bluuebunny/crossref_metadata_2025_split huggingface dataset:
The trafficking protein JFC1 regulates Rac1-GTP localization at the uropod controlling neutrophil chemotaxis and in vivo migration
Authors: Ramadass Mahalakshmi , Johnson Jennifer L , Marki Alex , Zhang Jinzhong , Wolf Dennis , Kiosses William B , Pestonjamasp Kersi , Ley Klaus , Catz Sergio D 
Published: February 2019

Abstract
Neutrophil chemotaxis is essential in responses to infection and underlies inflammation. In neutrophils, the small GTPase Rac1 has discrete functions at both the leading edge and in the retraction of the trailing structure at the cell’s rear (uropod), but how Rac1 is regulated at the uropod is unknown. Here, we identified a mechanism mediated by the trafficking protein synaptotagmin-like 1 (SYTL1 or JFC1) that controls Rac1-GTP recycling from the uropod and promotes directional migration of neutrophils. JFC1-null neutrophils displayed defective polarization and impaired directional migration to N-formyl-methionine-leucyl-phenylalanine in vitro, but chemoattractant-induced actin remodeling, calcium signaling and Erk activation were normal in these cells. Defective chemotaxis was not explained by impaired azurophilic granule exocytosis associated with JFC1 deficiency. Mechanistically, we show that active Rac1 localizes at dynamic vesicles where endogenous JFC1 colocalizes with Rac1-GTP. Super-resolution microscopy (STORM) analysis shows adjacent distribution of JFC1 and Rac1-GTP, which increases upon activation. JFC1 interacts with Rac1-GTP in a Rab27a-independent manner to regulate Rac1-GTP trafficking. JFC1-null cells exhibited Rac1-GTP accumulation at the uropod and increased tail length, and Rac1-GTP uropod accumulation was recapitulated by inhibition of ROCK or by interference with microtubule remodeling. In vivo, neutrophil dynamic studies in mixed bone marrow chimeric mice show that JFC1−/− neutrophils are unable to move directionally toward the source of the chemoattractant, supporting the notion that JFC1 deficiency results in defective neutrophil migration. Our results suggest that defective Rac1-GTP recycling from the uropod affects directionality and highlight JFC1-mediated Rac1 trafficking as a potential target to regulate chemotaxis in inflammation and immunity.
Activated NK cells kill hepatic stellate cells via p38/PI3K signaling in a TRAIL-involved degranulation manner
Authors: Li Tianyang , Yang Yang , Song Hongxiao , Li Haijun , Cui An , Liu Yanhou , Su Lishan , Crispe Ian Nicholas , Tu Zhengkun 
Published: February 2019

Abstract
NK cells are important in regulating hepatic fibrosis via their cytotoxic killing of hepatic stellate cells (HSCs). NK cells are activated by both cytokines such as IL-12 and IL-18, and innate immune stimuli such as ligation of TLRs. The secretion of IL-18 depends upon activation of the inflammasome, whereas TLRs are stimulated by microbial products. In the case of NK cells, IL-18 acts synergistically with stimulation of TLR3 to cause cell activation and cytotoxic function. In the present study, we activated NK cells to kill HSCs via IL-18 and TLR3 ligand stimulation, and dissected the signaling pathways or molecules critical for such activation or killing. We find that such activation depends on signaling via the p38/PI3K/AKT pathway, and that the activated NK cells mediate HSC death in a TRAIL-involved mechanism. As liver fibrosis is a major global health problem with no good solution, these results emphasize that the p38/PI3K/AKT pathway in NK cells may be a novel drug target to promote fibrosis regression.
Augmentation of chronic rotator cuff healing using adipose‐derived stem cell‐seeded human tendon‐derived hydrogel
Authors: Kaizawa Yukitoshi , Franklin Austin , Leyden Jacinta , Behn Anthony W. , Tulu Ustun S. , Sotelo Leon Daniel , Wang Zhen , Abrams Geoffrey D. , Chang James , Fox Paige M. 
Published: February 2019

