bluuebunny/crossref_metadata_2025_split huggingface dataset:
Review of Animal Models of Comorbidities in Fracture‐Healing Research
Authors: Haffner‐Luntzer Melanie , Hankenson Kurt D. , Ignatius Anita , Pfeifer Roman , Khader Basel A. , Hildebrand Frank , van Griensven Martijn , Pape Hans‐Christoph , Lehmicke Michael 
Published: August 2019

ABSTRACTThere is clinical evidence that patient‐specific comorbidities like osteoporosis, concomitant tissue injury, and ischemia may strongly interfere with bone regeneration. However, underlying mechanisms are still unclear. To study these mechanisms in detail, appropriate animal models are needed. For decades, bone healing has been studied in large animals, including dogs, rabbits, pigs, or sheep. However, large animal models display a limited ability to study molecular pathways and cellular functions. Therefore in recent years, mice and rats have become increasingly popular as a model organism for fracture healing research due to the availability of molecular analysis tools and transgenic models. Both large and small animals can be used to study comorbidities and risk factors, modelling the human clinical situation. However, attention has to be paid when choosing an appropriate model due to species differences between large animals, rodents, and humans. This review focuses on large and small animal models for the common comorbidities ischemic injury/reduced vascularization, osteoporosis, and polytrauma, and critically discusses the translational and molecular aspects of these models. Here, we review material which was presented at the workshop “Animal Models of Comorbidities in Fracture Healing Research” at the 2019 ORS Annual Meeting in Austin Texas. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2491–2498, 2019
Revisiting the effects of omitting aspirin in combined antithrombotic therapies for atrial fibrillation and acute coronary syndromes or percutaneous coronary interventions: meta-analysis of pooled data from the PIONEER AF-PCI, RE-DUAL PCI, and AUGUSTUS trials
Authors: Potpara Tatjana S , Mujovic Nebojsa , Proietti Marco , Dagres Nikolaos , Hindricks Gerhard , Collet Jean-Phillipe , Valgimigli Marco , Heidbuchel Hein , Lip Gregory Y H 
Published: August 2019

Abstract

Aims
Recently, three randomized trials reported that dual antithrombotic treatments (DATs) including non-vitamin K antagonist oral anticoagulants (NOACs) and a P2Y12 inhibitor without aspirin were associated with significantly less bleeding than vitamin K antagonist (VKA)-based triple antithrombotic therapy (TAT) in atrial fibrillation (AF) patients with acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI). We conducted an analysis of pooled data from these trials.

Methods and results
A meta-analysis of the PIONEER AF-PCI, RE-DUAL PCI, and AUGUSTUS trials considering major bleeding [International Society on Thrombosis and Haemostasis (ISTH) and Thrombolysis in Myocardial Infarction], clinically relevant non-major bleeding, all-cause/cardiovascular death, stroke, myocardial infarction (MI), and stent thrombosis. Treatment effect is reported as odds ratio (OR) and 95% confidence interval. Among 9463 patients (53% with ACS), DAT regimens were associated with significantly less bleeding than TAT (OR 0.598, 0.491 −0.727; P &lt; 0.001 for ISTH major bleeding), as were NOAC-based vs. VKA-based regimens (OR 0.577, 0.477 −0.698; P &lt; 0.001). Stroke and mortality rates were similar, but there was statistically non-significant trend towards greater risk of MI (OR 1.211, 0.955 −1.535; P = 0.115) and significantly higher risk for stent thrombosis (OR 1.672, 1.022 −2.733, P = 0.041) with DAT vs. TAT (but not NOAC- vs. VKA-based regimens). This was mainly driven by Dabigatran 110 mg; the trends were lower with full-dose NOAC or Rivaroxaban 15 mg-based DATs.

