bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of a low-dose fipronil deer feed: evaluation of efficacy against two medically important tick species parasitizing white-tailed deer (Odocoileus virginianus) under pen conditions
Authors: Poché David M. , Wagner Donald , Green Kylie , Smith Zachary , Hawthorne Noah , Tseveenjav Batchimeg , Poché Richard M. 
Published: March 2023

Abstract
Background
Odocoileus virginianus (the white-tailed deer) is a key reproductive host for medically important tick species, including Ixodes scapularis and Amblyomma americanum. Orally administering a systemic acaricide to white-tailed deer has the potential to reduce tick reproduction, abundance and pathogen-infected tick bites. Prior studies have demonstrated considerable efficacy of a low-dose fipronil mouse bait in controlling larval I. scapularis parasitizing the pathogen reservoir, Peromyscus leucopus. No prior studies have evaluated the efficacy of a fipronil product in controlling ticks parasitizing white-tailed deer.

Methods
A pen study was conducted to evaluate the efficacy of a fipronil deer feed in controlling I. scapularis and A. americanum adult ticks. Individually housed deer (n = 24) were exposed to deer feed containing 0.0025% fipronil (fipronil deer feed) for 48 h and 120 h, and a control group of deer were exposed to an untreated placebo. On post-exposure day 7 and day 21, all deer were parasitized with 20 mating pairs of feeding capsule-enclosed I. scapularis and A. americanum. Post-attachment, engorgement and mortality of ticks were recorded. The concentrations of fipronil in plasma, feces and tissues from euthanized deer were estimated using liquid chromatography-mass spectrometry.

Results
The fipronil deer feed efficaciously controlled ticks parasitizing pen-reared white-tailed deer. Efficacy in reducing survivorship of blood-feeding female I. scapularis exceeded 90% in all instances except for when ticks parasitized 48-h treated deer at day 21 post-exposure (47.2%). Efficacy in reducing survivorship of A. americanum females exceeded 80% in all instances. In the 120-h exposure group there was 100% tick mortality at day 7 post-exposure for both tick species. A significant correlation was observed between reductions in tick survivorship and concentrations of fipronil sulfone in plasma. The results of tissue analysis suggest that a withdrawal period may be needed to allow for fipronil degradation prior to hunting season.

Conclusions
The results provide proof-of-concept for the use of a fipronil-based oral acaricide in controlling two medically important tick species infesting a key reproductive host. A field trial is necessary to confirm the efficacy and toxicology of the product in wild deer populations. Fipronil deer feed may provide a means of controlling multiple tick species parasitizing wild ruminants to be integrated into tick management programs.

Graphical Abstract
Development and validation of a machine learning algorithm prediction for dense granule proteins in Apicomplexa
Authors: Lu Zhenxiao , Hu Hang , Song Yashan , Zhou Siyi , Ayanniyi Olalekan Opeyemi , Xu Qianming , Yue Zhenyu , Yang Congshan 
Published: March 2023

Abstract
Background
Apicomplexa consist of numerous pathogenic parasitic protistan genera that invade host cells and reside and replicate within the parasitophorous vacuole (PV). Through this interface, the parasite exchanges nutrients and affects transport and immune modulation. During the intracellular life-cycle, the specialized secretory organelles of the parasite secrete an array of proteins, among which dense granule proteins (GRAs) play a major role in the modification of the PV. Despite this important role of GRAs, a large number of potential GRAs remain unidentified in Apicomplexa.

Methods
A multi-view attention graph convolutional network (MVA-GCN) prediction model with multiple features was constructed using a combination of machine learning and genomic datasets, and the prediction was performed on selected Neospora caninum protein data. The candidate GRAs were verified by a CRISPR/Cas9 gene editing system, and the complete NcGRA64(a,b) gene knockout strain was constructed and the phenotypes of the mutant were analyzed.

Results
The MVA-GCN prediction model was used to screen N. caninum candidate GRAs, and two novel GRAs (NcGRA64a and NcGRA64b) were verified by gene endogenous tagging. Knockout of complete genes of NcGRA64(a,b) in N. caninum did not affect the parasite's growth and replication in vitro and virulence in vivo.

Conclusions
Our study showcases the utility of the MVA-GCN deep learning model for mining Apicomplexa GRAs in genomic datasets, and the prediction model also has certain potential in mining other functional proteins of apicomplexan parasites.

