bluuebunny/crossref_metadata_2025 huggingface dataset:
Expanding the molecular versatility of an optogenetic switch in yeast
Authors: Figueroa David , Baeza Camila , Ruiz Diego , Inzunza Claudia , Romero Andrés , Toro Rodrigo , Salinas Francisco
Published: November 2022

In the budding yeast Saccharomyces cerevisiae, the FUN-LOV (FUNgal Light Oxygen and Voltage) optogenetic switch enables high levels of light-activated gene expression in a reversible and tunable fashion. The FUN-LOV components, under identical promoter and terminator sequences, are encoded in two different plasmids, which limits its future applications in wild and industrial yeast strains. In this work, we aim to expand the molecular versatility of the FUN-LOV switch to increase its biotechnological applications. Initially, we generated new variants of this system by replacing the promoter and terminator sequences and by cloning the system in a single plasmid (FUN-LOVSP). In a second step, we included the nourseothricin (Nat) or hygromycin (Hph) antibiotic resistances genes in the new FUN-LOVSP plasmid, generating two new variants (FUN-LOVSP-Nat and FUN-LOVSP-Hph), to allow selection after genome integration. Then, we compared the levels of light-activated expression for each FUN-LOV variants using the luciferase reporter gene in the BY4741 yeast strain. The results indicate that FUN-LOVSP-Nat and FUN-LOVSP-Hph, either episomally or genome integrated, reached higher levels of luciferase expression upon blue-light stimulation compared the original FUN-LOV system. Finally, we demonstrated the functionality of FUN-LOVSP-Hph in the 59A-EC1118 wine yeast strain, showing similar levels of reporter gene induction under blue-light respect to the laboratory strain, and with lower luciferase expression background in darkness condition. Altogether, the new FUN-LOV variants described here are functional in different yeast strains, expanding the biotechnological applications of this optogenetic tool.
Vertical response of unbonded fiber reinforced elastomeric isolators (U-FREIs) under bidirectional shear loading
Authors: Galano Simone
Published: November 2022

Fiber Reinforced Elastomeric Isolators (FREIs) were generally studied in unbonded configuration. Due to combined axial and shear loads, the contact area between the bearing and horizontal supports reduces with the horizontal displacement. As a result, both the vertical and the horizontal stiffnesses decrease with the horizontal deformation while also the vertical deformation increases. This paper presents the results of a large set of full-scale 3D Finite Element Analyses on unbonded fiber reinforced bearings with different geometries, subjected to combined axial and multi-directional shear loads. The main vertical response parameters were studied, namely the vertical displacement, the vertical stiffness, and the effective compressive modulus, thus highlighting the influence of both geometry and horizontal loading direction on the vertical response of the FREIs. Conclusion of this study demonstrate to what extent the combined influence of geometric properties and loading conditions affects the vertical response of elastomeric bearings with flexible reinforcements.
Interlink between solubility, structure, surface and thermodynamics in the ThO2(s, hyd)–H2O(l) system
Authors: Kiefer Christian , Neill Thomas , Cevirim-Papaioannou Nese , Schild Dieter , Gaona Xavier , Vitova Tonya , Dardenne Kathy , Rothe Jörg , Altmaier Marcus , Geckeis Horst
Published: November 2022

The impact of temperature on a freshly precipitated ThO2(am, hyd) solid phase was investigated using a combination of undersaturation solubility experiments and a multi-method approach for the characterization of the solid phase. XRD and EXAFS confirm that ageing of ThO2(am, hyd) at T = 80°C promotes a significant increase of the particle size and crystallinity. TG-DTA and XPS support that the ageing process is accompanied by an important decrease in the number of hydration waters/hydroxide groups in the original amorphous Th(IV) hydrous oxide. However, while clear differences between the structure of freshly precipitated ThO2(am, hyd) and aged samples were observed, the characterization methods used in this work are unable to resolve clear differences between solid phases aged for different time periods or at different pH values. Solubility experiments conducted at T = 22°C with fresh and aged Th(IV) solid phases show a systematic decrease in the solubility of the solid phases aged at T = 80°C. In contrast to the observations gained by solid phase characterization, the ageing time and ageing pH significantly affect the solubility measured at T = 22°C. These observations can be consistently explained considering a solubility control by the outermost surface of the ThO2(s, hyd) solid, which cannot be properly probed by any of the techniques considered in this work. Solubility data are used to derive the thermodynamic properties (log *K°s,0, ΔfG°m) of the investigated solid phases, and discussed in terms of particle size using the Schindler equation. These results provide new insights on the interlink between solubility, structure, surface and thermodynamics in the ThO2(s, hyd)–H2O(l) system, with special emphasis on the transformation of the amorphous hydrous/hydroxide solid phases into the thermodynamically stable crystalline oxides.
Deep learning-based detection of functionally significant stenosis in coronary CT angiography
Authors: Hampe Nils , van Velzen Sanne G. M. , Planken R. Nils , Henriques José P. S. , Collet Carlos , Aben Jean-Paul , Voskuil Michiel , Leiner Tim , Išgum Ivana
Published: November 2022