Conclusion
Our findings support the use of full-dose NOAC (Apixaban 5 mg, Dabigatran 150 mg) or Rivaroxaban 15 mg-based treatments in most AF patients with ACS or undergoing PCI. Notwithstanding the better safety of DAT, an initial course of NOAC-based TAT may be desirable in most AF patients.
Tau Phosphorylation and Aggregation in the Developing Human Brain
Authors: Hefti Marco M , Kim SoongHo , Bell Aaron J , Betters Ryan K , Fiock Kimberly L , Iida Megan A , Smalley Martin E , Farrell Kurt , Fowkes Mary E , Crary John F 
Published: August 2019

AbstractTau hyperphosphorylation, mostly at serine (Ser) or threonine (Thr) residues, plays a key role in the pathogenesis of Alzheimer disease (AD) and other tauopathies. Rodent studies show similar hyperphosphorylation in the developing brain, which may be involved in regulating axonal growth and plasticity, but detailed human studies are lacking. Here, we examine tau phosphorylation by immunohistochemistry and immunoblotting in human fetal and adult autopsy brain tissue. Of the 20 cases with sufficient tissue preservation, 18 (90%) showed positive staining for S214 (pSer214), with the majority also positive for CP13 (pSer202), and PHF-1 (pSer396/pSer404). AT8 (pSer202/pThr205) and RZ3 (pThr231) were largely negative while PG5 (pSer409) was negative in all cases. Immunoblotting showed tau monomers with a similar staining pattern. We also observed phospho-tau aggregates in the fetal molecular layer, staining positively for S214, CP13, and PHF1 and negative for thioflavin S. These corresponded to high-molecular weight (∼150 kD) bands seen on Western blots probed with S214, PHF1, and PG5. We therefore conclude that fetal phosphorylation overlaps with AD in some residues, while others (e.g. T231, S409) appear to be unique to AD, and that tau is capable of forming nontoxic aggregates in the developing brain. These findings suggest that the fetal brain is resilient to formation of toxic aggregates, the mechanism for which may yield insights into the pathogenesis of tau aggregation and toxicity in the aging brain.
Formation of CO+ by radiative association
Authors: Zámečníková Martina , Soldán Pavel , Gustafsson Magnus , Nyman Gunnar 
Published: August 2019

ABSTRACT
We theoretically estimate formation rate coefficients for CO+ through the radiative association of C+(2P) with O(3P). In 1989, Petuchowski et al. claimed radiative association to be the most important route for CO+ formation in SN 1987A. In 1990, Dalgarno, Du and You challenged this claim. Therefore, in this study, we improve previous estimates of the radiative association rate coefficients for forming CO+ from C+(2P) and O(3P). To do this, we perform quantum mechanically based perturbation theory calculations as well as semiclassical calculations, which are combined with Breit–Wigner theory in order to add the effect of shape resonances. We explicitly include four electronic transitions. The required potential energy and transition dipole-moment curves are obtained through large basis set multireference configuration interaction electronic structure calculations. We report cross-sections and from these we obtain rate coefficients in the range of 10 –10 000 K, finding that the CO+ formation rate coefficient is larger than the previous estimate by Dalgarno et al. Still our results support their claim that in SN 1987A, CO is mainly formed through radiative association and not through the charge transfer reaction CO+ + O → CO + O+ as earlier suggested by Petuchowski et al.
Acute vascular effects of vascular endothelial growth factor inhibition in the forearm arterial circulation
Authors: Cameron Alan C. , Welsh Paul , Neves Karla B. , Newby David E. , Touyz Rhian M. , Lang Ninian N. 
Published: August 2019

Objective:
Although vascular endothelial growth factor inhibition (VEGFi) represents a major therapeutic advance in oncology, it is associated with hypertension and adverse vascular thrombotic events. Our objective was to determine whether VEGFi caused direct vascular dysfunction through increased endothelin-1 (ET-1) activity or impaired endothelial vasomotor or fibrinolytic function.

Methods:
Using forearm venous occlusion plethysmography, we measured forearm blood flow during intra-arterial infusions of bevacizumab (36–144 μg/dl forearm volume per minute) administered for 15–60 min in healthy volunteers (n = 6–8). On two separate occasions in 10 healthy volunteers, we further measured forearm blood flow and tissue plasminogen activator (t-PA) release during intra-arterial bradykinin infusion (100 and 1000 pmol/min) in the presence and absence of bevacizumab (144 μg/dl forearm volume per minute), and the presence and absence of endothelin A receptor antagonism with BQ-123 (10 nmol/min). Plasma t-PA and plasminogen activator inhibitor-1 (PAI-1) concentrations were measured at baseline and with each dose of bradykinin.

Results:
Baseline blood flow and plasma ET-1, t-PA and PAI-1 concentrations were unaffected by bevacizumab. Bradykinin caused dose-dependent vasodilatation (P < 0.0001) and t-PA release (P < 0.01) but had no effect on plasma PAI-1 concentrations. Neither bevacizumab nor BQ-123 affected bradykinin-induced vasodilatation and t-PA release.

