bluuebunny/crossref_metadata_2025_split huggingface dataset:
FilGAP, a GAP protein for Rac, regulates front‐rear polarity and tumor cell migration through the ECM
Authors: Saito Koji , Mori Mamiko , Kambara Norito , Ohta Yasutaka 
Published: March 2021

AbstractMigrating tumor cells are characterized by a sustained front‐rear asymmetry, with a front enriched in filamentous actin, which is induced by Rho small GTPase Rac. Regulation of Rac activity by its regulators should be required for effective motility. Here, we show that FilGAP, a GTPase‐activating protein (GAP) for Rac, controls front‐rear polarity and contributes to maintain effective tumor cell migration through the extracellular matrix (ECM). Overexpression of FilGAP in breast cancer cells induced polarized morphology and led to increased migration speed in collagen matrices, while depletion of FilGAP impaired the cell polarity and migration. FilGAP localizes to the cell front through its pleckstrin‐homology (PH) domain in a phosphatidylinositol 3,4,5‐trisphosphate (PIP3)‐dependent manner and appears to inactivate Rac at its site. We found that the affinity of PH domain to PIP3 is critically involved in the maintenance of cell polarity. Moreover, small GTPase ADP‐ribosylation factor 6 (Arf6), which binds to the FilGAP PH domain, also regulates FilGAP‐mediated cell polarity and migration of breast cancer cells. We propose that FilGAP regulates front‐rear polarity through its PIP3 and Arf6 binding in tumor cell migration through the ECM.
Adipocyte precursor cells from first degree relatives of type 2 diabetic patients feature changes in hsa‐mir‐23a‐5p, ‐193a‐5p, and ‐193b‐5p and insulin‐like growth factor 2 expression
Authors: Mirra Paola , Desiderio Antonella , Spinelli Rosa , Nigro Cecilia , Longo Michele , Parrillo Luca , D’Esposito Vittoria , Carissimo Annamaria , Hedjazifar Shahram , Smith Ulf , Formisano Pietro , Miele Claudia , Raciti Gregory A. , Beguinot Francesco 
Published: March 2021

AbstractFirst‐degree relatives (FDRs) of type 2 diabetics (T2D) feature dysfunction of subcutaneous adipose tissue (SAT) long before T2D onset. miRNAs have a role in adipocyte precursor cells (APC) differentiation and in adipocyte identity. Thus, impaired miRNA expression may contribute to SAT dysfunction in FDRs. In the present work, we have explored changes in miRNA expression associated with T2D family history which may affect gene expression in SAT APCs from FDRs. Small RNA‐seq was performed in APCs from healthy FDRs and matched controls and omics data were validated by qPCR. Integrative analyses of APC miRNome and transcriptome from FDRs revealed down‐regulated hsa‐miR‐23a‐5p, ‐193a‐5p and ‐193b‐5p accompanied by up‐regulated Insulin‐like Growth Factor 2 (IGF2) gene which proved to be their direct target. The expression changes in these marks were associated with SAT adipocyte hypertrophy in FDRs. APCs from FDRs further demonstrated reduced capability to differentiate into adipocytes. Treatment with IGF2 protein decreased APC adipogenesis, while over‐expression of hsa‐miR‐23a‐5p, ‐193a‐5p and ‐193b‐5p enhanced adipogenesis by IGF2 targeting. Indeed, IGF2 increased the Wnt Family Member 10B gene expression in APCs. Down‐regulation of the three miRNAs and IGF2 up‐regulation was also observed in Peripheral Blood Leukocytes (PBLs) from FDRs. In conclusion, APCs from FDRs feature a specific miRNA/gene profile, which associates with SAT adipocyte hypertrophy and appears to contribute to impaired adipogenesis. PBL detection of this profile may help in identifying adipocyte hypertrophy in individuals at high risk of T2D.
The use of fluorescence correlation spectroscopy to monitor cell surface β2‐adrenoceptors at low expression levels in human embryonic stem cell‐derived cardiomyocytes and fibroblasts
Authors: Goulding Joëlle , Kondrashov Alexander , Mistry Sarah J. , Melarangi Tony , Vo Nguyen T.N. , Hoang Duc M. , White Carl W. , Denning Chris , Briddon Stephen J. , Hill Stephen J. 
Published: March 2021

