bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence for the spread of SARS-CoV-2 and olfactory cell lineage impairment in close-contact infection Syrian hamster models
Authors: Ueha Rumi , Ito Toshihiro , Ueha Satoshi , Furukawa Ryutaro , Kitabatake Masahiro , Ouji-Sageshima Noriko , Uranaka Tsukasa , Tanaka Hirotaka , Nishijima Hironobu , Kondo Kenji , Yamasoba Tatsuya
Published: October 2022

Objectives

Close contact with patients with COVID-19 is speculated to be the most common cause of viral transmission, but the pathogenesis of COVID-19 by close contact remains to be elucidated. In addition, despite olfactory impairment being a unique complication of COVID-19, the impact of SARS-CoV-2 on the olfactory cell lineage has not been fully validated. This study aimed to elucidate close-contact viral transmission to the nose and lungs and to investigate the temporal damage in the olfactory receptor neuron (ORN) lineage caused by SARS-CoV-2.

Methods

Syrian hamsters were orally administered SARS-CoV-2 nonvariant nCoV-19/JPN/TY/WK521/2020 as direct-infection models. On day 3 after inoculation, infected and uninfected hamsters were housed in the same cage for 30 minutes. These uninfected hamsters were subsequently assigned to a close-contact group. First, viral presence in the nose and lungs was verified in the infection and close-contact groups at several time points. Next, the impacts on the olfactory epithelium, including olfactory progenitors, immature ORNs, and mature ORNs were examined histologically. Then, the viral transmission status and chronological changes in tissue damage were compared between the direct-infection and close-contact groups.

Results

In the close-contact group, viral presence could not be detected in both the nose and lungs on day 3, and the virus was identified in both tissues on day 7. In the direct-infection group, the viral load was highest in the nose and lungs on day 3, decreased on day 7, and was no longer detectable on day 14. Histologically, in the direct-infection group, mature ORNs were most depleted on day 3 (p <0.001) and showed a recovery trend on day 14, with similar trends for olfactory progenitors and immature ORNs. In the close-contact group, there was no obvious tissue damage on day 3, but on day 7, the number of all ORN lineage cells significantly decreased (p <0.001).

Conclusion

SARS-CoV-2 was transmitted even after brief contact and subsequent olfactory epithelium and lung damage occurred more than 3 days after the trigger of infection. The present study also indicated that SARS-CoV-2 damages all ORN lineage cells, but this damage can begin to recover approximately 14 days post infection.
Biological characteristics and genomic analysis of a novel Vibrio parahaemolyticus phage phiTY18 isolated from the coastal water of Xiamen China
Authors: Liu Bo , Zheng Tingyi , Quan Rui , Jiang Xinglong , Tong Guixiang , Wei Xinxian , Lin Mao
Published: October 2022

Vibrio parahaemolyticus is a common pathogen usually controlled by antibiotics in mariculture. Notably, traditional antibiotic therapy is becoming less effective because of the emergence of bacterial resistance, hence new strategies need to be found to overcome this challenge. Bacteriophages, a class of viruses that lyse bacteria, can help us control drug-resistant bacteria. In this study, a novel Vibrio parahaemolyticus phage phiTY18 isolated from the coastal water of Xiamen was explored. Transmission electron microscopy showed that phiTY18 had an icosahedral head of 130.0 ± 1.2 nm diameter and a contractile tail of length of 66.7 ± 0.6 nm. The phage titer could reach 7.2×1010 PFU/mL at the optimal MOI (0.01). The phage phiTY18 had a degree of tolerance to heat and acid and base. At the temperature of 50°C (pH7.0, 1h) the survival phages reached 1.28×106 PFU/mL, and at pH 5-9 (30°C, 1h), the survival phages was greater than 6.37×107 PFU/mL Analysis of the phage one-step growth curve revealed that it had a latent period of 10min, a rise period of 10min, and an average burst size of the phage was 48 PFU/cell. Genome sequencing and analysis drew that phage phiTY18 had double-stranded DNA (191,500 bp) with 34.90% G+C content and contained 117 open reading frames (ORFs) and 24 tRNAs. Phylogenetic tree based on major capsid protein (MCP) revealed that phage phiTY18 (MW451250) was highly related to two Vibrio phages phiKT1024 (OM249648) and Va1 (MK387337). The NCBI alignment results showed that the nucleotide sequence identity was 97% and 93%, respectively. In addition, proteomic tree analysis indicated that phage phiTY18, phiKT1024, and Va1 were belong to the same virus sub-cluster within Myoviridae. This study provides a theoretical basis for understanding the genomic characteristics and the interaction between Vibrio parahaemolyticus phages and their host.
Sources of cognitive cost in scalar implicature processing: A review
Authors: Khorsheed Ahmed , Price Jessica , van Tiel Bob
Published: October 2022

Research in Experimental Pragmatics has shown that deriving scalar implicatures involves effort and processing costs. This finding was robust and replicated across a wide variety of testing techniques, logical terms, populations, and languages. However, a question that remains disputed in the literature is whether this observed processing cost is a product of the inferential process itself or other logical properties whose computation taxes cognitive resources independently of the inferential mechanism. This paper has two objectives: one is to review the previous experimental work on scalar implicatures and how it evolved in the literature, and the other is to discuss possible factors that render computing scalar implicatures cognitively effortful. Implications and directions for future research are provided.
Heart failure with preserved ejection fraction: Calculating the risk of future heart failure events and death
Authors: Schrutka Lore , Seirer Benjamin , Rettl René , Dachs Theresa-Marie , Binder Christina , Duca Franz , Dalos Daniel , Badr-Eslam Roza , Kastner Johannes , Hengstenberg Christian , Frommlet Florian , Bonderman Diana
Published: October 2022

Objective

We sought to develop a clinical model to identify heart failure patients with preserved ejection fraction (HFpEF) at highest risk for acute HF events or death.