Patients with intermediate anatomical degree of coronary artery stenosis require determination of its functional significance. Currently, the reference standard for determining the functional significance of a stenosis is invasive measurement of the fractional flow reserve (FFR), which is associated with high cost and patient burden. To address these drawbacks, FFR can be predicted non-invasively from a coronary CT angiography (CCTA) scan. Hence, we propose a deep learning method for predicting the invasively measured FFR of an artery using a CCTA scan. The study includes CCTA scans of 569 patients from three hospitals. As reference for the functional significance of stenosis, FFR was measured in 514 arteries in 369 patients, and in the remaining 200 patients, obstructive coronary artery disease was ruled out by Coronary Artery Disease-Reporting and Data System (CAD-RADS) category 0 or 1. For prediction, the coronary tree is first extracted and used to reconstruct an MPR for the artery at hand. Thereafter, the coronary artery is characterized by its lumen, its attenuation and the area of the coronary artery calcium in each artery cross-section extracted from the MPR using a CNN. Additionally, characteristics indicating the presence of bifurcations and information indicating whether the artery is a main branch or a side-branch of a main artery are derived from the coronary artery tree. All characteristics are fed to a second network that predicts the FFR value and classifies the presence of functionally significant stenosis. The final result is obtained by merging the two predictions. Performance of our method is evaluated on held out test sets from multiple centers and vendors. The method achieves an area under the receiver operating characteristics curve (AUC) of 0.78, outperforming other works that do not require manual correction of the segmentation of the artery. This demonstrates that our method may reduce the number of patients that unnecessarily undergo invasive measurements.
Pharmacogenomics driven decision support prototype with machine learning: A framework for improving patient care
Authors: Kidwai-Khan Farah , Rentsch Christopher T. , Pulk Rebecca , Alcorn Charles , Brandt Cynthia A. , Justice Amy C.
Published: November 2022

Introduction

A growing number of healthcare providers make complex treatment decisions guided by electronic health record (EHR) software interfaces. Many interfaces integrate multiple sources of data (e.g., labs, pharmacy, diagnoses) successfully, though relatively few have incorporated genetic data.

Method

This study utilizes informatics methods with predictive modeling to create and validate algorithms to enable informed pharmacogenomic decision-making at the point of care in near real-time. The proposed framework integrates EHR and genetic data relevant to the patient's current medications including decision support mechanisms based on predictive modeling. We created a prototype with EHR and linked genetic data from the Department of Veterans Affairs (VA), the largest integrated healthcare system in the US. The EHR data included diagnoses, medication fills, and outpatient clinic visits for 2,600 people with HIV and matched uninfected controls linked to prototypic genetic data (variations in single or multiple positions in the DNA sequence). We then mapped the medications that patients were prescribed to medications defined in the drug-gene interaction mapping of the Clinical Pharmacogenomics Implementation Consortium's (CPIC) level A (i.e., sufficient evidence for at least one prescribing action) guidelines that predict adverse events. CPIC is a National Institute of Health funded group of experts who develop evidence based pharmacogenomic guidelines. Preventable adverse events (PAE) can be defined as a harmful outcome from an intervention that could have been prevented. For this study, we focused on potential PAEs resulting from a medication-gene interaction.

Results

The final model showed AUC scores of 0.972 with an F1 score of 0.97 with genetic data as compared to 0.766 and 0.73 respectively, without genetic data integration.

Discussion

Over 98% of people in the cohort were on at least one medication with CPIC level a guideline in their lifetime. We compared predictive power of machine learning models to detect a PAE between five modeling methods: Random Forest, Support Vector Machine (SVM), Extreme Gradient Boosting (XGBoost), K Nearest neighbors (KNN), and Decision Tree. We found that XGBoost performed best for the prototype when genetic data was added to the framework and improved prediction of PAE. We compared area under the curve (AUC) between the models in the testing dataset.
Every cloud has a silver lining: The experience of online learning in English language classes at Saudi universities in the post–COVID-19 era
Authors: Alqahtani Muneer Hezam
Published: November 2022

This study investigates the perceptions of 149 English language students about online language learning at a state university in Saudi Arabia and how this experience has prepared them to continue online learning in post-pandemic times. It also investigates any differences in students’ attainment of the four language skills of reading, listening, writing, and speaking with respect to the online learning experience. Data were collected using a questionnaire with close-ended items with each item having an open-ended query. The findings of the study indicate that, overall, the students had positive attitudes toward learning English online whether during the pandemic or after it is over. However, their views differed regarding the acquisition of the four language skills; learning the receptive skills of reading and listening online was perceived positively, while learning the productive skills of writing and speaking online was perceived negatively as a result of the online learning mode. The study concludes that more advanced technical features are needed to be introduced onto online learning platforms for more effective learning outcomes and that the current platforms at universities fall somewhat short of the English language students’ needs.
Crucial role of T cells in NAFLD-related disease: A review and prospect
Authors: Mao Tianyu , Yang Rui , Luo Yi , He Kang
Published: November 2022

Nonalcoholic fatty liver disease (NAFLD) includes a series of hepatic manifestations, starting with liver steatosis and potentially evolving towards nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis or even hepatocellular carcinoma (HCC). Its incidence is increasing worldwide. Several factors including metabolic dysfunction, oxidative stress, lipotoxicity contribute to the liver inflammation. Several immune cell-mediated inflammatory processes are involved in NAFLD in which T cells play a crucial part in the progression of the disease. In this review, we focus on the role of different subsets of both conventional and unconventional T cells in pathogenesis of NAFLD. Factors regarding inflammation and potential therapeutic approaches targeting immune cells in NASH are also discussed.
Decentralized robust optimal dispatch of user-level integrated electricity-gas-heat systems considering two-level integrated demand response
Authors: Ma Zhoujun , Yang Miao , Jia Wenhao , Ding Tao
Published: November 2022

