bluuebunny/crossref_metadata_2025 huggingface dataset:
Nanowire Waveguides and Lasers: Advances and Opportunities in Photonic Circuits
Authors: Gu Zhiyuan , Song Qinghai , Xiao Shumin
Published: January 2021

Due to their single-crystalline structures, comparatively large aspect ratios, tight optical confinement and smooth surfaces, nanowires have increasingly attracted research interests for both fundamental studies and technological applications in on-chip photonic devices. This class of nanostructures typically have cross-sections of 2~200 nm and lengths upwards of several micrometers, allowing for the bridging of the nanoscopic and macroscopic world. In particular, the lasing behaviors can be established from a nanowire resonator with positive feedback via end-facet reflection, making the nanowire a promising candidate in the next generation of optoelectronics. Consequently, versatile nanowire-based devices ranging from nanoscale coherent lasers, optical sensors, waveguides, optical switching, and photonic networks have been proposed and experimentally demonstrated in the past decade. In this article, significant progresses in the nanowire fabrication, lasers, circuits, and devices are reviewed. First, we focus on the achievements of nanowire synthesis and introduce the basics of nanowire optics. Following the cavity configurations and mode categories, then the different light sources consisting of nanowires are presented. Next, we review the recent progress and current status of functional nanowire devices. Finally, we offer our perspective of nanowires regarding their challenges and future opportunities in photonic circuits.
A Novel Triple-Fluorescent HCMV Strain Reveals Gene Expression Dynamics and Anti-Herpesviral Drug Mechanisms
Authors: Rand Ulfert , Kubsch Tobias , Kasmapour Bahram , Cicin-Sain Luka
Published: January 2021

Human Cytomegalovirus (HCMV) infection may result in severe outcomes in immunocompromised individuals such as AIDS patients, transplant recipients, and neonates. To date, no vaccines are available and there are only few drugs for anti-HCMV therapy. Adverse effects and the continuous emergence of drug-resistance strains require the identification of new drug candidates in the near future. Identification and characterization of such compounds and biological factors requires sensitive and reliable detection techniques of HCMV infection, gene expression and spread. In this work, we present and validate a novel concept for multi-reporter herpesviruses, identified through iterative testing of minimally invasive mutations. We integrated up to three fluorescence reporter genes into replication-competent HCMV strains, generating reporter HCMVs that allow the visualization of replication cycle stages of HCMV, namely the immediate early (IE), early (E), and late (L) phase. Fluorescent proteins with clearly distinguishable emission spectra were linked by 2A peptides to essential viral genes, allowing bicistronic expression of the viral and the fluorescent protein without major effects on viral fitness. By using this triple color reporter HCMV, we monitored gene expression dynamics of the IE, E, and L genes by measuring the fluorescent signal of the viral gene-associated fluorophores within infected cell populations and at high temporal resolution. We demonstrate distinct inhibitory profiles of foscarnet, fomivirsen, phosphonoacetic acid, ganciclovir, and letermovir reflecting their mode-of-action. In conclusion, our data argues that this experimental approach allows the identification and characterization of new drug candidates in a single step.
Challenge of Bovine Foot Skin Fibroblasts With Digital Dermatitis Treponemes Identifies Distinct Pathogenic Mechanisms
Authors: Newbrook Kerry , Carter Stuart D. , Crosby-Durrani Hayley , Evans Nicholas J.
Published: January 2021

Bovine digital dermatitis (BDD) is a common infectious disease of digital skin in cattle and an important cause of lameness worldwide, with limited treatment options. It is of increasing global concern for both animal welfare and food security, imposing a large economic burden on cattle farming industries each year. A polytreponemal etiology has been consistently identified, with three key phylogroups implicated globally:Treponema medium, Treponema phagedenis, andTreponema pedis.Pathogenic mechanisms which might enable targeted treatment/therapeutic development are poorly defined. This study used RNA sequencing to determine global differential mRNA expression in primary bovine foot skin fibroblasts following challenge with three representative BDD treponemes and a commensal treponeme,Treponema ruminis. A pro-inflammatory response was elicited by the BDD treponemes, mediated throughIL-8/IL-17signaling. Unexpectedly, the three BDD treponemes elicited distinct mechanisms of pathogenesis.T. phagedenisandT. pedisincreased abundance of mRNA transcripts associated with apoptosis, whileT. mediumandT. pedisincreased transcripts involved in actin rearrangement and loss of cell adhesion, likely promoting tissue invasion. The upregulation of antimicrobial peptide precursor, DEFB123, byT. phagedenisspirochaetes may present a microbial ecological advantage to all treponemes within BDD infected tissue, explaining their dominance within lesions. A commensal,T. ruminis, significantly dysregulated over three times the number of host mRNA transcripts compared to BDD treponemes, implying BDD treponemes, akin to the syphilis pathogen (Treponema pallidum), have evolved as “stealth pathogens” which avoid triggering substantial host immune/inflammatory responses to enable persistence and tissue invasion. Immunohistochemistry demonstrated increased IL-6, IL-8, RND1, and CFB protein expression in BDD lesions, confirmingin vitrofibroblast observations and highlighting the system’s value in modeling BDD pathogenesis. Several unique shared gene targets were identified, particularlyRGS16,GRO1,MAFF, andZC3H12A. The three key BDDTreponemaphylogroups elicited both distinct and shared pathogenic mechanisms in bovine foot skin; upregulating inflammation whilst simultaneously suppressing adaptive immunity. The novel gene targets identified here should enable future vaccine/therapeutic approaches.
Nanocarriers From Natural Lipids With In Vitro Activity Against Campylobacter jejuni
Authors: Ribeiro Lígia Nunes de Morais , de Paula Eneida , Rossi Daise Aparecida , Martins Flávia Alves , de Melo Roberta Torres , Monteiro Guilherme Paz , Breitkreitz Márcia Cristina , Goulart Luiz Ricardo , Fonseca Belchiolina Beatriz
Published: January 2021