AbstractThe importance of cell phenotype in determining the molecular mechanisms underlying β2‐adrenoceptor (β2AR) function has been noted previously when comparing responses in primary cells and recombinant model cell lines. Here, we have generated haplotype‐specific SNAP‐tagged β2AR human embryonic stem (ES) cell lines and applied fluorescence correlation spectroscopy (FCS) to study cell surface receptors in progenitor cells and in differentiated fibroblasts and cardiomyocytes. FCS was able to quantify SNAP‐tagged β2AR number and diffusion in both ES‐derived cardiomyocytes and CRISPR/Cas9 genome‐edited HEK293T cells, where the expression level was too low to detect using standard confocal microscopy. These studies demonstrate the power of FCS in investigating cell surface β2ARs at the very low expression levels often seen in endogenously expressing cells. Furthermore, the use of ES cell technology in combination with FCS allowed us to demonstrate that cell surface β2ARs internalize in response to formoterol‐stimulation in ES progenitor cells but not following their differentiation into ES‐derived fibroblasts. This indicates that the process of agonist‐induced receptor internalization is strongly influenced by cell phenotype and this may have important implications for drug treatment with long‐acting β2AR agonists.
Investigation of the putative role of antisense transcripts as regulators of sense transcripts by correlation analysis of sense‐antisense pairs in colorectal cancers
Authors: Choi Hye‐Mi , Lee Sang‐Hyeop , Lee Min‐Seok , Park Donghyun , Choi Sun Shim 
Published: March 2021

AbstractAntisense transcription occurs widely more expected than when it was first identified in bacteria in the 1980s. However, the functional relevance of antisense transcripts in transcription remains controversial. Here, we investigated the putative role of antisense transcripts in regulating their corresponding sense transcripts by analyzing changes in correlative relationships between sense‐antisense pairs under tumor and normal conditions. A total of 3469 sense‐antisense gene pairs (SAGPs) downloaded from BioMart mapped to a list of sense and antisense genes in RNA‐seq data derived from 80 paired colorectal cancer (CRC) samples were analyzed. As a result, cancer‐related genes were significantly enriched in the significantly correlated SAGPs (SCPs). Differentially expressed genes estimated between normal and tumor conditions were also significantly more enriched in SCPs than in non‐SCPs. Interestingly, using differential correlation analysis, we found that tumor samples had a significantly larger density of genes with higher correlation coefficients than normal samples, as verified by various cancer transcriptomes from The Cancer Genome Atlas (TCGA). Moreover, we found that the magnitude of the correlation between SAGPs could distinguish poor prognostic CRCs from good prognostic CRCs, showing that correlation coefficients between the SAGPs of CRCs with a poor prognosis were significantly stronger than CRCs with a good prognosis. Consistent with this finding, the Cox proportion hazards model showed that the survival rates were significantly different between patients with high and low expression of genes in the SCPs. All these results strongly support the idea that antisense transcripts are important regulators of their corresponding sense transcripts.
Cyclophilin A is an endogenous ligand for the triggering receptor expressed on myeloid cells‐2 (TREM2)
Authors: Ji Kon‐Young , Kim Su‐Man , Yee Su‐Min , Kim Min‐Jae , Ban Yu‐Jin , Kim Eun‐Mi , Lee Eun‐Hee , Choi Ha‐Rim , Yun Hyosuk , Lee Chul Won , Yun Chul‐Ho , Lee C. Justin , Lee Hyang Burm , Kang Hyung‐Sik 
Published: March 2021

AbstractTriggering receptor expressed on myeloid cells 2 (TREM2) is a cell surface receptor expressed on macrophages, microglial cells, and pre‐osteoclasts, and that participates in diverse cellular function, including inflammation, bone homeostasis, neurological development, and coagulation. In spite of the indispensable role of the TREM2 protein in the maintenance of immune homeostasis and osteoclast differentiation, the exact ligand for TREM2 has not yet been identified. Here, we report a putative TREM2 ligand which is secreted from MC38 cells and identified as a cyclophilin A (CypA). A specific interaction between CypA and TREM2 was shown at both protein and cellular levels. Exogenous CypA specifically interacted and co‐localized with TREM2 in RAW264.7 cells, and the physical interactions were shown to regulate TREM2 signaling transduction. The Pro144 residue in the extracellular domain of TREM2 was found to be the specific binding site of CypA. When considered together, this provides evidence that CypA interacts specifically with TREM2 as a potent ligand.
Omega‐3 fatty acids protect from colitis via an Alox15‐derived eicosanoid
Authors: Rohwer Nadine , Chiu Cheng‐Ying , Huang Dan , Smyl Christopher , Rothe Michael , Rund Katharina M. , Helge Schebb Nils , Kühn Hartmut , Weylandt Karsten‐Henrich 
Published: March 2021

