bluuebunny/crossref_metadata_2025_split huggingface dataset:
RSK1 and RSK2 serine/threonine kinases regulate different transcription programs in cancer
Authors: Yang Won Seok , Caliva Maisel J. , Khadka Vedbar S. , Tiirikainen Maarit , Matter Michelle L. , Deng Youping , Ramos Joe W. 
Published: January 2023

The 90 kDa ribosomal S6 kinases (RSKs) are serine threonine kinases comprising four isoforms. The isoforms can have overlapping functions in regulation of migration, invasion, proliferation, survival, and transcription in various cancer types. However, isoform specific differences in RSK1 versus RSK2 functions in gene regulation are not yet defined. Here, we delineate ribosomal S6 kinases isoform-specific transcriptional gene regulation by comparing transcription programs in RSK1 and RSK2 knockout cells using microarray analysis. Microarray analysis revealed significantly different mRNA expression patterns between RSK1 knockout and RSK2 knockout cell lines. Importantly some of these functions have not been previously recognized. Our analysis revealed RSK1 has specific roles in cell adhesion, cell cycle regulation and DNA replication and repair pathways, while RSK2 has specific roles in the immune response and interferon signaling pathways. We further validated that the identified gene sets significantly correlated with mRNA datasets from cancer patients. We examined the functional significance of the identified transcriptional programs using cell assays. In alignment with the microarray analysis, we found that RSK1 modulates the mRNA and protein expression of Fibronectin1, affecting cell adhesion and CDK2, affecting S-phase arrest in the cell cycle, and impairing DNA replication and repair. Under similar conditions, RSK2 showed increased ISG15 transcriptional expression, affecting the immune response pathway and cytokine expression. Collectively, our findings revealed the occurrence of RSK1 and RSK2 specific transcriptional regulation, defining separate functions of these closely related isoforms.
Interplay between integrins and cadherins to control bone differentiation upon BMP-2 stimulation
Authors: Valat Anne , Fourel Laure , Sales Adria , Machillot Paul , Bouin Anne-Pascale , Fournier Carole , Bosc Lauriane , Arboléas Mélanie , Bourrin-Reynard Ingrid , Wagoner Johnson Amy J. , Bruckert Franz , Albigès-Rizo Corinne , Picart Catherine 
Published: January 2023

Introduction: Upon BMP-2 stimulation, the osteoblastic lineage commitment in C2C12 myoblasts is associated with a microenvironmental change that occurs over several days. How does BMP-2 operate a switch in adhesive machinery to adapt to the new microenvironment and to drive bone cell fate is not well understood. Here, we addressed this question for BMP-2 delivered either in solution or physically bound of a biomimetic film, to mimic its presentation to cells via the extracellular matrix (ECM).Methods: Biommetics films were prepared using a recently developed automated method that enable high content studies of cellular processes. Comparative gene expressions were done using RNA sequencing from the encyclopedia of the regulatory elements (ENCODE). Gene expressions of transcription factors, beta chain (1, 3, 5) integrins and cadherins (M, N, and Cad11) were studied using quantitative PCR. ECM proteins and adhesion receptor expressions were also quantified by Western blots and dot blots. Their spatial organization in and around cells was studied using immuno-stainings. The individual effect of each receptor on osteogenic transcription factors and alkaline phosphatase expression were studied using silencing RNA of each integrin and cadherin receptor. The organization of fibronectin was studied using immuno-staining and quantitative microscopic analysis.Results: Our findings highlight a switch of integrin and cadherin expression during muscle to bone transdifferentiation upon BMP-2 stimulation. This switch occurs no matter the presentation mode, for BMP-2 presented in solution or via the biomimetic film. While C2C12 muscle cells express M-cadherin and Laminin-specific integrins, the BMP-2-induced transdifferentiation into bone cells is associated with an increase in the expression of cadherin-11 and collagen-specific integrins. Biomimetic films presenting matrix-bound BMP-2 enable the revelation of specific roles of the adhesive receptors depending on the transcription factor.Discussion: While β3 integrin and cadherin-11 work in concert to control early pSMAD1,5,9 signaling, β1 integrin and Cadherin-11 control RunX2, ALP activity and fibronectin organization around the cells. In contrast, while β1 integrin is also important for osterix transcriptional activity, Cadherin-11 and β5 integrin act as negative osterix regulators. In addition, β5 integrin negatively regulates RunX2. Our results show that biomimetic films can be used to delinate the specific events associated with BMP-2-mediated muscle to bone transdifferentiation. Our study reveals how integrins and cadherins work together, while exerting distinct functions to drive osteogenic programming. Different sets of integrins and cadherins have complementary mechanical roles during the time window of this transdifferentiation.
The effect of gut microbiota dysbiosis on patients with preeclampsia
Authors: Zhao Yefang , Wang Bingjie , Zhao Xiaoling , Cui Dan , Hou Shaoke , Zhang Hongzhen 
Published: January 2023