Campylobacter jejuni (CJ) is the most prevalent zoonotic pathogen of chicken meat and related products, which may lead to gastroenteritis and autoimmune diseases in humans. Although controlling this bacterium is important, CJ strains resistance against traditional antibiotic therapy has been increased. Vegetable oils and fats are natural biomaterials explored since the Ancient times, due to their therapeutic properties. Nanotechnology has promoted the miniaturization of materials, improving bioavailability and efficacy, while reducing the toxicity of loaded active molecules. In this work, a screening of 28 vegetable oils was firstly performed, in order to select anti-CJ candidates by the disc diffusion test. Thus, the selected liquid lipids were used as active molecules in nanostructured lipid carriers (NLC) formulations. The three resultant systems were characterized in terms of particle size (~200 nm), polydispersity index (~0.15), and zeta potential (~-35mV), and its physicochemical stability was confirmed for a year, at 25°C. The structural properties of NLC were assessed by infrared (FTIR-ATR) and differential scanning calorimetry (DSC) analyses. The spherical nanoparticle morphology and narrow size distribution was observed by transmission electron microscopy (TEM) and field emission scanning electron (FE-SEM) analyses, respectively. Then, the in vitro antimicrobial activity test determined the minimum inhibitory concentration (MIC) of each formulation against CJ strains, in both free (1–3 mg/ml−1) and sessile (0.78 mg/ml−1) forms. Finally, the in vitro biocompatibility of NLC was demonstrated through cell viability using VERO cell line, in which F6 was found twice less cytotoxic than pure olibanum oil. Considering the abovementioned achieved, F6 formulation is able to be evaluated in the in vivo anti-CJ efficacy assays.
Profiling the Blood Compartment of Hematopoietic Stem Cell Transplant Patients During Human Cytomegalovirus Reactivation
Authors: Bernshtein Biana , Nachshon Aharon , Shnayder Miri , Stern Lauren , Avdic Selmir , Blyth Emily , Gottlieb David , Abendroth Allison , Slobedman Barry , Stern-Ginossar Noam , Schwartz Michal
Published: January 2021

Human cytomegalovirus (HCMV) is a widespread pathogen establishing a latent infection in its host. HCMV reactivation is a major health burden in immunocompromised individuals, and is a major cause of morbidity and mortality following hematopoietic stem cell transplantation (HSCT). Here we determined HCMV genomic levels using droplet digital PCR in different peripheral blood mononuclear cell (PBMC) populations in HCMV reactivating HSCT patients. This high sensitivity approach revealed that all PBMC populations harbored extremely low levels of viral DNA at the peak of HCMV DNAemia. Transcriptomic analysis of PBMCs from high-DNAemia samples revealed elevated expression of genes typical of HCMV specific T cells, while regulatory T cell enhancers as well as additional genes related to immune response were downregulated. Viral transcript levels in these samples were extremely low, but remarkably, the detected transcripts were mainly immediate early viral genes. Overall, our data indicate that HCMV DNAemia is associated with distinct signatures of immune response in the blood compartment, however it is not necessarily accompanied by substantial infection of PBMCs and the residual infected PBMCs are not productively infected.
A Mobile Health Behavior Intervention to Reduce Pain and Improve Health in Older Adults With Obesity and Chronic Pain: The MORPH Pilot Trial
Authors: Fanning Jason , Brooks Amber K. , Ip Edward , Nicklas Barbara J. , Rejeski W. Jack , Nesbit Beverly , Ford Sherri
Published: January 2021

Chronic, multisite pain is a common phenomenon in aging and is associated with a host of negative health outcomes. It is a complex and multifaceted condition that may be exacerbated by weight gain and long periods of inactivity. Unfortunately, older adults suffering from chronic pain have unique barriers limiting access to center-based behavior change interventions. The MORPH study first adapted and iteratively refined an evidence-based group-mediated intervention for delivery in the home via mHealth tools (a smartphone app, teleconferencing software, wearable activity monitor, smart weight scale). This was followed by a pilot randomized controlled trial (RCT) meant to assess feasibility of the MORPH intervention, and to examine initial effects on physical function, pain, weight, and sedentary behavior. We recruited low-active and obese older adults with multisite pain to partake in a series of N-of-1 refinement studies (N = 5 total) or a 12-week pilot RCT delivered largely in the home (N = 28 assigned to active intervention or wait-list control). The refinement phase identified several key technological (e.g., selection of a new smart weight scale) and user interface (e.g., clarification of in-app phrasing) modifications that were made before initiating the RCT phase. Analyses of covariance, controlling for baseline values, sex, and age indicated effects favoring the intervention across all domains of interest: there was a substantially clinically meaningful difference in short physical performance battery scores (0.63 points, η2 = 0.08), a moderate-to-large difference in PROMIS pain intensity scores (5.52 points, η2 = 0.12), a large difference in body weight (2.90 kg, η2 = 0.207), and a moderate effect on adjusted ActivPAL-assessed sedentary time (64.90 min, η2 = 0.07) with a small effect on steps (297.7 steps, η2 = 0.01). These results suggest a largely-home delivered movement and weight loss program for older adults with pain is feasible and recommendations are provided for future programs of this nature.

