bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long term follow-up of Behçet’s syndrome patients treated with cyclophosphamide
Authors: Gurcan Mert , Esatoglu Sinem Nihal , Hamuryudan Vedat , Saygin Didem , Ugurlu Serdal , Seyahi Emire , Melikoglu Melike , Fresko Izzet , Yurdakul Sebahattin , Yazici Hasan , Hatemi Gulen 
Published: November 2019

Abstract

Objectives
CYC remains an important treatment option for Behçet’s syndrome (BS) patients with life-threatening manifestations. However, adverse events may occur with CYC and this has led to increased use of biologic agents in other vasculitides. We investigated short and long term adverse events associated with CYC use in BS patients.

Methods
We conducted a retrospective chart review of all BS patients treated with CYC between 1972 and 2006. Patients were called in and a standard form was used for collecting demographic characteristics, indication for CYC, its cumulative dose and short term adverse events, defined as those causing discontinuation of CYC, hospitalization and/or death, long term adverse events, including infertility and malignancy, and outcome.

Results
Of 5790 BS patients, 198 (3.4%) had used at least one dose of CYC. Main indications were vascular or neurological involvement. After a median follow-up of 17 years, 52 (26%) patients had died, 113 (57%) could be contacted, and 33 (17%) were lost to follow-up. Vascular involvement was the leading cause of death (n = 27). Seventeen (9%) patients experienced short term adverse events with haemorrhagic cystitis being the most common. After a median follow-up of 25 years (interquartile range: 15–26 years), 17 malignancies occurred in 15 (8%) patients. Infertility was experienced by 26 (30%) patients.

Conclusion
Long term adverse events such as malignancy and infertility were major problems in our BS patients treated with CYC. These results underline the need for safer treatment modalities that are at least as effective as CYC.
Complications of therapy for ANCA-associated vasculitis
Authors: Smith Rona 
Published: November 2019

AbstractThe introduction of immunosuppressive therapies has transformed ANCA-associated vasculitis (AAV) from a largely fatal condition to a chronic relapsing disorder. However, progressive organ damage and disability, both from the disease process itself and from therapies used for treatment, eventually affect the majority of patients. Infection, rather than uncontrolled vasculitis, is the greatest cause of early mortality and remains a major problem thereafter. Increased rates of malignancy and cardiovascular disease are additional important long term sequelae. This review focuses on the complications associated with the immunosuppressive therapies most commonly used to treat ANCA-associated vasculitis, and considers prophylactic and monitoring strategies to minimize these risks. Achieving a balance between immunosuppression to reduce relapse risk and minimizing the adverse effects associated with therapy has become key. The contribution of glucocorticoids to treatment toxicity is increasingly being recognized, and future therapeutic strategies must concentrate on glucocorticoid minimization or sparing strategies. Development of robust predictors of an individual’s future clinical course is needed in order to individually tailor treatment regimens.
Quantitative analysis of the placebo response in pharmacotherapy of insomnia and its application in clinical trials
Authors: Zheng Xijun , He Yingchun , Xu Ling , Li Yunfei , Yin Fang , Li Huafang , Liu Hongxia , Shen Yifeng , Zheng Qingshan , Li Lujin 
Published: November 2019

Abstract

Study Objectives
This study aimed to develop a robust placebo response model for the pharmacotherapy for insomnia to guide drug development and clinical practice.

Methods
PubMed, EMBASE, and Cochrane Library databases were systematically searched for randomized placebo-controlled trials of medications for insomnia dating from the inception dates of the databases to April 18, 2018. Three placebo response models were established to describe the time–course of sleep parameters measured by objective (polysomnography or actigraphy) or subjective methods (sleep diary or questionnaires). The established models were applied to simulate placebo response distribution under different conditions using Monte Carlo simulations.

Results
Fifty-four studies involving 6,416 subjects were included. Placebo response increased over time and reached a plateau at approximately 8 weeks from start of therapy. Established models described the observed data reasonably well based on various diagnostic plots. Baseline sleep parameters affected the placebo response. There were significant positive correlations with placebo response and the severity of sleep latency, wake after sleep onset, and total sleep time at baseline. In addition, placebo response, assessed by subjective and objective methods, was consistent after correcting the baseline levels.

