bluuebunny/crossref_metadata_2025 huggingface dataset:
El desmantelamiento de los viaductos del enlace de Sabino Arana en Bilbao
Authors: Baraibar José Manuel , Rivas Pedro
Published: May 2023

En el presente artículo se describen las obras de desmantelamiento de los viaductos del enlace de S. Arana, en Bilbao. Este enlace se componía de varias estructuras yuxtapuestas, de hormigón pretensado, que conectaban la autopista A-8 con el centro de la ciudad. Para llevar a cabo la demolición se emplearon dos procedimientos diferenciados. Por una parte, los tableros de menor altura se demolieron vano a vano de forma directa empleando retroexcavadoras equipadas con martillos hidráulicos, demoledores primarios y cizallas. El resto de vanos, bien por su mayor altura o por la cercanía a viviendas u otras infraestructuras sensibles, se desmantelaron siguiendo un procedimiento de corte con hilo de diamante, izado con una grúa de celosía de gran tonelaje y apoyo en el suelo, en donde se finalizaba su demolición empleando equipos mecánicos tradicionales. La actuación ha conseguido recuperar para el uso vecinal un ámbito de más de 43.000 m2, situado en una zona próxima al centro de la ciudad.
Kentsel mekânda katılımın kentlilik bilincine etkisi: Denizli kenti örneği
Authors: ÜNVER DİRLİK Özge , SAVAŞ YAVUZÇEHRE Pınar
Published: May 2023

Kentlilik bilinci, kentte yaşayan bireylerin, kentle özdeşleşmesi, kendini kente ait hissetmesi, kente karşı sorumluluk duyması, kentle ilgili kararlara aktif katılım göstermesidir. Katılım, kentlilik bilincinin önemli unsurlarındır. Katılımın gerçekleşebilmesi için kentlinin kentsel mekânı kullanabilmesi, kentin içinde olması gerekir. Kentin önemli aktörü olan kentlinin aktif katılım gerçekleştirebilmesi, kentlilik bilincine sahip olmasıyla mümkündür. Kentlilik bilinci yüksek bireylerin varlığı aktif katılımın gerçekleşmesinde; katılım ise insanların yaşadıkları kentlere sahip çıkması ve kentlerin korunmasında, sürdürülebilirliğinde, kentlilik bilincinin gelişiminde/oluşumunda önemli katkı sağlamaktadır. Bu çalışma, Denizli İli Pamukkale ve Merkezefendi İlçeleri sınırlarında yaşayan 18 yaş ve üzeri bireylerin, kentsel mekândaki katılım davranışları ile kentlilik bilinci arasındaki farkı ölçmek amacıyla gerçekleştirilmiştir. Saha araştırması kapsamında 1100 anket gerçekleştirilmiştir. Verilerin analizinde tek yönlü varyans analizi ve post-hoc testi kullanılmıştır. Araştırma sonuçlarına göre; katılım ile kentlilik bilinci ve bileşenleri arasında anlamlı fark olduğu ortaya çıkmıştır.
The many problems with S-representation (and how to solve them)
Authors: Lee Jonny , Calder Daniel
Published: May 2023

The structural representation (S-representation) account provides an increasingly popular way of understanding the role and value of representation in cognitive science. Yet critics remain unconvinced that the account has the resources to rescue representationalism. This paper reviews problems faced by the S-representation account. In doing so, it offers a novel taxonomy that divides objections into two broad camps that ought to be disambiguated: ‘conceptual’ and ‘empirical’. It further shows how these objections can be met, bolstering existing responses in the literature with novel solutions, thus strengthening the S-representation account. Finally, this paper suggests that the types of objections identified provide a generalisable taxonomy for a better understanding of any version of anti-representationalism. Thus, this review is of value to the representation debate more broadly.
Dimensions of animal wellbeing
Authors: Dung Leonard
Published: May 2023

Whether animals fare well or not is of ethical significance. For this reason, their capacity for wellbeing, i.e., how good or bad the lives of animals can go, is of ethical significance as well. I assume that the wellbeing of most animals is mainly determined by their phenomenally conscious experiences. If consciousness differences between species determine wellbeing differences, then the kinds of conscious experience species are capable of may entail that some species systematically (can) have higher or lower wellbeing than others. Then, I argue that not all phenomenally conscious states contribute to wellbeing equally. I discuss which features of consciousness are constituents of wellbeing and which can, for ethical purposes, be ignored. In addition, I scrutinize how much different features of experience contribute to wellbeing and how their presence can be detected empirically. This way, this paper exemplifies a novel consciousness-centered approach for the empirical investigation of animal wellbeing. The strengths and weaknesses of this approach are analyzed. While subsequent research is needed to refine the framework, I already note some preliminary implications for animal ethics.
"Atención Infantil Temprana: Un análisis multidisciplinar sobre su abordaje" Robles Bello, M. A., Muela Martínez, J. A. y Sánchez-Teruel, D. (2021)
Authors: Martín Barrado Antonio David
Published: May 2023

Robles Bello, M. A., Muela Martínez, J. A. y Sánchez-Teruel, D. (2021). Atención Infantil Temprana: Un análisis multidisciplinar sobre su abordaje (M. A. Robles Bello, J. A. Muela Martínez y D. Sánchez-Teruel, Eds.). Universidad de Jaén.
BrcaDx: precise identification of breast cancer from expression data using a minimal set of features
Authors: Muthamilselvan Sangeetha , Palaniappan Ashok
Published: May 2023

Background: Breast cancer is the foremost cancer in worldwide incidence, surpassing lung cancer notwithstanding the gender bias. One in four cancer cases among women are attributable to cancers of the breast, which are also the leading cause of death in women. Reliable options for early detection of breast cancer are needed.