Clinical Trial Registration:ClinicalTrials.gov, Identifier: NCT03377634.
Unified Scaling Law for Earthquakes: Space-Time Dependent Assessment in Friuli-Venezia Giulia Region
Authors: Nekrasova Anastasia , Peresan Antonella
Published: January 2021

The concept of the Unified Scaling Law for Earthquakes (USLE), which generalizes the Gutenberg-Richter relationship making use of the fractal distribution of earthquake sources in a seismic region, is applied to seismicity in the Friuli-Venezia Giulia region, FVG (Northeastern Italy) and its surroundings. In particular, the temporal variations of USLE coefficients are investigated, with the aim to get new insights in the evolving dynamics of seismicity within different tectonic domains of FVG. To this purpose, we consider all magnitude 2.0 or larger earthquakes that occurred in 1995–2019, as reported in the catalog compiled at the National Institute of Oceanography and Applied Geophysics (OGS catalog), within the territory of its homogeneous completeness. The observed variability of seismic dynamics for three sub-regions of the territory under investigation, delimited based on main geological and tectonic features, is characterized in terms of several moving averages, including: the inter-event time,τ; the cumulative Benioff strain release, Ʃ; the USLE coefficients estimated for moving six-years time intervals, and the USLE control parameter,η. We found that: 1) the USLE coefficients in FVG region are time-dependent and show up correlated; 2) the dynamical changes ofτ, Ʃ, andηin the three sub-regions highlight a number of different seismic regimes; 3) seismic dynamics, prior and after the occurrence of the 1998 and 2004 Kobarid (Slovenia) strong main shocks, is characterized by different parameters in the related sub-region. The results obtained for the FVG region confirm similar analysis performed on a global scale, in advance and after the largest earthquakes worldwide. Moreover, our analysis highlights the spatially heterogeneous and non-stationary features of seismicity in the investigated territory, thus suggesting the opportunity of resorting to time-dependent estimates for improving local seismic hazard assessment. The applied methods and obtained parameters provide quantitative basis for developing suitable models and forecasting tools, toward a better characterization of future seismic hazard in the region.
Reflection and Quality Assessment in Service-Learning Projects. When, With Whom, and Why
Authors: Lorenzo Moledo María del Mar , Sáez-Gambín Daniel , Ferraces Otero María José , Varela Portela Cristina
Published: January 2021

Among all the elements likely to be considered criteria that determine the quality of a service-learning (SL) project, the scientific literature points to reflection. This work is aimed at analyzing the association of reflection with certain variables that mediate the educational performance of university students, as well as their satisfaction with the acquired knowledge. More specifically, the main focus was to analyze how this reflective process should be, thus we defined three independent variables: the time at which it is performed, the actors involved, and its objectives. The sample was made up of 295 students from the University of Santiago de Compostela, who were participating in SL projects that had been developed in different degree programs. Three instruments were used for data collection, two aimed at the students and one at the teaching staff responsible for the project. The main conclusion, given the results, is that reflection must be carried out from the beginning to the end of the project or, failing this, only at the end. Secondly, priority should be given to involving all the actors concerned, paying particular attention at least to the work group. Finally, it must be oriented both toward sharing feelings about the experience, relating the service to the contents of the subject, and developing attitudes and values. In this way, the status of reflection as one of the key factors in the development of quality experiences in SL is confirmed, showing that those that present a more rigorous and structured reflection have a greater impact on the variables mediating performance and on the students' satisfaction with their learning.
Image-Guided Thermal Ablation as an Alternative to Surgery for Papillary Thyroid Microcarcinoma: Preliminary Results of an Italian Experience
Authors: Mauri Giovanni , Orsi Franco , Carriero Serena , Della Vigna Paolo , De Fiori Elvio , Monzani Dario , Pravettoni Gabriella , Grosso Enrica , Manzoni Marco F. , Ansarin Mohssen , Giugliano Gioacchino
Published: January 2021

Purpose

To report the results of our preliminary experience in treating patients with papillary thyroid microcarcinoma (PTMC) with image-guided thermal ablation, in particular estimating the feasibility, safety and short-term efficacy

Materials and Methods

From 2018 patients with cytologically proven PTMC < 10 mm were discussed in a multidisciplinary team and evaluated for feasibility of image-guided thermal ablation. In case of technical feasibility, the three possible alternatives (i.e., image-guided thermal ablation, surgery, and active surveillance) were discussed with patients. Patients who agreed to be treated with image guided thermal ablation underwent radiofrequency (RFA) or laser ablation under local anesthesia and conscious sedation. Treatment feasibility, technical success, technique efficacy, change in thyroid function tests, side effects, minor and major complications, patients satisfaction and pain/discomfort perception during and after treatment, and disease recurrence during follow-up were recorded.

Results

A total of 13 patients were evaluated, and 11/13 (84.6%) patients (9 female, 2 male, mean age 49.3 ± 8.7 years) resulted suitable for image-guided thermal ablation. All 11 patients agreed to be treated with image-guided thermal ablation. In addition, 3/11 (27.3%) were treated with laser ablation and 8/11 (72.7%) with RFA. All procedures were completed as preoperatively planned (technical success 100%). Technique efficacy was achieved in all 11/11 (100%) cases. Ablated volume significantly reduced from 0.87 ± 0.67 ml at first follow-up to 0.17 ± 0.36 at last follow-up (p = 0.003). No change in thyroid function tests occurred. No minor or major complications occurred. All patients graded 10 the satisfaction for the treatment, and mean pain after the procedure was reported as 1.4 ± 1.7, and mean pain after the procedure as 1.2 ± 1.1 At a median follow-up of 10.2 months (range 1.5–12 months), no local recurrence or distant metastases were found.