Conclusion:
Acute exposure to bevacizumab does not directly cause endothelial vasomotor or fibrinolytic dysfunction in healthy young volunteers.
Concurrent High Condylectomy and Orthognathic Surgery to Address Mandibular and Facial Asymmetry
Authors: Maniskas Seija , Parsaei Yassmin , Bruckman Karl C. , Steinbacher Derek 
Published: August 2019

Abstract
Correction of facial asymmetry caused by active unilateral condylar hyperplasia (CH) requires proper diagnosis, arrested ongoing condylar growth, and ultimately orthognathic surgery. Traditionally, prior to performing orthognathic surgery, active CH is addressed either by: awaiting natural cessation of condylar overgrowth, or performing an interval high condylectomy (to stop growth). However, these strategies both add to the total treatment time, by either waiting and confirming no active growth, or performing a first stage growth-arresting procedure. In this report, the authors describe concurrent high condylectomy, and 3-jaw orthognathic surgery, to address the root of the problem and provide aesthetic correction in the same setting. This clinical series illustrates a detailed description of this approach, highlighting operative order, and an analysis of outcomes.
Genomic variant identification methods alter Mycobacterium tuberculosis transmission inference
Authors: Walter Katharine S. , Colijn Caroline , Cohen Ted , Mathema Barun , Liu Qingyun , Bowers Jolene , Engelthaler David M. , Narechania Apurva , Croda Julio , Andrews Jason R. 
Published: August 2019

AbstractPathogen genomic data are increasingly used to characterize global and local transmission patterns of important human pathogens and to inform public health interventions. Yet there is no current consensus on how to measure genomic variation. We investigated the effects of variant identification approaches on transmission inferences for M. tuberculosis by comparing variants identified by five different groups in the same sequence data from a clonal outbreak. We then measured the performance of commonly used variant calling approaches in recovering variation in a simulated tuberculosis outbreak and tested the effect of applying increasingly stringent filters on transmission inferences and phylogenies. We found that variant calling approaches used by different groups do not recover consistent sets of variants, often leading to conflicting transmission inferences. Further, performance in recovering true outbreak variation varied widely across approaches. Finally, stringent filters rapidly eroded the accuracy of transmission inferences and quality of phylogenies reconstructed from outbreak variation. We conclude that measurements of genetic distance and phylogenetic structure are dependent on variant calling approach. Variant calling algorithms trained upon true sequence data outperform other approaches and enable inclusion of repetitive regions typically excluded from genomic epidemiology studies, maximizing the information gleaned from outbreak genomes.
Determining the serotype composition of mixed samples of pneumococcus using whole genome sequencing
Authors: Knight James R. , Dunne Eileen M. , Mulholland E. Kim , Saha Sudipta , Satzke Catherine , Tothpal Adrienn , Weinberger Daniel M. 
Published: August 2019

ABSTRACTSerotyping of Streptococcus pneumoniae is a critical tool in the surveillance of the pathogen and development and evaluation of vaccines. Whole-genome DNA sequencing and analysis is becoming increasingly common and is an effective method for pneumococcal serotype identification of pure isolates. However, because of the complexities of the pneumococcal capsular loci, current analysis software requires samples to be pure (or nearly pure) and only contain a single pneumococcal serotype. We introduce a new software tool called SeroCall, which can identify and quantitate the serotypes present in samples, even when several serotypes are present. The sample preparation, library preparation and sequencing follow standard laboratory protocols. The software runs as fast or faster than existing identification tools on typical computing servers and is freely available under an open source license at https://github.com/knightjimr/serocall. Using samples with known concentrations of different serotypes as well as blinded samples, we were able to accurately quantify the abundance of different serotypes of pneumococcus in mixed cultures, with 100% accuracy for detecting the major serotype and up to 86% accuracy for detecting minor serotypes. We were also able to track changes in serotype frequency over time in an experimental setting. This approach could be applied in both epidemiologic field studies of pneumococcal colonization as well as in experimental lab studies and could provide a cheaper and more efficient method for serotyping than alternative approaches.
Quantitative PCR (qPCR) vs culture-dependent detection to assess honey contamination by Paenibacillus larvae
Authors: Crudele Simone , Ricchiuti Luciano , Ruberto Addolorato , Rossi Franca 
Published: August 2019