With the change of users’ energy consumption concept, the users are no longer rigid as the traditional inelasticity but can be flexible to carry out integrated demand response (IDR). The load has also been transformed from a traditional purely consumptive load to a new type of load that combines production and consumption with the improvement and popularization of renewable energy production technologies such as wind power and photovoltaic. In this paper, considering the IDR of loads and the uncertainty of renewable energy output, a decentralized robust optimal dispatch study is conducted on user-level integrated electricity-gas-heat systems (IEGHSs) composed of energy hubs (EHs) and some users. This paper firstly developed the comprehensive model of the user-level IEGHS, including the detailed mathematical model of EH, IDR, and users. Then, based on the established model, an optimal dispatching model is established with the goal of the lowest operating cost for the system. In order to cope with the uncertainty of the output of renewable energy equipment while protecting the security and privacy of different participants in the integrated energy system (IES), a decentralized robust algorithm is used to solve the model. Finally, the proposed model is analyzed and verified by an IES example composed of one EH and three users with the ability of IDRs, and the feasibility of the proposed model and algorithm is verified.
Effects of crude oil and gas condensate spill on coastal benthic microbial populations
Authors: Kababu E. , Angel D. L. , Sisma-Ventura G. , Belkin N. , Rubin-Blum M. , Rahav E.
Published: November 2022

Marine sediments are ecologically-important environments that act as a long-term depository for different contaminants from natural and anthropogenic sources. We investigated the response of crude-oil and gas-condensate spills on benthic microbial populations in the oligotrophic southeastern Mediterranean Sea using costume-design benthocosms. Additions of crude oil and gas condensate significantly changed the sediment’s chemical properties, with 2-fold elevated levels of total organic carbon (TOC) and up to ∼ 6-fold higher concentration of total polycyclic aromatic hydrocarbons (∑PAHs) relative to unamended sediments. Naphthalene and benzo(a)pyrene were the dominant species comprising the PAHs in both the crude-oil and gas-condensate treatments (29–43% and 26–35%, respectively). Porewater PO43+ drastically declined throughout the experiment, whereas NO2− + NO3− decreased ∼100 days post hydrocarbons addition and then increased in the remaining ∼100 days till the conclusion of the experiment. This temporal variability in NO2− + NO3− hints that hydrocarbon pollution may affect the interplay between benthic denitrification and N2 fixation, thus affecting nutrient limitation for benthic heterotrophic bacteria and phytoplankton. Moreover, our results show that crude oil and gas-condensate usually lead to a decline in benthic autotrophic microbial biomass (50–80%), while heterotrophic bacterial abundances remained unchanged, and bacterial production rapidly increased (maximal 1,600%, crude-oil > gas-cindensate). These effects were prolonged and lasted several months post hydrocarbons addition, highlighting the sediments as a repository for oil contaminants. Amplicon sequencing of the 16S rRNA gene revealed hydrocarbonoclastic bacteria including Methylophaga, Ponticaulis and Alcanivorax genera post crude-oil addition and Actinobacterota 67–14 lineage following gas-condensate amendments. Our results may enable applying a better science-based environmental policy for the benthic marine environment.
Some historical thoughts on the functional responses of predators to prey density
Authors: Krebs Charles J.
Published: November 2022

The introduction of the functional response into population ecology in 1949 by Maurice Solomon was focused on explaining population regulation by density-dependent mortality caused by predators and natural enemies. Like many simple ecological measures originating at the population level, it was soon being used for other purposes at the single species and individual predator level. It is thus necessary when we use this important response function that we have a clear hypothesis in mind that is being tested. Here I provide a capsular summary of the origins of the functional response and suggest five problems with its application in population and community ecology. The functional response has much utility as a critical component of understanding population and community dynamics but must be carefully aimed at specific questions.
Construction of a potentially functional lncRNA-miRNA-mRNA network in sepsis by bioinformatics analysis
Authors: Zheng Li-ming , Ye Jun-qiu , Li Heng-fei , Liu Quan
Published: November 2022

Objective: Sepsis is a common disease in internal medicine, with a high incidence and dangerous condition. Due to the limited understanding of its pathogenesis, the prognosis is poor. The goal of this project is to screen potential biomarkers for the diagnosis of sepsis and to identify competitive endogenous RNA (ceRNA) networks associated with sepsis.

Methods: The expression profiles of long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and messenger RNAs (mRNAs) were derived from the Gene Expression Omnibus (GEO) dataset. The differentially expressed lncRNAs (DElncRNAs), miRNAs (DEmiRNAs) and mRNAs (DEmRNAs) were screened by bioinformatics analysis. DEmRNAs were analyzed by protein-protein interaction (PPI) network analysis, transcription factor enrichment analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Set Enrichment Analysis (GSEA). After the prediction of the relevant database, the competitive ceRNA network is built in Cytoscape. The gene-drug interaction was predicted by DGIgb. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) was used to confirm five lncRNAs from the ceRNA network.