Conclusions
The established placebo response models can serve as a tool to predict placebo response at different baseline levels, which can provide valuable reference for clinical trial design, decision-making in drug development, and clinical practice.
Sleepiness as motivation: a potential mechanism for how sleep deprivation affects behavior
Authors: Axelsson John , Ingre Michael , Kecklund Göran , Lekander Mats , Wright Kenneth P , Sundelin Tina 
Published: November 2019

Abstract

Study Objectives
To determine how sleepiness and sleep deprivation drive the motivation to engage in different behaviors.

Methods
We studied the sleepiness of 123 participants who had been randomized to sleep deprivation or normal sleep, and their willingness to engage in a range of everyday behaviors.

Results
Self-reported sleepiness was a strong predictor of the motivation to engage in sleep-preparatory behaviors such as shutting one’s eyes (OR = 2.78, 95% CI: 2.19–3.52 for each step up on the Karolinska Sleepiness Scale) and resting (OR = 3.20, CI: 2.46–4.16). Sleepiness was also related to the desire to be cared for by a loved one (OR = 1.49, CI: 1.22–1.82), and preparedness to utilize monetary and energy resources to get to sleep. Conversely, increased sleepiness was associated with a decreased motivation for social and physical activities (e.g. be with friends OR = 0.71, CI: 0.61–0.82; exercise OR = 0.65, CI: 0.56–0.76). Sleep deprivation had similar effects as sleepiness on these behaviors. Neither sleepiness nor sleep deprivation had strong associations with hunger, thirst, or food preferences.

Conclusions
Our findings indicate that sleepiness is a dynamic motivational drive that promotes sleep-preparatory behaviors and competes with other drives and desired outcomes. Consequently, sleepiness may be a central mechanism by which impaired alertness, for example, due to insufficient sleep, contributes to poor quality of life and adverse health. We propose that sleepiness helps organize behaviors toward the specific goal of assuring sufficient sleep, in competition with other needs and incentives. A theoretical framework on sleepiness and its behavioral consequences are likely to improve our understanding of several disease mechanisms.
Protease activated receptors (PAR)‐1 and ‐2 mediate cellular effects of factor VII activating protease (FSAP)
Authors: Byskov Kristina , Le Gall Sylvain M. , Thiede Bernd , Camerer Eric , Kanse Sandip M. 
Published: November 2019

AbstractFactor VII activating protease (FSAP) is a circulating serine protease implicated in thrombosis, atherosclerosis, stroke, and cancer. Using an overexpression strategy, we have systematically investigated the role of protease activated receptors (PAR)‐1, ‐2, ‐3, and ‐4 on FSAP‐mediated signaling in HEK293T and A549 cells. Cleavage of PAR‐reporter constructs and MAPK phosphorylation was used to monitor receptor activation. FSAP cleaved PAR‐2 and to a lesser degree PAR‐1, but not PAR‐3 or PAR‐4 in both cell types. Robust MAPK activation in response to FSAP was observed after PAR‐2, but not PAR‐1 overexpression in HEK293T. Recombinant serine protease domain of wild type FSAP, but not the Marburg I isoform of FSAP, could reproduce the effects of plasma purified FSAP. Canonical cleavage of both PARs was suggested by mass spectrometric analysis of synthetic peptide substrates from the N‐terminus of PARs and site directed mutagenesis studies. Surprisingly, knockdown of endogenous PAR‐1, but not PAR‐2, prevented the apoptosis‐inhibitory effect of FSAP, suggesting that PAR1 is nevertheless a direct or indirect target in some cell types. This molecular characterization of PAR‐1 and ‐2 as cellular receptors of FSAP will help to define the actions of FSAP in the context of cancer and vascular biology.
Ischemia‐induced Netrin‐4 promotes neovascularization through endothelial progenitor cell activation via Unc‐5 Netrin receptor B
Authors: Lee Na Geum , Jeung In Cheul , Heo Soon Chul , Song Jinhoi , Kim Wooil , Hwang Byungtae , Kwon Min‐Gi , Kim Yeon‐Gu , Lee Jangwook , Park Jong‐Gil , Shin Min‐Gyeong , Cho Young‐Lai , Son Mi‐Young , Bae Kwang‐Hee , Lee Sang‐Hyun , Kim Jae Ho , Min Jeong‐Ki 
Published: November 2019