SummaryThe detection/quantification in honey of spores of the bacterial pathogen Paenibacillus larvae, the etiological agent of the American Foulbrood (AFB) infectious disease of honey bee, represents a useful diagnostic tool to identify apiaries at risk of infection and carry out focused prevention measures. Plate count is currently the recommended method used to analyze presence and number of spores for this pathogen. However, its validity needs to be re-assessed since P. larvae field strains have a low rate of germination in culture media.Therefore, in this study, culture-dependent P. larvae detection/quantification was compared with quantitative PCR (qPCR) based analysis for 139 honey samples collected in 2017 and 2018 from as many apiaries in the Abruzzo region. According to qPCR based detection, 58.27% samples were positive for P. larvae, while only 33.8 % samples were positive by plate count.Moreover, the levels of contamination with the two methods differed for most samples. Potential false positives were obtained by plate count for 12.9% samples that were negative with the qPCR test. On the other hand, 26.6% samples were culture negative but qPCR positive, suggesting that not all the field strains were able to develop in plate. This was confirmed by obtaining P. larvae growth from those samples after supplementing the medium with germination stimulants.Results strongly suggested the necessity to improve culture methods or replace them with molecular detection/quantification for a more reliable AFB risk estimation.
Pathogenic impact of transcript isoform switching in 1209 cancer samples covering 27 cancer types using an isoform-specific interaction network
Authors: Kahraman Abdullah , Karakulak Tülay , Szklarczyk Damian , von Mering Christian 
Published: August 2019

AbstractUnder normal conditions, cells of almost all tissue types express the same predominant canonical transcript isoform at each gene locus. In cancer, however, splicing regulation is often disturbed, leading to cancer-specific switches in the most dominant transcripts (MDT). But what is the pathogenic impact of these switches and how are they driving oncogenesis? To address these questions, we have analyzed isoform-specific protein-protein interaction disruptions in 1209 cancer samples covering 27 different cancer types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) project of the International Cancer Genomics Consortium (ICGC). Our study revealed large variations in the number of cancer-specific MDT (cMDT) between cancer types. While carcinomas of the head and neck, or brain, had none or only a few cMDT, cancers of the female reproduction organs showed the highest number of cMDT. Interestingly, in contrast to the mutational load, the number of cMDT was tissue-specific, i.e. cancers arising from the same primary tissue had a similar number of cMDT. Some cMDT were found in 100% of all samples in a cancer type, making them candidates for diagnostic biomarkers. cMDT showed a tendency to fall at densely populated network regions where they disrupted protein interactions in the proximity of pathogenic cancer genes. A gene ontology enrichment analysis showed that these disruptions occurred mostly in enzyme signaling, protein translation, and RNA splicing pathways. Interestingly, no significant correlation between the number of cMDT and the number of coding or non-coding mutations could be identified. However, some transcript expressions correlated with mutations in non-coding splice-site and promoter regions of their genes. This work demonstrates for the first time the large extent of cancer-specific alterations in alternative splicing for 27 different cancer types. It highlights distinct and common patterns of cMDT and suggests novel pathogenic transcripts and markers that induce large network disruptions in cancers.
Sleep deprivation selectively down-regulates astrocytic 5-HT2B receptors and triggers depressive-like behaviors via stimulating P2X7 receptors
Authors: Xia Maosheng , Li Shuai , Liang Shanshan , Li Xiaowei , Li Zexiong , Verkhratsky Alexei , Guan Dawei , Li Baoman 
Published: August 2019

