bluuebunny/crossref_metadata_2025_split huggingface dataset:
Osteoarthritis genetic risk acting on the galactosyltransferase gene COLGALT2 has opposing functional effects in articulating joint tissues
Authors: Kehayova Yulia S. , Wilkinson J. Mark , Rice Sarah J. , Loughlin John 
Published: May 2023

Abstract
Background
Investigation of cartilage and chondrocytes has revealed that the osteoarthritis risk marked by the independent DNA variants rs11583641 and rs1046934 mediate their effects by decreasing the methylation status of CpG dinucleotides in enhancers and increasing the expression of shared target gene COLGALT2. We set out to investigate if these functional effects operate in a non-cartilaginous joint tissue.

Methods
Nucleic acids were extracted from the synovium of osteoarthritis patients. Samples were genotyped, and DNA methylation was quantified by pyrosequencing at CpGs within the COLGALT2 enhancers. CpGs were tested for enhancer effects using a synovial cell line and a reporter gene assay. DNA methylation was altered using epigenetic editing, with the impact on gene expression determined using quantitative polymerase chain reaction. In silico analysis complemented laboratory experiments.

Results
The rs1046934 genotype did not associate with DNA methylation or COLGALT2 expression in the synovium, whereas the rs11583641 genotype did. Surprisingly, the effects for rs11583641 were opposite to those previously observed in cartilage. Epigenetic editing in synovial cells revealed that enhancer methylation is causally linked to COLGALT2 expression.

Conclusions
This is the first direct demonstration for osteoarthritis genetic risk of a functional link between DNA methylation and gene expression operating in opposite directions between articular joint tissues. It highlights pleiotropy in the action of osteoarthritis risk and provides a cautionary note in the application of future genetically based osteoarthritis therapies: an intervention that decreases the detrimental effect of a risk allele in one joint tissue may inadvertently increase its detrimental effect in another joint tissue.
Therapeutic and prophylactic effects of oral administration of probiotic Enterococcus faecium Smr18 in Salmonella enterica-infected mice
Authors: Rashid Muzamil , Narang Anmol , Thakur Shubham , Jain Subheet Kumar , Kaur Sukhraj 
Published: May 2023

AbstractSalmonella enterica serotype Typhi causes chronic enteric fever known as typhoid. Prolonged treatment regimen used for the treatment of typhoid and indiscriminate use of antibiotics has led to the emergence of resistant strains of S. enterica that has further increased the severity of the disease. Therefore, alternative therapeutic agents are urgently required. In this study, probiotic and enterocin-producing bacteria Enterococcus faecium Smr18 was compared for both its prophylactic and therapeutic efficacy in S. enterica infection mouse model. E. faecium Smr18 possessed high tolerance to bile salts and simulated gastric juice, as treatment for 3 and 2 h resulted in 0.5 and 0.23 log10 reduction in the colony forming units, respectively. It exhibited 70% auto aggregation after 24 h of incubation and formed strong biofilms at both pH 5 and 7. Oral administration of E. faecium in BALB/c mice infected with S. enterica significantly (p < 0.05) reduced the mortality of the infected mice and prevented the weight loss in mice. Administration of E. faecium prior to infection inhibited the translocation of S. enterica to liver and spleen, whereas, its administration post-infection completely cleared the pathogen from the organs within 8 days. Further, in both pre- and post-E. faecium-treated infected groups, sera levels of liver enzymes were restored back to normal; whereas the levels of creatinine, urea and antioxidant enzymes were significantly (p < 0.05) reduced compared to the untreated-infected group. E. faecium Smr18 administration significantly increased the sera levels of nitrate by 1.63-fold and 3.22-fold in pre- and post-administration group, respectively. Sera levels of interferon-γ was highest (tenfold) in the untreated-infected group, whereas the levels of interleukin-10 was highest in the post-infection E. faecium-treated group thereby indicating the resolution of infection in the probiotic-treated group, plausibly due to the increased production of reactive nitrogen intermediates.
Combatting over-specialization bias in growing chemical databases
Authors: Dost Katharina , Pullar-Strecker Zac , Brydon Liam , Zhang Kunyang , Hafner Jasmin , Riddle Patricia J. , Wicker Jörg S. 
Published: May 2023

Abstract
Background
Predicting in advance the behavior of new chemical compounds can support the design process of new products by directing the research toward the most promising candidates and ruling out others. Such predictive models can be data-driven using Machine Learning or based on researchers’ experience and depend on the collection of past results. In either case: models (or researchers) can only make reliable assumptions about compounds that are similar to what they have seen before. Therefore, consequent usage of these predictive models shapes the dataset and causes a continuous specialization shrinking the applicability domain of all trained models on this dataset in the future, and increasingly harming model-based exploration of the space.