Graphical Abstract
The survival of Amblyomma sculptum ticks upon blood-feeding depends on the expression of an inhibitor of apoptosis protein
Authors: Nassar Marcelly , Martins Larissa A. , de Assis Josiane Betim , Esteves Eliane , Sá-Nunes Anderson , Labruna Marcelo B. , Daffre Sirlei , Fogaça Andrea C. 
Published: March 2023

Abstract
Background
The tick Amblyomma sculptum is the major vector of Rickettsia rickettsii, the causative agent of the highly lethal Brazilian spotted fever. It has been shown that R. rickettsii inhibits apoptosis in both human endothelial cells and tick cells. Apoptosis is regulated by different factors, among which inhibitors of apoptosis proteins (IAPs) play a central role. In the study reported here, we selected an IAP of A. sculptum that has not yet been characterized to assess its role in cell death and to determine the effects of its gene silencing on tick fitness and R. rickettsii infection.

Methods
An A. sculptum cell line (IBU/ASE-16) was treated with specific double-stranded RNA (dsRNA) for either IAP (dsIAP) or green fluorescent protein (dsGFP; as a control). The activity of caspase-3 and the exposure of phosphatidylserine were determined in both groups. In addition, unfed adult ticks, infected or not infected with R. rickettsii, were treated with either dsIAP or dsGFP and allowed to feed on noninfected rabbits. In parallel, noninfected ticks were allowed to feed on an R. rickettsii-infected rabbit. Ticks (infected or not with R. rickettsii) that remained unfed were used as a control.

Results
Caspase-3 activity and the externalization of phosphatidylserine were significantly higher in IBU/ASE-16 cells treated with dsIAP than in those treated with dsGFP. The mortality rates of ticks in the dsIAP group were much higher than those in the dsGFP group when they were allowed to feed on rabbits, independent of the presence of R. rickettsii. Conversely, lower mortality rates were recorded in unfed ticks.

Conclusions
Our results show that IAP negatively regulates apoptosis in A. sculptum cells. Moreover, IAP-silenced ticks experienced higher mortality rates following the acquisition of a blood meal, suggesting that feeding may trigger the activation of apoptosis in the absence of this physiological regulator. These findings indicate that IAP is a potential antigen for an anti-tick vaccine.

Graphical Abstract
Evolution of tetraspanin antigens in the zoonotic Asian blood fluke Schistosoma japonicum
Authors: Parsons Daniel A. J. , Walker Anthony J. , Emery Aidan M. , Webster Joanne P. , Lawton Scott P. 
Published: March 2023

Abstract
Background
Despite successful control efforts in China over the past 60 years, zoonotic schistosomiasis caused by Schistosoma japonicum remains a threat with transmission ongoing and the risk of localised resurgences prompting calls for a novel integrated control strategy, with an anti-schistosome vaccine as a core element. Anti-schistosome vaccine development and immunisation attempts in non-human mammalian host species, intended to interrupt transmission, and utilising various antigen targets, have yielded mixed success, with some studies highlighting variation in schistosome antigen coding genes (ACGs) as possible confounders of vaccine efficacy. Thus, robust selection of target ACGs, including assessment of their genetic diversity and antigenic variability, is paramount. Tetraspanins (TSPs), a family of tegument-surface antigens in schistosomes, interact directly with the host’s immune system and are promising vaccine candidates. Here, for the first time to our knowledge, diversity in S. japonicum TSPs (SjTSPs) and the impact of diversifying selection and sequence variation on immunogenicity in these protiens were evaluated.

Methods
SjTSP sequences, representing parasite populations from seven provinces across China, were gathered by baiting published short-read NGS data and were analysed using in silico methods to measure sequence variation and selection pressures and predict the impact of selection on variation in antigen protein structure, function and antigenic propensity.

Results
Here, 27 SjTSPs were identified across three subfamilies, highlighting the diversity of TSPs in S. japonicum. Considerable variation was demonstrated for several SjTSPs between geographical regions/provinces, revealing that episodic, diversifying positive selection pressures promote amino acid variation/variability in the large extracellular loop (LEL) domain of certain SjTSPs. Accumulating polymorphisms in the LEL domain of SjTSP-2, -8 and -23 led to altered structural, functional and antibody binding characteristics, which are predicted to impact antibody recognition and possibly blunt the host’s ability to respond to infection. Such changes, therefore, appear to represent a mechanism utilised by S. japonicum to evade the host’s immune system.

