bluuebunny/crossref_metadata_2025_split huggingface dataset:
Irradiation-induced exosomal HMGB1 to confer radioresistance via the PI3K/AKT/FOXO3A signaling pathway in ESCC
Authors: Du Xingyu , Zhang Xueyuan , Dong Jing , Zou Naiyi , Guo Dong , Yao Weinan , Wang Xiaobin , Li Shuguang , Song Chunyang , Yan Ke , Shen Wenbin , Zhu Shuchai 
Published: November 2022

Abstract
Background
Radioresistance is a major cause of treatment failure in esophageal squamous cell carcinoma (ESCC) radiotherapy, and the underlying mechanisms of radioresistance are still unclear. Irradiation (IR) stimulates changes in tumor-derived exosome contents, which can be taken up by recipient cells, playing an important role in the proliferation, cell cycle and apoptosis of recipient cells. This study investigated the effect of IR-induced exosomal high mobility group box 1 (HMGB1) on radioresistance in ESCC cells.

Methods
Plasma exosomes were isolated from 21 ESCC patients and 24 healthy volunteers, and the expression of HMGB1 was examined. Then, the therapeutic effect of radiotherapy was analyzed according to the different expression levels of plasma exosomal HMGB1 in ESCC patients. The uptake of exosomes by recipient cells was verified by immunofluorescence staining, and the localization of exosomes and HMGB1 in cells before and after IR was evaluated. The effects of IR-induced exosomes on cell proliferation, invasion, apoptosis, cell cycle distribution and radioresistance after HMGB1 knockdown were verified. Moreover, western blotting was used to measure changes in the expression of cyclin B1, CDK1, Bax, Bcl2, phosphorylated histone H2AX and the PI3K/AKT/FOXO3A pathway in the HMGB1-knockdown exosome group and the negative control group.

Results
The expression of HMGB1 in ESCC plasma exosomes was significantly increased compared with that in healthy volunteers, and high expression of HMGB1 in plasma exosomes was associated with radioresistance (P = 0.016). IR-induced the release of exosomal HMGB1 and promoted proliferation and radioresistance in recipient cells, with a sensitization enhancement ratio (SER) of 0.906 and 0.919, respectively. In addition, IR-induced exosomal HMGB1 promotes G2/M phase arrest by regulating the proteins cyclin B1 and CDK1, cooperating with the proteins Bax and Bcl2 to reduce the apoptosis rate through the PI3K/AKT/FOXO3A signaling pathway, and participated in IR-induced DNA damage repair through γH2AX.

Conclusion
These findings indicate that high expression of plasma exosomal HMGB1 is associated with an adverse radiotherapy response. IR-induced exosomal HMGB1 enhances the radioresistance of ESCC cells.
A review of user needs to drive the development of lower limb prostheses
Authors: Manz Sabina , Valette Romain , Damonte Federica , Avanci Gaudio Lucas , Gonzalez-Vargas Jose , Sartori Massimo , Dosen Strahinja , Rietman Johan 
Published: November 2022

AbstractBackgroundThe development of bionic legs has seen substantial improvements in the past years but people with lower-limb amputation still suffer from impairments in mobility (e.g., altered balance and gait control) due to significant limitations of the contemporary prostheses. Approaching the problem from a human-centered perspective by focusing on user-specific needs can allow identifying critical improvements that can increase the quality of life. While there are several reviews of user needs regarding upper limb prostheses, a comprehensive summary of such needs for those affected by lower limb loss does not exist.MethodsWe have conducted a systematic review of the literature to extract important needs of the users of lower-limb prostheses. The review included 56 articles in which a need (desire, wish) was reported explicitly by the recruited people with lower limb amputation (N = 8149).ResultsAn exhaustive list of user needs was collected and subdivided into functional, psychological, cognitive, ergonomics, and other domain. Where appropriate, we have also briefly discussed the developments in prosthetic devices that are related to or could have an impact on those needs. In summary, the users would like to lead an independent life and reintegrate into society by coming back to work and participating in social and leisure activities. Efficient, versatile, and stable gait, but also support to other activities (e.g., sit to stand), contribute to safety and confidence, while appearance and comfort are important for the body image. However, the relation between specific needs, objective measures of performance, and overall satisfaction and quality of life is still an open question.ConclusionsIdentifying user needs is a critical step for the development of new generation lower limb prostheses that aim to improve the quality of life of their users. However, this is not a simple task, as the needs interact with each other and depend on multiple factors (e.g., mobility level, age, gender), while evolving in time with the use of the device. Hence, novel assessment methods are required that can evaluate the impact of the system from a holistic perspective, capturing objective outcomes but also overall user experience and satisfaction in the relevant environment (daily life).
Three-dimensional microenvironment regulates gene expression, function, and tight junction dynamics of iPSC-derived blood–brain barrier microvessels
Authors: Linville Raleigh M. , Sklar Matthew B. , Grifno Gabrielle N. , Nerenberg Renée F. , Zhou Justin , Ye Robert , DeStefano Jackson G. , Guo Zhaobin , Jha Ria , Jamieson John J. , Zhao Nan , Searson Peter C. 
Published: November 2022

