common life-threatening disease in the intensive care unit (ICU) that is usually treated empirically without pathogen identification. As a non-invasive and high-throughput technology, plasma microbial cell-free DNA (mcfDNA) sequencing can detect unknown pathogens independent of previous clinical or laboratory information. In this study, a total of 199 cases suspected of bloodstream infection (BSI) from January 2020 to June 2020 were collected, and potential pathogens were detected by simultaneous blood culture and plasma mcfDNA sequencing. Other clinical microbiological assays were performed within 7 days of plasma mcfDNA sequencing, including smear, culture of samples taken from relevant infected sites, and β-D-glucan/galactomannan (BDG/GM) tests, among others. The diagnoses were classified as sepsis [94 (47.2%)], non-sepsis [87 (43.7%)], and non-infectious disease [18 (9.0%)]. The sensitivity and specificity of plasma mcfDNA sequencing for diagnosing sepsis were 68.1 and 63.2%, respectively, which were significantly better than those of blood culture, especially for the common bacteria that cause hospital-acquired infection, namely, Acinetobacter baumannii (p < 0.01) and Klebsiella pneumoniae (p < 0.01), and DNA viruses (plasma mcfDNA sequencing only, p < 0.01). However, there was no significant difference in the rate of positivity between plasma mcfDNA sequencing and blood culture for antibiotic-non-exposed cases (43.6 vs. 30.9%, p = 0.17). In the non-sepsis group, 44.8% of cases (13/29) detected only by plasma mcfDNA sequencing showed infections in other parts of the body, such as lower respiratory infection (LRI), intra-abdominal infection (IAI) and central nervous system infection (CNSI). For some common pathogens (not including anaerobes), turnaround time (TAT) 3 (TAT from the initiation of blood sample processing by nucleic acid extraction to the completion of sequencing analysis) was longer than TAT1 (TAT from blood culture bottles in Virtuo to off Virtuo). With disease progression, significant dynamic changes in microbial species were clearly detected by plasma mcfDNA sequencing.
Analyzing and Validating the Prognostic Value of a TNF-Related Signature in Kidney Renal Clear Cell Carcinoma
Authors: Zhang Wenhao , Li Changjiu , Wu Fanding , Li Ning , Wang Yuwei , Hu Yixuan , Fang Tiantian , Yuan Hui , He Huadong
Published: May 2021

Background: Kidney renal clear cell carcinoma (KIRC) has the highest incidence rate in renal cell carcinoma (RCC). Although bioinformatics is widely used in cancer, few reliable biomarkers of KIRC have been found. Therefore, continued efforts are required to elucidate the potential mechanism of the biogenesis and progression of KIRC.

Methods: We evaluated the expression of tumor necrosis factor (TNF) family genes in KIRC, and constructed a prognostic signature. We validated the signature by another database and explored the relationship between the signature and progression of KIRC. We assessed the prognostic value, immune infiltration, and tumor mutation burden (TMB) of the signature in KIRC.

Results: We selected four key genes (TNFSF14, TNFRSF19, TNFRSF21, and EDA) to construct the TNF-related signature. We divided the KIRC patients into high- and low-risk groups based on the signature. Patients with higher risk scores had shorter overall survival and worse prognosis. With another database, we validated the value of the signature. The signature was considered as an independent risk factor. A higher level of risk score was relevant to higher level of immune infiltration, especially T regulatory cells, CD8+ T cells, and macrophages. The signature was also associated with TMB scores, and it may have an effect on assessing the efficacy of immunotherapy.

Conclusion: This is the first TNF-family-related signature of KIRC and we demonstrated its effectiveness. It played a significant role in predicting the prognosis of patients with KIRC. It also has the potential to become a powerful tool in guiding the immunotherapy of KIRC patients in clinical practice.
The Role of Plasma Neurofilament Light Protein for Assessing Cognitive Impairment in Patients With End-Stage Renal Disease
Authors: Hou Yi-Chou , Huang Chuen-Lin , Lu Chien-Lin , Zheng Cai-Mei , Lin Yuh-Feng , Lu Kuo-Cheng , Chung Ya-Lin , Chen Ruei-Ming
Published: May 2021

Introduction:End-stage renal disease (ESRD) is defined as the irreversible loss of renal function, necessitating renal replacement therapy. Patients with ESRD tend to have more risk factors for cognitive impairment than the general population, including hypertension, accumulative uremic toxin, anemia, and old age. The association between these risk factors and the pathologic protein was lacking. Blood-based assays for detecting pathologic protein, such as amyloid beta (Aβ), total tau protein, and neurofilament light chain (NfL), have the advantages of being less invasive and more cost-effective for diagnosing patients with cognitive impairment. The aim of the study is to validate if the common neurologic biomarkers were different in ESRD patients and to differentiate if the specific biomarkers could correlate with specific correctable risk factors.