PurposeTo compare the difference of gut microbiota between preeclampsia (PE) and healthy normal pregnant women, providing new therapeutic strategy for preeclampsia.MethodsForty-one PE patients and 45 age- and pre-pregnancy body mass index- matched healthy controls were enrolled from Nov 2021 to May 2022 in this retrospective case-control study. Fecal microbiota was detected by 16S rRNA gene sequencing, followed by bioinformatics analysis including microbial α diversity, microbial β diversity, and linear discriminant analysis effect size (LEfSe) analysis. Serum inflammatory factors were also detected and compared between the two groups.ResultsThere were significant differences in Bacteroidetes (2.68% in PE patients vs 11.04% in healthy controls, P &lt; 0.001), Proteobacteria (4.04% in PE patients vs 1.22% in healthy controls, P = 0.041), and Fusobacteria (1.07% in PE patients vs 0.01% in healthy controls, P = 0.042) between the two groups at the phylum level. Microbial α diversity was lower in PE patients than that in healthy controls. In addition, there was significant difference in microbial β diversity between the two groups. LEfSe analysis showed that there are 24 different taxa between the two groups. The levels of proinflammatory factors including serum tumor necrosis factor-α and Interleukin-6 were statistically significant higher in PE patients than those in healthy controls (both P &lt; 0.001), while there were no significant differences in the levels of serum anti-inflammatory factors including Interleukin-4 and Interleukin-10 between the two groups (P = 0.234 and P = 0.096, respectively).ConclusionPE patients demonstrated gut microbiota disturbances and increasing serum proinflammatory factors, leading to a better understanding of the relationship between the gut microbiota dysbiosis and PE.
Clinical and genomic analysis of hypermucoviscous Klebsiella pneumoniae isolates: Identification of new hypermucoviscosity associated genes
Authors: Jin Meiling , Jia Tianye , Liu Xiong , Yang Meitao , Zhang Na , Chen Jiali , Yang Xiaojing , Qin Shiyu , Liu Fangni , Tang Yue , Wang Yong , Guo Jinpeng , Chen Yong , Li Boan , Wang Changjun 
Published: January 2023