AbstractChronic loss of sleep damages health and disturbs quality of life. The long-lasting sleep deprivation (SD) as well as sleep abnormalities is a substantial risk factor for major depressive disorder (MDD), although the underlying mechanisms are not clear. In our previous studies, we report the activation of nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome induced by long-term SD is P2X7 receptors (P2X7R) dependent, and antidepressant fluoxetine could alleviate this neuroinflammasome via 5-HT2B receptors (5-HT2BR) in astrocytes. Here, we discovered that the chronic SD activates astroglial P2X7 receptors, which in turn selectively down-regulated expression of 5-HT2BR in astrocytes. Stimulation of P2X7R induced by SD suppressed the phosphorylation of AKT and FoxO3a selectively in astrocytes, but not in neurones. The over-expression of FoxO3a in astrocytes inhibited expression of 5-HT2BR. Down-regulation of 5-HT2BR instigated by SD suppressed activation of STAT3 and relieved the inhibition of Ca2+-dependent phospholipase A2 (cPLA2). This latter cascade promoted the release of arachidonic acid (AA) and prostaglandin E2 (PGE2). The depressive-like behaviours induced by SD were alleviated in P2X7R-KO mice. Our study reveals the mechanism underlying chronic SD-induced depressive-like behaviors and highlights that blocking P2X7 receptors or activating 5-HT2BR in astrocytes could play a key role for exploring the therapeutic strategies aimed at the depression evoked by sleep disorders.Main PointsChronic SD selectively down-regulates expression of 5-HT2BR through activation of P2X7R in astrocytes. SD promotes the release of AA and PGE2 via the decreased 5-HT2BR, these factors induce depressive-like behaviors.
The putative Gαq-inhibiting pepducin P4Pal10 distinctly modulates function of the Gαi-coupled receptors FPR2 and FFA2R in neutrophils
Authors: Holdfeldt André , Lind Simon , Dahlgren Claes , Forsman Huamei 
Published: August 2019

AbstractA novel mechanism of action was described, when a protease-activated receptor 4 (P4Pal10) derived lipopeptide (pepducin) was shown to inhibit signaling downstream of several unrelated Gαq-coupled receptors. We show that this putative Gαq-inhibiting pepducin lacks inhibitory effects on signaling downstream of the Gαq-coupled receptors for ATP (P2Y2R) and PAF (PAFR) expressed in human neutrophils. P4Pal10 inhibited however, signaling in neutrophils activated with agonists for the Gαi-coupled formyl peptide receptor 2 (FPR2) but not the closely related FPR1. In addition, the P4Pal10 pepducin was turned into an activating agonist in the presence of an allosteric modulator selective for free fatty acid receptor 2 (FFA2R). The results presented thus reveal Gαq-independent effects of P4Pal10 in modulating FPR2- and FFA2R-mediated neutrophil activation.
Hypusinated eIF5A is expressed in pancreas and spleen of individuals with type 1 and type 2 diabetes
Authors: Mastracci Teresa L. , Colvin Stephanie C. , Padgett Leah R. , Mirmira Raghavendra G. 
Published: August 2019

ABSTRACTEukaryotic initiation factor 5A (EIF5A) is found in diabetes-susceptibility loci in mouse and human. eIF5A is the only protein known to contain hypusine (hydroxyputrescine lysine), a polyamine-derived amino acid formed post-translationally in a reaction catalyzed by deoxyhypusine synthase (DHPS). Previous studies showed pharmacologic blockade of DHPS in type 1 diabetic NOD mice and type 2 diabetic db/db mice improved glucose tolerance and preserved beta-cell mass, which suggests that hypusinated eIF5A (eIF5AHyp) may play a role in diabetes pathogenesis by direct action on the beta cells and/or altering the adaptive or innate immune responses. To translate these findings to human, we examined tissue from individuals with and without type 1 and type 2 diabetes to determine the expression of eIF5AHyp. We detected eIF5AHypin beta cells, exocrine cells and immune cells; however, there was also unexpected enrichment of eIF5AHypin pancreatic polypeptide-expressing PP cells. Interestingly, the presence of eIF5AHypco-expressing PP cells was not enhanced with disease. These data identify new aspects of eIF5A biology and highlight the need to examine human tissue to understand disease.
Chromosome-level genome reference ofVenturia effusa, causative agent of pecan scab
Authors: Winter David J. , Charlton Nikki D. , Krom Nick , Shiller Jason , Bock Clive H. , Cox Murray P. , Young Carolyn A. 
Published: August 2019

AbstractPecan scab, caused byVenturia effusa, is a devastating disease of pecan (Carya illinoinensis), which results in economic losses on susceptible cultivars throughout the southeastern U.S. To enhance our understanding of pathogenicity inV. effusa, we have generated a complete telomere-to-telomere genome reference ofV. effusaisolate FRT5LL7-Albino. By combining Illumina MiSeq and Oxford Nanopore MinION data, we assembled a 45.2 Mb genome represented by 20 chromosomes and containing 10,820 genes, of which 7,619 have at least one functional annotation. The likely causative mutation of the albino phenotype was identified as a single base insertion and a resulting frameshift in the gene encoding the polyketide synthaseALM1. This genome represents the first full chromosome level assembly of anyVenturiaspecies.