ABSTRACTRotator cuff (RTC) repair outcomes are unsatisfactory due to the poor healing capacity of the tendon bone interface (TBI). In our preceding study, tendon hydrogel (tHG), which is a type I collagen rich gel derived from human tendons, improved biomechanical properties of the TBI in a rat chronic RTC injury model. Here we investigated whether adipose‐derived stem cell (ASC)‐seeded tHG injection at the repair site would further improve RTC healing. Rats underwent bilateral supraspinatus tendon detachment. Eight weeks later injured supraspinatus tendons were repaired with one of four treatments. In the control group, standard transosseous suture repair was performed. In the ASC, tHG, tHGASC groups, ASC in media, tHG, and ASC‐seeded tHG were injected at repair site after transosseous suture repair, respectively. Eight weeks after repair, the TBI was evaluated biomechanically, histologically, and via micro CT. Implanted ASCs were detected in ASC and tHGASC groups 7 weeks after implantation. ACS implantation improved bone morphometry at the supraspinatus insertion on the humerus. Injection of tHG improved biomechanical properties of the repaired TBI. RTC healing in tHGASC group was significantly better than control but statistically equivalent to the tHG group based on biomechanical properties, fibrocartilage area at the TBI, and bone morphometry at the supraspinatus insertion. In a rat RTC chronic injury model, no biomechanical advantage was gained with ASC augmentation of tHG. Clinical Significance: Tendon hydrogel augmentation with adipose derived stem cells does not significantly improve TBI healing over tHG alone in a chronic rotator cuff injury model. © 2019 Orthopaedic Research Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.
Functional Brush Poly(2‐ethyl‐2‐oxazine)s: Synthesis by CROP and RAFT, Thermoresponsiveness and Grafting onto Iron Oxide Nanoparticles
Authors: Klein Tobias , Parkin Joshua , de Jongh Patrick A. J. M. , Esser Lars , Sepehrizadeh Tara , Zheng Gang , De Veer Michael , Alt Karen , Hagemeyer Christoph E. , Haddleton David M. , Davis Thomas P. , Thelakkat Mukundan , Kempe Kristian 
Published: February 2019

AbstractBrush polymers are highly functional polymeric materials combining the properties of different polymer classes and have found numerous applications, for example, in nanomedicine. Here, the synthesis of functional phosphonate‐ester‐bearing brush polymers based on poly(2‐oxazine)s is reported through a combination of cationic ring‐opening polymerization (CROP) of 2‐ethyl‐2‐oxazine and reversible addition‐fragmentation chain transfer (RAFT) polymerization. In this way, a small library of well‐defined (Đ ≤ 1.17) poly(oligo(2‐ethyl‐2‐oxazine) methacrylate) P(OEtOzMA)n brushes with tunable lower critical solution temperature (LCST) behavior and negligible cell toxicity is prepared. Upon deprotection, the phosphonic acid end‐group of the P(OEtOzMA)n brush enables the successful grafting‐onto iron oxide nanoparticles (IONPs). Colloidal stability of the particle suspension in combination with suitable magnetic resonance imaging (MRI) relaxivities demonstrates the potential of these particles for future applications as negative MRI contrast agents.
Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy
Authors: Arnst Kinsie E , Banerjee Souvik , Chen Hao , Deng Shanshan , Hwang Dong‐Jin , Li Wei , Miller Duane D 
Published: February 2019

AbstractMicrotubule (MT)‐targeting agents are highly successful drugs as chemotherapeutic agents, and this is attributed to their ability to target MT dynamics and interfere with critical cellular functions, including, mitosis, cell signaling, intracellular trafficking, and angiogenesis. Because MT dynamics vary in the different stages of the cell cycle, these drugs tend to be the most effective against mitotic cells. While this class of drug has proven to be effective against many cancer types, significant hurdles still exist and include overcoming aspects such as dose limited toxicities and the development of resistance. Newer generations of developed drugs attack these problems and alternative approaches such as the development of dual tubulin and kinase inhibitors are being investigated. This approach offers the potential to show increased efficacy and lower toxicities. This review covers different categories of MT‐targeting agents, recent advances in dual inhibitors, and current challenges for this drug target.
Methylation of HIF3A promoter CpG islands contributes to insulin resistance in gestational diabetes mellitus
Authors: Zhang Yinghong , Chen Yangyang , Qu Hongmei , Wang Yuanli 
Published: February 2019

AbstractBackgroundGestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance during pregnancy, and will lead to high risk of diabetes even after pregnancy. Hypoxia‐inducible factor (HIF) family proteins are transcriptional factors that are highly correlated with methylation, which might be involved in the regulation of GDM.MethodsBaseline clinical characteristics of the GDM patients and healthy women were analyzed. Omental tissue from GDM patients and control groups were collected and detected for the expression levels of HIF1A, HIF2A, and HIF3A. The CpG islands of HIF3A promoter were predicted by “methprimer” software, and the methylation level of CpG islands was detected by bisulfite sequencing PCR.ResultsHIF3A was downregulated in the omental tissue from GDM patients, whereas HIF1A and HIF2A were not affected. Furthermore, HIF3A expression was positively correlated with levels of estrogen receptor α (ESR1) and solute carrier family 2 member 4 (SLC2A4). Moreover, CpG islands of HIF3A promoter were highly methylated in GDM patients. In addition, methylation level of CpG islands could be upregulated by Estradiol (E2) treatment, since high dose of E2 reduced HIF3A mRNA expression in 3T3‐L1 adipocytes.ConclusionOur findings demonstrate that the expression level of HIF3A, but not HIF1A or HIF2A, is downregulated in GDM patients. The methylation status of HIF3A promoter region is highly correlated with GDM, which could be a novel therapeutic target for GDM treatment.
The Acid Strength of the Lewis‐Brønsted Superacids – A QSPR Study
Authors: Sosnowska Anita , Brzeski Jakub , Skurski Piotr , Puzyn Tomasz 
Published: February 2019

AbstractThe acidity of Lewis‐Brønsted superacids can be derived from the theoretical calculations as the Gibbs free energy of the deprotonation reaction (ΔGacid), which describes the tendency of a studied compound to donate a proton. This paper presents the first Quantitative Structure – Property Relationship (QSPR) model that correlates the ΔGacid of superacid (HF/MeX3 formula (X=F, Cl, Br)) with their structure. Developed model is well fitted, roubustness, has good predictive abilities, fulfills all OECD recommendation for good model. Obtained results provide the insight into the relation of structural features of superacids, which are responsible for their acid strength – the structures characterized by strong F‐Me dative bond (with relatively large vibrational frequency), small positive partial atomic charge on Me central atom, possibly large polarity exhibit large acid strength. Such assumption can be used in the future as valuable information in the process of the designing new, stronger, more effective superacids.
Monitoring dendrimer conformational transition using 19F and 1H2O NMR
Authors: Taraban Marc B. , Deredge Daniel J. , Smith Margaret E. , Briggs Katharine T. , Li Yu , Jiang Zhong‐Xing , Wintrode Patrick L. , Yu Yihua Bruce 
Published: February 2019

AbstractThe conformational transition of a fluorinated amphiphilic dendrimer is monitored by the 1H signal from water, alongside the 19F signal from the dendrimer. High‐field NMR data (chemical shift δ, self‐diffusion coefficient D, longitudinal relaxation rate R1, and transverse relaxation rate R2) for both dendrimer (19F) and water (1H) match each other in detecting the conformational transition. Among all parameters for both nuclei, the water proton transverse‐relaxation rate R2(1H2O) displays the highest relative scale of change upon conformational transition of the dendrimer. Hydrogen/deuterium‐exchange mass spectrometry reveals that the compact form of the dendrimer has slower proton exchange with water than the extended form. This result suggests that the sensitivity of R2(1H2O) toward dendrimer conformation originates, at least partially, from the difference in proton exchange efficiency between different dendrimer conformations. Finally, we also demonstrated that this conformational transition could be conveniently monitored using a low‐field benchtop NMR spectrometer via R2(1H2O). The 1H2O signal thus offers a simple way to monitor structural changes of macromolecules using benchtop time‐domain NMR.
Signaling pathways involved in human sperm hyperactivated motility stimulated by Zn2+
Authors: Allouche‐Fitoussi Deborah , Bakhshi Danit , Breitbart Haim 
Published: February 2019

AbstractTo fertilize the egg, sperm cells must reside in the female reproductive tract for several hours during which they undergo chemical and motility changes collectively called capacitation. During capacitation, the sperm develop a unique type of motility known as hyperactivated motility (HAM). The semen contains Zn2+ in millimolar concentrations, whereas in the female reproductive tract the concentration is around 1 µM. In this study, we characterize the role of Zn
2+ in human sperm capacitation focusing on its effect on HAM. Western blot analysis revealed the presence of G protein‐coupled receptor 39 (GPR39) type Zn‐receptor localized mainly in the sperm tail. Zn
2+ at micromolar concentration stimulates HAM, which is mediated by a cascade involving GPR39‐AC‐cAMP‐PKA‐Src‐EGFR and phospholipase C. Both the transmembrane adenylyl cyclase (AC) and the soluble‐AC are involved in the stimulation of HAM by Zn
2+. The development of HAM is precisely regulated by cyclic adenosine monophosphate, in which relatively low concentration (5–10 µM) stimulated HAM, whereas at 30 µM no stimulation occurred. A similar response was seen when different concentrations of Zn
2+ were added to the cells; low Zn
2+ stimulated HAM, whereas at relatively high Zn
2+, no effect was seen. We further demonstrate that the Ca
2+‐channel CatSper involved in Zn
2+‐stimulated HAM. These data support a role for extracellular Zn
2+ acting via GPR39 to regulate signaling pathways in sperm capacitation, leading to HAM induction.
Intimate Consumption and New Sexual Subjects Among the Sambia of Papua New Guinea
Authors: Herdt Gilbert 
Published: February 2019