Conclusions

Image guided thermal ablations appear to be feasible and safe in the treatment of PTMC. These techniques hold the potential to offer patients a minimally invasive curative alternative to surgical resection or active surveillance. These techniques appear to be largely preferred by patients.
Amylin and Calcitonin: Potential Therapeutic Strategies to Reduce Body Weight and Liver Fat
Authors: Mathiesen David S. , Lund Asger , Vilsbøll Tina , Knop Filip K. , Bagger Jonatan I.
Published: January 2021

The hormones amylin and calcitonin interact with receptors within the same family to exert their effects on the human organism. Calcitonin, derived from thyroid C cells, is known for its inhibitory effect on osteoclasts. Calcitonin of mammalian origin promotes insulin sensitivity, while the more potent calcitonin extracted from salmon additionally inhibits gastric emptying, promotes gallbladder relaxation, increases energy expenditure and induces satiety as well as weight loss. Amylin, derived from pancreatic beta cells, regulates plasma glucose by delaying gastric emptying after meal ingestion, and modulates glucagon secretion and central satiety signals in the brain. Thus, both hormones seem to have metabolic effects of relevance in the context of non-alcoholic fatty liver disease (NAFLD) and other metabolic diseases. In rats, studies with dual amylin and calcitonin receptor agonists have demonstrated robust body weight loss, improved glucose tolerance and a decreased deposition of fat in liver tissue beyond what is observed after a body weight loss. The translational aspects of these preclinical data currently remain unknown. Here, we describe the physiology, pathophysiology, and pharmacological effects of amylin and calcitonin and review preclinical and clinical findings alluding to the future potential of amylin and calcitonin-based drugs for the treatment of obesity and NAFLD.
Three-Phase Four-Wire OPF-Based Collaborative Control of PV Inverter and ESS for Low-Voltage Distribution Networks With High Proportion PVs
Authors: Fu Jinwei , Li Tianrui , Guan Shilei , Wu Yan , Tang Kexin , Ding Yan , Song Zhi
Published: January 2021

The use of photovoltaic reactive power and energy storage active power can solve the problems of voltage violation, network loss, and three-phase unbalance caused by photovoltaic connection to low-voltage distribution networks. However, the three-phase four-wire structure of the low-voltage distribution network brings difficulties to power flow calculation. In order to achieve photovoltaic utilization through optimal power flow, a photovoltaic-energy storage collaborative control method for low-voltage distribution networks based on the optimal power flow of a three-phase four-wire system is proposed. Considering the amplitude and phase angle of voltage and current, a three-phase four-wire node admittance matrix was used to establish the network topology of the low-voltage distribution network. Also, to minimize the network loss, the three-phase unbalance and voltage deviation. a multi-objective optimization model based on three-phase four-wire network topology was established considering the voltage constraints, reverse power flow constraints and neutral line current constraints. Through improving the node admittance matrix and model convexity, the complexity of solving the problem is reduced. The CPLEX algorithm package was used to solve the problem. Based on a 21-bus three-phase four-wire low-voltage distribution network, a 24-h multi-period simulation was undertaken to verify the feasibility and effectiveness of the proposed scheme.
CRISPR-Based Genetic Manipulation of Candida Species: Historical Perspectives and Current Approaches
Authors: Uthayakumar Deeva , Sharma Jehoshua , Wensing Lauren , Shapiro Rebecca S.
Published: January 2021

TheCandidagenus encompasses a diverse group of ascomycete fungi that have captured the attention of the scientific community, due to both their role in pathogenesis and emerging applications in biotechnology; the development of gene editing tools such as CRISPR, to analyze fungal genetics and perform functional genomic studies in these organisms, is essential to fully understand and exploit this genus, to further advance antifungal drug discovery and industrial value. However, genetic manipulation ofCandidaspecies has been met with several distinctive barriers to progress, such as unconventional codon usage in some species, as well as the absence of a complete sexual cycle in its diploid members. Despite these challenges, the last few decades have witnessed an expansion of theCandidagenetic toolbox, allowing for diverse genome editing applications that range from introducing a single point mutation to generating large-scale mutant libraries for functional genomic studies. Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 technology is among the most recent of these advancements, bringing unparalleled versatility and precision to genetic manipulation ofCandidaspecies. Since its initial applications inCandida albicans, CRISPR-Cas9 platforms are rapidly evolving to permit efficient gene editing in other members of the genus. The technology has proven useful in elucidating the pathogenesis and host-pathogen interactions of medically relevantCandidaspecies, and has led to novel insights on antifungal drug susceptibility and resistance, as well as innovative treatment strategies. CRISPR-Cas9 tools have also been exploited to uncover potential applications ofCandidaspecies in industrial contexts. This review is intended to provide a historical overview of genetic approaches used to study theCandidagenus and to discuss the state of the art of CRISPR-based genetic manipulation ofCandidaspecies, highlighting its contributions to deciphering the biology of this genus, as well as providing perspectives for the future ofCandidagenetics.
Association Between Circulating Linoleic Acid and Risk of Ischemic Stroke
Authors: Ye Ding , Huang Huijun , Wu David J. H. , Zhang Wanting , Zhou Feixiang , Qian Yu , Zheng Jusheng , Mao Yingying
Published: January 2021

Background

Observational studies have shown an inverse association between circulating linoleic acid (LA) and risk of ischemic stroke (IS).