AbstractThe blood–brain barrier (BBB) plays a pivotal role in brain health and disease. In the BBB, brain microvascular endothelial cells (BMECs) are connected by tight junctions which regulate paracellular transport, and express specialized transporter systems which regulate transcellular transport. However, existing in vitro models of the BBB display variable accuracy across a wide range of characteristics including gene/protein expression and barrier function. Here, we use an isogenic family of fluorescently-labeled iPSC-derived BMEC-like cells (iBMECs) and brain pericyte-like cells (iPCs) within two-dimensional confluent monolayers (2D) and three-dimensional (3D) tissue-engineered microvessels to explore how 3D microenvironment regulates gene expression and function of the in vitro BBB. We show that 3D microenvironment (shear stress, cell-ECM interactions, and cylindrical geometry) increases BBB phenotype and endothelial identity, and alters angiogenic and cytokine responses in synergy with pericyte co-culture. Tissue-engineered microvessels incorporating junction-labeled iBMECs enable study of the real-time dynamics of tight junctions during homeostasis and in response to physical and chemical perturbations.
Calcaneal osteotomy due to insertional calcaneal tendinopathy: preoperative planning
Authors: Mazura Matej , Goldman Tomas , Stanislav Popelka , Kachlik David , Hromadka Rastislav 
Published: November 2022

Abstract
Purpose
Dorsal closing wedge calcaneal osteotomy (DCWCO) is indicated in patients with insertional tendinopathy of the calcaneal (Achilles) tendon. The Chauveaus-Liet’s (CL) angle is represented by the difference between the angle of verticalization (α) and morphological angle (β) of the calcaneus (CL angle = α − β). The purpose of the study was to assess whether the DCWCO affects the Chauveaus-Liet’s angle.

Methods
The study included 12 patients indicated to DCWCO. Three directions of close wedge osteotomy were designed for each patient—horizontal, vertical and in the middle type of osteotomy and a virtual osteotomy was created in each of them in the ABAQUS system in cooperation with Czech Technical University. The most used directions of osteotomy according to the available literature were used. We evaluated α and β angles before and after osteotomy, changes of the length plantar aponeurosis and the elevation of distal insertional point of the calcaneal tendon. The changes of grades, median and standard deviation were observed.

Results
The change of the alfa angle was dependent on the direction of the osteotomy and the change of the beta angle was affected by the size of the osteotomy. The greatest elevation of the distal insertional point of the calcaneal tendon occurred in the horizontal type of the osteotomy.

Conclusion
Our study shows that the more we want to reduce the tension in the calcaneal tendon, the more we have to perform an osteotomy horizontally. This study could serve as a preoperative guide for osteotomy planning.
Deciphering the impact of genetic variation on human polyadenylation using APARENT2
Authors: Linder Johannes , Koplik Samantha E. , Kundaje Anshul , Seelig Georg 
Published: November 2022