Methods: Using public-domain datasets, we screened transcriptomic profiles of breast cancer samples, and identified progression-significant linear and ordinal model genes using stage-informed models. We then applied a sequence of machine learning techniques, namely, feature selection, principal components analysis, and k-means clustering, to train a learner to discriminate “cancer” from “normal” based on expression levels of identified biomarkers.

Results: Our computational pipeline yielded an optimal set of nine biomarker features for training the learner, namely, NEK2, PKMYT1, MMP11, CPA1, COL10A1, HSD17B13, CA4, MYOC, and LYVE1. Validation of the learned model on an independent test dataset yielded a performance of 99.5% accuracy. Blind validation on an out-of-domain external dataset yielded a balanced accuracy of 95.5%, demonstrating that the model has effectively reduced the dimensionality of the problem, and learnt the solution. The model was rebuilt using the full dataset, and then deployed as a web app for non-profit purposes at: https://apalania.shinyapps.io/brcadx/. To our knowledge, this is the best-performing freely available tool for the high-confidence diagnosis of breast cancer, and represents a promising aid to medical diagnosis.
Evaluation of expanded peripheral blood derived CD34+ cells for the treatment of moderate knee osteoarthritis
Authors: Vignon Christine , Hilpert Morgane , Toupet Karine , Goubaud Aurélien , Noël Danièle , de Kalbermatten Matthieu , Hénon Philippe , Jorgensen Christian , Barbero Andrea , Garitaonandia Ibon
Published: May 2023

Knee osteoarthritis (OA) is a degenerative joint disease of the knee that results from the progressive loss of articular cartilage. It is most common in the elderly and affects millions of people worldwide, leading to a continuous increase in the number of total knee replacement surgeries. These surgeries improve the patient's physical mobility, but can lead to late infection, loosening of the prosthesis, and persistent pain. We would like to investigate if cell-based therapies can avoid or delay such surgeries in patients with moderate OA by injecting expanded autologous peripheral blood derived CD34+ cells (ProtheraCytes®) into the articular joint. In this study we evaluated the survival of ProtheraCytes® when exposed to synovial fluid and their performance in vitro with a model consisting of their co-culture with human OA chondrocytes in separate layers of Transwells and in vivo with a murine model of OA. Here we show that ProtheraCytes® maintain high viability (>95%) when exposed for up to 96 hours to synovial fluid from OA patients. Additionally, when co-cultured with OA chondrocytes, ProtheraCytes® can modulate the expression of some chondrogenic (collagen II and Sox9) and inflammatory/degrading (IL1β, TNF, and MMP-13) markers at gene or protein levels. Finally, ProtheraCytes® survive after injection into the knee of a collagenase-induced osteoarthritis mouse model, engrafting mainly in the synovial membrane, probably due to the fact that ProtheraCytes® express CD44, a receptor of hyaluronic acid, which is abundantly present in the synovial membrane. This report provides preliminary evidence of the therapeutic potential of CD34+ cells on OA chondrocytes in vitro and their survival after in vivo implantation in the knee of mice and merits further investigation in future preclinical studies in OA models.
Identifying fibrogenic cells following salivary gland obstructive injury
Authors: Altrieth Amber L. , O’Keefe Kevin J. , Gellatly Victoria A. , Tavarez Joey R. , Feminella Sage M. , Moskwa Nicholas L. , Cordi Carmalena V. , Turrieta Judy C. , Nelson Deirdre A. , Larsen Melinda
Published: May 2023

Fibrosis results from excess extracellular matrix accumulation, which alters normal tissue architecture and impedes function. In the salivary gland, fibrosis can be induced by irradiation treatment for cancer therapy, Sjögren’s Disease, and other causes; however, it is unclear which stromal cells and signals participate in injury responses and disease progression. As hedgehog signaling has been implicated in fibrosis of the salivary gland and other organs, we examined contributions of the hedgehog effector, Gli1, to fibrotic responses in salivary glands. To experimentally induce a fibrotic response in female murine submandibular salivary glands, we performed ductal ligation surgery. We detected a progressive fibrotic response where both extracellular matrix accumulation and actively remodeled collagen significantly increased at 14 days post-ligation. Macrophages, which participate in extracellular matrix remodeling, and Gli1+ and PDGFRα+ stromal cells, which may deposit extracellular matrix, both increased with injury. Using single-cell RNA-sequencing, Gli1+ cells were not found in discrete clusters at embryonic day 16 but were found in clusters expressing the stromal genes Pdgfra and/or Pdgfrb. In adult mice, Gli1+ cells were similarly heterogeneous but more cells co-expressed PDGFRα and PDGFRβ. Using Gli1-CreERT2; ROSA26tdTomato lineage-tracing mice, we found that Gli1-derived cells expand with ductal ligation injury. Although some of the Gli1 lineage-traced tdTomato+ cells expressed vimentin and PDGFRβ following injury, there was no increase in the classic myofibroblast marker, smooth muscle alpha-actin. Additionally, there was little change in extracellular matrix area, remodeled collagen area, PDGFRα, PDGFRβ, endothelial cells, neurons, or macrophages in Gli1 null salivary glands following injury when compared with controls, suggesting that Gli1 signaling and Gli1+ cells have only a minor contribution to mechanical injury-induced fibrotic changes in the salivary gland. We used scRNA-seq to examine cell populations that expand with ligation and/or showed increased expression of matrisome genes. Some Pdgfra+/Pdgfrb+ stromal cell subpopulations expanded in response to ligation, with two stromal cell subpopulations showing increased expression of Col1a1 and a greater diversity of matrisome genes, consistent with these cells being fibrogenic. However, only a few cells in these subpopulations expressed Gli1, consistent with a minor contribution of these cells to extracellular matrix production. Defining the signaling pathways driving fibrotic responses in stromal cell sub-types could reveal future therapeutic targets.
Number of prior live births is associated with higher arterial stiffness but not its change in older women: the atherosclerosis risk in communities study
Authors: Bonner Alison N. , Jayawickreme Shantal , Malek Angela M. , Vladutiu Catherine J. , Oliver-Williams Clare , Cortés Yamnia I. , Tanaka Hirofumi , Meyer Michelle L.
Published: May 2023