Methods and results

Between 2010 and 2019, 422 patients with HFpEF were followed. Acute HF events occurred in 190 patients (45%), including 110 (58%) with recurrent hospitalizations. Those with recurrent events had worse 6-min walk test (p < 0.001), higher brain N-terminal prohormone natriuretic peptide (NT-proBNP, p < 0.001), and higher New York Heart Association functional class (NYHA, p < 0.001). Overall survival rates in patients with 1 HF event vs > 1 HF events were: at 1-year 91.6 vs. 91.8%, at 3-years 84.7 vs. 68.3% and at 5-years 67.4 vs. 42.7%, respectively (p < 0.04). The Hfpef survivAL hOspitalization (HALO) score revealed best predictive capability for all-cause mortality combining the variables age (p = 0.08), BMI (p = 0.124), NYHA class (p = 0.004), need for diuretic therapy (p = 0.06), left atrial volume index (p = 0.048), systolic pulmonary artery pressure (p = 0.013), NT-proBNP (p = 0.076), and number of prior hospitalizations (p = 0.006). HALO score predicted future HF hospitalizations in an ordinal logistic regression model (OR 3.24, 95% CI: 2.45–4.37, p < 0.001). The score performance was externally validated in 75 HFpEF patients, confirming a strong survival prediction (HR 2.13, 95% CI: 1.30–3.47, p = 0.002).

Conclusions

We developed a model to identify HFpEF patients at increased risk of death and HF hospitalization. NYHA class and recurrent HF hospitalizations were the strongest drivers of outcome.
Current status of diagnosis and treatment of primary benign cardiac tumors in children
Authors: Sheng Chuqiao , Yang Chunfeng , Cheng Yongkang , Li Yu-Mei
Published: October 2022

Primary cardiac tumors in children are exceedingly rare overall, which benign account for most part. The onset of the disease is occult, while the clinical manifestations are non-specific-patients may be asymptomatic or show a range of obstructive, arrhythmic, embolic or systemic symptoms. The clinical presentations generally depend on the tumors’ size, localization, and pace of growth of the tumor. Moreover, the diagnosis needs comprehensive judgment based on imaging results and pathological examination. With advances in cardiac imagining and the introduction of cardiopulmonary support, the diagnosis and treatment of these rare tumors have improved the prognosis and outlook for benign tumors. To sum up the above, we sought to integrate articles from recent years for the latest comprehensive review of the clinical manifestations, imaging characteristics, clinic pathologic features and treatment of benign cardiac tumors in children to provide a broader idea for pediatricians to recognize and treat such diseases.
Real-world data mining meets clinical practice: Research challenges and perspective
Authors: Mandreoli Federica , Ferrari Davide , Guidetti Veronica , Motta Federico , Missier Paolo
Published: October 2022

As Big Data Analysis meets healthcare applications, domain-specific challenges and opportunities materialize in all aspects of data science. Advanced statistical methods and Artificial Intelligence (AI) on Electronic Health Records (EHRs) are used both for knowledge discovery purposes and clinical decision support. Such techniques enable the emerging Predictive, Preventative, Personalized, and Participatory Medicine (P4M) paradigm. Working with the Infectious Disease Clinic of the University Hospital of Modena, Italy, we have developed a range of Data–Driven (DD) approaches to solve critical clinical applications using statistics, Machine Learning (ML) and Big Data Analytics on real-world EHR. Here, we describe our perspective on the challenges we encountered. Some are connected to medical data and their sparse, scarce, and unbalanced nature. Others are bound to the application environment, as medical AI tools can affect people's health and life. For each of these problems, we report some available techniques to tackle them, present examples drawn from our experience, and propose which approaches, in our opinion, could lead to successful real-world, end-to-end implementations.

DESY report number

DESY-22-153.
Local-scale spatial variability in firn properties in Southwest Greenland
Authors: Xiao Jing , Rennermalm Åsa K. , Covi Federico , Hock Regine , Leidman Sasha Z. , Miège Clément , MacFerrin Michael J. , Samimi Samira
Published: October 2022