AbstractBackground3′-end processing by cleavage and polyadenylation is an important and finely tuned regulatory process during mRNA maturation. Numerous genetic variants are known to cause or contribute to human disorders by disrupting the cis-regulatory code of polyadenylation signals. Yet, due to the complexity of this code, variant interpretation remains challenging.ResultsWe introduce a residual neural network model,APARENT2, that can infer 3′-cleavage and polyadenylation from DNA sequence more accurately than any previous model. This model generalizes to the case of alternative polyadenylation (APA) for a variable number of polyadenylation signals. We demonstrate APARENT2’s performance on several variant datasets, including functional reporter data and human 3′ aQTLs from GTEx. We apply neural network interpretation methods to gain insights into disrupted or protective higher-order features of polyadenylation. We fine-tune APARENT2 on human tissue-resolved transcriptomic data to elucidate tissue-specific variant effects. By combining APARENT2 with models of mRNA stability, we extend aQTL effect size predictions to the entire 3′ untranslated region. Finally, we perform in silico saturation mutagenesis of all human polyadenylation signals and compare the predicted effects of$${>}43$$>43million variants against gnomAD. While loss-of-function variants were generally selected against, we also find specific clinical conditions linked to gain-of-function mutations. For example, we detect an association between gain-of-function mutations in the 3′-end and autism spectrum disorder. To experimentally validate APARENT2’s predictions, we assayed clinically relevant variants in multiple cell lines, including microglia-derived cells.ConclusionsA sequence-to-function model based on deep residual learning enables accurate functional interpretation of genetic variants in polyadenylation signals and, when coupled with large human variation databases, elucidates the link between functional 3′-end mutations and human health.
The clinical value and cost-effectiveness of treatments for patients with coronary artery disease
Authors: Weiting Huang , Yaoxian Alwin Zhang , Keong Yeo Khung , Lam Shao Wei , How Lau Yee , Sahlén Anders Olof , Pourghaderi Ahmadreza , Che Matthew , Terrance Chua Siang Jin , Graves Nicholas 
Published: November 2022

Abstract
Background
The clinical value and cost-effectiveness of invasive treatments for patients with coronary artery disease is unclear. Invasive treatments such as coronary artery bypass grafting and percutaneous coronary intervention are frequently used as a starting treatment, yet they are much more costly than optimal medical therapy. While patients may transition into other treatments over time, the choices of starting treatments are likely important determinants of costs and health outcomes. The aim is to predict by how much costs and health outcomes will change from a decision to use different starting treatments for patients with coronary artery disease in an Asian setting.

Methods
A cost-effectiveness study using a Markov model informed by data from Singapore General Hospital was done. All patients with initial presentations of stable coronary disease and no acute coronary syndromes who received medical treatments and interventional therapies were included. We compare existing practice, where the starting treatment can be medical therapy or stent percutaneous coronary interventions or coronary artery bypass grafting, with alternate starting treatment strategies.

Results
When compared to ‘existing practice’ a policy of starting 14% of patients with coronary artery bypass grafting and 86% with optimal medical therapy showed savings of $1,743 per patient and 0.23 additional quality adjusted life years. A change to policy nationwide would save $10 million and generate 1,380 quality adjusted life years.

Conclusions
Increasing coronary artery bypass grafting and use of medical therapy in the setting of coronary artery disease is likely to saves costs and improve health outcomes. A definitive study to address the question we investigate would be very difficult to undertake and so using existing data to model the expected outcomes is a useful tool. There are likely to be large and complex barriers to the implementation of any policy change based on the findings of this study.
Parameter estimation and tracking algorithm for resolvable group targets based on GLMB filter and RLS algorithm
Authors: Liu Weifeng , Zhao Zhi , Liu Qiliang , Peng Zhangming 
Published: November 2022

AbstractCurrent resolvable group targets tracking algorithms can only track a small number of group targets assuming the standard deviation vectors (SDVs) are known. Based on generalized labeled multi-Bernoulli filter, this paper first proposes a serial tracking algorithm, in order to save the computational cost of filter tracking large-batch and multi-structure group targets. Then, the least squares and the k-means algorithms are used to jointly estimate the SDVs and the group target states. The experimental simulation results verify the effectiveness of the proposed methods.
Decomposition and nutrient release patterns of municipal solid waste compost in two agro-ecological zones of Uganda
Authors: Kabasiita Juliet Kiiza , Opolot Emmanuel , Sande Eric , Malinga Geoffrey Maxwell 
Published: November 2022

Abstract
Background
Deteriorating soil fertility is a major constraint to agricultural production and food security among smallholder farmers in Uganda and throughout sub-Saharan Africa, where the majority of the population relies on subsistence farming for its livelihoods.
Unfortunately, inorganic fertiliser used as a significant soil nutrient replenishment is unsustainable, causing adverse environmental effects, including soil acidification and pollution of water bodies. Therefore, finding alternative, more sustainable, low-cost nutrient management systems is vital. This study assessed the decomposition and nutrient release patterns of municipal solid waste compost (MSWC) in a 36 weeks litter bag experiment under field conditions in two agro-ecological zones (AEZs) of Uganda.