Results: Through Venn diagram analysis, we found that 57 DElncRNAs, 6 DEmiRNAs and 317 DEmRNAs expressed abnormally in patients with sepsis. GO analysis and KEGG pathway analysis showed that 789 GO terms and 36 KEGG pathways were enriched. Through intersection analysis and data mining, 5 key KEGG pathways and related core genes were revealed by GSEA. The PPI network consists of 247 nodes and 1,163 edges, and 50 hub genes are screened by the MCODE plug-in. In addition, there are 5 DElncRNAs, 6 DEmiRNAs and 28 DEmRNAs in the ceRNA network. Drug action analysis showed that 7 genes were predicted to be molecular targets of drugs. Five lncRNAs in ceRNA network are verified by qRT-PCR, and the results showed that the relative expression of five lncRNAs was significantly different between sepsis patients and healthy control subjects.

Conclusion: A sepsis-specific ceRNA network has been effectively created, which is helpful to understand the interaction between lncRNAs, miRNAs and mRNAs. We discovered prospective sepsis peripheral blood indicators and proposed potential treatment medicines, providing new insights into the progression and development of sepsis.
SPCMLMI: A structural perturbation-based matrix completion method to predict lncRNA–miRNA interactions
Authors: Wang Mei-Neng , Lei Li-Lan , He Wei , Ding De-Wu
Published: November 2022

Accumulating evidence indicated that the interaction between lncRNA and miRNA is crucial for gene regulation, which can regulate gene transcription, further affecting the occurrence and development of many complex diseases. Accurate identification of interactions between lncRNAs and miRNAs is helpful for the diagnosis and therapeutics of complex diseases. However, the number of known interactions of lncRNA with miRNA is still very limited, and identifying their interactions through biological experiments is time-consuming and expensive. There is an urgent need to develop more accurate and efficient computational methods to infer lncRNA–miRNA interactions. In this work, we developed a matrix completion approach based on structural perturbation to infer lncRNA–miRNA interactions (SPCMLMI). Specifically, we first calculated the similarities of lncRNA and miRNA, including the lncRNA expression profile similarity, miRNA expression profile similarity, lncRNA sequence similarity, and miRNA sequence similarity. Second, a bilayer network was constructed by integrating the known interaction network, lncRNA similarity network, and miRNA similarity network. Finally, a structural perturbation-based matrix completion method was used to predict potential interactions of lncRNA with miRNA. To evaluate the prediction performance of SPCMLMI, five-fold cross validation and a series of comparison experiments were implemented. SPCMLMI achieved AUCs of 0.8984 and 0.9891 on two different datasets, which is superior to other compared methods. Case studies for lncRNA XIST and miRNA hsa-mir-195–5-p further confirmed the effectiveness of our method in inferring lncRNA–miRNA interactions. Furthermore, we found that the structural consistency of the bilayer network was higher than that of other related networks. The results suggest that SPCMLMI can be used as a useful tool to predict interactions between lncRNAs and miRNAs.
Diverse roles of the CIPK gene family in transcription regulation and various biotic and abiotic stresses: A literature review and bibliometric study
Authors: Yang Chen , Yi-feng Jin , Yushu Wang , Yansong Gao , Qi Wang , Xue You
Published: November 2022

CIPKs are a subclass of serine/threonine (Ser/Thr) protein kinases. CBLs are ubiquitous Ca2+ sensors that interact with CIPK with the aid of secondary Ca2+ messengers for regulation of growth and development and response to stresses faced by plants. The divergent roles of the CIPK-CBL interaction in plants include responding to environmental stresses (salt, cold, drought, pH, ABA signaling, and ion toxicity), ion homeostasis (K+, NH4+, NO3−, and microelement homeostasis), biotic stress, and plant development. Each member of this gene family produces distinct proteins that help plants adapt to diverse stresses or stimuli by interacting with calcium ion signals. CIPK consists of two structural domains—an N-terminal domain and a C-terminal domain—connected by a junction domain. The N-terminal domain, the site of phosphorylation, is also called the activation domain and kinase domain. The C-terminal, also known as the regulatory domain of CIPK, further comprises NAF/FISL and PPI. CBL comprises four EF domains and conserved PFPF motifs and is the site of binding with the NAF/FISL domain of CIPK to form a CBL-CIPK complex. In addition, we also performed a bibliometric analysis of the CIPK gene family of data extracted from the WoSCC. A total of 95 documents were retrieved, which had been published by 47 sources. The production over time was zigzagged. The top key terms were gene, CIPK, abiotic stress, and gene expression. Beijing Forestry University was the top affiliation, while The Plant Cell was the top source. The genomics and metabolomics of this gene family require more study.
Differentially expressed tRNA-derived fragments in bovine fetuses with assisted reproduction induced congenital overgrowth syndrome
Authors: Goldkamp Anna K. , Li Yahan , Rivera Rocio M. , Hagen Darren E.
Published: November 2022

Background: As couples struggle with infertility and livestock producers wish to rapidly improve genetic merit in their herd, assisted reproductive technologies (ART) have become increasingly popular in human medicine as well as the livestock industry. Utilizing ART can cause an increased risk of congenital overgrowth syndromes, such as Large Offspring Syndrome (LOS) in ruminants. A dysregulation of transcripts has been observed in bovine fetuses with LOS, which is suggested to be a cause of the phenotype. Our recent study identified variations in tRNA expression in LOS individuals, leading us to hypothesize that variations in tRNA expression can influence the availability of their processed regulatory products, tRNA-derived fragments (tRFs). Due to their resemblance in size to microRNAs, studies suggest that tRFs target mRNA transcripts and regulate gene expression. Thus, we have sequenced small RNA isolated from skeletal muscle and liver of day 105 bovine fetuses to elucidate the mechanisms contributing to LOS. Moreover, we have utilized our previously generated tRNA sequencing data to analyze the contribution of tRNA availability to tRF abundance.