Introduction

Although studies have demonstrated a J-shaped association between parity and cardiovascular disease (CVD), the association with arterial stiffness is not fully understood.

Methods

We examined the association between parity and carotid-femoral pulse wave velocity (cfPWV), a measure of central arterial stiffness. We conducted a longitudinal analysis of 1220 women (mean age 73.7 years) who attended the Atherosclerosis Risk in Communities Study visit 5 (2011-2013). At visit 2 (1990-1992), women self-reported parity (number of prior live births), which we categorized as: 0 (never pregnant or pregnant with no live births); 1-2 (referent); 3-4; and 5+ live births. Technicians measured cfPWV at visit 5 (2011-2013) and visit 6 or 7 (2016-2019). Multivariable linear regression modeled the associations of parity with visit 5 cfPWV and cfPWV change between visit 5 and 6/7 adjusted for demographics and potential confounding factors.

Results

Participants reported 0 (7.7%), 1-2 (38.7%), 3-4 (40.0%), or 5+ (13.6%) prior live births. In adjusted analyses, women with 5+ live births had a higher visit 5 cfPWV (β=50.6 cm/s, 95% confidence interval: 3.6, 97.7 cm/s) than those with 1-2 live births. No statistically significant associations were observed for other parity groups with visit 5 cfPWV or with cfPWV change.

Discussion

In later life, women with 5+ live births had higher arterial stiffness than those with 1-2 live births, but cfPWV change did not differ by parity, suggesting women with 5+ live births should be targeted for early primary prevention of CVD given their higher arterial stiffness at later-life.
Computed tomography–based pericoronary adipose tissue attenuation in patients undergoing TAVR: a novel method for risk assessment
Authors: Steyer Alexandra , Mas-Peiro Silvia , Leistner David M. , Puntmann Valentina O. , Nagel Eike , Dey Damini , Goeller Markus , Koch Vitali , Booz Christian , Vogl Thomas J. , Martin Simon S.
Published: May 2023

Objectives

This study aims to assess the attenuation of pericoronary adipose tissue (PCAT) surrounding the proximal right coronary artery (RCA) in patients with aortic stenosis (AS) and undergoing transcatheter aortic valve replacement (TAVR). RCA PCAT attenuation is a novel computed tomography (CT)–based marker for evaluating coronary inflammation. Coronary artery disease (CAD) in TAVR patients is common and usually evaluated prior to intervention. The most sensible screening method and consequential treatment approach are unclear and remain a matter of ceaseless discussion. Thus, interest remains for safe and low-demand predictive markers to identify patients at risk for adverse outcomes postaortic valve replacement.

Methods

This single-center retrospective study included patients receiving a standard planning CT scan prior to TAVR. Conventional CAD diagnostic tools, such as coronary artery calcium score and significant stenosis via invasive coronary angiography and coronary computed tomography angiography, were determined in addition to RCA PCAT attenuation using semiautomated software. These were assessed for their relationship with major adverse cardiovascular events (MACE) during a 24-month follow-up period.

Results

From a total of 62 patients (mean age: 82 ± 6.7 years), 15 (24.2%) patients experienced an event within the observation period, 10 of which were attributed to cardiovascular death. The mean RCA PCAT attenuation was higher in patients enduring MACE than that in those without an endpoint (−69.8 ± 7.5 vs. −74.6 ± 6.2, P = 0.02). Using a predefined cutoff of >−70.5 HU, 20 patients (32.3%) with high RCA PCAT attenuation were identified, nine (45%) of which met the endpoint within 2 years after TAVR. In a multivariate Cox regression model including conventional CAD diagnostic tools, RCA PCAT attenuation prevailed as the only marker with significant association with MACE (P = 0.02). After dichotomization of patients into high- and low-RCA PCAT attenuation groups, high attenuation was related to greater risk of MACE (hazard ration: 3.82, P = 0.011).

Conclusion

RCA PCAT attenuation appears to have predictive value also in a setting of concomitant AS in patients receiving TAVR. RCA PCAT attenuation was more reliable than conventional CAD diagnostic tools in identifying patients at risk for MACE .
Spatiotemporal variability of magmatic products under a changing structural and tectonic context: a case study in the Andes of southern Central Chile
Authors: Piquer José , Fischer Tomás , Torres Francisco , Plissart Gaëlle
Published: May 2023