IntroductionHypermucoviscous Klebsiella pneumoniae (HmKp) poses an emerging and highly pathogenic global health threat. This study aimed to investigate the clinical and genomic characteristics of HmKp isolates to better understand the virulence mechanisms of the hypermucoviscous (HMV) phenotype.MethodsFrom May 2018 to August 2021, 203 non-repeat K. pneumoniae isolates causing invasive infections were collected from a hospital in Beijing, China. Isolates were divided into HmKp (n=90, 44.3%) and non-HmKp (n=113, 55.7%) groups according to string test results.ResultsMultivariate regression showed that diabetes mellitus (odds ratio [OR]=2.20, 95% confidence interval (CI): 1.20-4.05, p=0.010) and liver abscess (OR=2.93, CI 95%:1.29-7.03, p=0.012) were associated with HmKp infections. K. pneumoniae was highly diverse, comprising 87 sequence types (STs) and 54 serotypes. Among HmKp isolates, ST23 was the most frequent ST (25/90, 27.8%), and the most prevalent serotypes were KL2 (31/90, 34.4%) and KL1 (27/90, 30.0%). Thirteen virulence genes were located on the capsular polysaccharide synthesis region of KL1 strains. HmKp isolates were sensitive to multiple antibiotics but carried more SHV-type extended spectrum β-lactamase (ESBL) resistance genes (p&lt;0.05), suggesting that the emergence of ESBL-mediated multidrug resistance in HmKp should be monitored carefully during treatment. Phylogenetic analysis disclosed that HmKp isolates were highly diverse. Comparative genomic analysis confirmed that the HMV phenotype is a plasmid-encoded virulence factor. Seventeen HmKp genes were highly associated with HmKp, and included rmpAC, 7 iron-acquisition-related genes, and pagO, which may promote liver abscess formation.DiscussionThis investigation provides insight into the mechanisms producing the HMV phenotype.
Plasma VWF: Ag levels predict long-term clinical outcomes in patients with acute myocardial infarction
Authors: Xier Zulipiyemu , Zhu Yu-Xia , Tang Shou-Wei , Kong Can , Aili Dilihumaer , Huojia Guzailinuer , Peng Hui 
Published: January 2023

BackgroundA vital role in coronary artery disease is played by Von Willebrand factor (VWF), which serves as a bridge between platelets and the subendothelial matrix after vessel damage. The purpose of the study was to assess the validity of plasma VWF antigen (VWF: Ag) levels as a predictor of clinical outcomes after acute myocardial infarction (AMI).MethodsThree hundred and seventy-four patients were studied following coronary angiography, including 209 patients suffering from acute myocardial infarction and 165 healthy participants. Coronary angiography was followed by measurement of plasma VWF: Ag levels. Over a 2-year follow-up period, major adverse cardiopulmonary and cerebrovascular events (MACEs) were the primary endpoint. All-cause mortality was investigated as a secondary endpoint.ResultsWhen compared to controls, patients with AMI had mean plasma VWF: Ag levels that were ~1.63 times higher (0.860 ± 0.309 vs. 0.529 ± 0.258 IU/ml; P &lt; 0.001). The plasma VWF: Ag levels were substantially higher in patients who experienced MACEs after myocardial infarction vs. those without MACEs (1.088 ± 0.253 vs. 0.731 ± 0.252 IU/ml; P &lt; 0.001). For predicting long-term MACEs using the optimal cut-off value (0.7884 IU/ml) of VWF: Ag, ROC curve area for VWF: Ag was 0.847, with a sensitivity of 87.2% and a specificity of 66.3% (95%CI: 0.792–0.902; P = 0.001). Two-year follow-up revealed a strong link between higher plasma VWF: Ag levels and long-term MACEs. At the 2-year follow-up, multivariate regression analysis revealed an independent relationship between plasma VWF: Ag levels and MACEs (HR = 6.004, 95%CI: 2.987–12.070).ConclusionWe found evidence that plasma VWF: Ag levels were independent risk factors for AMI. Meanwhile, higher plasma VWF: Ag levels are associated with long-term MACEs in people with AMI.
Semi-automatic thresholding of RV trabeculation improves repeatability and diagnostic value in suspected pulmonary hypertension
Authors: Macdonald Alistair , Salehi Mahan , Alabed Samer , Maiter Ahmed , Goh Ze Ming , Dwivedi Krit , Johns Chris , Cogliano Marcella , Alandejani Faisal , Condliffe Robin , Wild James M. , Kiely David G. , Garg Pankaj , Swift Andrew J. 
Published: January 2023