Results
We found a higher rate of decomposition in the South-western Grass Farmlands (SGF) agro-ecological zone (0.041 week−1, with 20% of initial compost mass remaining after 36 weeks of decay) compared to Southern and Eastern Lake Kyoga Basin (SEKB) (0.043 week−1, 32% of initial litter mass remaining). The half-life values were 16 and 17 weeks for SGF and SEKB AEZs, respectively. The nutrient release rates differed between the two study sites. The macronutrient release pattern in both sites followed the order K > P > N. The secondary macronutrients release followed the order Ca > Mg in the SGF, while in SEKB, the order was reversed. The micronutrients followed the order Cu > Mn > Fe > Zn and Cu > Mn > Zn > Fe in SGF and SEKB AEZs, respectively. The MSWC mass loss during decomposition was negatively correlated with rainfall in both AEZs and with temperature in SGF AEZ, while it was positively correlated with temperature in SEKB AEZ. However, the relationship with nutrient release rates was inconsistent in both AEZs.

Conclusions
Our results showed consistent release of nutrients in all AEZs throughout the study period, which coincides with the two cropping seasons in Uganda, suggesting that smallholder farmers can use MSWC as a soil amendment to address soil fertility decline and improve crop productivity. However, because most nutrients were released almost right away in both AEZs, planting should be done at the beginning of high rainfall months when soil moisture is high to synchronise nutrient release from MSWC with crop demand and maximise nutrient uptake by crops while minimising losses to the environment. Furthermore, the inconsistent relationships between the climatic variables and nutrient release suggest that other factors, such as site-specific microbial composition, influenced MSWC nutrient release. Therefore, long-term research is needed to examine other factors affecting nutrient release in these AEZs.
Drivers of fish choice: an exploratory analysis in Mediterranean countries
Authors: Saidi A. , Sacchi G. , Cavallo C. , Cicia G. , Di Monaco R. , Puleo S. , Del Giudice T. 
Published: November 2022

AbstractFish is an important source of healthy proteins and an important economic sector in Mediterranean countries. Despite the wealth of knowledge acquired in Western countries, a gap has been found in studies in developing countries, as in the Mediterranean southern shore. Therefore, we aimed to investigate consumers’ perceptions of finfish attributes, with qualitative tools as focus groups, given the exploratory nature of the research. The focus groups have been held in Italy, Lebanon, Spain, and Tunisia; in each country, one was held in seaside areas and one in inland areas, in order to control for the availability of fish that shapes consumers’ evaluations and expectations. The focus groups have been analysed through content and semantic analyses. Results of the study yielded main themes recurring in the discussions that have been categorized along such dimensions: (1) definition of fish products; (2) context; (3) search attributes; (4) experience attributes; and (5) credence attributes. Among attributes, the ones mostly guiding consumers’ choices seem to be freshness and fish species, which are used as proxies for quality and sensory attributes. Most of the respondents preferred delicate white fish, while some exceptions were found in Tunisian respondents preferring blue fish and they also were the only ones who were not looking for convenient and already cleaned products. Trust also represented a critical element in guiding the decisions of consumers: with a lack of trust, consumers deviate from preferring local products, as noticeable especially in Lebanese respondents’ opinions. Credence attributes such as animal welfare and sustainability received a minor attention from all the respondents.
Gut fungi enhances immunosuppressive function of myeloid-derived suppressor cells by activating PKM2-dependent glycolysis to promote colorectal tumorigenesis
Authors: Zhang Zhiyong , Zheng Yaojun , Chen Ying , Yin Yuxin , Chen Yuxi , Chen Qianyu , Hou Yayi , Shen Sunan , Lv Mingming , Wang Tingting 
Published: November 2022

Abstract
Background
Accumulating evidence implicates that gut fungi are associated with the pathogenesis of colorectal cancer (CRC). Our previous study has revealed that Candida tropicalis (C. tropicalis) promotes colorectal tumorigenesis by enhancing immunosuppressive function of myeloid-derived suppressor cells (MDSCs) and increasing accumulation of MDSCs, but the underlying mechanisms remain unestablished.