In a subduction setting, the type of magmatic products which reach the upper crust, and eventually the surface, depends on several variables, among which some of the most relevant are the tectonic regime, and the orientation of magma pathways relative to the predominant stress tensor. To better understand this relationship, we studied in detail an area of the Andes of southern Central Chile in which subduction-related magmatism has been active at least during the last 18 m.y. The relationship between high-angle faults and magmatism was studied, and the spatiotemporal variations on the stress tensor were analyzed. The chemistry of the different magmatic products was used to evaluate the magma “fertility”, understood as its potential to form a giant porphyry-type deposit. The age of the studied units is constrained by new U-Pb zircon ages, complemented with previous geochronological studies. Three main high-angle fault systems are present: ∼NW striking structures control the emplacement of plutonic bodies, while ∼NE–ENE and N–NNE faults, more parallel to the prevailing orientation of σ1 since the middle Miocene, control the emplacement of dike swarms and volcanic alignments. Regarding the geochemical characterization, a transition towards steeper REE patterns and higher fertility indices is observed in the earliest facies of the La Invernada Plutonic Complex (∼15-14 Ma), coincident with a middle Miocene orogenic event described at this latitude by previous authors. The Pliocene La Resolana intrusions show higher magma fertility indices; however, they are still considerably lower than those typical for porphyry-forming magmas in the same Andean region. It is concluded that the contrasting fertility observed in coeval intrusions emplaced under the same tectonic context, cannot be explained by continental-scale processes; instead, they are related to differences in the local pathways of magma ascent through the crust. Fault systems which are miss-oriented relative to the predominant orientation of σ1 appear to favor longer magma residence times, achieving a higher degree of differentiation and fertility in most cases crystalizing within the upper crust, while magmas ascending through more favorably oriented faults are more primitive, and often reach the surface forming stratovolcanoes and alignments of monogenetic vents.
Assessing the scientific value and vulnerability of paleontological sites: a new analytic operational procedure
Authors: Faggi Andrea , Bartolini-Lucenti Saverio , Rook Lorenzo
Published: May 2023

Introduction:Paleontological heritage rarely receives the same legislative attention as archeological heritage. Part of the problem seems to be, at least in some contexts (e.g., Italy), the difficulty of acknowledging fossils as distinct assets from other cultural heritage objects and the lack of expertise among the administrative functionaries. This study aims to describe and test an objective analytic operational procedure that could allow for the assessment of the relevance of any fossiliferous site and its potential vulnerability in its present state.

Methods:The estimations were obtained using several quantitative and qualitative parameters that could describe the probability of fossil recovery for each site (Pr) and the scientific and cultural interest of the locality (In). Each parameter has subcategories for better defining. The product of probability and interest results in the scientific value (S), generally expressed as a percentage (S*). The vulnerability index (V) of productive and active sites considers the use of the land (U) and the natural erosion (E). The parameters were thought to apply to any type of fossil locality. We tested the indexes on 22 localities (7 of which were with paleoichnological records and 15 with direct body-fossil evidence), all different from one another.

Results:The results show that the proposed indexes well describe and characterize each locality. Most of the sites are moderately vulnerable (V between 1 and 3) except for large quarry sites (e.g., Pirro Nord, Italy and Solnhofen, Germany) whose vulnerability indexes fell in the maximum degree of risk.

Discussion:The operational procedure presented here is a simple, objective, and remotely applicable method allowing paleontologists and non-expert personnel to categorize localities and, therefore, act as a base to plan actions in paleontological heritage management relative to territorial development and land use.
Association between breast cancer and thyroid cancer risk: a two-sample Mendelian randomization study
Authors: Tan Hong , Wang Sisi , Huang Feifei , Tong Zhongyi
Published: May 2023

Background

Breast and thyroid cancer are increasingly prevalent, but it remains unclear whether the observed associations are due to heightened medical surveillance or intrinsic etiological factors. Observational studies are vulnerable to residual confounding, reverse causality, and bias, which can compromise causal inference. In this study, we employed a two-sample Mendelian randomization (MR) analysis to establish a causal link between breast cancer and heightened thyroid cancer risk.

Methods

We obtained the single nucleotide polymorphisms (SNPs) associated with breast cancer from a genome-wide association study (GWAS) conducted by the Breast Cancer Association Consortium (BCAC). The FinnGen consortium’s latest and largest accessible GWAS thyroid cancer data at the summary level. We performed four MR analyses, including the inverse-variance-weighted (IVW), weighted median, MR-Egger regression, and weighted mode, to evaluate the potential causal connection between genetically predicted breast cancer and higher risk for thyroid cancer. Sensitivity analysis, heterogeneity and pleiotropy tests were used to ensure the reliability of our findings.

Results

Our study revealed causal relationship between genetically predicted breast cancer and thyroid cancer (IVW method, odds ratio (OR) = 1.135, 95% confidence interval (CI): 1.006 to 1.279, P = 0.038). However, there was no causal association between genetically predicted triple-negative breast cancer and thyroid cancer (OR = 0.817, 95% CI: 0.610 to 1.095, P = 0.177). There was no directional pleiotropy or horizontal pleiotropy in the present study.

Conclusion

This two-sample MR study supports a causal link between ER-positive breast cancer and heightened the risk of thyroid cancer. Our analysis did not reveal a direct correlation between triple-negative breast cancer and thyroid cancer.
Circulating adrenal 11-oxygenated androgens are associated with clinical outcome in endometrial cancer
Authors: Dahmani Cylia , Caron Patrick , Simonyan David , Turcotte Véronique , Grégoire Jean , Plante Marie , Guillemette Chantal
Published: May 2023

Context

Recent evidence support that androgens play an important role in the etiology of endometrial cancer (EC). Adrenal-derived 11-oxygenated androgens are highly potent agonists of the androgen receptor (AR), comparable to testosterone (T) and dihydrotestosterone (DHT) that have not been studied in the context of EC.