Proposed solution
In this paper, we propose cancels (CounterActiNg Compound spEciaLization biaS), a technique that helps to break the dataset specialization spiral. Aiming for a smooth distribution of the compounds in the dataset, we identify areas in the space that fall short and suggest additional experiments that help bridge the gap. Thereby, we generally improve the dataset quality in an entirely unsupervised manner and create awareness of potential flaws in the data. cancels does not aim to cover the entire compound space and hence retains a desirable degree of specialization to a specified research domain.

Results
An extensive set of experiments on the use-case of biodegradation pathway prediction not only reveals that the bias spiral can indeed be observed but also that cancels produces meaningful results. Additionally, we demonstrate that mitigating the observed bias is crucial as it cannot only intervene with the continuous specialization process, but also significantly improves a predictor’s performance while reducing the number of required experiments. Overall, we believe that cancels can support researchers in their experimentation process to not only better understand their data and potential flaws, but also to grow the dataset in a sustainable way. All code is available under github.com/KatDost/Cancels.
Overview of multifunctional cysteinyl cathepsins in atherosclerosis-based cardiovascular disease: from insights into molecular functions to clinical implications
Authors: Cheng Xian Wu , Narisawa Megumi , Wang Hailong , Piao Limei 
Published: May 2023

AbstractCysteinyl cathepsins (CTSs) are widely known to have a proteolysis function that mediates recycling of unwanted proteins in endosomes and lysosomes, and investigation of CTSs has greatly improved with advances in live-imaging techniques both in vivo and in vitro, leading to three key findings. (1) CTSs are relocated from the lysosomes to other cellular spaces (i.e., cytosol, nucleus, nuclear membrane, plasma membrane, and extracellular milieu). (2) In addition to acidic cellular compartments, CTSs also exert biological activity in neutral environments. (3) CTSs also exert multiple nontraditional functions in, for example, extracellular matrix metabolism, cell signaling transduction, protein processing/trafficking, and cellular events. Various stimuli regulate the expression and activities of CTSs in vivo and vitro—e.g., inflammatory cytokines, oxidative stress, neurohormones, and growth factors. Accumulating evidence has confirmed the participation of CTSs in vascular diseases characterized by atherosclerosis, plaque rupture, thrombosis, calcification, aneurysm, restenosis/in-stent-restenosis, and neovasel formation. Circulating and tissue CTSs are promising as biomarkers and as a diagnostic imaging tool in patients with atherosclerosis-based cardiovascular disease (ACVD), and pharmacological interventions with their specific and non-specific inhibitors, and cardiovascular drugs might have potential for the therapeutic targeting of CTSs in animals. This review focuses on the update findings on CTS biology and the involvement of CTSs in the initiation and progression of ACVD and discusses the potential use of CTSs as biomarkers and small-molecule targets to prevent deleterious nontraditional functions in ACVD.
Integrated single-nucleus sequencing and spatial architecture analysis identified distinct injured-proximal tubular types in calculi rats
Authors: Wang Zhu , Deng Qiong , Gu Yanli , Li Min , Chen Yeda , Wang Jieyan , Zhang Ying , Zhang Jianwen , Hu Qiyi , Zhang Shenping , Chen Wei , Chen Zhenhua , Li Jiaying , Wang Xisheng , Liang Hui 
Published: May 2023

Abstract
Background
Urolithiasis with high prevalence and recurrence rate, has impacts on kidney injury in patients, becomes a socioeconomic and healthcare problem in worldwide. However, the biology of kidney with crystal formation and proximal tubular injury remains essentially unclear. The present study aims to evaluate the cell biology and immune-communications in urolithiasis mediated kidney injury, to provide new insights in the kidney stone treatment and prevention.