Results: 22,289 and 7,737 unique tRFs were predicted in the liver and muscle tissue respectively. The greatest number of reads originated from 5′ tRFs in muscle and 5′ halves in liver. In addition, mitochondrial (MT) and nuclear derived tRF expression was tissue-specific with most MT-tRFs and nuclear tRFs derived from LysUUU and iMetCAU in muscle, and AsnGUU and GlyGCC in liver. Despite variation in tRF abundance within treatment groups, we identified differentially expressed (DE) tRFs across Control-AI, ART-Normal, and ART-LOS groups with the most DE tRFs between ART-Normal and ART-LOS groups. Many DE tRFs target transcripts enriched in pathways related to growth and development in the muscle and tumor development in the liver. Finally, we found positive correlation coefficients between tRNA availability and tRF expression in muscle (R = 0.47) and liver (0.6).

Conclusion: Our results highlight the dysregulation of tRF expression and its regulatory roles in LOS. These tRFs were found to target both imprinted and non-imprinted genes in muscle as well as genes linked to tumor development in the liver. Furthermore, we found that tRNA transcription is a highly modulated event that plays a part in the biogenesis of tRFs. This study is the first to investigate the relationship between tRNA and tRF expression in combination with ART-induced LOS.
Diagnostic implication of a circulating serum-based three-microRNA signature in hepatocellular carcinoma
Authors: Yousuf Tahira , Dar Sadaf Bashir , Bangri Sadaf Ali , Choh Naseer A. , Rasool Zubaida , Shah Altaf , Rather Rafiq Ahmed , Rah Bilal , Bhat Gh Rasool , Ali Shazia , Afroze Dil
Published: November 2022

Owing to the diagnostic dilemma, the prognosis of hepatocellular carcinoma (HCC) remains impoverished, contributing to the globally high mortality rate. Currently, HCC diagnosis depends on the combination of imaging modalities and the measurement of serum alpha-fetoprotein (AFP) levels. Nevertheless, these conventional modalities exhibit poor performance in detecting HCC at early stages. Thus, there is a pressing need to identify novel circulating biomarkers to promote diagnostic accuracy and surveillance. Circulating miRNAs are emerging as promising diagnostic tools in screening various cancers, including HCC. However, because of heterogenous and, at times, contradictory reports, the universality of miRNAs in clinical settings remains elusive. Consequently, we proposed to explore the diagnostic potential of ten miRNAs selected on a candidate-based approach in HCC diagnosis. The expression of ten candidate miRNAs (Let-7a, miR-15a, miR-26a, miR-124, miR-126, miR-155, miR-219, miR-221, miR-222, and miR-340) was investigated in serum and tissue of 66 subjects, including 33 HCC patients and 33 healthy controls (HC), by rt-PCR. Receiver operating characteristic curve (ROC) analysis was used to determine the diagnostic accuracy of the prospective serum miRNA panel. To anticipate the potential biological roles of a three-miRNA signature, the target genes were evaluated using the Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway. The serum and tissue expression of miRNAs (Let-7a, miR-26a, miR-124, miR-155, miR-221, miR-222, and miR-340) were differentially expressed in HCC patients (p < 0.05). The ROC analysis revealed promising diagnostic performance of Let-7a (AUC = 0.801), miR-221 (AUC = 0.786), and miR-2 (AUC = 0.758) in discriminating HCC from HC. Furthermore, in a logistic regression equation, we identified a three-miRNA panel (Let-7a, miR-221, and miR-222; AUC = 0.932) with improved diagnostic efficiency in differentiating HCC from HC. Remarkably, the combination of AFP and a three-miRNA panel offered a higher accuracy of HCC diagnosis (AUC = 0.961) than AFP alone. The functional enrichment analysis demonstrated that target genes may contribute to pathways associated with HCC and cell-cycle regulation, indicating possible crosstalk of miRNAs with HCC development. To conclude, the combined classifier of a three-miRNA panel and AFP could be indispensable circulating biomarkers for HCC diagnosis. Furthermore, targeting predicted genes may provide new therapeutic clues for the treatment of aggressive HCC.
Towards an accurate and robust analysis pipeline for somatic mutation calling
Authors: Jin Jingjie , Chen Zixi , Liu Jinchao , Du Hongli , Zhang Gong
Published: November 2022

Accurate and robust somatic mutation detection is essential for cancer treatment, diagnostics and research. Various analysis pipelines give different results and thus should be systematically evaluated. In this study, we benchmarked 5 commonly-used somatic mutation calling pipelines (VarScan, VarDictJava, Mutect2, Strelka2 and FANSe) for their precision, recall and speed, using standard benchmarking datasets based on a series of real-world whole-exome sequencing datasets. All the 5 pipelines showed very high precision in all cases, and high recall rate in mutation rates higher than 10%. However, for the low frequency mutations, these pipelines showed large difference. FANSe showed the highest accuracy (especially the sensitivity) in all cases, and VarScan and VarDictJava outperformed Mutect2 and Strelka2 in low frequency mutations at all sequencing depths. The flaws in filter was the major cause of the low sensitivity of the four pipelines other than FANSe. Concerning the speed, FANSe pipeline was 8.8∼19x faster than the other pipelines. Our benchmarking results demonstrated performance of the somatic calling pipelines and provided a reference for a proper choice of such pipelines in cancer applications.
Development of European apple canker on different cultivars in relation to planting time at three sites in the UK
Authors: Xu Xiangming , Passey Tom , Robinson-Boyer Louisa , Mclean Hamish , Saville Robert , Papp-Rupar Matevz
Published: November 2022