Methodology

We studied a cohort of 272 newly diagnosed postmenopausal EC cases undergoing surgical treatment. Circulating concentrations of seven 11-oxygenated androgens including precursors, potent androgens and their metabolites were established in serum samples collected before and 1 month after surgery using a validated liquid chromatography tandem mass spectrometry method (LC-MS/MS). Free (unconjugated) and total (free + sulfate and glucuronide conjugates following enzymatic hydrolysis) were analyzed in relation to clinicopathological features, recurrence and disease-free survival (DFS).

Results

Levels of 11-oxygenated androgens were weakly correlated to those of canonical androgens such as testosterone (T) and dihydrotestosterone (DHT), with no evidence of their association with clinicopathological features. Levels of 11-oxygenated androgens declined after surgery but remained higher in overweight and obese compared to normal weight cases. Higher levels of preoperative free 11-ketoandrosterone (11KAST) were associated with an increased risk of recurrence (Hazard ratio (HR) of 2.99 (95%CI=1.09-8.18); P=0.03). Postoperative free 11β-hydroxyandrosterone (11OHAST) levels were adversely associated with recurrence and DFS (HR = 3.23 (1.11-9.40); P=0.03 and 3.27 (1.34-8.00); P=0.009, respectively).

Conclusion

11-oxygenated androgen metabolites emerge as potential prognostic markers of EC.
Underground energy storage system supported resilience enhancement for power system in high penetration of renewable energy
Authors: Qin Boyu , Shi Wen , Fang Ruoquan , Wu Dongyang , Zhu Yu , Wang Hongzhen
Published: May 2023

High penetration of renewable energy is becoming an important development trend in new generation power system. However, frequent extreme weather events and fragile renewable energy sources pose a huge challenge to the power system resilience. As an important support technology of renewables, energy storage system is of great significance in improving the resilience of the power system. In this paper, a resilience enhancement method for power systems with high penetration of renewable energy based on underground energy storage systems (UESS) is proposed. Firstly, a resilience assessment model is established and the influence of extreme weather is quantified as the failure rate of power system components. Secondly, a bi-level optimization model for UESS operation and planning under extreme weather is built, and the life cycle of UESS is considered. Finally, taking the modified IEEE RTS-79 as an example, the optimal scheme for UESS configuration and operation is given, the investment and effectiveness of UESS is also analyzed. The results show that UESS can significantly enhance the power system resilience under extreme weather events.
Integrative profiling of gene expression and chromatin accessibility elucidates specific transcriptional networks in porcine neutrophils
Authors: Herrera-Uribe Juber , Lim Kyu-Sang , Byrne Kristen A. , Daharsh Lance , Liu Haibo , Corbett Ryan J. , Marco Gianna , Schroyen Martine , Koltes James E. , Loving Crystal L. , Tuggle Christopher K.
Published: May 2023

Neutrophils are vital components of the immune system for limiting the invasion and proliferation of pathogens in the body. Surprisingly, the functional annotation of porcine neutrophils is still limited. The transcriptomic and epigenetic assessment of porcine neutrophils from healthy pigs was performed by bulk RNA sequencing and transposase accessible chromatin sequencing (ATAC-seq). First, we sequenced and compared the transcriptome of porcine neutrophils with eight other immune cell transcriptomes to identify a neutrophil-enriched gene list within a detected neutrophil co-expression module. Second, we used ATAC-seq analysis to report for the first time the genome-wide chromatin accessible regions of porcine neutrophils. A combined analysis using both transcriptomic and chromatin accessibility data further defined the neutrophil co-expression network controlled by transcription factors likely important for neutrophil lineage commitment and function. We identified chromatin accessible regions around promoters of neutrophil-specific genes that were predicted to be bound by neutrophil-specific transcription factors. Additionally, published DNA methylation data from porcine immune cells including neutrophils were used to link low DNA methylation patterns to accessible chromatin regions and genes with highly enriched expression in porcine neutrophils. In summary, our data provides the first integrative analysis of the accessible chromatin regions and transcriptional status of porcine neutrophils, contributing to the Functional Annotation of Animal Genomes (FAANG) project, and demonstrates the utility of chromatin accessible regions to identify and enrich our understanding of transcriptional networks in a cell type such as neutrophils.
Comprehensive analysis of endoplasmic reticulum stress-associated genes signature of ulcerative colitis
Authors: Deng Beiying , Liao Fei , Liu Yinghui , He Pengzhan , Wei Shuchun , Liu Chuan , Dong Weiguo
Published: May 2023

Background

Endoplasmic reticulum stress (ERS) is a critical factor in the development of ulcerative colitis (UC); however, the underlying molecular mechanisms remain unclear. This study aims to identify pivotal molecular mechanisms related to ERS in UC pathogenesis and provide novel therapeutic targets for UC.

Methods

Colon tissue gene expression profiles and clinical information of UC patients and healthy controls were obtained from the Gene Expression Omnibus (GEO) database, and the ERS-related gene set was downloaded from GeneCards for analysis. Weighted gene co-expression network analysis (WGCNA) and differential expression analysis were utilized to identify pivotal modules and genes associated with UC. A consensus clustering algorithm was used to classify UC patients. The CIBERSORT algorithm was employed to evaluate the immune cell infiltration. Gene Set Variation Analysis (GSVA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to explore potential biological mechanisms. The external sets were used to validate and identify the relationship of ERS-related genes with biologics. Small molecule compounds were predicted using the Connectivity Map (CMap) database. Molecular docking was performed to simulate the binding conformation of small molecule compounds and key targets.