Conclusion
Whilst the genetic and antigenic geographic variability observed amongst certain SjTSPs could present challenges to vaccine development, here we demonstrate conservation amongst SjTSP-1, -13 and -14, revealing their likely improved utility as efficacious vaccine candidates. Importantly, our data highlight that robust evaluation of vaccine target variability in natural parasite populations should be a prerequisite for anti-schistosome vaccine development.

Graphical abstract
Effect of somatic antigens of Dirofilaria repens adult worms on angiogenesis, cell proliferation and migration and pseudo-capillary formation in human endothelial cells
Authors: Pérez Rodríguez María del Pilar , Alarcón-Torrecillas Claudia , Pericacho Miguel , Rodríguez-Escolar Iván , Carretón Elena , Morchón Rodrigo 
Published: March 2023

Abstract
Background
Angiogenesis is defined as the formation of new vessels by sprouting of endothelial cells from pre-existing vessels in response to stimuli, such as hypoxia or inflammation. Subcutaneous dirofilariasis, caused by Dirofilaria repens, is a zoonotic disease characterized by the formation of subcutaneous nodules with the presence of at least one encapsulated worm, showing perivascular vascularization around it. The aim of this study is to analyze whether the somatic antigen of adult D. repens worms interacts with and modulates the angiogenic mechanism, cell proliferation and migration, and formation of pseudo-capillaries.

Methods
The expression of VEGF-A, VEGFR-1/sFlt, VEGFR-2, mEnd and sEnd in cultures of human vascular endothelial cells stimulated with somatic antigen of adult worms of D. repens (DrSA), vascular endothelial growth factor (VEGF) and DrSA + VEGF were evaluated by using ELISA commercial kits. Cellular viability was analyzed by live cell count, cytotoxicity assays by using a commercial kit, cell proliferation by MTT-based assay, cell migration by wound-healing assay carried out by scratching wounds and capacity of formation of pseudo-capillaries analyzing cell connections and cell groups in Matrigel cell cultures. In all cases unstimulated cultures were used as controls.

Results
DrSA + VEGF significantly increased the expression of VEGF-A, VEGFR-2 and mEndoglin compared to other groups and unstimulated cultures. Moreover, DrSA + VEGF produced cell proliferation and migration and increased the formation of pseudo-capillaries.

Conclusions
Somatic antigen of adult D. repens worms activated the proangiogenic mechanism, cell proliferation and cell migration as well as formation of pseudo-capillaries in this in vitro human endothelial cell model. These processes could be related to the survival of adult D. repens in subcutaneous nodules in infected hosts.

Graphical Abstract
Geographic variation in point of care ultrasound provision: results from a national audit
Authors: Aggarwal Sunil , Shanmugam Reshma , Knight Thomas , Atkin Catherine , Clare Sarbjit , Smallwood Nicholas , Lasserson Daniel 
Published: March 2023

Abstract
Background
There is an emerging consensus that point-of-care ultrasound is an essential skill in acute care. This is reflected in recent changes to the Acute Internal Medicine curriculum in the UK. The need to develop and maintain specific ultrasound competencies is now a mandatory component of training. There is a degree of uncertainty as to how existing training infrastructure can best accommodate these changes.

Methods
Data were obtained from the latest annual Society for Acute Medicine Benchmarking Audit 2021. All Acute Medical Units in the UK are eligible to participate. Data pertaining to the number of ultrasound machines and number of clinicians that regularly use point of care ultrasound were collected. This was used to develop a series of maps demonstrating variation in provision at the national level.

Results
In total, 123 AMUs responded to the questions related to ultrasound prevalence and numbers of trained clinicians. Of these, 78.9% (97/123) reported having access to at least one ultrasound machine. There was at least one clinician that regularly used ultrasound in 81 responding hospitals (65.9%). There was significant geographic heterogeneity in the use of ultrasound and availability of accredited supervisors. At a regional level, ultrasound expertise is typically concentrated within a relatively small number of hospitals.

Conclusion
Geographic variation in the use of ultrasound and availability of registered supervisors represents a significant challenge to ultrasound training provision at the national level. Targeted interventions in areas with less developed training infrastructure, such as regional training hubs may be required to ensure more equitable access to training opportunities.
Predictive value of estimated pulse wave velocity for cardiovascular and all-cause mortality in individuals with obesity
Authors: Li Daidi , Cao Feng , Cheng Wenke , Xu Yanyan , Yang Chuang 
Published: March 2023

Abstract
Background
Estimated pulse wave velocity (ePWV) has revealed excellent performance in predicting cardiovascular disease (CVD) risk. However, whether ePWV predicts all-cause mortality and CVD mortality in populations with obesity remains elusive.