Objective

The aim of this study was to explore whether genetic variants predicting levels of circulating LA are associated with IS and its subtypes using a two-sample Mendelian randomization (MR) analysis.

Methods

LA-related single-nucleotide polymorphisms (SNPs) were selected from a genome-wide association study of 8,631 participants, and summary statistics of IS and IS subtypes were obtained from the MEGASTROKE consortium. MR analysis was performed using the inverse-variance weighted (IVW) method complemented with other approaches, including weighted-median, weighted-mode, MR Pleiotropy RESidual Sum and Outlier test and MR-Egger regression, to test for the robustness of the association. Moreover, we conducted bidirectional MR analysis to assess the impact of IS-associated SNPs on circulating LA levels. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated.

Results

We found that genetically predicted circulating LA levels were inversely associated with the risk of IS by the IVW method (OR = 0.98, 95% CI: 0.97–0.99, and P = 0.003). Subgroup analyses showed a statistically significant association between LA and risk of large artery stroke (LAS; OR = 0.95, 95% CI: 0.92–0.98, and P = 0.004), but not for other IS subtypes. The results were stable in sensitivity analyses, and no evidence of reverse association between LA and risk of IS, or LAS was observed.

Conclusion

Our study supports a potential inverse association of genetically predicted circulating LA levels with risk of IS, particularly LAS.
The Clinical Significance of DNA Damage Repair Signatures in Clear Cell Renal Cell Carcinoma
Authors: Guo Ergang , Wu Cheng , Ming Jun , Zhang Wei , Zhang Linli , Hu Guoqing
Published: January 2021

DNA damage repair plays an important role in cancer’s initiation and progression, and in therapeutic resistance. The prognostic potential of damage repair indicators was studied in the case of clear cell renal cell carcinoma (ccRCC). Gene expression profiles of the disease were downloaded from cancer genome databases and gene ontology was applied to the DNA repair-related genes. Twenty-six differentially expressed DNA repair genes were identified, and regression analysis was used to identify those with prognostic potential and to construct a risk model. The model accurately predicted patient outcomes and distinguished among patients with different expression levels of immune evasion genes. The data indicate that DNA repair genes can be valuable for predicting the progression of clear cell renal cell carcinoma and the clinical benefits of immunotherapy.
How Well Can Multivariate and Univariate GWAS Distinguish Between True and Spurious Pleiotropy?
Authors: Fernandes Samuel B. , Zhang Kevin S. , Jamann Tiffany M. , Lipka Alexander E.
Published: January 2021

Quantification of the simultaneous contributions of loci to multiple traits, a phenomenon called pleiotropy, is facilitated by the increased availability of high-throughput genotypic and phenotypic data. To understand the prevalence and nature of pleiotropy, the ability of multivariate and univariate genome-wide association study (GWAS) models to distinguish between pleiotropic and non-pleiotropic loci in linkage disequilibrium (LD) first needs to be evaluated. Therefore, we used publicly available maize and soybean genotypic data to simulate multiple pairs of traits that were either (i) controlled by quantitative trait nucleotides (QTNs) on separate chromosomes, (ii) controlled by QTNs in various degrees of LD with each other, or (iii) controlled by a single pleiotropic QTN. We showed that multivariate GWAS could not distinguish between QTNs in LD and a single pleiotropic QTN. In contrast, a unique QTN detection rate pattern was observed for univariate GWAS whenever the simulated QTNs were in high LD or pleiotropic. Collectively, these results suggest that multivariate and univariate GWAS should both be used to infer whether or not causal mutations underlying peak GWAS associations are pleiotropic. Therefore, we recommend that future studies use a combination of multivariate and univariate GWAS models, as both models could be useful for identifying and narrowing down candidate loci with potential pleiotropic effects for downstream biological experiments.
Inference of Intercellular Communications and Multilayer Gene-Regulations of Epithelial–Mesenchymal Transition From Single-Cell Transcriptomic Data
Authors: Sha Yutong , Wang Shuxiong , Bocci Federico , Zhou Peijie , Nie Qing
Published: January 2021

Epithelial-to-mesenchymal transition (EMT) plays an important role in many biological processes during development and cancer. The advent of single-cell transcriptome sequencing techniques allows the dissection of dynamical details underlying EMT with unprecedented resolution. Despite several single-cell data analysis on EMT, how cell communicates and regulates dynamics along the EMT trajectory remains elusive. Using single-cell transcriptomic datasets, here we infer the cell–cell communications and the multilayer gene–gene regulation networks to analyze and visualize the complex cellular crosstalk and the underlying gene regulatory dynamics along EMT. Combining with trajectory analysis, our approach reveals the existence of multiple intermediate cell states (ICSs) with hybrid epithelial and mesenchymal features. Analyses on the time-series datasets from cancer cell lines with different inducing factors show that the induced EMTs are context-specific: the EMT induced by transforming growth factor B1 (TGFB1) is synchronous, whereas the EMTs induced by epidermal growth factor and tumor necrosis factor are asynchronous, and the responses of TGF-β pathway in terms of gene expression regulations are heterogeneous under different treatments or among various cell states. Meanwhile, network topology analysis suggests that the ICSs during EMT serve as the signaling in cellular communication under different conditions. Interestingly, our analysis of a mouse skin squamous cell carcinoma dataset also suggests regardless of the significant discrepancy in concrete genes between in vitro and in vivo EMT systems, the ICSs play dominant role in the TGF-β signaling crosstalk. Overall, our approach reveals the multiscale mechanisms coupling cell–cell communications and gene–gene regulations responsible for complex cell-state transitions.
An Efficient and Easy-to-Use Network-Based Integrative Method of Multi-Omics Data for Cancer Genes Discovery
Authors: Wei Ting , Fa Botao , Luo Chengwen , Johnston Luke , Zhang Yue , Yu Zhangsheng
Published: January 2021