European apple canker, caused by Neonectria ditissima, is a damaging disease of apple in many production regions worldwide. The pathogen infects apple trees through artificial or natural wounds. The most damaging phase of the disease is that cankers on main stems post-planting, most likely originating from infection in nurseries, can result in tree death in young orchards. Apple cultivars differ in their responses to the pathogen, which may be additionally affected by specific site factors. An experiment was conducted to study i) the susceptibility of seven cultivars to N. ditissima at three sites and ii) the effects of cold storage duration prior to planting on subsequent development of both main stem and peripheral cankers. Planting date had significant (albeit minimal effects) on the development of peripheral cankers only. Canker development differed greatly among the three sites and between the tested cultivars, with ‘Grenadier’ and ‘Golden Delicious’ being most resistant at all sites. The relative performance of cultivars in terms of canker development was generally consistent across the three sites. Nevertheless, the interaction between cultivar and site was still statistically significant for the development of main stem cankers, indicating that some site-specific factors may interact with cultivars to affect development of latent infections. Given the close proximity of the three sites (similar climatic conditions), the results indicate that further research is needed to investigate the effects of soil characteristics on canker development post-planting.
Understanding AL amyloidosis with a little help from in vivo models
Authors: Martinez-Rivas Gemma , Bender Sébastien , Sirac Christophe
Published: November 2022

Monoclonal immunoglobulin (Ig) light chain amyloidosis (AL) is a rare but severe disease that may occur when a B or plasma cell clone secretes an excess of free Ig light chains (LCs). Some of these LCs tend to aggregate into organized fibrils with a β-sheet structure, the so-called amyloid fibrils, and deposit into the extracellular compartment of organs, such as the heart or kidneys, causing their dysfunction. Recent findings have confirmed that the core of the amyloid fibrils is constituted by the variable (V) domain of the LCs, but the mechanisms underlying the unfolding and aggregation of this fragment and its deposition are still unclear. Moreover, in addition to the mechanical constraints exerted by the massive accumulation of amyloid fibrils in organs, the direct toxicity of these variable domain LCs, full-length light chains, or primary amyloid precursors (oligomers) seems to play a role in the pathogenesis of the disease. Many in vitro studies have focused on these topics, but the variability of this disease, in which each LC presents unique properties, and the extent and complexity of affected organs make its study in vivo very difficult. Accordingly, several groups have focused on the development of animal models for years, with some encouraging but mostly disappointing results. In this review, we discuss the experimental models that have been used to better understand the unknowns of this pathology with an emphasis on in vivo approaches. We also focus on why reliable AL amyloidosis animal models remain so difficult to obtain and what this tells us about the pathophysiology of the disease.
Constrast-enhanced computed tomography radiomics predicts CD27 expression and clinical prognosis in head and neck squamous cell carcinoma
Authors: Wang Fang , Zhang Wenhao , Chai Ying , Wang Hanshao , Liu Zhonglong , He Yue
Published: November 2022

Objective

This study aimed to construct a radiomics model that predicts the expression level of CD27 in patients with head and neck squamous cell carcinoma (HNSCC).

Materials and methods

Genomic data and contrast-enhanced computed tomography (CT) images of patients with HNSCC were downloaded from the Cancer Genome Atlas and Cancer Imaging Archive for prognosis analysis, image feature extraction, and model construction. We explored the potential molecular mechanisms underlying CD27 expression and its relationship with the immune microenvironment and predicted CD27 mRNA expression in HNSCC tissues. Using non-invasive, CT-based radiomics technology, we generated a radiomics model and evaluated its correlation with the related genes and HNSCC prognosis.