The increasing mass loss from the Greenland ice sheet is becoming growingly important to present-day global sea level rise. Meltwater export to the ocean may be amplified by near-surface ice layers in firn (i.e., snow that has survived at least one melt season) which prevent infiltration. Such ice layers have been documented at various sites in southwest Greenland, but little is known about the local-scale (less than 1 km) variability in firn and ice properties. Here we investigate the local variability in firn density and ice content (ice layer thickness fraction) by analyzing 45 shallow firn cores retrieved from 15 sites in southwest Greenland between 2012 and 2019. The core dataset contains groups of cores that were collected at the same site (1–632 m apart from each other) and in the same year (here referred to as same site/year cores). The two-sided Mann-Whitney U-tests suggest that most same site/year cores do not have statistically significant differences in median density or ice content over the upper 0–4.5, 4.5–9, and 9–13.5 m sections below the winter snow layer. That said, the same site/year cores still exhibit substantial density and ice content differences as well as variable ice layer stratigraphy (especially the distribution of centimeters-thick ice lenses) not explainable by measurement uncertainties. The local-scale variability in density and ice content (calculated from the same site/year cores) over the three 4.5-m sections is 4% and 19–29%, respectively. The variability is comparable to the regional gradient in our study area within an elevation difference of up to ∼200 m. The local variability is non-negligible particularly at mid- to high-elevation sites (>2,000 m a.s.l.), where firn structure changes such as ice layer formation are more recent phenomena compared to lower elevations. This study confirms that single cores can provide representative bulk statistics such as mean density and ice content of one site. However, these mean values mask substantial local variability which can compromise regional comparisons. Therefore, collection of same site/year cores and consideration of local variability are necessary for an in-depth analysis of regional variability.
Tri-clustering–based exploration of spatio-temporal heterogeneity of six criteria air pollutants and their relationships in China
Authors: Wu Xiaojing
Published: October 2022

Severe air pollution in China has become a challenging issue because of its adverse health effects. The distribution of air pollutants and their relationships exhibits spatio-temporal heterogeneity due to influences by meteorological and socioeconomic factors. Investigation of spatio-temporal variations of criteria air pollutants and their relationships, thus, helps understand the current status and further assist pollution prevention and control. Even though many studies have been conducted, relationships among pollutants are non-linear due to complicated chemical reactions and were difficult to model by linear analyses in previous studies. Here, we presented a tri-clustering–based method, the Bregman cuboid average tri-clustering algorithm with I-divergence (BCAT_I), to explore spatio-temporal heterogeneity of air pollutants and their relationships in China. Concentrations of PM2.5, PM10, CO, SO2, NO2, and O3 in 31 provincial cities in 2021 were used as the case study dataset. Results showed that air pollutants except O3 exhibited spatial and seasonal variations, i.e., low in summer in southern cities and high in winter in northern cities. Variations of PMs were more similar to those of CO than other pollutants in southern cities in 2021. Results also found that relationships among these air pollutants were heterogeneous in different regions and time periods in China. Moreover, with the increasing level of NO2 from summer to winter in northern cities, concentrations of O3 first decreased and then increased. This is because the response of O3 to NO2 was negative at the low pollution level due to the titration reaction, which, however, changed to positive when concentrations of NO2 became high.
Leveraging the strengths of mice, human stem cells, and organoids to model pancreas development and diabetes
Authors: Lorberbaum David S. , Sarbaugh Dylan , Sussel Lori
Published: October 2022

Diabetes is an epidemic with increasing incidence across the world. Most individuals who are afflicted by this disease have type 2 diabetes, but there are many who suffer from type 1, an autoimmune disorder. Both types of diabetes have complex genetic underpinnings that are further complicated by epigenetic and environmental factors. A less prevalent and often under diagnosed subset of diabetes cases are characterized by single genetic mutations and include Maturity Onset Diabetes of the Young (MODY) and Neonatal Diabetes Mellitus (NDM). While the mode of action and courses of treatment for all forms of diabetes are distinct, the diseases all eventually result in the dysfunction and/or death of the pancreatic β cell - the body’s source of insulin. With loss of β cell function, blood glucose homeostasis is disrupted, and life-threatening complications arise. In this review, we focus on how model systems provide substantial insights into understanding β cell biology to inform our understanding of all forms of diabetes. The strengths and weaknesses of animal, hPSC derived β-like cell, and organoid models are considered along with discussion of GATA6, a critical transcription factor frequently implicated in pancreatic dysfunction with developmental origins; experimental studies of GATA6 have highlighted the advantages and disadvantages of how each of these model systems can be used to inform our understanding of β cell specification and function in health and disease.
Single-cell RNA-seq analysis and cell-cluster deconvolution of the human preovulatory follicular fluid cells provide insights into the pathophysiology of ovarian hyporesponse
Authors: Roos Kristine , Rooda Ilmatar , Keif Robyn-Stefany , Liivrand Maria , Smolander Olli-Pekka , Salumets Andres , Velthut-Meikas Agne
Published: October 2022