ABSTRACTThis article examines the transformation of sexual meanings, attitudes, norms, and practices surrounding depletion and pollution across decades (1974–2010) among the Sambia of Papua New Guinea. In the premodern village, all sexual intercourse, whether with boy‐initiates or women, was ritualized and ultimately controlled by the men's secret society. Intimate consumption refers traditionally to a symbolic complex of beliefs, concepts, emotions, and ritual experiences involving sexuality, bodily health, social relationships, and gendered politics. But it also covers sexual anxieties corresponding to the transfer and loss of bodily fluids via the perceived depletion and pollution of self and body. For adult men, the sense of intimate consumption requires repeated substance replenishment and purification. Intimate consumption made oral and vaginal sex highly rule‐bound, taboo laden, and intensely regulated in terms of the meaning, scope, duration, and intended goals of sexual exchange. Pacification, colonization, out‐migration, Seventh Day Adventist (SDA) Christianity, and primary schooling in the Sambia Valley over a period of decades instigated social transformations that challenged and wore down this system of sexual regulation. Thus, the transition from ritual to non‐ritual practices, i.e., more individualistic sexual relationships, highlight narratives of change in the Sambia sexuality. With the demise of ritual initiation in the 1980s and 1990s, and the appearance of HIV and SikAids in the Sambia Valley, explicit ritual sexual techniques were no longer socialized. Modernity (in the sense of a set of policies, attitudes, and rules introduced through institutions such as the government community school) and SDA church sociality influenced both the pace and form of this sexual transformation. Among the greatest changes was the expansion of female agency and sexual autonomy, and personal decision‐making vis‐à‐vis especially marriage and also romance, courtship, and sex. Notably, oral sex, once universal and mandatory, largely disappeared from Sambia intimate relations. Today, spousal intimacy reveals a different set of more ‘modern’ meanings and behaviors compared to two generations ago, e.g., more mutualistic and companionate. Intimate consumption remains a worry for certain Sambia young men and women today however, influenced in part by the rise of the HIV pandemic, mobility, and the absence of normative narratives of sexuality in villages and town settlements. This creates public spaces wherein new sexual subjects have emerged in the villages and urban settlements within the Sambia Valley and in settlements throughout PNG.
Ulcer‐associated cell lineage expresses genes involved in regeneration and is hallmarked by high neutrophil gelatinase‐associated lipocalin (NGAL) levels
Authors: Thorsvik Silje , van Beelen Granlund Atle , Svendsen Tarjei D , Bakke Ingunn , Røyset Elin S , Flo Trude H , Damås Jan K , Østvik Ann E , Bruland Torunn , Sandvik Arne K 
Published: February 2019

AbstractNeutrophil gelatinase‐associated lipocalin (NGAL), also known as Lipocalin 2, is an antimicrobial protein, encoded by the gene LCN2, strongly upregulated in inflammatory bowel disease (IBD) and a promising biomarker for IBD. Here we demonstrate that NGAL is highly expressed in all parts of pyloric metaplasia, also known as the ulcer‐associated cell lineage (UACL), a metaplastic cell lineage suggested to play a role in wound healing in Crohn's disease (CD). We further show NGAL expression in regenerative intestinal crypts and in undifferentiated patient‐derived colonoids. This indicates that NGAL is important in the tissue regeneration process. The remarkable overexpression of NGAL in UACL led us to explore the pathobiology of these cells by transcriptome‐wide RNA sequencing. This study is, to our knowledge, the first to characterize the UACL at this level. Biopsies with UACL and inflamed non‐UACL epithelium from the terminal ileum of CD patients and epithelium from healthy controls were laser capture microdissected for RNA sequencing. Among the 180 genes differentially expressed between UACL and control epithelium, the ten most‐upregulated genes specific for UACL were MUC5AC, PGC, MUC6, MUC5B, LCN2, POU2AF1, MUC1, SDC3, IGFBP5, and SLC7A5. PDX1 was among the most upregulated in both UACL and inflamed non‐UACL epithelium. Immunohistochemistry and iDisco 3D visualization was used to characterize UACL histo‐morphologically, and to validate protein expression of 11 selected differentially expressed genes. Among these genes, LCN2, NOTCH2, PHLDA1, IGFBP5, SDC3, BPIFB1, and RCN1 have previously not been linked to UACL. Gene expression results were analyzed for functional implications using MetaCore, showing that differentially expressed genes are enriched for genes involved in cell migration and motility, and for biomarkers of gastrointestinal neoplasia. These results support a role for UACL as part of the reepithelialization process during and after destructive intestinal inflammation. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Indications and results of diagnostic biopsy in pediatric renal tumors: A retrospective analysis of 317 patients with critical review of SIOP guidelines
Authors: de la Monneraye Yvan , Michon J. , Pacquement H. , Aerts I. , Orbach Daniel. , Doz F. , Bourdeaut F. , Sarnacki S. , Philippe‐Chomette P. , Audry G. , Coulomb A. , Fréneaux P. , Klijanienko J. , Berrebi D. , Zucker J.‐M. , Schleiermacher G. , Brisse H.J. 
Published: February 2019