Results and conclusion

The expression level of CD27 in HNSCC may significantly influence the prognosis of patients with HNSCC. Radiomics based on contrast-enhanced CT is potentially effective in predicting the expression level of CD27.
Mouse models of lung-specific SARS-CoV-2 infection with moderate pathological traits
Authors: Kim Sung-Hee , Kim Jiseon , Jang Ji Yun , Noh Hyuna , Park Jisun , Jeong Haengdueng , Jeon Donghun , Uhm Chanyang , Oh Heeju , Cho Kyungrae , Jeon Yoon , On Dain , Yoon Suhyeon , Lim Soo-Yeon , Kim Sol Pin , Lee Youn Woo , Jang Hui Jeong , Park In Ho , Oh Jooyeon , Seo Jung Seon , Kim Jeong Jin , Seok Sang-Hyuk , Lee Yu Jin , Hong Seung-Min , An Se-Hee , Kim Seo Yeon , Kim Young Been , Hwang Ji-Yeon , Lee Hyo-Jung , Kim Hong Bin , Choi Kang-Seuk , Park Jun Won , Seo Jun-Young , Yun Jun-Won , Shin Jeon-Soo , Lee Ho-Young , Kim Kyoungmi , Lee Daekee , Lee Ho , Nam Ki Taek , Seong Je Kyung
Published: November 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) has been a global health concern since 2019. The viral spike protein infects the host by binding to angiotensin-converting enzyme 2 (ACE2) expressed on the cell surface, which is then processed by type II transmembrane serine protease. However, ACE2 does not react to SARS-CoV-2 in inbred wild-type mice, which poses a challenge for preclinical research with animal models, necessitating a human ACE2 (hACE2)-expressing transgenic mouse model. Cytokeratin 18 (K18) promoter-derived hACE2 transgenic mice [B6.Cg-Tg(K18-ACE2)2Prlmn/J] are widely used for research on SARS-CoV-1, MERS-CoV, and SARS-CoV-2. However, SARS-CoV-2 infection is lethal at ≥105 PFU and SARS-CoV-2 target cells are limited to type-1 alveolar pneumocytes in K18-hACE2 mice, making this model incompatible with infections in the human lung. Hence, we developed lung-specific SARS-CoV-2 infection mouse models with surfactant protein B (SFTPB) and secretoglobin family 1a member 1 (Scgb1a1) promoters. After inoculation of 105 PFU of SARS-CoV-2 to the K18-hACE2, SFTPB-hACE2, and SCGB1A1-hACE2 models, the peak viral titer was detected at 2 days post-infection and then gradually decreased. In K18-hACE2 mice, the body temperature decreased by approximately 10°C, body weight decreased by over 20%, and the survival rate was reduced. However, SFTPB-hACE2 and SCGB1A1-hACE2 mice showed minimal clinical signs after infection. The virus targeted type I pneumocytes in K18-hACE2 mice; type II pneumocytes in SFTPB-hACE2 mice; and club, goblet, and ciliated cells in SCGB1A1-hACE2 mice. A time-dependent increase in severe lung lesions was detected in K18-hACE2 mice, whereas mild lesions developed in SFTPB-hACE2 and SCGB1A1-hACE2 mice. Spleen, small intestine, and brain lesions developed in K18-hACE2 mice but not in SFTPB-hACE2 and SCGB1A1-hACE2 mice. These newly developed SFTPB-hACE2 and SCGB1A1-hACE2 mice should prove useful to expand research on hACE2-mediated respiratory viruses.
Harnessing the small intestinal axis to resolve systemic inflammation
Authors: Bodmer Mark , Itano Andrea , McInnes Iain
Published: November 2022

This Perspective presents the potential of the Small Intestinal Axis, a sub-division of the Gut-immune Axis, to modulate systemic inflammation based on sensing contents of the gut lumen. Gut mucosal immunity regulates tolerance to food and gut contents and is a significant factor in maintaining systemic homeostasis without compromising immunity to pathogens. This is achieved through anatomical structures and signaling pathways that link the tolerogenic potential of the proximal small intestine to systemic immunity. Non-live preparations of microbes isolated from human small intestinal mucosa, and the extracellular vesicles (EVs) which they shed, can resolve systemic inflammation without systemic exposure after oral delivery. The mechanism involves primary interactions with pattern recognition receptors followed by trafficking of immune cells through mesenteric lymph nodes. This generates in the periphery a population of circulating CD4+ T cells which have regulatory function but an atypical FoxP3- phenotype. There is no modification of the resident gut microbiome. Discoveries using this novel approach of targeting mucosal microbial elements to the tolerogenic proximal regions of the small intestine are revealing some of the mysteries of the relationship between the gut and immune system.
Case report: The remarkable response of pembrolizumab combined with RC48 in the third-line treatment of metastatic urothelial carcinoma
Authors: Xu Zhenying , Ma Jiaman , Chen Ting , Yang Yu
Published: November 2022

Background

Systemic chemotherapy has been the mainstay treatment for locally advanced or metastatic urothelial carcinoma (UC). In the past few years, novel immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs) have improved the treatment of advanced UC.

Case presentation

Here, we report systemic therapy of a 68-year-old male diagnosed with HER2 positive (immunohistochemistry 3+), programmed cell death ligand 1(PD-L1) negative metastatic UC, and renal insufficiency. He had encountered numerous metastases and failed first-line platinum-based chemotherapy and second-line treatment with pembrolizumab and trastuzumab. During third-line treatment with RC48 (a HER2 targeting ADC) combined with pembrolizumab, he achieved a rapid partial response (PR) in the first evaluation and subsequent complete response (CR) on PET/CT and long-term progression-free survival (>12 months) at the last follow-up on 25 August 2022. There are no grade 3 or 4 adverse events or aggravations of renal insufficiency during the third-line therapy.

Discussion

RC48 combined with pembrolizumab demonstrated outstanding efficacy and safety in this HER2-positive metastatic UC patient. ADC combined with ICI is a promising anti-tumor strategy that deserves further exploration in advanced UC.
The β-carboline Harmine improves the therapeutic benefit of anti-PD1 in melanoma by increasing the MHC-I-dependent antigen presentation
Authors: Noman Muhammad Zaeem , Bocci Irene Adelaide , Karam Manale , Moer Kris Van , Bosseler Manon , Kumar Akinchan , Berchem Guy , Auclair Christian , Janji Bassam
Published: November 2022