ObjectivesRight ventricle (RV) mass is an imaging biomarker of mean pulmonary artery pressure (MPAP) and pulmonary vascular resistance (PVR). Some methods of RV mass measurement on cardiac MRI (CMR) exclude RV trabeculation. This study assessed the reproducibility of measurement methods and evaluated whether the inclusion of trabeculation in RV mass affects diagnostic accuracy in suspected pulmonary hypertension (PH).Materials and methodsTwo populations were enrolled prospectively. (i) A total of 144 patients with suspected PH who underwent CMR followed by right heart catheterization (RHC). Total RV mass (including trabeculation) and compacted RV mass (excluding trabeculation) were measured on the end-diastolic CMR images using both semi-automated pixel-intensity-based thresholding and manual contouring techniques. (ii) A total of 15 healthy volunteers and 15 patients with known PH. Interobserver agreement and scan-scan reproducibility were evaluated for RV mass measurements using the semi-automated thresholding and manual contouring techniques.ResultsTotal RV mass correlated more strongly with MPAP and PVR (r = 0.59 and 0.63) than compacted RV mass (r = 0.25 and 0.38). Using a diagnostic threshold of MPAP ≥ 25 mmHg, ROC analysis showed better performance for total RV mass (AUC 0.77 and 0.81) compared to compacted RV mass (AUC 0.61 and 0.66) when both parameters were indexed for LV mass. Semi-automated thresholding was twice as fast as manual contouring (p &lt; 0.001).ConclusionUsing a semi-automated thresholding technique, inclusion of trabecular mass and indexing RV mass for LV mass (ventricular mass index), improves the diagnostic accuracy of CMR measurements in suspected PH.
Trends in outcomes of women with myocardial infarction undergoing primary angioplasty—Analysis of randomized trials
Authors: Motovska Zuzana , Hlinomaz Ota , Aschermann Michael , Jarkovsky Jiri , Želízko Michael , Kala Petr , Groch Ladislav , Svoboda Michal , Hromadka Milan , Widimsky Petr 
Published: January 2023

BackgroundSex- and gender-associated differences determine the disease response to treatment.AimThe study aimed to explore the hypothesis that progress in the management of STE-myocardial infarction (STEMI) overcomes the worse outcome in women.Methods and resultsWe performed an analysis of three randomized trials enrolling patients treated with primary PCI more than 10 years apart. PRAGUE-1,-2 validated the preference of transport for primary PCI over on-site fibrinolysis. PRAGUE-18 enrollment was ongoing at the time of the functional network of 24/7PCI centers, and the intervention was supported by intensive antiplatelets. The proportion of patients with an initial Killip ≥ 3 was substantially higher in the more recent study (0.6 vs. 6.7%, p = 0.004). Median time from symptom onset to the door of the PCI center shortened from 3.8 to 3.0 h, p &lt; 0.001. The proportion of women having total ischemic time ≤3 h was higher in the PRAGUE-18 (OR [95% C.I.] 2.65 [2.03–3.47]). However, the percentage of patients with time-to-reperfusion &gt;6 h was still significant (22.3 vs. 27.2% in PRAGUE-18). There was an increase in probability for an initial TIMI flow &gt;0 in the later study (1.49 [1.0–2.23]), and also for an optimal procedural result (4.24 [2.12–8.49], p &lt; 0.001). The risk of 30-day mortality decreased by 61% (0.39 [0.17–0.91], p = 0.029).ConclusionThe prognosis of women with MI treated with primary PCI improved substantially with 24/7 regional availability of mechanical reperfusion, performance-enhancing technical progress, and intensive adjuvant antithrombotic therapy. A major modifiable hindrance to achieving this benefit in a broad population of women is the timely diagnosis by health professional services.
Subsurface structure of magmatic segments during continental breakup: Perspectives from a gravity data analysis along the Main Ethiopian Rift
Authors: Nigussie Wubamlak , Mickus Kevin , Keir Derek , Alemu Abera , Muhabaw Yoseph , Muluneh Ameha A. , Yehualaw Esubalew , Demissie Zelalem 
Published: January 2023