AbstractObjectivesAccording to the Renal Tumor Study Group (RTSG) of the International Society of Paediatric Oncology (SIOP), diagnostic biopsy of renal tumors prior to neoadjuvant chemotherapy is not mandatory unless the presentation is atypical for a Wilms tumor (WT). This study addresses the relevance of this strategy as well as the accuracy and safety of image‐guided needle biopsy.MethodsClinical, radiological, and pathological data from 317 children (141 males/176 females, mean age: 4 years, range, 0–17.6) consecutively treated in one SIOP‐affiliated institution were retrospectively analyzed.ResultsPresumptive chemotherapy for WT was decided for 182 patients (57% of the cohort), 24 (8%) were operated upfront, and 111 (35%) were biopsied at diagnosis. A non‐WT was confirmed after surgery in 5/182 (3%), 11/24 (46%), and 28/111 (25%), respectively. Age at diagnosis was the most commonly (46%) used criterion to go for biopsy but a nine‐year threshold should be retrospectively considered more relevant. Tumor volumes of clear cell sarcoma of the kidney and WT were significantly higher than those of other tumors (P = 0.002). The agreement between core‐needle biopsy (CNB) and final histology was 99%. No significant morbidity was associated with CNB.ConclusionThe use of SIOP criteria to identify patients eligible for presumptive WT neoadjuvant chemotherapy or upfront surgery avoided biopsy in 65% of children and led to a 97% rate of appropriate preoperative chemotherapy. Image‐guided CNB is a safe and accurate diagnostic procedure. The relevance of SIOP biopsy criteria might be improved by using an older age threshold (9 years instead of 6 years) and by adding initial tumor volume.
A new analytic tool developed to assess safe use recommendations
Authors: Cocoros Noelle M. , Wagner Anita , Haynes Kevin , Petrone Andrew B. , Fazio‐Eynullayeva Elnara , Ding Yulan , Izem Rima , Lee Joo‐Yeon , Major Jacqueline M. , Nguyen Michael , Ju Jing 
Published: February 2019

AbstractPurposeDevelop a flexible analytic tool for the Food and Drug Administration's (FDA's) Sentinel System to assess adherence to safe use recommendations with two capabilities: characterize adherence to patient monitoring recommendations for a drug, and characterize concomitant medication use before, during, and/or after drug therapy.MethodsWe applied the tool in the Sentinel Distributed Database to assess adherence to the labeled recommendation that patients treated with dronedarone undergo electrocardiogram (ECG) testing no less often than every 3 months. Measures of length of treatment, time to first ECG, number of ECGs, and time between ECGs were assessed. We also assessed concomitant use of contraception among female users of mycophenolate per label recommendations (concomitancy 4 weeks before through 6 weeks after discontinuation of mycophenolate). Unadjusted results were stratified by age, month‐year, and sex.ResultsWe identified 21 457 new episodes of dronedarone use of greater than or equal to 90 days (July 2009 to September 2015); 86% had greater than or equal to one ECG, and 22% met the recommendation of an ECG no less often than every 3 months. We identified 21 942 new episodes of mycophenolate use among females 12 to 55 years (January 2016 to September 2015); 16% had greater than or equal to 1 day of concomitant contraception dispensed, 12% had concomitant contraception use for greater than or equal to 50% of the 4 weeks before initiation through 6 weeks after mycophenolate; younger females had more concomitancy. These results may be underestimates as the analyses are limited to claims data.ConclusionsWe developed a tool for use in databases formatted to the Sentinel Common Data Model that can assess adherence to safe use recommendations involving patient monitoring and concomitant drug use over time.