Harmine is a dual-specificity tyrosine-regulated kinase 1A (DYRK1A) inhibitor that displays a number of biological and pharmacological properties. Also referred to as ACB1801 molecule, we have previously reported that harmine increases the presentation of major histocompatibility complex (MHC)-I-dependent antigen on melanoma cells. Here, we show that ACB1801 upregulates the mRNA expression of several proteins of the MHC-I such as Transporter Associated with antigen Processing TAP1 and 2, Tapasin and Lmp2 (hereafter referred to as MHC-I signature) in melanoma cells. Treatment of mice bearing melanoma B16-F10 with ACB1801 inhibits the growth and weight of tumors and induces a profound modification of the tumor immune landscape. Strikingly, combining ACB1801 with anti-PD1 significantly improves its therapeutic benefit in B16-F10 melanoma-bearing mice. These results suggest that, by increasing the MHC-I, ACB1801 can be combined with anti-PD1/PD-L1 therapy to improve the survival benefit in cancer patients displaying a defect in MHC-I expression. This is further supported by data showing thati)high expression levels of TAP1, Tapasin and Lmp2 was observed in melanoma patients that respond to anti-PD1;ii)the survival is significantly improved in melanoma patients who express high MHC-I signature relative to those expressing low MHC-I signature; andiii)high expression of MHC-I signature in melanoma patients was correlated with increased expression of CD8 and NK cell markers and overexpression of proinflammatory chemokines involved in the recruitment of CD8+ T cells.
Patients with inflammatory bowel disease are more hesitant about Coronavirus disease 2019 vaccination
Authors: Kwon Hyuk Joon , Panagos Katherine , Alizadeh Madeline , Bell Mack , Bourmaf Mohammad , Zisman Erin , Paul Pinkle , Sibel Lauren , Wong Uni
Published: November 2022

Despite the impact of the Coronavirus Disease 2019 (COVID-19) pandemic, vaccine hesitancy remains common in the general public and patients with Inflammatory Bowel Diseases (IBD). We sought to examine the reasons for vaccine hesitancy in patients with IBD. In this case-control study, we performed a retrospective chart review of 1,349 IBD patients and 215 non-IBD patients seen at University of Maryland Medical Center, a tertiary referral medical center, between March 2020 and October 2021. Data obtained included demographics, vaccination records, disease history, number of IBD-related surgeries, and IBD medications. 813/1,349 (60.3%) IBD patients received at least one dose of either the Pfizer/BioNTech, Moderna, or Johnson & Johnson vaccines. In a multivariate logistic regression, COVID vaccination was found to be positively associated with older age (p-value = 1.65e-5), female sex (p = 0.00194), Asian and White races (p = 0.02330, 0.00169), number of clinic visits (p = 1.11e-08), and biologic use (p = 7.82e-5). There was no association between vaccination and other types of vaccination nor with the use of other IBD medications. There was a negative association between vaccination status and the total number of IBD related surgeries (p = 0.02857). In non-IBD patients, only the number of clinic visits was positively associated with COVID-19 vaccination. Although the majority of IBD patients are immunosuppressed, COVID-19 vaccination rate was only 60.3%. Younger adults, males, African Americans, and those requiring IBD-related surgeries were less likely to receive COVID-19 vaccine. Healthcare providers need to recognize these potential risk factors for COVID-19 vaccine hesitancy.
The prevalence, comorbidities, influencing factors, and identifying factors of non-obese fatty liver disease
Authors: Gao Ning , Deng Jiang , Wang Jinhai , Zhou Zhihua , Yao Cong , Zhou Mimi , Xing Xin , Wang Qian , Lu Xiaolan , Shi Haitao
Published: November 2022

Objective

To analyze the prevalence, associated comorbidities, influencing factors, and identifying factors of non-obese fatty liver disease and to provide a reference for its prevention and treatment.

Materials and methods

Firstly, to screen data obtained from the physical examinations of individuals conducted in the Second Affiliated Hospital of Xi’an Jiaotong University in 2021, subjects with complete data of abdominal ultrasonography, body mass index, age and sex were selected to analyze the prevalence of fatty liver disease and non-obese fatty liver disease. Secondly, to screen non-obese subjects who had data for triglycerides, fasting blood glucose, and so on, to analyze the complications, influencing factors, and identifying factors of non-obese fatty liver disease.

Results

The prevalence of fatty liver disease was 27.8% (18,416/66,221), including 33.9% (11,921/35,131) in males and 20.9% (6,495/31,090) in females, revealing that the prevalence was significantly higher in males than in females (P < 0.001). There were 40,673 non-obese subjects screened in total, and the prevalence of non-obese fatty liver disease was 13.0% (5,307/40,673). The prevalence of non-obese fatty liver disease was 13.3% (2,208/16,572) in males and 12.9% (3,099/24,101) in females; the difference was not statistically significant (P = 0.17). The serum triglycerides level was elevated in 54.2% of subjects with non-obese fatty liver disease, and this was the most common abnormal metabolic index accompanying the disease. Logistic regression analysis showed that gender, age, body mass index, blood pressure, alanine aminotransferase, aspartate aminotransferase, fasting blood glucose, triglycerides, total cholesterol, and serum uric acid were independent risk factors for non-obese fatty liver disease (P < 0.001). For triglycerides, the area under the receiver operating characteristic curve in predicting non-obese fatty liver disease was the greatest (0.806).

Conclusion

The prevalence of fatty liver disease and non-obese fatty liver disease determined by the physical examination of individuals was high, and the triglycerides is likely to be useful for the extensive screening of non-obese fatty liver disease.