Results
We identified 3 distinct injured-proximal tubular cell types based on the differentially expression injury markers (Havcr1 and lcn2) and functional solute carriers (slc34a3, slc22a8, slc38a3 and slc7a13), and characterized 4 main immune cell types in kidney and one undefined cell population, where F13a1+/high/CD163+/high monocyte & macrophage and Sirpa/Fcgr1a/Fcgr2a+/high granulocyte were the most enriched. We performed intercellular crosstalk analysis based on the snRNA-seq data and explored the potential immunomodulation of calculi stone formation, and founded that the interaction between ligand Gas6 and its receptors (Gas6-Axl, Gas6-Mertk) was specifically observed in the injured-PT1 cells, but not injured-PT2 and -PT3 cells. The interaction of Ptn-Plxnb2 was only observed between the injured-PT3 cells and its receptor enriched cells.

Conclusions
Present study comprehensively characterized the gene expression profile in the calculi rat kidney at single nucleus level, identified novel marker genes for all cell types of rat kidney, and determined 3 distinct sub-population of injured-PT clusters, as well as intercellular communication between injured-PTs and immune cells. Our collection of data provides a reliable resource and reference for studies on renal cell biology and kidney disease.
Do Information and Communications Technology (ICT) and financial development contribute to economic diversification? Evidence from sub-Saharan Africa
Authors: Owolabi Oluwarotimi Ayokunnu , Adedeji Adedayo Oluseun , Aderounmu Busayo , Oku Asa-Ruth Oboko , Ogunbiyi Toun 
Published: May 2023

AbstractThis study based on a panel of 37 sub-Saharan Africa countries over the period of 2000–2019 explores the effect of a number of Information and Communications Technology variables namely fixed broad band, fixed line telephone, Information and Communications Technology good imports, internet, mobile, and secure internet servers, and financial development measured by private sector domestic credit to GDP on economic diversification as measured by a computed Herfindahl–Hirschman Index of economic diversification. Model estimation was performed using pooled ordinary least squares regression, panel data fixed effects regression, and generalized method of moments regression. The results from findings indicated that the Information and Communications Technology variables: fixed-line telephone, and ICT imports significantly reduced economic diversification, while internet and mobile were, respectively, insignificant for boosting economic diversification, and fixed broadband and secure internet servers were insignificant in adversely affecting economic diversification. As regards financial development, it was insignificant in boosting economic diversification of sub-Saharan Africa countries. The study recommended amongst others that individuals in sub-Saharan Africa countries should have improved access to Information and Communications Technology infrastructure and governments should ensure adequate provision of quality Information and Communications Technology infrastructure.
A heterozygous mutation in UBE2H in a patient with developmental delay leads to an aberrant brain development in zebrafish
Authors: Shin Unbeom , Choi Yeonsong , Ko Hwa Soo , Myung Kyungjae , Lee Semin , Cheon Chong Kun , Lee Yoonsung 
Published: May 2023

Abstract
Background
Ubiquitin-related rare diseases are generally characterized by developmental delays and mental retardation, but the exact incidence or prevalence is not yet fully understood. The clinical application of next-generation sequencing for pediatric seizures and developmental delay of unknown causes has become common in studies aimed at identification of a causal gene in patients with ubiquitin-related rare diseases that cannot be diagnosed using conventional fluorescence in situ hybridization or chromosome microarray tests. Our study aimed to investigate the effects of ubiquitin–proteasome system on ultra-rare neurodevelopmental diseases, through functional identification of candidate genes and variants.

Methods
In our present work, we carried out genome analysis of a patient with clinical phenotypes of developmental delay and intractable convulsion, to identify causal mutations. Further characterization of the candidate gene was performed using zebrafish, through gene knockdown approaches. Transcriptomic analysis using whole embryos of zebrafish knockdown morphants and additional functional studies identified downstream pathways of the candidate gene affecting neurogenesis.

Results
Through trio-based whole-genome sequencing analysis, we identified a de novo missense variant of the ubiquitin system-related gene UBE2H (c.449C>T; p.Thr150Met) in the proband. Using zebrafish, we found that Ube2h is required for normal brain development. Differential gene expression analysis revealed activation of the ATM-p53 signaling pathway in the absence of Ube2h. Moreover, depletion of ube2h led to induction of apoptosis, specifically in the differentiated neural cells. Finally, we found that a missense mutation in zebrafish, ube2h (c.449C>T; p.Thr150Met), which mimics a variant identified in a patient with neurodevelopmental defects, causes aberrant Ube2h function in zebrafish embryos.