Reduction in responsiveness to gonadotropins or hyporesponsiveness may lead to the failure of in vitro fertilization (IVF), due to a low number of retrieved oocytes. The ovarian sensitivity index (OSI) is used to reflect the ovarian responsiveness to gonadotropin stimulation before IVF. Although introduced to clinical practice already years ago, its usefulness to predict clinical outcomes requires further research. Nevertheless, pathophysiological mechanisms of ovarian hyporesponse, along with advanced maternal age and in younger women, have not been fully elucidated. Follicles consist of multiple cell types responsible for a repertoire of biological processes including responding to pituitary gonadotropins necessary for follicle growth and oocyte maturation as well as ovulation. Encouraging evidence suggests that hyporesponse could be influenced by many contributing factors, therefore, investigating the variability of ovarian follicular cell types and their gene expression in hyporesponders is highly informative for increasing their prognosis for IVF live birth. Due to advancements in single-cell analysis technologies, the role of somatic cell populations in the development of infertility of ovarian etiology can be clarified. Here, somatic cells were collected from the fluid of preovulatory ovarian follicles of patients undergoing IVF, and RNA-seq was performed to study the associations between OSI and gene expression. We identified 12 molecular pathways differentially regulated between hypo- and normoresponder patient groups (FDR<0.05) from which extracellular matrix organization, post-translational protein phosphorylation, and regulation of Insulin-like Growth Factor (IGF) transport and uptake by IGF Binding Proteins were regulated age-independently. We then generated single-cell RNA-seq data from matching follicles revealing 14 distinct cell clusters. Using cell cluster-specific deconvolution from the bulk RNA-seq data of 18 IVF patients we integrated the datasets as a novel approach and discovered that the abundance of three cell clusters significantly varied between hypo- and normoresponder groups suggesting their role in contributing to the deviations from normal ovarian response to gonadotropin stimulation. Our work uncovers new information regarding the differences in the follicular gene expression between hypo- and normoresponders. In addition, the current study fills the gap in understanding the inter-patient variability of cell types in human preovulatory follicles, as revealed by single-cell analysis of follicular fluid cells.
Activation of G protein-coupled receptors by ketone bodies: Clinical implication of the ketogenic diet in metabolic disorders
Authors: Spigoni Valentina , Cinquegrani Gloria , Iannozzi Nicolas Thomas , Frigeri Giulia , Maggiolo Giulia , Maggi Marta , Parello Vanessa , Dei Cas Alessandra
Published: October 2022

Ketogenesis takes place in hepatocyte mitochondria where acetyl-CoA derived from fatty acid catabolism is converted to ketone bodies (KB), namely β-hydroxybutyrate (β-OHB), acetoacetate and acetone. KB represent important alternative energy sources under metabolic stress conditions. Ketogenic diets (KDs) are low-carbohydrate, fat-rich eating strategies which have been widely proposed as valid nutritional interventions in several metabolic disorders due to its substantial efficacy in weight loss achievement. Carbohydrate restriction during KD forces the use of FFA, which are subsequently transformed into KB in hepatocytes to provide energy, leading to a significant increase in ketone levels known as “nutritional ketosis”. The recent discovery of KB as ligands of G protein-coupled receptors (GPCR) - cellular transducers implicated in a wide range of body functions - has aroused a great interest in understanding whether some of the clinical effects associated to KD consumption might be mediated by the ketone/GPCR axis. Specifically, anti-inflammatory effects associated to KD regimen are presumably due to GPR109A-mediated inhibition of NLRP3 inflammasome by β-OHB, whilst lipid profile amelioration by KDs could be ascribed to the actions of acetoacetate via GPR43 and of β-OHB via GPR109A on lipolysis. Thus, this review will focus on the effects of KD-induced nutritional ketosis potentially mediated by specific GPCRs in metabolic and endocrinological disorders. To discriminate the effects of ketone bodies per se, independently of weight loss, only studies comparing ketogenic vs isocaloric non-ketogenic diets will be considered as well as short-term tolerability and safety of KDs.
Enhancing the functionality of environmental flows through an understanding of biophysical processes in the riverine landscape
Authors: Yarnell Sarah M. , Thoms Martin
Published: October 2022

While water resource managers and river scientists recognize the inherent interconnections among hydrology, river structure, biophysical processes and ecological patterns, management of environmental flows still pays insufficient attention to the ecological and geomorphological functionality of particular aspects of the flow regime. Implementation of more natural flow regimes has improved habitat conditions for native species in many moderately impaired rivers but mimicking a natural flow regime in heavily modified riverine landscapes cannot be expected to yield successful ecological outcomes unless such flows trigger functional processes. For example, the restoration of peak flows may not regenerate habitats if the river is starved of sediment or if the river channel is highly confined. High biodiversity is supported when variable flow regimes interact with spatially variable (heterogeneous) river channel and floodplain forms. In contrast, as rivers become homogeneous, biodiversity decreases when these dynamic spatiotemporal interactions are limited by flow alterations, blocked by channel levees, or perturbed by sediment deficit or surplus. Thus, the design of a more natural environmental flow regime without consideration of the implications for sediment transport and implicit recognition of channel–floodplain geomorphology is likely to have limited success in river management and restoration. To enhance the functionality of environmental flows, considerations of physical, biogeochemical, and ecological processes and the inherent heterogeneity of the riverine landscape must be included. A Functional Flows approach enhances the benefits from limited environmental flow allocations by focusing on the ecological and geomorphological functionality of particular aspects of the flow regime, considering geomorphic context, and emphasizing spatiotemporal diversity at key locations in the riverscape, such as adjacent floodplains or tributary junctions. In this paper, we outline and illustrate the concept of Functional Flows using a flow-chain model and provide two case study examples from Australia and the United States, where improvements in channel habitat and reconnection with the floodplain help to achieve the desired functionality of environmental flows.
Good news! Sampling intensity needed for accurate assessments of dung beetle diversity may be lower in the Neotropics
Authors: Rivera Jose D. , Favila Mario E.
Published: October 2022