AbstractAn increased omega‐3 polyunsaturated fatty acid (n‐3 PUFA) tissue status can lead to a significant formation of anti‐inflammatory lipid mediators and effective reduction in inflammation and tissue injury in murine colitis. Arachidonic acid lipoxygenases (ALOX) have been implicated in the pathogenesis of inflammatory bowel disease as well as in the formation of pro‐ and anti‐inflammatory lipid mediators. To explore the role of Alox15 in the protective response found in fat1 transgenic mice with endogenously increased n‐3 PUFA tissue status fat1 transgenic mice were crossed with Alox15‐deficient animals and challenged in the dextran sulfate sodium (DSS)‐ and the 2,4,6‐trinitrobenzene sulphonic acid (TNBS)‐induced colitis model. Transgenic fat1 mice rich in endogenous n‐3 PUFAs were protected from colitis. However, additional systemic inactivation of the Alox15 gene counteracted this protective effect. To explore the molecular basis for this effect Alox15 lipid metabolites derived from n‐3 PUFA were analyzed in the different mice. Alox15 deficiency suppressed the formation of n‐3 PUFA‐derived 15‐hydroxy eicosapentaenoic acid (15‐HEPE). In contrast, treating mice with intraperitoneal injections of 15S‐HEPE protected wild‐type mice from DSS‐ and TNBS‐induced colitis. These data suggest that the anti‐colitis effect of increased n‐3 PUFA in the transgenic fat1 mouse model is mediated in part via Alox15‐derived 15‐HEPE formation.
Neurotensin: A novel mediator of ovulation?
Authors: Campbell Genevieve E. , Bender Hannah R. , Parker Grace A. , Curry Thomas E. , Duffy Diane M. 
Published: March 2021

AbstractThe midcycle luteinizing hormone (LH) surge initiates a cascade of events within the ovarian follicle which culminates in ovulation. Only mural granulosa cells and theca cells express large numbers of LH receptors, and LH‐stimulated paracrine mediators communicate the ovulatory signal within the follicle. Recent reports identified the neuropeptide neurotensin (NTS) as a product of granulosa cells. Here, we demonstrate that granulosa cells were the primary site of NTS expression in macaque ovulatory follicles. Granulosa cell NTS mRNA and protein increased after human chorionic gonadotropin (hCG) administration, which substitutes for the LH surge. To identify ovulatory actions of NTS, a NTS‐neutralizing antibody was injected into preovulatory macaque follicles. hCG administration immediately followed, and ovaries were removed 48 hours later to evaluate ovulatory events. Follicles injected with control IgG ovulated normally. In contrast, 75% of NTS antibody‐injected follicles failed to ovulate, containing oocytes trapped within unruptured, hemorrhagic follicles. Serum progesterone was unchanged. Of the three NTS receptors, SORT1 was highly expressed in follicular granulosa, theca, and endothelial cells; NTSR1 and NTSR2 were expressed at lower levels. Excessive blood cells in NTS antibody‐injected follicles indicated vascular anomalies, so the response of monkey ovarian endothelial cells to NTS was evaluated in vitro. NTS stimulated endothelial cell migration and capillary sprout formation, consistent with a role for NTS in vascular remodeling associated with ovulation. In summary, we identified NTS as a possible paracrine mediator of ovulation. Further investigation of the NTS synthesis/response pathway may lead to improved treatments for infertility and novel targets for contraception.
Gender Differences in Milestone Ratings and Medical Knowledge Examination Scores Among Internal Medicine Residents
Authors: Hauer Karen E. , Jurich Daniel , Vandergrift Jonathan , Lipner Rebecca S. , McDonald Furman S. , Yamazaki Kenji , Chick Davoren , McAllister Kevin , Holmboe Eric S. 
Published: March 2021

Purpose
To examine whether there are group differences in milestone ratings submitted by program directors working with clinical competency committees (CCCs) based on gender for internal medicine (IM) residents and whether women and men rated similarly on milestones perform comparably on subsequent in-training and certification examinations.