Conclusion
A de novo heterozygous variant in the UBE2H c.449C>T (p.Thr150Met) has been identified in a pediatric patient with global developmental delay and UBE2H is essential for normal neurogenesis in the brain.
Comparing intraoperative hemodynamics and medication use during cranial nerve monitoring with partial muscle relaxants versus without in cerebellopontine angle tumors: a randomized controlled trial
Authors: Osman Safinaz H. , Gaber Muhammad M. , Fadel Nasser A. , Aboldahab Hesham A. , Mohamed Mohamed M. 
Published: May 2023

Abstract
Background
There are many methods used for cranial nerve monitoring in cerebellopontine angle (CPA) tumor excision with or without muscle relaxant which may affect hemodynamics and consumption of drug doses. The partial neuromuscular blockade, on the other hand, appears to be compatible with monitoring in some patients, according to clinical experience. In this study, we evaluated hemodynamic changes and drug consumption differences between partial and without muscle relaxants.
Forty patients ages ranging from 18 to 60 years old had CPA surgery and were given either a muscle relaxant to maintain neuromuscular blockade level train-of-four (TOF) count two (group A) or a placebo of normal saline to maintain train-of-four (TOF) count four (group B). Fentanyl was given to both groups. The dose of fentanyl was modified to 0.5–1 mcg\kg/h, while the dose of propofol was modified to have bi-spectral index between 40 and 60. The total amount of propofol and fentanyl, as well as mean blood pressure and heart rate, are all measured intraoperatively.

Results
There was a statistically significant difference in propofol and fentanyl doses between both research groups (p = 0.003, p = 0.002) respectively during the intraoperative period. Furthermore, there is a difference in as there were significant differences between two groups in time between stop of anesthesia and eye opening which is shorter in group with partial muscle relaxant reflecting shorter duration of anesthesia and recovery time (stop anesthesia to eye opening time) (p = 0.003, p > 0.001) respectively. Also, there was no statistically significant difference in the incidence of nausea and vomiting, shivering, bradycardia, or hypotension between the two study groups.

Conclusions
We demonstrated that partial muscle relaxant (train of four count 2) has benefits over no muscle relaxant (train of four count 4) for patients undergoing cerebellopontine angle tumor surgery because it can reduce anesthetic duration and generate rabid recovery. Furthermore, partial muscle relaxants exhibit the same hemodynamic stability, side effects, and surgical interruptions as group without muscle relaxants.
Systematic review on the application of computational fluid dynamics as a tool for the design of coronary artery stents
Authors: Valentim Moisés Xavier Guimarães , Zinani Flávia Schwarz Franceschini , da Fonseca Cleiton Elsner , Wermuth Diego Pacheco 
Published: May 2023

Abstract
Background
Every year thousands of people die from atherosclerosis. This heart disease causes artery hardening, which impairs blood flow. For this type of disease, the primary treatment is the application of stents. Observing the importance of the application of stents in the treatment of atherosclerosis, the present work aimed to carry out a systematic review of the literature on the applicability of computational fluid dynamics in the design of stents for coronary arteries.

Main body of abstract
To achieve the objective of this work, a review protocol was used. According to the method employed, we selected 16 articles to be read and analyzed in detail. Based on these studies, it was possible to verify that the works had two primary goals. The first was to model blood flow precisely to have CFD as a simulation and design tool. The second was to search for geometries of better performance, considering flow parameters that are believed to affect the stent lifespan—increasing time for stent replacement. Regarding the mathematical models for blood flow, it was verified that non-Newtonian models in transient regimes presented the best results. Regarding stent geometry, it was found that strut geometry and stent thickness can greatly influence wall shear stress parameters, which affect restenosis formation, and that the design of stents with innovative geometries has the potential to increase the lifespan of arterial stents.