Ecological studies with Scarabaeinae dung beetles have increased exponentially over the past 30 years, using lethal pitfall traps baited with mammal feces or carrion as the preferred sampling method. Different studies have determined the distance between pitfall traps for effective sampling, but the number of traps is often subjective, leading to excessive or poor sampling. This study provides quantitative guidelines for establishing the sample size for optimal completeness of dung beetle diversity by systematically reviewing the relationship between sampling intensity and sampling coverage, habitat type, and the journal impact factor in peer-reviewed research. We gathered 94 studies covering a range from México to Argentina. Sampling was conducted mainly in forested habitats, followed by treeless agriculture and agroforestry systems, with a median value of 50 pitfall traps per sampled habitat. Sampling completeness was above 0.9 in 95% of the studies. Oversampling ranged from 1 to more than 96,000 individuals, and sampling deficit varied between 2 and 3,300 specimens. Sampling intensity and the journal impact factor were significantly and positively correlated with oversampling, but these variables did not explain the sampling deficit. The positive correlation between journal impact factor and oversampling may reflect a publication bias where high-impact journals and researchers seek more generalizable information obtained with a higher sampling intensity. Dung beetle oversampling was not homogeneous between habitats, being highest in old-growth forests and lowest in disturbed habitats such as pastures and forest edges. Our results show that the collection intensity used in dung beetle studies should be reconsidered carefully. By incorporating ethical principles used in animal science, we suggest sampling guidelines for a robust sampling scheme of dung beetle diversity, which would also prevent oversampling. Consciously reducing sampling intensity will make resource use more cost-effective. We suggest increasing the number of independent sampling units rather than intensifying subsampling, thereby increasing the predictive power of statistical models to obtain more robust evidence of the phenomena under study.
Multi-omic data integration for the study of production, carcass, and meat quality traits in Nellore cattle
Authors: Novais Francisco José de , Yu Haipeng , Cesar Aline Silva Mello , Momen Mehdi , Poleti Mirele Daiana , Petry Bruna , Mourão Gerson Barreto , Regitano Luciana Correia de Almeida , Morota Gota , Coutinho Luiz Lehmann
Published: October 2022

Data integration using hierarchical analysis based on the central dogma or common pathway enrichment analysis may not reveal non-obvious relationships among omic data. Here, we applied factor analysis (FA) and Bayesian network (BN) modeling to integrate different omic data and complex traits by latent variables (production, carcass, and meat quality traits). A total of 14 latent variables were identified: five for phenotype, three for miRNA, four for protein, and two for mRNA data. Pearson correlation coefficients showed negative correlations between latent variables miRNA 1 (mirna1) and miRNA 2 (mirna2) (−0.47), ribeye area (REA) and protein 4 (prot4) (−0.33), REA and protein 2 (prot2) (−0.3), carcass and prot4 (−0.31), carcass and prot2 (−0.28), and backfat thickness (BFT) and miRNA 3 (mirna3) (−0.25). Positive correlations were observed among the four protein factors (0.45–0.83): between meat quality and fat content (0.71), fat content and carcass (0.74), fat content and REA (0.76), and REA and carcass (0.99). BN presented arcs from the carcass, meat quality, prot2, and prot4 latent variables to REA; from meat quality, REA, mirna2, and gene expression mRNA1 to fat content; from protein 1 (prot1) and mirna2 to protein 5 (prot5); and from prot5 and carcass to prot2. The relations of protein latent variables suggest new hypotheses about the impact of these proteins on REA. The network also showed relationships among miRNAs and nebulin proteins. REA seems to be the central node in the network, influencing carcass, prot2, prot4, mRNA1, and meat quality, suggesting that REA is a good indicator of meat quality. The connection among miRNA latent variables, BFT, and fat content relates to the influence of miRNAs on lipid metabolism. The relationship between mirna1 and prot5 composed of isoforms of nebulin needs further investigation. The FA identified latent variables, decreasing the dimensionality and complexity of the data. The BN was capable of generating interrelationships among latent variables from different types of data, allowing the integration of omics and complex traits and identifying conditional independencies. Our framework based on FA and BN is capable of generating new hypotheses for molecular research, by integrating different types of data and exploring non-obvious relationships.
Prognosis and immune response of a cuproptosis-related lncRNA signature in low grade glioma
Authors: Xu Yifan , Wang Chao , Li Shifang , Zhou Han , Feng Yugong
Published: October 2022

Cuproptosis is a newly discovered new mechanism of programmed cell death, and its unique pathway to regulate cell death is thought to have a unique role in understanding cancer progression and guiding cancer therapy. However, this regulation has not been studied in low grade glioma (LGG) at present. In this study, data on low grade glioma patients were downloaded from the TCGA database. We screened the genes related to cuproptosis from the published papers and confirmed the lncRNAs related to them. We applied univariate/multivariate, and LASSO regression algorithms, finally identified 11 lncRNAs for constructing prognosis prediction models, and constructed a risk scoring model. The reliability and validity test of the model indicated that the model could well distinguish the prognosis and survival of LGG patients. Furthermore, the analyses of immunotherapy, immune microenvironment, as well as functional enrichment were also performed. Finally, we verified the expression of these six prognostic key lncRNAs using real-time polymerase chain reaction (RT-PCR). In conclusion, this study is the first analysis based on cuproptosis-related lncRNAs in LGG and aims to open up new directions for LGG therapy.
Ensemble learning-based feature selection for phosphorylation site detection
Authors: Liu Songbo , Cui Chengmin , Chen Huipeng , Liu Tong
Published: October 2022