Results

The study identified 915 differentially expressed genes (DEGs) and 11 ERS-related genes (ERSRGs) from the colonic mucosa of UC patients and healthy controls, and these genes had good diagnostic value and were highly correlated. Five potential small-molecule drugs sharing tubulin inhibitors were identified, including albendazole, fenbendazole, flubendazole, griseofulvin, and noscapine, among which noscapine exhibited the highest correlation with a high binding affinity to the targets. Active UC and 10 ERSRGs were associated with a large number of immune cells, and ERS was also associated with colon mucosal invasion of active UC. Significant differences in gene expression patterns and immune cell infiltration abundance were observed among ERS-related subtypes.

Conclusion

The results suggest that ERS plays a vital role in UC pathogenesis, and noscapine may be a promising therapeutic agent for UC by affecting ERS.
Akkermansia muciniphila-Nlrp3 is involved in the neuroprotection of phosphoglycerate mutase 5 deficiency in traumatic brain injury mice
Authors: Chen Yuhua , Chen Junhui , Wei Hong , Gong Kai , Meng Jiao , Long Tianlin , Guo Jianfeng , Hong Jun , Yang Lingjian , Qiu Junling , Xiong Kun , Wang Zhanxiang , Xu Quanhua
Published: May 2023

Introduction

Gut-microbiota-brain axis is a potential treatment to decrease the risk of chronic traumatic encephalopathy following traumatic brain injury (TBI). Phosphoglycerate mutase 5 (PGAM5), a mitochondrial serine/threonine protein phosphatase, resides in mitochondrial membrane and regulates mitochondrial homeostasis and metabolism. Mitochondria mediates intestinal barrier and gut microbiome.

Objectives

This study investigated the association between PGAM5 and gut microbiota in mice with TBI.

Methods

The controlled cortical impact injury was established in mice with genetically-ablated Pgam5 (Pgam5−/−) or wild type, and WT male mice were treated with fecal microbiota transplantation (FMT) from male Pgam5−/− mice or Akkermansia muciniphila (A. muciniphila). Then the gut microbiota abundance, blood metabolites, neurological function, and nerve injury were detected.

Results

Treated with antibiotics for suppressing gut microbiota in Pgam5−/− mice partially relieved the role of Pgam5 deficiency in the improvement of initial inflammatory factors and motor dysfunction post-TBI. Pgam5 knockout exhibited an increased abundance of A. muciniphila in mice. FMT from male Pgam5−/− mice enabled better maintenance of amino acid metabolism and peripherial environment than that in TBI-vehicle mice, which suppressed neuroinflammation and improved neurological deficits, and A. muciniphila was negatively associated with intestinal mucosal injury and neuroinflammation post-TBI. Moreover, A. muciniphila treatment ameliorated neuroinflammation and nerve injury by regulating Nlrp3 inflammasome activation in cerebral cortex with TBI.

Conclusion

Thus, the present study provides evidence that Pgam5 is involved in gut microbiota-mediated neuroinflammation and nerve injury, with A. muciniphila-Nlrp3 contributing to peripheral effects.
IRF4 downregulation improves sensitivity and endurance of CAR T cell functional capacities
Authors: Harrer Dennis Christoph , Bezler Valerie , Hartley Jordan , Herr Wolfgang , Abken Hinrich
Published: May 2023

Chimeric antigen receptor (CAR) modified T cells can induce complete remissions in patients with advanced hematological malignancies. Nevertheless, the efficacy is mostly transient and remains so far poor in the treatment of solid tumors. Crucial barriers to long-term CAR T cell success encompass loss of functional capacities known as “exhaustion”, among others. To extend CAR T cell functionality, we reduced interferon regulatory factor 4 (IRF4) levels in CAR T cells using a one-vector system encoding a specific short-hairpin (sh) RNA along with constitutive CAR expression. At baseline, CAR T cells with downregulated IRF4 showed equal cytotoxicity and cytokine release compared to conventional CAR T cells. However, under conditions of repetitive antigen encounter, IRF4low CAR T cells displayed enhanced functionality with superior cancer cell control in the long-term compared with conventional CAR T cells. Mechanistically, the downregulation of IRF4 in CAR T cells resulted in prolonged functional capacities and upregulation of CD27. Moreover, IRF4low CAR T cells were more sensitive to cancer cells with low levels of target antigen. Overall, IRF4 downregulation capacitates CAR T cells to recognize and respond to target cells with improved sensitivity and endurance.
Insensitivity to propagation timing in a preview-enabled wind turbine control experiment
Authors: Sinner Michael , Petrović Vlaho , Stockhouse David , Langidis Apostolos , Pusch Manuel , Kühn Martin , Pao Lucy Y.
Published: May 2023

Lidar scanners are capable of taking measurements of a wind field upstream of a wind turbine. The wind turbine controller can use these measurements as a “preview” of future disturbances impacting the turbine. Such preview-enabled (or feedforward) controllers show superior performance to standard wind turbine control configurations based purely on a feedback architecture. To capitalize on the performance improvements that preview wind measurements can provide, feedforward control actions should be timed to coincide with the arrival of the wind field at the wind turbine location. However, the time of propagation of the wind field between the lidar measurement location and the wind turbine is not perfectly known. Moreover, the best time to take feedforward control action may not perfectly coincide with the true arrival time of the wind disturbance. This contribution presents results from an experiment where preview-enabled model predictive control was deployed on a fully-actuated, scaled model wind turbine operating in a wind tunnel testbed. In the study, we investigate the sensitivity of the controller performance to the assumed propagation delay using a range of wind input sequences. We find that the preview-enabled controller outperforms the feedback only case across a wide range of assumed propagation delays, demonstrating a level of robustness to the time alignment of the incoming disturbances.
Identifying a novel cuproptosis-related necroptosis gene subtype-related signature for predicting the prognosis, tumor microenvironment, and immunotherapy of hepatocellular carcinoma
Authors: Shi Yuanxin , Qiu Peng , Zhao Kai , Li Xiangyu , Feng Yunxiang , Deng Zhengdong , Wang Jianming
Published: May 2023

Background: Cuproptosis and necroptosis represent two distinct programmed cell death modalities implicated in neoplastic progression; however, the role of combining cuproptosis and necroptosis in hepatocellular carcinoma (HCC) remains to be elucidated.