Methods
Bone marrow–derived MDSCs were stimulated with C. tropicalis. RNA-sequencing analysis was performed to screen the differentially expressed genes. Quantitative real-time PCR and western blot were used to measure the expression of related proteins. Co-culture assay of MDSCs and CD8+ T cells was used to determine the immunosuppressive ability of MDSCs. Metabolomic analysis was conducted to detect metabolic reprogramming of MDSCs. Aerobic glycolysis of MDSCs was assessed by extracellular acidification rate (ECAR), glucose consumption and lactate production. A CAC mouse model was induced by AOM and DSS to determine the therapeutic action of TEPP-46. IHC and immunofluorescence were performed to examine the expression of PKM2, PKM2 (p-Y105) and iNOS in human CRC-infiltrated MDSCs.

Results
C. tropicalis facilitates immunosuppressive function of MDSCs by increasing the expression of iNOS, COX2 and NOX2, production of nitric oxide (NO) and reactive oxygen species (ROS). Mechanistically, C. tropicalis facilitates the immunosuppressive function of MDSCs through the C-type lectin receptors Dectin-3 and Syk. C. tropicalis-enhanced immunosuppressive function of MDSCs is further dependent on aerobic glycolysis. On the one hand, NO produced by MDSCs enhanced aerobic glycolysis in a positive feedback manner. On the other hand, C. tropicalis promotes p-Syk binding to PKM2, which results in PKM2 Tyr105 phosphorylation and PKM2 nuclear translocation in MDSCs. Nuclear PKM2 interacts with HIF-1α and subsequently upregulates the expression of HIF-1α target genes encoding glycolytic enzymes, GLUT1, HK2, PKM2, LDHA and PDK1, which are required for the C. tropicalis-induced aerobic glycolysis of MDSCs. Blockade of PKM2 nuclear translocation attenuates C. tropicalis-mediated colorectal tumorigenesis. The high expression of PKM2, PKM2 (p-Y105) and iNOS in CRC-infiltrated MDSCs correlates with the development of human CRC.

Conclusion
C. tropicalis enhances immunosuppressive function of MDSCs via Syk-PKM2-HIF-1α-glycolysis signaling axis, which drives CRC. Therefore, we identify the Syk-PKM2-HIF-1α-glycolysis signaling axis as a potential therapeutic target for CRC.
Pan-cancer landscape of aberrant DNA Methylation across childhood Cancers: Molecular Characteristics and Clinical relevance
Authors: Dong Zheng , Zhou Hongyu 
Published: November 2022

AbstractAberrant DNA methylation (DNAm) is an important epigenetic regulator in various cancers. Pan-cancer DNAm analyses have investigated the potential common mechanisms of DNAm in tumorigenesis. However, these pan-cancer studies focused on adult cancers rather than pediatric cancers, which may have distinct pathology and treatment responses. Here, we performed a pan-cancer analysis of genome-wide DNAm in over 2,000 samples from nine pediatric cancers to elucidate the DNAm landscape of pediatric cancers. We identified 217,586 differentially methylated CpG sites (DMCs) in pediatric cancers, with a tendency toward hypermethylation as opposed to hypomethylation (P = 0.02). Amongst them, 75.65% also presented DNAm alterations in adult cancers. In nine pediatric cancers, we defined 54 shared DMCs (SDMCs), which were also observed in at least one adult cancer type. Furthermore, methylation patterns in SDMCs influenced the transcription of several genes (MEIS1, MIA3, PCDHAC2, SH3BP4, and ATP8B1) involved in well-known cancer-related pathways and cancer hallmarks (FDR < 0.05). Moreover, SDMCs were significantly associated with patient survival, and this association was independent of sex, age, and tumor stage (P < 0.05). Interestingly, SDMCs could affect patient survival not only in the nine pediatric cancers that were used to identify SDMCs but also in other untested pediatric cancers (P < 0.05). Collectively, our data depicts a comprehensive landscape of aberrant DNA methylation in pediatric cancers, which is partly similar to that of adult cancers. We also suggest a potential clinical application of SDMCs as biomarkers for the prognosis of pediatric cancer.