SARS-COV-2 is prevalent all over the world, causing more than six million deaths and seriously affecting human health. At present, there is no specific drug against SARS-COV-2. Protein phosphorylation is an important way to understand the mechanism of SARS -COV-2 infection. It is often expensive and time-consuming to identify phosphorylation sites with specific modified residues through experiments. A method that uses machine learning to make predictions about them is proposed. As all the methods of extracting protein sequence features are knowledge-driven, these features may not be effective for detecting phosphorylation sites without a complete understanding of the mechanism of protein. Moreover, redundant features also have a great impact on the fitting degree of the model. To solve these problems, we propose a feature selection method based on ensemble learning, which firstly extracts protein sequence features based on knowledge, then quantifies the importance score of each feature based on data, and finally uses the subset of important features as the final features to predict phosphorylation sites.
Rhinovirus-induced anti-viral interferon secretion is not deficient and not delayed in sinonasal epithelial cells of patients with chronic rhinosinusitis with nasal polyp
Authors: Lee Sang Hag , Han Mun Soo , Lee Tae Hoon , Lee Da Bin , Park Jae Hyung , Lee Seung Hyeok , Kim Tae Hoon
Published: October 2022

Dysregulated innate and adaptive immune response to rhinoviral infection plays an important role in the exacerbation or progressive course of chronic rhinosinusitis (CRS). However, few studies have evaluated whether rhinovirus-induced production of anti-viral interferon is deficient or delayed in inflammatory epithelial cells of patients with CRS with nasal polyps. The aim of the present study is to investigate the replication rates of rhinovirus 16 (RV 16), RV16-induced antiviral interferon secretion, and the expression levels of pattern recognition receptors after RV 16 infection or TLR3 stimulation with poly (I: C) in normal and inflammatory epithelial cells. Inflammatory epithelial cells were obtained from CRS patients with nasal polyps and normal epithelial cells were derived from ethmoid sinus mucosa during endoscopic reduction of blowout fracture or uncinate process mucosa of patients with septal deviation. Cultured cells were infected with RV 16 or treated with poly (I: C) for 24, 48, and 72 h. Cells and media were harvested at each time point and used to evaluate RV16 replication rates, the secretion of IFN-β, -λ1, -λ2, viperin, Mx, and OAS, and the expression levels of TRL3, RIG-I, MDA5, phospho-NFκB, and phospho-IRF3. RV replication rates reached peak levels 48 h after inoculation in both normal and inflammatory epithelial cells and showed no difference between both groups of epithelial cells at any time point. The release of IFN-β, -λ1, and -λ2 in normal and inflammatory epithelial cells was also strongly induced 48 h after RV16 inoculation but reached peak levels 24 h after poly (I: C) treatment. The expression levels of viperin, Mx, OAS, TLR3, RIG-I, MDA5, phospho-NFκB, and phospho-IRF3 showed similar patterns in both groups of epithelial cells. These results suggest that the production of RV16-induced antiviral interferons is not deficient or delayed in inflammatory epithelial cells from CRS patients with nasal polyps.
Case report: ETS1 gene deletion associated with a low number of recent thymic emigrants in three patients with Jacobsen syndrome
Authors: Trachsel Tina , Prader Seraina , Steindl Katharina , Pachlopnik Schmid Jana
Published: October 2022

Jacobsen syndrome is a rare genetic disorder associated with a terminal deletion in chromosome 11. The clinical presentation is variable. Although immunodeficiency has been described in patients with Jacobsen syndrome, a clear genotype-phenotype correlation has not yet been established. Here, we report on the immunologic phenotypes of four patients with Jacobsen syndrome. All four patients showed one or more atypical immunologic features. One patient suffered from recurrent viral infections, two patients had experienced a severe bacterial infection and one had received antibiotic prophylaxis since early childhood. One patient had experienced severe, transient immune dysregulation. Hypogammaglobulinemia and low B cell counts were found in two patients, while the number of recent thymic emigrants (CD31+CD45RA+ CD4 cells) was abnormally low in three. When considering the six immune-related genes located within the affected part of chromosome 11 (ETS1, TIRAP, FLI1, NFRKB, THYN1, and SNX19), only the ETS1 gene was found be deleted in the three patients with low numbers of recent thymic emigrants and non-switched memory B cells. Our findings support the hypothesis whereby Jacobsen syndrome is associated with a combined immunodeficiency with variable presentation. Further investigations of potential genotype-phenotype correlations are warranted and might help to personalize patient management in individuals lacking immune-related genes. In addition, we recommend immunologic follow-up for all patients with Jacobsen syndrome, as immune abnormalities may develop over time.
Effects of hypoxia on antigen presentation and T cell-based immune recognition of HPV16-transformed cells
Authors: Mohan Nitya , Wellach Kathrin , Özerdem Ceren , Veits Nisha , Förster Jonas D. , Foehr Sophia , Bonsack Maria , Riemer Angelika B.
Published: October 2022