Methods: A total of 29 cuproptosis-related necroptosis genes (CRNGs) were identified, followed by an extensive analysis of their mutational characteristics, expression patterns, prognostic implications, and associations with the tumor microenvironment (TME). Subsequently, a CRNG subtype-related signature was developed, and its value of prognostic prediction, TME, and therapeutic responses in HCC were thoroughly investigated. Last, quantitative real-time PCR and Western blotting were employed for investigating the signature gene expression in 15 paired clinical tissue samples.

Results: Two distinct CRNG subtypes were discerned, demonstrating associations between CRNG expression patterns, clinicopathological attributes, prognosis, and the TME. A CRNG subtype-related prognostic signature, subjected to external validation, was constructed, serving as an independent prognostic factor for HCC patients, indicating poor prognosis for high-risk individuals. Concurrently, the signature’s correlations with an immune-suppressive TME, mutational features, stemness properties, immune checkpoint genes, chemoresistance-associated genes, and drug sensitivity were observed, signifying its utility in predicting treatment responses. Subsequently, highly accurate and clinically convenient nomograms were developed, and the signature genes were validated via quantitative real-time PCR and Western blotting, further substantiating the stability and dependability of the CRNG subtype-related prognostic signature.

Conclusion: Overall, this investigation presented an extensive panorama of CRNGs and developed the CRNG subtype-related prognostic signature, which holds potential for implementation in personalized treatment strategies and prognostic forecasting for HCC patients.
Comparative dosimetric study of radiotherapy in high-grade gliomas based on the guidelines of EORTC and NRG-2019 target delineation
Authors: Yan Ouying , Teng Haibo , Jiang Cuihong , He Lili , Xiao Shuai , Li Yanxian , Wu Wenqiong , Zhao Qi , Ye Xu , Liu Wen , Fan Changgen , Wu Xiangwei , Liu Feng
Published: May 2023

Purpose

Radiotherapy is one of the most important treatments for high-grade glioma (HGG), but the best way to delineate the target areas for radiotherapy remains controversial, so our aim was to compare the dosimetric differences in radiation treatment plans generated based on the European Organization for Research and Treatment of Cancer (EORTC) and National Research Group (NRG) consensus to provide evidence for optimal target delineation for HGG.

Methods

We prospectively enrolled 13 patients with a confirmed HGG from our hospital and assessed dosimetric differences in radiotherapy treatment plans generated according to the EORTC and NRG-2019 guidelines. For each patient, two treatment plans were generated. Dosimetric parameters were compared by dose–volume histograms for each plan.

Results

The median volume for planning target volume (PTV) of EORTC plans, PTV1 of NRG-2019 plans, and PTV2 of NRG-2019 plans were 336.6 cm3 (range, 161.1–511.5 cm3), 365.3 cm3 (range, 123.4–535.0 cm3), and 263.2 cm3 (range, 116.8–497.7 cm3), respectively. Both treatment plans were found to have similar efficiency and evaluated as acceptable for patient treatment. Both treatment plans showed well conformal index and homogeneity index and were not statistically significantly different (P = 0.397 and P = 0.427, respectively). There was no significant difference in the volume percent of brain irradiated to 30, 46, and 60 Gy according to different target delineations (P = 0.397, P = 0.590, and P = 0.739, respectively). These two plans also showed no significant differences in the doses to the brain stem, optic chiasm, left and right optic nerves, left and right lens, left and right eyes, pituitary, and left and right temporal lobes (P = 0.858, P = 0.858, P = 0.701 and P = 0.794, P = 0.701 and P = 0.427, P = 0.489 and P = 0.898, P = 0.626, and P = 0.942 and P = 0.161, respectively).

Conclusion

The NRG-2019 project did not increase the dose of organs at risk (OARs) radiation. This is a significant finding that further lays the groundwork for the application of the NRG-2019 consensus in the treatment of patients with HGGs.

Clinical trial registration

The effect of radiotherapy target area and glial fibrillary acidic protein (GFAP) on the prognosis of high-grade glioma and its mechanism, number ChiCTR2100046667. Registered 26 May 2021.
Conventional ultrasound and contrast-enhanced ultrasound radiomics in breast cancer and molecular subtype diagnosis
Authors: Gong Xuantong , Li Qingfeng , Gu Lishuang , Chen Chen , Liu Xuefeng , Zhang Xuan , Wang Bo , Sun Chao , Yang Di , Li Lin , Wang Yong
Published: May 2023

Objectives

This study aimed to explore the value of conventional ultrasound (CUS) and contrast-enhanced ultrasound (CEUS) radiomics to diagnose breast cancer and predict its molecular subtype.