Identifying personalized driver genes is essential for discovering critical biomarkers and developing effective personalized therapies of cancers. However, few methods consider weights for different types of mutations and efficiently distinguish driver genes over a larger number of passenger genes. We propose MinNetRank (Minimum used for Network-based Ranking), a new method for prioritizing cancer genes that sets weights for different types of mutations, considers the incoming and outgoing degree of interaction network simultaneously, and uses minimum strategy to integrate multi-omics data. MinNetRank prioritizes cancer genes among multi-omics data for each sample. The sample-specific rankings of genes are then integrated into a population-level ranking. When evaluating the accuracy and robustness of prioritizing driver genes, our method almost always significantly outperforms other methods in terms of precision, F1 score, and partial area under the curve (AUC) on six cancer datasets. Importantly, MinNetRank is efficient in discovering novel driver genes. SP1 is selected as a candidate driver gene only by our method (ranked top three), and SP1 RNA and protein differential expression between tumor and normal samples are statistically significant in liver hepatocellular carcinoma. The top seven genes stratify patients into two subtypes exhibiting statistically significant survival differences in five cancer types. These top seven genes are associated with overall survival, as illustrated by previous researchers. MinNetRank can be very useful for identifying cancer driver genes, and these biologically relevant marker genes are associated with clinical outcome. The R package of MinNetRank is available at https://github.com/weitinging/MinNetRank.
Research Progress Concerning Dual Blockade of Lymphocyte-Activation Gene 3 and Programmed Death-1/Programmed Death-1 Ligand-1 Blockade in Cancer Immunotherapy: Preclinical and Clinical Evidence of This Potentially More Effective Immunotherapy Strategy
Authors: Qi Yihang , Chen Li , Liu Qiang , Kong Xiangyi , Fang Yi , Wang Jing
Published: January 2021

Although various immunotherapies have exerted promising effects on cancer treatment, many patients with cancer continue to exhibit poor responses. Because of its negative regulatory effects on T cells and its biological functions related to immune and inflammatory responses, there has been considerable emphasis on a protein-coding gene named lymphocyte-activation gene 3 (LAG3). Recently, evidence demonstrated marked synergy in its targeted therapy with programmed death-1 and programmed death-1 ligand-1 (PD-1/PD-L1) blockade, and a variety of LAG3 targeted agents are in clinical trials, indicating the important role of LAG3 in immunotherapy. This mini-review discusses preclinical and clinical studies investigating PD-1 pathway blockade in combination with LAG3 inhibition as a potentially more effective immunotherapy strategy for further development in the clinic. This strategy might provide a new approach for the design of more effective and precise cancer immune checkpoint therapies.
CD80 on Human T Cells Is Associated With FoxP3 Expression and Supports Treg Homeostasis
Authors: Soskic Blagoje , Jeffery Louisa E. , Kennedy Alan , Gardner David H. , Hou Tie Zheng , Halliday Neil , Williams Cayman , Janman Daniel , Rowshanravan Behzad , Hirschfield Gideon M. , Sansom David M.
Published: January 2021

CD80 and CD86 are expressed on antigen presenting cells (APCs) and their role in providing costimulation to T cells is well established. However, it has been shown that these molecules can also be expressed by T cells, but the significance of this observation remains unknown. We have investigated stimuli that control CD80 and CD86 expression on T cells and show that in APC-free conditions around 40% of activated, proliferating CD4+T cells express either CD80, CD86 or both. Expression of CD80 and CD86 was strongly dependent upon provision of CD28 costimulation as ligands were not expressed following TCR stimulation alone. Furthermore, we observed that CD80+T cells possessed the hallmarks of induced regulatory T cells (iTreg), expressing Foxp3 and high levels of CTLA-4 whilst proliferating less extensively. In contrast, CD86 was preferentially expressed on INF-γ producing cells, which proliferated more extensively and had characteristics of effector T cells. Finally, we demonstrated that CD80 expressed on T cells inhibits CTLA-4 function and facilitates the growth of iTreg. Together these data establish endogenous expression of CD80 and CD86 by activated T cells is not due to ligand capture by transendocytosis and highlight clear differences in their expression patterns and associated functions.
C4b Binding Protein Acts as an Innate Immune Effector Against Influenza A Virus
Authors: Varghese Praveen M. , Murugaiah Valarmathy , Beirag Nazar , Temperton Nigel , Khan Haseeb A. , Alrokayan Salman H. , Al-Ahdal Mohammed N. , Nal Beatrice , Al-Mohanna Futwan A. , Sim Robert B. , Kishore Uday
Published: January 2021