Methods:In total, 67 participants aged >45 years were enrolled. The definition of ESRD was receiving maintenance hemodialysis for >3 months. Cognitive impairment was defined as a Mini-Mental State Examination score of <24. The participants were divided into groups for ESRD with and without cognitive impairment. The blood-based biomarkers (tau protein, Aβ1/40, Aβ1/42, and NfL) were analyzed through immunomagnetic reduction assay. Other biochemical and hematologic data were obtained simultaneously.

Summary of results:The study enrolled 43 patients with ESRD who did not have cognitive impairment and 24 patients with ESRD who had cognitive impairment [Mini-Mental State Examination (MMSE): 27.60 ± 1.80 vs. 16.84 ± 6.40,p< 0.05]. Among the blood-based biomarkers, NfL was marginally higher in the ESRD with cognitive impairment group than in the ESRD without cognitive impairment group (10.41 ± 3.26 vs. 8.74 ± 2.81 pg/mL,p= 0.037). The concentrations of tau protein, amyloid β 1/42, and amyloid β 1/40 (p= 0.504, 0.393, and 0.952, respectively) were similar between the two groups. The area under the curve of NfL to distinguish cognitively impaired and unimpaired ESRD patients was 0.687 (95% confidence interval: 0.548–0.825,p= 0.034). There was no correlation between the concentration of NfL and MMSE among total population (r= −0.153,p= 0.277), patients with (r= 0.137,p= 0.583) or without cognitive impairment (r= 0.155,p= 0.333).

Conclusion:Patients with ESRD who had cognitive impairment had marginally higher plasma NfL concentrations. NfL concentration was not correlated with the biochemical parameters, total MMSE among total population or individual groups with or without cognitive impairment. The concentrations of Aβ1/40, Aβ1/42, and tau were similar between the groups.
Positive Effect of Cognitive Reserve on Episodic Memory, Executive and Attentional Functions Taking Into Account Amyloid-Beta, Tau, and Apolipoprotein E Status
Authors: Narbutas Justinas , Chylinski Daphne , Van Egroo Maxime , Bahri Mohamed Ali , Koshmanova Ekaterina , Besson Gabriel , Muto Vincenzo , Schmidt Christina , Luxen André , Balteau Evelyne , Phillips Christophe , Maquet Pierre , Salmon Eric , Vandewalle Gilles , Bastin Christine , Collette Fabienne
Published: May 2021

Studies exploring the simultaneous influence of several physiological and environmental factors on domain-specific cognition in late middle-age remain scarce. Therefore, our objective was to determine the respective contribution of modifiable risk/protective factors (cognitive reserve and allostatic load) on specific cognitive domains (episodic memory, executive functions, and attention), taking into account non-modifiable factors [sex, age, and genetic risk for Alzheimer’s disease (AD)] and AD-related biomarker amount (amyloid-beta and tau/neuroinflammation) in a healthy late-middle-aged population. One hundred and one healthy participants (59.4 ± 5 years; 68 women) were evaluated for episodic memory, executive and attentional functioning via neuropsychological test battery. Cognitive reserve was determined by the National Adult Reading Test. The allostatic load consisted of measures of lipid metabolism and sympathetic nervous system functioning. The amyloid-beta level was assessed using positron emission tomography in all participants, whereas tau/neuroinflammation positron emission tomography scans and apolipoprotein E genotype were available for 58 participants. Higher cognitive reserve was the main correlate of better cognitive performance across all domains. Moreover, age was negatively associated with attentional functioning, whereas sex was a significant predictor for episodic memory, with women having better performance than men. Finally, our results did not show clear significant associations between performance over any cognitive domain and apolipoprotein E genotype and AD biomarkers. This suggests that domain-specific cognition in late healthy midlife is mainly determined by a combination of modifiable (cognitive reserve) and non-modifiable factors (sex and age) rather than by AD biomarkers and genetic risk for AD.
Maturation-Dependent Differences in the Re-innervation of the Denervated Dentate Gyrus by Sprouting Associational and Commissural Mossy Cell Axons in Organotypic Tissue Cultures of Entorhinal Cortex and Hippocampus
Authors: Paul Mandy H. , Hildebrandt-Einfeldt Lars , Beeg Moreno Viktor J. , Del Turco Domenico , Deller Thomas
Published: May 2021