Short conclusion
After completing the work, a document that serves as a knowledge base for works that apply stents as a treatment and support material for further research was obtained.
Real-World Perspectives and Practices for Pneumonitis/Interstitial Lung Disease Associated With Trastuzumab Deruxtecan Use in Human Epidermal Growth Factor Receptor 2–Expressing Metastatic Breast Cancer
Authors: Rugo Hope S. , Crossno Christine L. , Gesthalter Yaron B. , Kelley Kristen , Moore Heather N. , Rimawi Mothaffar F. , Westbrook Kelly E. , Buys Saundra S. 
Published: May 2023

Trastuzumab deruxtecan (T-DXd) is an antibody drug conjugate with a topoisomerase I payload that targets the human epidermal growth factor receptor 2 (HER2). T-DXd is approved for patients with previously treated HER2-positive or HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/ISH−) metastatic/unresectable breast cancer (BC). In a second-line HER2-positive metastatic BC (mBC) population (DESTINY-Breast03 [ClinicalTrials.gov identifier: NCT03529110 ]), T-DXd demonstrated significantly improved progression-free survival (PFS) over ado-trastuzumab emtansine (12-month rate: 75.8% v 34.1%; hazard ratio, 0.28; P < .001), and in patients with HER2-low mBC treated with one prior line of chemotherapy (DESTINY-Breast04 [ClinicalTrials.gov identifier: NCT03734029 ]), T-DXd demonstrated significantly longer PFS and overall survival than physician's choice chemotherapy (10.1 v 5.4 months; hazard ratio, 0.51; P < .001, and 23.4 v 16.8 months; hazard ratio, 0.64; P < .001, respectively). Interstitial lung disease (ILD) is an umbrella term used for a group of diseases characterized by lung injury including pneumonitis, which can lead to irreversible lung fibrosis. ILD is a well-described adverse event associated with certain anticancer therapies, including T-DXd. An important part of T-DXd therapy for mBC consists of monitoring for and managing ILD. Although information on ILD management strategies is included in the prescribing information, additional information on patient selection, monitoring, and treatment can be beneficial in routine clinical practice. The objective of this review is to describe real-world, multidisciplinary clinical practices and institutional protocols used for patient selection/screening, monitoring, and management related to T-DXd–associated ILD.
Survival and Symptomatic Relief After Cytoreductive Hepatectomy for Neuroendocrine Tumor Liver Metastases: Long-Term Follow-up Evaluation of More Than 500 Patients
Authors: Gudmundsdottir Hallbera , Habermann Elizabeth B. , Vierkant Robert A. , Starlinger Patrick , Thiels Cornelius A. , Warner Susanne G. , Smoot Rory L. , Truty Mark J. , Kendrick Michael L. , Halfdanarson Thorvardur R. , Nagorney David M. , Cleary Sean P. 
Published: May 2023

Abstract
Background
Distant metastases are the strongest predictor of poor prognosis for patients with neuroendocrine tumors (NETs). Cytoreductive hepatectomy (CRH) can relieve symptoms of hormonal excess and prolong survival for patients with liver metastases (NETLMs), but long-term outcomes are poorly characterized.

Methods
This retrospective single-institution analysis analyzed patients who underwent CRH for well-differentiated NETLMs from 2000 to 2020. Kaplan-Meier analysis estimated symptom-free interval and overall and progression-free survival. Multivariable Cox regression analysis evaluated factors associated with survival.

Results
The inclusion criteria were met by 546 patients. The most common primary sites were the small intestine (n = 279) and the pancreas (n = 194). Simultaneous primary tumor resection was performed for 60 % of the cases. Major hepatectomy comprised 27% of the cases, but this rate decreased during the study period (p < 0.001). Major complications occurred in 20%, and the 90-day mortality rate was 1.6%. Functional disease was present in 37 %, and symptomatic relief was achieved in 96%. The median symptom-free interval was 41 months (62 months after complete cytoreduction and 21 months with gross residual disease) (p = 0.021). The median overall survival was 122 months, and progression-free survival was 17 months. In the multivariable analysis, worse overall survival was associated with age, pancreatic primary tumor, Ki-67, number and size of lesions, and extrahepatic metastases, with Ki-67 as the strongest predictor (odds ratio [OR], 1.90 for Ki-67 [3–20%; p = 0.018] and OR, 4.25 for Ki-67 [>20%; p < 0.001]).

Conclusion
The study showed that CRH for NETLMs is associated with low perioperative morbidity and mortality and excellent overall survival, although the majority will experience recurrence/progression. For patients with functional tumors, CRH can provide durable symptomatic relief.