Methods
We performed a prospective cohort including 49,116 participants from the National Health and Nutrition Examination Survey from 2005 to 2014. Arterial stiffness was evaluated by ePWV. Weighted univariate, multivariate Cox regression and receiver operating characteristic curve (ROC) analysis was used to assess the effects of ePWV on the risk of all-cause and CVD mortality. In addition, the two-piecewise linear regression analysis was used to describe the trend of ePWV affecting mortality and identify the thresholds that significantly affect mortality.

Results
A total of 9929 participants with obesity with ePWV data and 833 deaths were enrolled. Based on the multivariate Cox regression results, the high ePWV group had a 1.25-fold higher risk of all-cause mortality and a 5.76-fold higher risk of CVD mortality than the low-ePWV group. All-cause and CVD mortality risk increased by 123% and 44%, respectively, for every 1 m/s increase in ePWV. ROC results showed that ePWV had an excellent accuracy in predicting all-cause mortality (AUC = 0.801) and CVD mortality (AUC = 0.806). Furthermore, the two-piecewise linear regression analysis exhibited that the minimal threshold at which ePWV affected participant mortality was 6.7 m/s for all-cause mortality and 7.2 m/s for CVD mortality.

Conclusions
ePWV was an independent risk factor for mortality in populations with obesity. High ePWV levels were associated with an increased all-cause and CVD mortality. Thus, ePWV can be considered a novel biomarker to assess mortality risk in patients with obesity.
Mortality prediction in patients with hyperglycaemic crisis using explainable machine learning: a prospective, multicentre study based on tertiary hospitals
Authors: Xie Puguang , Yang Cheng , Yang Gangyi , Jiang Youzhao , He Min , Jiang Xiaoyan , Chen Yan , Deng Liling , Wang Min , Armstrong David G. , Ma Yu , Deng Wuquan 
Published: March 2023

Abstract
Background
Experiencing a hyperglycaemic crisis is associated with a short- and long-term increased risk of mortality. We aimed to develop an explainable machine learning model for predicting 3-year mortality and providing individualized risk factor assessment of patients with hyperglycaemic crisis after admission.

Methods
Based on five representative machine learning algorithms, we trained prediction models on data from patients with hyperglycaemic crisis admitted to two tertiary hospitals between 2016 and 2020. The models were internally validated by tenfold cross-validation and externally validated using previously unseen data from two other tertiary hospitals. A SHapley Additive exPlanations algorithm was used to interpret the predictions of the best performing model, and the relative importance of the features in the model was compared with the traditional statistical test results.

Results
A total of 337 patients with hyperglycaemic crisis were enrolled in the study, 3-year mortality was 13.6% (46 patients). 257 patients were used to train the models, and 80 patients were used for model validation. The Light Gradient Boosting Machine model performed best across testing cohorts (area under the ROC curve 0.89 [95% CI 0.77–0.97]). Advanced age, higher blood glucose and blood urea nitrogen were the three most important predictors for increased mortality.

Conclusion
The developed explainable model can provide estimates of the mortality and visual contribution of the features to the prediction for an individual patient with hyperglycaemic crisis. Advanced age, metabolic disorders, and impaired renal and cardiac function were important factors that predicted non-survival.
Trial Registration Number: ChiCTR1800015981, 2018/05/04.
Expression of down-regulated ERV LTR elements associates with immune activation in human small-cell lung cancers
Authors: Russo Marco , Morelli Sara , Capranico Giovanni 
Published: March 2023