C4b Binding Protein (C4BP) is a major fluid phase inhibitor of the classical and lectin pathways of the complement system. Complement inhibition is achieved by binding to and restricting the role of activated complement component C4b. C4BP functions as a co-factor for factor I in proteolytic inactivation of both soluble and cell surface-bound C4b, thus restricting the formation of the C3-convertase, C4b2a. C4BP also accelerates the natural decay/dissociation of the C3 convertase. This makes C4BP a prime target for exploitation by pathogens to escape complement attack, as seen in Streptococcuspyogenesor Flavivirus. Here, we examined whether C4BP can act on its own in a complement independent manner, against pathogens. C4BP bound H1N1 and H3N2 subtypes of Influenza A Virus (IAV) most likelyviamultiple sites in Complement Control Protein (CCP) 1-2, 4-5, and 7-8 domains of its α-chain. In addition, C4BP CCP1-2 bound H3N2 better than H1N1. C4BP bound three IAV envelope proteins: Haemagglutinin (~70 kDa), Neuraminidase (~55 kDa), and Matrix protein 1 (~25kDa). C4BP suppressed H1N1 subtype infection into the lung epithelial cell line, A549, while it promoted infection by H3N2 subtype. C4BP restricted viral entry for H1N1 but had the opposite effect on H3N2, as evident from experiments using pseudo-typed viral particles. C4BP downregulated mRNA levels of pro-inflammatory IFN-α, IL-12, and NFκB in the case of H1N1, while it promoted a pro-inflammatory immune response by upregulating IFN- α, TNF-α, RANTES, and IL-6 in the case of H3N2. We conclude that C4BP differentially modulates the efficacy of IAV entry, and hence, replication in a target cell in a strain-dependent manner, and acts as an entry inhibitor for H1N1. Thus, CCP containing complement proteins such as factor H and C4BP may have additional defense roles against IAV that do not rely on the regulation of complement activation.
Immunodiagnosis and Immunotherapeutics Based on Human Papillomavirus for HPV-Induced Cancers
Authors: Dong Zhen , Hu Renjian , Du Yan , Tan Li , Li Lin , Du Juan , Bai Longchang , Ma Yingkang , Cui Hongjuan
Published: January 2021

Infection with human papillomavirus (HPV) is one of the main causes of malignant neoplasms, especially cervical, anogenital, and oropharyngeal cancers. Although we have developed preventive vaccines that can protect from HPV infection, there are still many new cases of HPV-related cancers worldwide. Early diagnosis and therapy are therefore important for the treatment of these diseases. As HPVs are the major contributors to these cancers, it is reasonable to develop reagents, kits, or devices to detect and eliminate HPVs for early diagnosis and therapeutics. Immunological methods are precise strategies that are promising for the accurate detection and blockade of HPVs. During the last decades, the mechanism of how HPVs induce neoplasms has been extensively elucidated, and several oncogenic HPV early proteins, including E5, E6, and E7, have been shown to be positively related to the oncogenesis and malignancy of HPV-induced cancers. These oncoproteins are promising biomarkers for diagnosis and as targets for the therapeutics of HPV-related cancers. Importantly, many specific monoclonal antibodies (mAbs), or newly designed antibody mimics, as well as new immunological kits, devices, and reagents have been developed for both the immunodiagnosis and immunotherapeutics of HPV-induced cancers. In the current review, we summarize the research progress in the immunodiagnosis and immunotherapeutics based on HPV for HPV-induced cancers. In particular, we depict the most promising serological methods for the detection of HPV infection and several therapeutical immunotherapeutics based on HPV, using immunological tools, including native mAbs, radio-labelled mAbs, affitoxins (affibody-linked toxins), intracellular single-chain antibodies (scFvs), nanobodies, therapeutical vaccines, and T-cell-based therapies. Our review aims to provide new clues for researchers to develop novel strategies and methods for the diagnosis and treatment of HPV-induced tumors.
Grass Carp (Ctenopharyngodon idellus) NIMA-Related Kinase 6 Blocks dsRNA-Induced IFN I Response by Targeting IRF3
Authors: Xu Xiaowen , Li Meifeng , Deng Zeyuan , Hu Jihuan , Jiang Zeyin , Liu Yapeng , Chang Kaile , Hu Chengyu
Published: January 2021

Accumulating evidence indicates that mammalian NIMA (never in mitosis, gene A)-related kinase 6 (NEK6) plays potential roles during the course of tumorigenesis, but little is known about NEK6 in lower vertebrates. Herein, we reported a mammalian ortholog of NEK6 in grass carp (Ctenopharyngodon idellus) (CiNEK6). Multiple alignment of amino acid sequences and phylogenetic analysis showed that CiNEK6 shares a high level of sequence similarity with its counterparts in birds. CiNEK6 was ubiquitously expressed in all tested tissues, and its expression level was increased under treatment with GCRV (dsRNA virus) or poly I:C (dsRNA analog). Q-PCR and dual-luciferase assays suggested that CiNEK6 overexpression suppressed IFN I activity in CIK cells treated with poly I:C. Knockdown of CiNEK6 resulted in a higher level of IFN I expression in CIK cells treated with poly I:C compared to those which received PBS. Interestingly, analysis of subcellular localization demonstrated that CiNEK6 protein scattered throughout the cytoplasm is gradually congregated together at the edges of karyotheca upon stimulation with poly I:C. Co-IP and co-localization assays suggested that CiNEK6 interacts with CiIRF3 after poly I:C challenge. In poly I:C-treated cells, the phosphorylation of CiIRF3 was increased by CiNEK6 knockdown, but was suppressed by CiNEK6 overexpression, suggesting that CiNEK6 decreases IFN I expression through inhibiting CiIRF3 activity. Cell viability assay, crystal violet staining, and detection of Vp5 also showed that CiNEK6 plays an inhibitory role in IRF3-mediated antiviral responses.
A Novel Biallelic STING1 Gene Variant Causing SAVI in Two Siblings
Authors: Alghamdi Malak Ali , Mulla Jaazeel , Saheb Sharif-Askari Narjes , Guzmán-Vega Francisco J. , Arold Stefan T. , Abd-Alwahed Mervat , Alharbi Nasser , Kashour Tarek , Halwani Rabih
Published: January 2021