In magma-rich continental rifts, extension is commonly localized as dike injection in discrete magmatic segments which appear from surface geology to mimic the along-axis segmentation of ocean ridges. However, the subsurface morphology of these zones of localized magma injection is unclear, and whether and at what depth range they remain with discrete subvolcanic plumbing systems is not fully understood. In addition, the relationship between zones of magma injection and tectonic faulting is also debated. The Main Ethiopian Rift (MER) provides a unique opportunity to examine the spatial scale, locus, and subsurface geometries of magmatic localization in active continental rifts. We examined spatial variations in the structure of the crust in the MER using gravity data to better understand the subsurface pattern of magma injection. Results of our study reveal discrete Bouguer gravity highs in the centers of the distinct right-stepping magmatic segments of the MER (Aluto, Gedemsa, and Boseti), and interpreted as the locus of mafic intrusions. The gravity data show that the boundary between each magmatic segment is observed down to depths of ∼20 km, suggesting that magmatic segments have discrete subvolcanic plumbing systems at least down to the mid-crust. Additionally, incorporating the fault network shows that the densest faulting occurs at the tips of the zones of densest magma injection shown by Bouguer gravity highs. This is similar to the axial segmentation observed at slow and ultra-slow spreading ridges and suggests strong along-axis variations in deformation mechanism, with magma injection accommodating extension at the segment centers and faulting dominating towards the segment ends. In addition, rift margin volcanic zones (Siltie Debrezeit, Yerer Tulu, and Galema) are also inferred from bandpass gravity anomaly maps, supported by petrologic evidence, which implies that extension by dike injection has also occurred near the rift flanks.
Impact of body composition analysis on male sexual function: A metabolic age study
Authors: Majzoub Ahmad , Elbardisi Haitham , Madani Sarah , Leisegang Kristian , Mahdi Mohamed , Agarwal Ashok , Henkel Ralf , Khalafalla Kareim , ElSaid Sami , Arafa Mohamed 
Published: January 2023

IntroductionMetabolic Age (MetAge) and body composition analysis may reflect an individual’s metabolic status, which is believed to influence male sexual and gonadal functions. Although erectile dysfunction (ED) and hypogonadism are increasingly prevalent with age, they are also detected among younger men. This study aims to assess the impact of MetAge and body composition on male sexual and gonadal status overall, and particularly in men younger than 40 years of age.MethodsThis was a cross-sectional study of 90 male healthcare workers, between the ages of 18-55, randomly selected based on their corporation numbers. In addition to Bioelectric Impedance Analysis, subjects were requested to fill the International Index of Erectile Function questionnaire (IIEF-5) and to provide an early morning serum testosterone (T) sample. ResultsThe mean participants’ age was 39.4 ± 9.4 years, MetAge was 45.54 ± 10.35 years, serum T level was 13.68 ± 4.49 nmol/L and BMI was 28.8 ± 4.7 kg/m2. Significant negative correlations were obtained between serum T, MetAge, body weight and fat composition. Significant negative correlations between the IIEF-5 score, MetAge, and fat composition, were only reported in subjects &lt;40 years of age. Significantly lower T levels (p=0.002), significantly older MetAge (p=0.034), and higher BMI (p=0.044) and degree of obesity (p=0.042) were observed in participants &lt;40 years with erectile dysfunction (ED) compared to their counterparts without ED.DiscussionMetAge and body composition parameters significantly impact the androgenic state. ED in men &lt;40 years is associated with lower T levels, older MetAge and higher BMI and degree of obesity.
Reduced mitochondrial DNA content correlate with poor clinical outcomes in cryotransfers with day 6 single euploid embryos
Authors: Chuang Tzu-Hsuan , Chen Chih-Yen , Kuan Chin-Sheng , Lai Hsing-Hua , Hsieh Chia-Lin , Lee Meng-Ju , Liang Yi-Ting , Chang Yu-Jen , Chen Chien-Yu , Chen Shee-Uan 
Published: January 2023