Attempts to develop a therapeutic vaccine against human papillomavirus (HPV)-induced malignancies have mostly not been clinically successful to date. One reason may be the hypoxic microenvironment present in most tumors, including cervical cancer. Hypoxia dysregulates the levels of human leukocyte antigen (HLA) class I molecules in different tumor entities, impacts the function of cytotoxic T cells, and leads to decreased protein levels of the oncoproteins E6 and E7 in HPV-transformed cells. Therefore, we investigated the effect of hypoxia on the presentation of HPV16 E6- and E7-derived epitopes in cervical cancer cells and its effect on epitope-specific T cell cytotoxicity. Hypoxia induced downregulation of E7 protein levels in all analyzed cell lines, as assessed by Western blotting. However, contrary to previous reports, no perturbation of antigen processing and presentation machinery (APM) components and HLA-A2 surface expression upon hypoxia treatment was detected by mass spectrometry and flow cytometry, respectively. Cytotoxicity assays performed in hypoxic conditions showed differential effects on the specific killing of HPV16-positive cervical cancer cells by epitope-specific CD8+ T cell lines in a donor- and peptide-specific manner. Effects of hypoxia on the expression of PD-L1 were ruled out by flow cytometry analysis. Altogether, our results under hypoxia show a decreased expression of E6 and E7, but an intact APM, and epitope- and donor-dependent effects on T cell cytotoxicity towards HPV16-positive target cells. This suggests that successful immunotherapies can be developed for hypoxic HPV-induced cervical cancer, with careful choice of target epitopes, and ideally in combination with hypoxia-alleviating measures.
Research trends on clinical fecal microbiota transplantation: A biliometric analysis from 2001 to 2021
Authors: Li Yu , Ouyang Yaobin , He Cong
Published: October 2022

Background

Numerous studies on fecal microbiota transplantation (FMT) have been conducted in the past two decades. We aimed to assess the research trends and hotspots in the field of FMT through a quantitative method.

Materials and Methods

The clinical studies of FMT published from 2001 to 2021 were extracted from the Web of Science database. We analyzed the countries, institutions, authors, and keywords of these articles and visually illustrated using VOSviewer and CiteSpace software. The current application of FMT in clinical practice, including indications, efficacy, adverse events, as well as its methodology, such as donor, delivery route, were also evaluated.

Results

A total of 227 records were finally identified. The number and rate of annual publications increased gradually. The USA ranked highest in the number of publications. Harvard University was the most influential institution, and Digestive Diseases and Sciences was the most productive journal. Kassam Zain published the most papers, and the high-frequency keywords were mainly related to diseases and techniques. Healthy donors were the most widely used donors, and frozen stool had the highest frequency of use. The predominant delivery route was endoscopy followed by oral capsules and enema. FMT was most frequently performed for the treatment of recurrent Clostridium Difficile Infection. The overall efficacy of FMT was 76.88%, and the incidence of minor and severe adverse events were 11.63% and 1.59%, respectively.

Conclusions

This study delineated a comprehensive landscape of the advancement in FMT field. Although in its infancy, FMT is a burgeoning option for the treatment of a variety of diseases associated with gut dysbiosis. To improve the efficacy and reduce adverse events, future studies are warranted to optimize the methodology of FMT.
Biological screening of a unique drug library targeting MRGPRX2
Authors: Yang Fan , Limjunyawong Nathachit , Peng Qi , Schroeder John T. , Saini Sarbjit , MacGlashan Donald , Dong Xinzhong , Gao Li
Published: October 2022

Background

Allergic drug reaction or drug allergy is an immunologically mediated drug hypersensitivity reaction (DHR). G-protein coupled receptors (GPCRs) are common drug targets and communicate extracellular signals that initiate cellular responses. Recent evidence shows that GPCR MRGPRX2 is of major importance in IgE-independent pseudo-allergic DHRs based on the suspected interactions between many FDA-approved peptidergic compounds and MRGPRX2.

Objective

Our aim was to uncover novel MRGPRX2-selective and -potent agonists as drug candidates responsible for clinical features of pseudo-allergic DHRs.

Methods

We conducted a primary high-throughput screening (HTS), coupled with mutagenesis targeting the MRGPRX2 N62S mutation, on a panel of 3,456 library compounds. We discovered pharmacologically active hit compounds as agonists of the MRGPRX2 protein according to high degrees of potency evaluated by the calcium response and validated by the degranulation assay. Using the molecular tool Forge, we also characterized the structure-activity relationship shared by identified hit compounds.

Results

The alternative allele of single nucleotide polymorphism rs10833049 (N62S) in MRGPRX2 demonstrated loss-of-function property in response to substance P and antineoplastic agent daunorubicin hydrochloride. We applied a unique assay system targeting the N62S mutation to the HTS and identified 84 MRGPRX2-selective active hit compounds representing diverse classes according to primary drug indications. The top five highly represented groups included fluoroquinolone and non-fluoroquinolone antibiotics; antidepressive/antipsychotic; antihistaminic and antineoplastic agents. We classified hit compounds into 14 clusters representing a variety of chemical and drug classes beyond those reported, such as opioids, neuromuscular blocking agents, and fluoroquinolones. We further demonstrated MRGPRX2-dependent degranulation in the human mast cell line LAD2 cells induced by three novel agonists representing the non-fluoroquinolone antibiotics (bacitracin A), anti-allergic agents (brompheniramine maleate) and tyrosine-kinase inhibitors (imatinib mesylate).