AbstractSmall-cell lung cancer (SCLC) is an aggressive cancer characterized by immunosuppressive features leading to poor responses to current immunotherapies. Activation of transposable elements (TE) can trigger an innate immune response, which can synergize with immunotherapeutic protocols in patients. However, TE activity in relation to immune gene response is not fully known in human SCLC. Here, we compared TE expression in 104 human SCLC and 24 normal tissues and established their involvement in innate immune responses. We observed that different intergenic TEs, mainly endogenous retroviral (ERV) families, are deregulated in SCLC. Similarly to other cancers, we detected a subset of LTRs that correlate with innate immune gene signatures and cytosolic RNA sensors, such as RIG-I. These LTRs are downregulated in SCLC tumors vs. normal tissues, and are mainly located at transcriptional repressed regions, marked with H3K4me2 in different cell lines. Analyses of different genomic datasets show that chromatin repression is likely due to de-methylase LSD1 activity. Moreover, high expression levels of ERV LTRs predict a better survival upon chemotherapy of SCLC patients. The findings reveal a specific pattern of TE-mediated activation of innate immune genes in SCLC, which can be exploited to establish more effective immunotherapeutic combinations.
Low occurrence of MRI spinal changes in elite climbing athletes; a cross-sectional study
Authors: Identeg Fredrik , Lagerstrand Kerstin , Hedelin Henrik , Senorski Eric Hamrin , Sansone Mikael , Hebelka Hanna 
Published: March 2023

Abstract
Objectives
To examine the occurrence of magnetic resonance imaging (MRI) changes in the thoracolumbar spine among elite climbing athletes.

Methods
All climbers of the Swedish national sport climbing team (n = 8), and individuals having trained for selection to the national team (n = 11), were prospectively included. A control group, matched in age and sex, were recruited. All participants underwent a thoracolumbar MRI (1.5 T, T1- and T2-weighted imaging), evaluated according to Pfirrmann classification, modified Endplate defect score, Modic changes, apophyseal injuries and spondylolisthesis. Pfirrmann ≥ 3, Endplate defect score ≥ 2 and Modic ≥ 1 was defined as degenerative findings.

Results
Fifteen individuals, 8 women, participated in both the climbing group (mean age 23.1, SD 3.2 years) and the control group respectively (mean age 24.3, SD 1.5 years). In the climbing group, 6.1% of the thoracic and 10.6% of the lumbar intervertebral discs showed signs of degeneration according to Pfirrmann. One disc with a grade above 3 was present. Modic changes in the thoracic/lumbar spine were prevalent in 1.7%/1.3% of the vertebrae. Degenerative endplate changes according to the Endplate defect score were found in 8.9% and 6.6% of the thoracic and lumbar spinal segments of the climbing group, respectively. Two apophyseal injuries were found, while no participants displayed signs of spondylolisthesis. There was no difference in point-prevalence of radiographic spinal changes between climbers and controls (0.07 < p < 1.0).

Conclusion
In this small cross-sectional study, only a low proportion of elite climbers displayed changes of the spinal endplates or intervertebral discs, as opposed to other sports with high spinal loads. Most observed abnormalities were low grade degenerative changes and did not differ statistically compared to controls.
Factors contributing to exercise tolerance in patients with coronary artery disease undergoing percutaneous coronary intervention
Authors: Li Husheng , Wei Minqian , Zhang Lili , Huang Lan , Wang Yiyan , Wang Jiaqi , Zhuang Shaowei , Wu Xubo , Wu Jing 
Published: March 2023

Abstract
Background
Exercise tolerance plays a vital role in the process of cardiac rehabilitation in patients undergoing percutaneous coronary intervention (PCI). The study sought to determine the characteristics, risks and correlates of post-PCI exercise tolerance in patients with coronary artery disease (CAD).

Methods
We analyzed clinical data of 299 CAD patients undergoing elective PCI and completing cardiopulmonary exercise testing (CPET). According to the Weber classification, post-PCI exercise tolerance was evaluated by peak oxygen uptake (VO2 peak). We assessed the impact of 34 predefined clinical features, cardiac functional parameters, and blood biochemistry data on exercise tolerance by univariate analysis and logistics regression analysis.

Results
Of 299 patients, 74.92% were men and average age was 60.90 ± 10.68 years. VO2 peak in the entire population was 17.54 ± 3.38 ml/kg/min, and 24.41% (n = 73) were less than 16 ml/kg/min, who were considered to have exercise intolerance. Multivariate logistics regression results showed that sex, diabetes mellitus, number of stents, left atrial diameter (LAD), end-diastolic volume (EDV), and hemoglobin influenced the peak oxygen uptake of CAD patients undergoing elective PCI. (All p < 0.05).

Conclusions
Nearly one quarter of CAD patients have exercise intolerance in the early post-PCI period. Female, diabetes mellitus, number of stents, LAD, EDV might negatively impacted post-PCI exercise tolerance, which need further warrant by large scale cohort study.