ObjectiveTo investigate whether the mitochondrial DNA (mtDNA) content of a single biopsy at trophoblast correlates with the developmental potential and reproductive outcomes of blastocyst.MethodsA retrospective analysis applied the dataset of 1,675 embryos with preimplantation genetic testing for aneuploidy (PGT-A) from 1,305 individuals, and 1,383 embryos involved cryotransfers of single euploid embryo between January 2015 and December 2019. The studied cohort was divided for algorithm establishment on the NGS platform (n=40), correlation of biological features (n=1,635), and correlation of reproductive outcomes (n=1,340). Of the algorithm derived from the NGS platform, the reliability and repeatability were validated via qPCR assay and inter-run controls, respectively. Of the correlation across biological features, stratification analyses were applied to evaluate the effect from a single contributor. Eventually, the correlation between the mtDNA ratios and reproductive outcomes was adjusted according to the significant effector(s).ResultsThe mtDNA ratios showed statistically different between embryos with different days of blastocyst formation ([Day 5]: 1.06 vs. [Day 6]: 0.66, p=0.021), and between embryos with different expansion stages ([Expansion 5]: 1.05 vs. [Expansion 6]: 0.49, p=0.012). None or weakly correlated with the maternal age, morphology, ploidy, and gender. Analyzed by the different days of blastocyst formation with fixed expansion score as 5 in the euploid single embryo transfers (eSET), the day 6 eSET showed significantly lower reduced mtDNA ratio (n=139) in failure groups of fetal heartbeat (p=0.004), ongoing pregnancy (p=0.007), and live birth (p=0.01); however, no correlation between mtDNA ratios and pregnancy outcomes was observed in the day 5 eSET (n=1,201).ConclusionsThe study first demonstrated that mtDNA ratio was dependent on the days of blastocyst formation while expansion stage was fixed. Lower mtDNA ratios were observed in the day 6 eSET with adverse outcomes. The present stratification analyses reveal that the timeline of embryo is an important covariate to the mtDNA content.
Live birth rate following frozen-thawed blastocyst transfer is higher in high-grade day 6 blastocysts than in low-grade day 5 blastocysts
Authors: Shi Wenhao , Zhou Hanying , Chen Lijuan , Xue Xia , Shi Juanzi 
Published: January 2023

BackgroundDay 5 (D5) blastocysts are generally given priority to transfer than day 6 (D6) blastocysts; however, which one should be prioritized to transfer when only low-grade D5 and high-grade D6 blastocysts are available?MethodsA large retrospective cohort study was carried out to evaluate the live birth rate (LBR) following D5 and D6 blastocysts in single frozen-thawed blastocyst transfer (FBT) during January 2014 and December 2018. A multivariate logistic regression was conducted to evaluate the combined impact of expansion day (D5 and D6) and blastocyst quality (high grade/low grade) on LBR, accounting for the potential confounding factors. The biopsied blastocysts from a consecutive PGT-A case series during February 2013 to December 2021 were analyzed in a supplementary study.ResultsThe LBR achieved in high-grade D6 blastocyst transfer was significantly higher than that in low-grade D5 blastocyst transfer (50.43% vs. 40.70%, aOR 1.54, 95% CI 1.05–2.26, p = 0.027). There were no significant differences in preterm birth rate, very preterm birth rate, mean live birth weight, and birth weight &lt;1,500 g and &gt;4,000 g between the two cohorts. As for aneuploidy analysis in PGT, there were 54.55% of euploid blastocysts (30/55) among high-grade D6 blastocysts, significantly higher than the 41.39% of euploid blastocysts (565/1,365) among low-grade D5 blastocysts (p &lt; 0.001).ConclusionsOur data suggest that D6 blastocysts with high morphology grading are preferred than D5 blastocysts with low morphology grading when selecting blastocyst transfer to shorten the time of conception.