Method
This national retrospective study examined end-of-year medical knowledge (MK) and patient care (PC) milestone ratings and IM In-Training Examination (IM-ITE) and IM Certification Examination (IM-CE) scores for 2 cohorts (2014–2017, 2015–2018) of U.S. IM residents at ACGME-accredited programs. It included 20,098/21,440 (94%) residents, with 9,424 women (47%) and 10,674 men (53%). Descriptive statistics and differential prediction techniques using hierarchical linear models were performed.

Results
For MK milestone ratings in PGY-1, men and women showed no statistical difference at a significance level of .01 (P = .02). In PGY-2 and PGY-3, men received statistically higher average MK ratings than women (P = .002 and P < .001, respectively). In contrast, men and women received equivalent average PC ratings in each PGY (P = .47, P = .72, and P = .80, for PGY-1, PGY-2, and PGY-3, respectively). Men slightly outperformed women with similar MK or PC ratings in PGY-1 and PGY-2 on the IM-ITE by about 1.7 and 1.5 percentage points, respectively, after adjusting for covariates. For PGY-3 ratings, women and men with similar milestone ratings performed equivalently on the IM-CE.

Conclusions
Milestone ratings were largely similar for women and men. Generally, women and men with similar MK or PC milestone ratings performed similarly on future examinations. Although there were small differences favoring men on earlier examinations, these differences disappeared by the final training year. It is questionable whether these small differences are educationally or clinically meaningful. The findings suggest fair, unbiased milestone ratings generated by program directors and CCCs assessing residents.
Medical School Accreditation Factors Associated With Certification by the Educational Commission for Foreign Medical Graduates (ECFMG): A 10-Year International Study
Authors: Tackett Sean , Boulet John R. , van Zanten Marta 
Published: March 2021

Purpose
In 2024, international medical graduates seeking Educational Commission for Foreign Medical Graduates (ECFMG) certification will be required to graduate from an accredited medical school. This study’s goal was to examine relationships between medical school accreditation variables and ECFMG certification for a global sample.

Method
Using ECFMG databases, the authors created a 10-year cohort (January 1, 2007–December 31, 2016) of certification applicants, defined as individuals who had attempted at least 2 examinations required for certification. The authors aggregated applicant data at the school level, excluding schools with < 80 applicants. School accreditation statuses were based on agency websites. School region, age, and time of first accreditation were included. Analyses included descriptive and bivariate statistics and multiple linear regressions adjusting for school start year and year of first accreditation.

Results
The cohort included 128,046 applicants from 1,973 medical schools across 162 countries. After excluding low-volume schools, 318 schools across 81 countries remained. These provided 99,598 applicants and 77,919 certificate holders, three-quarters of whom came from the Caribbean, South-Central Asia, and West Asia regions. Two hundred and fifty (78.6%) schools were accredited; 68 (21.4%) were not. Most ECFMG applicants (n = 84,776, 85.1%) and certificate holders (n = 68,444, 87.8%) attended accredited medical schools. Accredited schools had higher rates of ECFMG certification among graduates than nonaccredited schools in comparisons that included all schools (75.0% [standard deviation (SD) = 10.6%] vs 68.3% (SD = 15.9%), P < .001), and for countries that had both accredited and nonaccredited schools (73.9% [SD = 11.4%] vs 67.3% [SD = 16.8%], P = .023). After adjusting for age of school, longer duration of accreditation was associated with higher certification rates (P < .001).

Conclusions
Accreditation had a positive association with ECFMG certification rates. Future studies should investigate how accreditation processes might account for higher certification rates.
ICU Bed Utilization During the Coronavirus Disease 2019 Pandemic in a Multistate Analysis—March to June 2020
Authors: Douin David J. , Ward Michael J. , Lindsell Christopher J. , Howell Michelle P. , Hough Catherine L. , Exline Matthew C. , Gong Michelle N. , Aboodi Michael S. , Tenforde Mark W. , Feldstein Leora R. , Stubblefield William B. , Steingrub Jay S. , Prekker Matthew E. , Brown Samuel M. , Peltan Ithan D. , Khan Akram , Files D. Clark , Gibbs Kevin W. , Rice Todd W. , Casey Jonathan D. , Hager David N. , Qadir Nida , Henning Daniel J. , Wilson Jennifer G. , Patel Manish M. , Self Wesley H. , Ginde Adit A. 
Published: March 2021

Objectives:
Given finite ICU bed capacity, knowledge of ICU bed utilization during the coronavirus disease 2019 pandemic is critical to ensure future strategies for resource allocation and utilization. We sought to examine ICU census trends in relation to ICU bed capacity during the rapid increase in severe coronavirus disease 2019 cases early during the pandemic.