Method

A total of 170 lesions (121 malignant, 49 benign) were selected from March 2019 to January 2022. Malignant lesions were further divided into six categories of molecular subtype: (non-)Luminal A, (non-)Luminal B, (non-)human epidermal growth factor receptor 2 (HER2) overexpression, (non-)triple-negative breast cancer (TNBC), hormone receptor (HR) positivity/negativity, and HER2 positivity/negativity. Participants were examined using CUS and CEUS before surgery. Regions of interest images were manually segmented. The pyradiomics toolkit and the maximum relevance minimum redundancy algorithm were utilized to extract and select features, multivariate logistic regression models of CUS, CEUS, and CUS combined with CEUS radiomics were then constructed and evaluated by fivefold cross-validation.

Results

The accuracy of the CUS combined with CEUS model was superior to CUS model (85.4% vs. 81.3%, p<0.01). The accuracy of the CUS radiomics model in predicting the six categories of breast cancer is 68.2% (82/120), 69.3% (83/120), 83.7% (100/120), 86.7% (104/120), 73.5% (88/120), and 70.8% (85/120), respectively. In predicting breast cancer of Luminal A, HER2 overexpression, HR-positivity, and HER2 positivity, CEUS video improved the predictive performance of CUS radiomics model [accuracy=70.2% (84/120), 84.0% (101/120), 74.5% (89/120), and 72.5% (87/120), p<0.01].

Conclusion

CUS radiomics has the potential to diagnose breast cancer and predict its molecular subtype. Moreover, CEUS video has auxiliary predictive value for CUS radiomics.
Treatment paradigm and prognostic factor analyses of rectal squamous cell carcinoma
Authors: Liu Rui , Zhang Jiahui , Zhang Yinjie , Yan Jin
Published: May 2023

Background

Rectal squamous cell carcinoma (rSCC) is a rare pathological subtype of rectal cancer. There is no consensus on the treatment paradigm for patients with rSCC. This study aimed to provide a paradigm for clinical treatment and develop a prognostic nomogram.

Methods

Patients diagnosed with rSCC between 2010 and 2019 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. According to the TNM staging system, Kaplan−Meier (K-M) survival analysis was used to identify the survival benefits of different treatments in patients with rSCC. The Cox regression method was used to identify independent prognostic risk factors. Nomograms were evaluated by Harrell’s concordance index (C-index), calibration curves, decision curve analysis (DCA) and K-M curves.

Results

Data for 463 patients with rSCC were extracted from the SEER database. Survival analysis showed that there was no significant difference in median cancer-specific survival (CSS) among patients with TNM stage 1 rSCC treated with radiotherapy (RT), chemoradiotherapy (CRT) or surgery (P = 0.285). In TNM stage 2 patients, there was a significant difference in median CSS among those treated with surgery (49.5 months), RT (24 months), and CRT (63 months) (P = 0.003). In TNM stage 3 patients, there was a significant difference in median CSS among those treated with CRT (58 months), CRT plus surgery (56 months) and no treatment (9.5 months) (P < 0.001). In TNM stage 4 patients, there was no significant difference in median CSS among those treated with CRT, chemotherapy (CT), CRT plus surgery and no treatment (P = 0.122). Cox regression analysis showed that age, marital status, T stage, N stage, M stage, PNI, tumor size, RT, CT, and surgery were independent risk factors for CSS. The 1-, 3-, and 5-year C-indexes were 0.877, 0.781, and 0.767, respectively. The calibration curve showed that the model had excellent calibration. The DCA curve showed that the model had excellent clinical application value.

Conclusion

RT or surgery is recommended for patients with stage 1 rSCC, and CRT is recommended for patients with stage 2, and stage 3 rSCC. Age, marital status, T stage, N stage, M stage, PNI, tumor size, RT, CT, and surgery are independent risk factors for CSS in patients with rSCC. The model based on the above independent risk factors has excellent prediction efficiency.
Review of acute kidney injury and progression to chronic kidney disease in pediatric patients undergoing hematopoietic cell transplant
Authors: Vuong Kim T. , Joseph Catherine , Angelo Joseph R.
Published: May 2023

While acute kidney injury (AKI) after hematopoietic cell transplant (HCT) has been well-described in pediatric patients, literature regarding the long term renal consequences of HCT-related AKI, the development of chronic kidney disease (CKD), and CKD care in pediatric patients post-HCT is limited. CKD affects almost 50% of patients after HCT with multifactorial etiology including infection, nephrotoxic medications, transplant-associated thrombotic microangiopathy, graft-versus-host disease, and sinusoidal obstruction syndrome. As renal function declines in CKD, eventually progressing to end stage kidney disease (ESKD), mortality increases and is more than 80% among patients requiring dialysis. Using society guidelines and current literature, this review summarizes definitions and etiologies of and management strategies among patients with AKI and CKD post-HCT with an emphasis on albuminuria, hypertension, nutrition, metabolic acidosis, anemia, and mineral bone disease. The goal of this review is to aid early identification and intervention in patients with renal dysfunction prior to development of ESKD, and to discuss ESKD and renal transplant in these patients post-HCT.
Between Scylla and Charybdis: thrombosis in children with hemophilia
Authors: El Maamari Jad , Amid Ali , Pelland-Marcotte Marie-Claude , Tole Soumitra
Published: May 2023

Thromboembolism is an infrequent complication in children with hemophilia that has been traditionally associated with the presence of a central venous access device. Novel rebalancing agents have shown promising results as prophylactic therapies to minimize the risk of bleeding but both thromboembolism and thrombotic microangiopathy have been reported as complications. The management of thrombosis in children with hemophilia is particularly challenging given the inherent risk of bleeding. In this paper, we present clinical vignettes to review the literature, highlight challenges, and describe our approach to managing thromboembolism in children with hemophilia.