Sprouting of surviving axons is one of the major reorganization mechanisms of the injured brain contributing to a partial restoration of function. Of note, sprouting is maturation as well as age-dependent and strong in juvenile brains, moderate in adult and weak in aged brains. We have established a model system of complex organotypic tissue cultures to study sprouting in the dentate gyrus following entorhinal denervation. Entorhinal denervation performed after 2 weeks postnatally resulted in a robust, rapid, and very extensive sprouting response of commissural/associational fibers, which could be visualized using calretinin as an axonal marker. In the present study, we analyzed the effect of maturation on this form of sprouting and compared cultures denervated at 2 weeks postnatally with cultures denervated at 4 weeks postnatally. Calretinin immunofluorescence labeling as well as time-lapse imaging of virally-labeled (AAV2-hSyn1-GFP) commissural axons was employed to study the sprouting response in aged cultures. Compared to the young cultures commissural/associational sprouting was attenuated and showed a pattern similar to the one following entorhinal denervation in adult animals in vivo. We conclude that a maturation-dependent attenuation of sprouting occurs also in vitro, which now offers the chance to study, understand and influence maturation-dependent differences in brain repair in these culture preparations.
Public Opinion Early Warning Agent Model: A Deep Learning Cascade Virality Prediction Model Based on Multi-Feature Fusion
Authors: Gao Liqun , Liu Yujia , Zhuang Hongwu , Wang Haiyang , Zhou Bin , Li Aiping
Published: May 2021

With the rapid popularity of agent technology, a public opinion early warning agent has attracted wide attention. Furthermore, a deep learning model can make the agent more automatic and efficient. Therefore, for the agency of a public opinion early warning task, the deep learning model is very suitable for completing tasks such as popularity prediction or emergency outbreak. In this context, improving the ability to automatically analyze and predict the virality of information cascades is one of the tasks that deep learning model approaches address. However, most of the existing studies sought to address this task by analyzing cascade underlying network structure. Recent studies proposed cascade virality prediction for agnostic-networks (without network structure), but did not consider the fusion of more effective features. In this paper, we propose an innovative cascade virus prediction model named CasWarn. It can be quickly deployed in intelligent agents to effectively predict the virality of public opinion information for different industries. Inspired by the agnostic-network model, this model extracts the key features (independent of the underlying network structure) of an information cascade, including dissemination scale, emotional polarity ratio, and semantic evolution. We use two improved neural network frameworks to embed these features, and then apply the classification task to predict the cascade virality. We conduct comprehensive experiments on two large social network datasets. Furthermore, the experimental results prove that CasWarn can make timely and effective cascade virality predictions and verify that each feature model of CasWarn is beneficial to improve performance.
All-Optical Electrophysiology in hiPSC-Derived Neurons With Synthetic Voltage Sensors
Authors: Puppo Francesca , Sadegh Sanaz , Trujillo Cleber A. , Thunemann Martin , Campbell Evan P. , Vandenberghe Matthieu , Shan Xiwei , Akkouh Ibrahim A. , Miller Evan W. , Bloodgood Brenda L. , Silva Gabriel A. , Dale Anders M. , Einevoll Gaute T. , Djurovic Srdjan , Andreassen Ole A. , Muotri Alysson R. , Devor Anna
Published: May 2021

Voltage imaging and “all-optical electrophysiology” in human induced pluripotent stem cell (hiPSC)-derived neurons have opened unprecedented opportunities for high-throughput phenotyping of activity in neurons possessing unique genetic backgrounds of individual patients. While prior all-optical electrophysiology studies relied on genetically encoded voltage indicators, here, we demonstrate an alternative protocol using a synthetic voltage sensor and genetically encoded optogenetic actuator that generate robust and reproducible results. We demonstrate the functionality of this method by measuring spontaneous and evoked activity in three independent hiPSC-derived neuronal cell lines with distinct genetic backgrounds.
The Association Between Heart Rate Variability and 90-Day Prognosis in Patients With Transient Ischemic Attack and Minor Stroke
Authors: Li Changhong , Meng Xia , Pan Yuesong , Li Zixiao , Wang Mengxing , Wang Yongjun
Published: May 2021

Background: Low heart rate variability (HRV) is known to be associated with increased all-cause, cardiovascular, and cerebrovascular mortality but its association with clinical outcomes in patients with transient ischemic attack (TIA) or minor stroke is unclear.

Methods: We selected TIA and minor stroke patients from a prospective registration study. From each continuous electrocardiograph (ECG) record, each QRS complex was detected and normal-to-normal (N-N) intervals were determined. The standard deviation of all N-N intervals (SDNN) and the square root of the mean squared differences of successive N-N intervals (RMSSD) were calculated. Logistic regression analysis and Cox regression analysis were performed to assess the outcomes of patients at 90 days, and the odds and risk ratios (OR/HR) of each index quartile were compared.