STING-associated vasculopathy of infantile-onset (SAVI) is one of the newly identified types of interferonopathies. SAVI is caused by heterozygous gain-of-function mutations in the STING1. We herein report for the first time a homozygous variant in the STING1 gene in two siblings that resulted in constitutive activation of STING gene and the SAVI phenotype. Exome sequencing revealed a novel homozygous NM_198282.3: c.841C>T; p.(Arg281Trp) variant in exon 7 of the STING1 gene. The variant segregated in the family to be homozygous in all affected and either heterozygous or wild type in all healthy. Computational structural analysis of the mutants revealed changes in the STING protein structure/function. Elevated serum beta-interferon levels were observed in the patients compared to the control family members. Treatment with Janus kinase inhibitor (JAK-I) Ruxolitinib suppressed the inflammatory process, decreased beta-interferon levels, and stopped the progression of the disease.
HLA, Immune Response, and Susceptibility to COVID-19
Authors: Tavasolian Fataneh , Rashidi Mohsen , Hatam Gholam Reza , Jeddi Marjan , Hosseini Ahmad Zavaran , Mosawi Sayed Hussain , Abdollahi Elham , Inman Robert D.
Published: January 2021

The severe acute respiratory syndrome caused by Coronavirus 2 (SARS-CoV-2) that appeared in December 2019 has precipitated the global pandemic Coronavirus Disease 2019 (COVID-19). However, in many parts of Africa fewer than expected cases of COVID-19, with lower rates of mortality, have been reported. Individual human leukocyte antigen (HLA) alleles can affect both the susceptibility and the severity of viral infections. In the case of COVID-19 such an analysis may contribute to identifying individuals at higher risk of the disease and the epidemiological level to understanding the differences between countries in the epidemic patterns. It is also recognized that first antigen exposure influences the consequence of subsequent exposure. We thus propose a theory incorporating HLA antigens, the “original antigenic sin (OAS)” effect, and presentation of viral peptides which could explain with differential susceptibility or resistance to SARS-CoV-2 infections.
Stimulation of Vibratory Urticaria-Associated Adhesion-GPCR, EMR2/ADGRE2, Triggers the NLRP3 Inflammasome Activation Signal in Human Monocytes
Authors: I Kuan-Yu , Tseng Wen-Yi , Wang Wen-Chih , Gordon Siamon , Ng Kwai-Fong , Lin Hsi-Hsien
Published: January 2021

EMR2/ADGRE2 is an adhesion G protein-coupled receptor differentially expressed by human myeloid cells. It modulates diverse cellular functions of innate immune cells and a missense EMR2 variant is directly responsible for vibratory urticaria. Recently, EMR2 was found to activate NLRP3 inflammasome in monocytes via interaction with FHR1, a regulatory protein of complement Factor H. However, the functional involvement of EMR2 activation and its signaling mechanisms in eliciting NLRP3 inflammasome activation remain elusive. In this study, we show that EMR2-mediated signaling plays a critical role in triggering the activation (2nd) signal for the NLRP3 inflammasome in both THP-1 monocytic cell line and primary monocytes. Stimulation of EMR2 by its agonistic 2A1 monoclonal antibody elicits a Gα16-dependent PLC-β activation pathway, inducing the activity of downstream Akt, MAPK, NF-κB, and Ca2+ mobilization, eventually leading to K+ efflux. These results identify EMR2 and its associated signaling intermediates as potential intervention targets of NLRP3 inflammasome activation in inflammatory disorders.
CD39+ Regulatory T Cells Attenuate Lipopolysaccharide-Induced Acute Lung Injury via Autophagy and the ERK/FOS Pathway
Authors: Chen Cen , Li Xinying , Li Chuling , Jin Jiajia , Wang Donghui , Zhao Yuan , Gu Yanli , Chen Meizi , Zhu Suhua , Liu Hongbing , Lv Tangfeng , Zhang Fang , Song Yong
Published: January 2021

Acute respiratory distress syndrome (ARDS) is characterized by an uncontrollable cytokine storm, which is associated with high mortality due to lack of effective treatment. Regulatory T cells (Tregs) play an indispensable role in maintaining immune homeostasis and CD39 is considered as a functional cell marker of Tregs. In this study, we aimed to evaluate the effect of CD39+ Tregs on acute lung injury (ALI) and investigate the frequency of CD39+ Tregs in ARDS patients. We found that after lipopolysaccharide (LPS) treatment, CD39−/− mice exhibited more severe inflammation and wild type (WT) mice exhibited a decreased frequency of CD39+ Tregs in the peripheral blood. Furthermore, CD39+ Tregs had a protective effect on LPS-induced inflammation in vitro and the adoptive transfer of CD39+ Tregs had a therapeutic effect on ALI in vivo. We further sought to explore the mechanisms that affect CD39 expression on Tregs. LPS-induced inflammation in the lung impaired the immunosuppressive effect of Tregs via the autophagy-mediated downregulation of CD39. In addition, CD39 induced the expression of itself in Tregs via activating the ERK1/2-FOS pathway. Consistent with this finding, the frequency of CD39+ Tregs was also decreased in the peripheral blood of ARDS patients and was positively correlated with disease severity. Our results suggested that the adoptive transfer of CD39+ Tregs may provide a novel method for the clinical prevention and treatment of ARDS.