AbstractEndothelial progenitor cells (EPCs) promote neovascularization and tissue repair by migrating to vascular injury sites; therefore, factors that enhance EPC homing to damaged tissues are of interest. Here, we provide evidence of the prominent role of the Netrin‐4 (NTN4)–Unc‐5 Netrin receptor B (UNC5B) axis in EPC‐specific promotion of ischemic neovascularization. Our results showed that NTN4 promoted the proliferation, chemotactic migration, and paracrine effects of small EPCs (SEPCs) and significantly increased the incorporation of large EPCs (LEPCs) into tubule networks. Additionally, NTN4 prominently augmented neovascularization in mice with hindlimb ischemia by increasing the homing of exogenously transplanted EPCs to the ischemic limb and incorporating EPCs into vessels. Moreover, silencing of UNC5B, an NTN4 receptor, abrogated the NTN4‐induced cellular activities of SEPCs in vitro and blood‐flow recovery and neovascularization in vivo in ischemic muscle by reducing EPC homing and incorporation. These findings suggest NTN4 as an EPC‐based therapy for treating angiogenesis‐dependent diseases.
A novel F‐box domain containing cyclin F like gene is required for maintaining the genome stability and survival of chicken primordial germ cells
Authors: Lee Bo Ram , Rengaraj Deivendran , Choi Hee Jung , Han Jae Yong 
Published: November 2019

AbstractThe stability and survival of germ cells are controlled by the germline‐specific genes, however, such genes are less known in the avian species. Using a microarray‐based the National Center for Biotechnology Information Gene Expression Omnibus dataset, we found an unigene (Gga.9721) that upregulated in the chicken primordial germ cells (PGCs). The unigene showed 97% identities with an uncharacterized chicken cyclin F like gene. The predicted chicken cyclin F like gene was further characterized through expression and regulation in the chicken PGCs. The sequence analysis revealed that the gene shows identities with cyclin F gene and contains an F‐box domain. The expression of chicken cyclin F like was detected specifically in the gonads, PGCs, and germline cells. The knockdown of cyclin F like gene resulted in DNA damage and apoptosis in the PGCs. The genes related to stemness and germness were downregulated, whereas, genes related to apoptosis and DNA damage response were increased in the PGCs after the knockdown of chicken cyclin F like. We further observed that the Nanog homeobox controlled the transcriptional activity of chicken cyclin F like gene in PGCs. Collectively, the chicken cyclin F like gene, which is not reported in any other species, is required for maintaining the genome stability of germ cells.
Glucosylceramide synthase regulates adipo‐osteogenic differentiation through synergistic activation of PPARγ with GlcCer
Authors: Jang Hyun‐Jun , Lim Seyoung , Kim Jung‐Min , Yoon Sora , Lee Chae Young , Hwang Hyeon‐Jeong , Shin Jeong Woo , Shin Kyeong Jin , Kim Hye Yun , Park Kwang Il , Nam Dougu , Lee Ja Yil , Yea Kyungmoo , Hirabayashi Yoshio , Lee Yu Jin , Chae Young Chan , Suh Pann‐Ghill , Choi Jang Hyun 
Published: November 2019