Results: Compared with SDNN patients in the lowest quartile, neurological disability was significantly reduced in other quartile groups at 90 days, with significant differences [OR of group Q2 was 0.659; 95% confidence interval (CI), 0.482–0.900; p = 0.0088; OR of group Q3 was 0.662; 95% CI, 0.478–0.916; p = 0.0127; OR of group Q4 was 0.441; 95% CI, 0.305–0.639; p <0.0001]. Compared with the lowest quartile, the recurrence rate of TIA or minor stroke in patients of the two higher quartiles (Q3 and Q4) of SDNN was significantly reduced at 90 days (HR of Q3 group was 0.732; 95% CI, 0.539–0.995; p = 0.0461; HR of Q4 group was 0.528; 95% CI, 0.374–0.745; p = 0.0003).

Conclusions: Based on our findings, autonomic dysfunction is an adverse indicator for neurological function prognosis and stroke recurrence 90 days after TIA or minor stroke.
Altered Protein Profiles During Epileptogenesis in the Pilocarpine Mouse Model of Temporal Lobe Epilepsy
Authors: Ahmed Md. Mahiuddin , Carrel Andrew J. , Cruz Del Angel Yasmin , Carlsen Jessica , Thomas Ajay X. , González Marco I. , Gardiner Katheleen J. , Brooks-Kayal Amy
Published: May 2021

Epilepsy is characterized by recurrent, spontaneous seizures and is a major contributor to the global burden of neurological disease. Although epilepsy can result from a variety of brain insults, in many cases the cause is unknown and, in a significant proportion of cases, seizures cannot be controlled by available treatments. Understanding the molecular alterations that underlie or are triggered by epileptogenesis would help to identify therapeutics to prevent or control progression to epilepsy. To this end, the moderate throughput technique of Reverse Phase Protein Arrays (RPPA) was used to profile changes in protein expression in a pilocarpine mouse model of acquired epilepsy. Levels of 54 proteins, comprising phosphorylation-dependent and phosphorylation-independent components of major signaling pathways and cellular complexes, were measured in hippocampus, cortex and cerebellum of mice at six time points, spanning 15 min to 2 weeks after induction of status epilepticus. Results illustrate the time dependence of levels of the commonly studied MTOR pathway component, pS6, and show, for the first time, detailed responses during epileptogenesis of multiple components of the MTOR, MAPK, JAK/STAT and apoptosis pathways, NMDA receptors, and additional cellular complexes. Also noted are time- and brain region- specific changes in correlations among levels of functionally related proteins affecting both neurons and glia. While hippocampus and cortex are primary areas studied in pilocarpine-induced epilepsy, cerebellum also shows significant time-dependent molecular responses.
Temporal-Spatial Feature Extraction of DSA Video and Its Application in AVM Diagnosis
Authors: Shi Keke , Xiao Weiping , Wu Guoqing , Xiao Yang , Lei Yu , Yu Jinhua , Gu Yuxiang
Published: May 2021

Objectives: Brain arteriovenous malformation (AVM) is one of the most common causes of intracranial hemorrhage in young adults, and its expeditious diagnosis on digital subtraction angiography (DSA) is essential for clinical decision-making. This paper firstly proposed a deep learning network to extract vascular time-domain features from DSA videos. Then, the temporal features were combined with spatial radiomics features to build an AVM-assisted diagnosis model.

Materials and method: Anteroposterior position (AP) DSA videos from 305 patients, 153 normal and 152 with AVM, were analyzed. A deep learning network based on Faster-RCNN was proposed to track important vascular features in DSA. Then the appearance order of important vascular structures was quantified as the temporal features. The structure distribution and morphological features of vessels were quantified as 1,750 radiomics features. Temporal features and radiomics features were fused in a classifier based on sparse representation and support vector machine. An AVM diagnosis and grading system that combined the temporal and spatial radiomics features of DSA was finally proposed. Accuracy (ACC), sensitivity (SENS), specificity (SPEC), and area under the receiver operating characteristic curve (AUC) were calculated to evaluate the performance of the radiomics model.

Results: For cerebrovascular structure detection, the average precision (AP) was 0.922, 0.991, 0.769, 0.899, and 0.929 for internal carotid artery, Willis circle, vessels, large veins, and venous sinuses, respectively. The mean average precision (mAP) of five time phases was 0.902. For AVM diagnosis, the models based on temporal features, radiomics features, and combined features achieved AUC of 0.916, 0.918, and 0.942, respectively. In the AVM grading task, the proposed combined model also achieved AUC of 0.871 in the independent testing set.

Conclusion: DSA videos provide rich temporal and spatial distribution characteristics of cerebral blood vessels. Clinicians often interpret these features based on subjective experience. This paper proposes a scheme based on deep learning and traditional machine learning, which effectively integrates the complex spatiotemporal features in DSA, and verifies the value of this scheme in the diagnosis of AVM.