Conclusion

Our findings could facilitate the development of interventions for personalized prevention and treatment of DHRs, as well as future pharmacogenetic investigations of MRGPRX2 in relevant disease cohorts.
Hallucinating structure-conditioned antibody libraries for target-specific binders
Authors: Mahajan Sai Pooja , Ruffolo Jeffrey A. , Frick Rahel , Gray Jeffrey J.
Published: October 2022

Antibodies are widely developed and used as therapeutics to treat cancer, infectious disease, and inflammation. During development, initial leads routinely undergo additional engineering to increase their target affinity. Experimental methods for affinity maturation are expensive, laborious, and time-consuming and rarely allow the efficient exploration of the relevant design space. Deep learning (DL) models are transforming the field of protein engineering and design. While several DL-based protein design methods have shown promise, the antibody design problem is distinct, and specialized models for antibody design are desirable. Inspired by hallucination frameworks that leverage accurate structure prediction DL models, we propose the FvHallucinator for designing antibody sequences, especially the CDR loops, conditioned on an antibody structure. Such a strategy generates targeted CDR libraries that retain the conformation of the binder and thereby the mode of binding to the epitope on the antigen. On a benchmark set of 60 antibodies, FvHallucinator generates sequences resembling natural CDRs and recapitulates perplexity of canonical CDR clusters. Furthermore, the FvHallucinator designs amino acid substitutions at the VH-VL interface that are enriched in human antibody repertoires and therapeutic antibodies. We propose a pipeline that screens FvHallucinator designs to obtain a library enriched in binders for an antigen of interest. We apply this pipeline to the CDR H3 of the Trastuzumab-HER2 complex to generate in silico designs predicted to improve upon the binding affinity and interfacial properties of the original antibody. Thus, the FvHallucinator pipeline enables generation of inexpensive, diverse, and targeted antibody libraries enriched in binders for antibody affinity maturation.
Spatial-temporal variations of the gas hydrate stability zone and hydrate accumulation models in the Dongsha region, China
Authors: Song Yingrui , Lei Yuhong , Zhang Likuan , Cheng Ming , Miao Laicheng , Li Chao , Liu Naigui
Published: October 2022

It is of great significance to study the spatial-temporal variations of the thickness of the gas hydrate stability zone (GHSZ) to understand the decomposition, migration, accumulation and dissipation of gas hydrate, the corresponding relationship between bottom-simulating reflectors (BSRs) and gas hydrate, and the distribution of heterogeneous gas hydrate. We selected the Dongsha region in the South China Sea (SCS) as the research object to calculate the spatial-temporal variation of the GHSZ since 10 Ma, analyzed the main factors affecting the thickness of the GHSZ, discussed the dynamic accumulation processes of gas hydrate, and proposed an accumulation model of gas hydrate in the Dongsha region. The results show that the thicknesses of the GHSZ in the study area were between 0 m and 100 m from 10 to 5.11 Ma, and the relatively higher bottom water temperature (BWT) was the key factor leading to the thinner thickness of the GHSZ during this period. From 5.11-0 Ma, the thickness of the GHSZ gradually increased but showed several fluctuations in thickness due to changes in the geothermal gradient, seawater depth, BWT, and other factors. The decrease in the BWT was the main factor leading to GHSZ thickening from 5.11 to 0 Ma. The thicknesses of the GHSZ are between 110 m and 415 m at present. The present spatial distribution features show the following characteristics. The GHSZ in the deep canyon area is relatively thick, with thicknesses generally between 225 m and 415 m, while the GHSZ in other areas is relatively thin, with thicknesses between 110 m and 225 m. Based on the characteristics of the GHSZ, two hydrate accumulation models are proposed: a double-BSRs model due to thinning of the GHSZ and a multilayer hydrate model due to thickness changes of the GHSZ, with single or multiple BSRs.
Effects of air-entraining agent and polypropylene fiber on the mechanical properties, autogenous shrinkage, and fracture properties of fully recycled aggregate concrete
Authors: Ding Dong , Zhang Lijuan , Zhao Jun , Li Changbin , Wang Zhi
Published: October 2022

The effects of air-entraining agent (AEA) and polypropylene fiber (PPF) on the autogenous shrinkage and fracture properties of fully recycled aggregate concrete (FRAC) are studied to obtain FRAC with low density, low autogenous shrinkage, and superior fracture properties. Six groups of FRAC with different AEA (0, 5%, 10%) and PPF (0, 1.2 kg/m3) contents were prepared for test. The results illustrate that AEA can slightly reduce density but that it has an adverse effect on the strength and fracture properties of FRAC. The incorporation of PPFs can reduce the adverse effect of AEA on compressive strength and splitting tensile strength, but it will increase the adverse effect on fracture properties. Furthermore, the addition of PPFs alone will significantly reduce compressive strength and splitting tensile strength, whereas flexural strength and fracture properties are increased. The addition of AEA can improve the adverse effect of PPFs on compressive strength and splitting tensile strength, but flexural strength and fracture properties will decrease rather than increase. The addition of 10% AEA can greatly reduce autogenous shrinkage, and 5% AEA can reduce autogenous shrinkage at an early age. Incorporating PPFs can further reduce autogenous shrinkage. The study mainly examines the effects of AEA and PPF on the autogenous shrinkage of FRAC, and provides some new ideas for producing high-performance FRAC. At the same time, the cooperative effect of AEA and PPF on the properties of FRAC is also studied.