Design:
Observational cohort study.

Setting:
Thirteen geographically dispersed academic medical centers in the United States.

Patients/Subjects:
We obtained daily ICU censuses from March 26 to June 30, 2020, as well as prepandemic ICU bed capacities. The primary outcome was daily census of ICU patients stratified by coronavirus disease 2019 and mechanical ventilation status in relation to ICU capacity.

Interventions:
None.

Measurements and Main Results:
Prepandemic overall ICU capacity ranged from 62 to 225 beds (median 109). During the study period, the median daily coronavirus disease 2019 ICU census per hospital ranged from 1 to 84 patients, and the daily ICU census exceeded overall ICU capacity for at least 1 day at five institutions. The number of critically ill patients exceeded ICU capacity for a median (interquartile range) of 17 (12–50) of 97 days at these five sites. All 13 institutions experienced decreases in their noncoronavirus disease ICU population, whereas local coronavirus disease 2019 cases increased. Coronavirus disease 2019 patients reached their greatest proportion of ICU capacity on April 12, 2020, when they accounted for 44% of ICU patients across all participating hospitals. Maximum ICU census ranged from 52% to 289% of overall ICU capacity, with three sites less than 80%, four sites 80–100%, five sites 100–128%, and one site 289%.

Conclusions:
From March to June 2020, the coronavirus disease 2019 pandemic led to ICU censuses greater than ICU bed capacity at fives of 13 institutions evaluated. These findings demonstrate the short-term adaptability of U.S. healthcare institutions in redirecting limited resources to accommodate a public health emergency.
Comparison of Anticoagulation Strategies in Patients Requiring Venovenous Extracorporeal Membrane Oxygenation: Heparin Versus Bivalirudin*
Authors: Rivosecchi Ryan M. , Arakelians Aris R. , Ryan John , Murray Holt , Ramanan Raj , Gomez Hernando , Phillips Dennis , Sciortino Christopher , Arlia Peter , Freeman Danielle , Sappington Penny L. , Sanchez Pablo G. 
Published: March 2021

OBJECTIVES:
Extracorporeal membrane oxygenation is a life-sustaining therapy for severe respiratory failure. Extracorporeal membrane oxygenation circuits require systemic anticoagulation that creates a delicate balance between circuit-related thrombosis and bleeding-related complications. Although unfractionated heparin is most widely used anticoagulant, alternative agents such as bivalirudin have been used. We sought to compare extracorporeal membrane oxygenation circuit thrombosis and bleeding-related outcomes in respiratory failure patients receiving either unfractionated heparin or bivalirudin for anticoagulation on venovenous extracorporeal membrane oxygenation support.

DESIGN:
Retrospective cohort study.

SETTING:
Single-center, cardiothoracic ICU.

PATIENTS:
Consecutive patients requiring venovenous extracorporeal membrane oxygenation who were maintained on anticoagulation between 2013 and 2020.

INTERNVENTIONS:
IV bivalirudin or IV unfractionated heparin.

MEASUREMENTS AND MAIN RESULTS:
Primary outcomes were the presence of extracorporeal membrane oxygenation in-circuit–related thrombotic complications and volume of blood products administered during extracorporeal membrane oxygenation duration. One hundred sixty-two patients receiving unfractionated heparin were compared with 133 patients receiving bivalirudin for anticoagulation on venovenous extracorporeal membrane oxygenation. In patients receiving bivalirudin, there was an overall decrease in the number of extracorporeal membrane oxygenation circuit thrombotic complications (p < 0.005) and a significant increase in time to circuit thrombosis (p = 0.007). Multivariable Cox regression found that heparin was associated with a significant increase in risk of clots (Exp[B] = 2.31, p = 0.001). Patients who received bivalirudin received significantly less volume of packed RBCs, fresh frozen plasma, and platelet transfusion (p < 0.001 for each). There was a significant decrease in the number major bleeding events in patients receiving bivalirudin, 40.7% versus 11.7%, p < 0.001.

CONCLUSIONS:
Patients receiving bivalirudin for systemic anticoagulation on venovenous extracorporeal membrane oxygenation experienced a decrease in the number of extracorporeal membrane oxygenation circuit-related thrombotic events as well as a significant decrease in volume of blood products administered.