AbstractDysregulation of the adipo‐osteogenic differentiation balance of mesenchymal stem cells (MSCs), which are common progenitor cells of adipocytes and osteoblasts, has been associated with many pathophysiologic diseases, such as obesity, osteopenia, and osteoporosis. Growing evidence suggests that lipid metabolism is crucial for maintaining stem cell homeostasis and cell differentiation; however, the detailed underlying mechanisms are largely unknown. Here, we demonstrate that glucosylceramide (GlcCer) and its synthase, glucosylceramide synthase (GCS), are key determinants of MSC differentiation into adipocytes or osteoblasts. GCS expression was increased during adipogenesis and decreased during osteogenesis. Targeting GCS using RNA interference or a chemical inhibitor enhanced osteogenesis and inhibited adipogenesis by controlling the transcriptional activity of peroxisome proliferator‐activated receptor γ (PPARγ). Treatment with GlcCer sufficiently rescued adipogenesis and inhibited osteogenesis in GCS knockdown MSCs. Mechanistically, GlcCer interacted directly with PPARγ through A/B domain and synergistically enhanced rosiglitazone‐induced PPARγ activation without changing PPARγ expression, thereby treatment with exogenous GlcCer increased adipogenesis and inhibited osteogenesis. Animal studies demonstrated that inhibiting GCS reduced adipocyte formation in white adipose tissues under normal chow diet and high‐fat diet feeding and accelerated bone repair in a calvarial defect model. Taken together, our findings identify a novel lipid metabolic regulator for the control of MSC differentiation and may have important therapeutic implications.
Lack of PDZD7 long isoform disrupts ankle‐link complex and causes hearing loss in mice
Authors: Du Haibo , Zou Linzhi , Ren Rui , Li Nana , Li Jie , Wang Yanfei , Sun Jinpeng , Yang Jun , Xiong Wei , Xu Zhigang 
Published: November 2019

AbstractUsher syndrome (USH) is the most frequent form of combined hereditary deafness‐blindness, characterized by hearing loss and retinitis pigmentosa, with or without vestibular dysfunction. PDZD7 is a PDZ domain‐containing scaffold protein that was suggested to be a USH modifier and a contributor to digenic USH. In the inner ear hair cells, PDZD7 localizes at the ankle region of the stereocilia and constitutes the so‐called ankle‐link complex together with three other USH proteins Usherin, WHRN, and ADGRV1. PDZD7 gene is subjected to alternative splicing, which gives rise to two types of PDZD7 isoforms, namely the long and short isoforms. At present, little is known which specific isoform is involved in ankle‐link formation and stereocilia development. In this work, we showed that PDZD7 long isoform, but not short isoforms, localizes at the ankle region of the stereocilia. Moreover, we established Pdzd7 mutant mice by introducing deletions into exon 14 of the Pdzd7 gene, which causes potential premature translational stop in the long isoform but leaves short isoforms unaffected. We found that lack of PDZD7 long isoform affects the localization of other ankle‐link complex components in the stereocilia. Consequently, Pdzd7 mutant mice showed stereocilia development deficits and hearing loss as well as reduced mechanotransduction (MET) currents, suggesting that PDZD7 long isoform is indispensable for hair cells. Furthermore, by performing yeast two‐hybrid screening, we identified a PDZD7 long isoform‐specific binding partner PIP5K1C, which has been shown to play important roles in hearing and might participate in the function and/or transportation of PDZD7.
Therapies targeting Frizzled‐7/β‐catenin pathway prevent the development of pathological angiogenesis in an ischemic retinopathy model
Authors: Bats Marie‐Lise , Bougaran Pauline , Peghaire Claire , Gueniot Florian , Abelanet Alice , Chan Hélène , Séguy Camille , Jeanningros Sylvie , Jaspard‐Vinassa Béatrice , Couffinhal Thierry , Duplàa Cécile , Dufourcq Pascale 
Published: November 2019

AbstractRetinopathies remain major causes of visual impairment in diabetic patients and premature infants. Introduction of anti‐angiogenic drugs targeting vascular endothelial growth factor (VEGF) has transformed therapy for these proliferative retinopathies. However, limitations associated with anti‐VEGF medications require to unravel new pathways of vessel growth to identify potential drug targets. Here, we investigated the role of Wnt/Frizzled‐7 (Fzd7) pathway in a mouse model of oxygen‐induced retinopathy (OIR). Using transgenic mice, which enabled endothelium‐specific and time‐specific Fzd7 deletion, we demonstrated that Fzd7 controls both vaso‐obliteration and neovascular phases (NV). Deletion of Fzd7 at P12, after the ischemic phase of OIR, prevented formation of aberrant neovessels into the vitreous by suppressing proliferation of endothelial cells (EC) in tufts. Next we validated in vitro two Frd7 blocking strategies: a monoclonal antibody (mAbFzd7) against Fzd7 and a soluble Fzd7 receptor (CRD). In vivo a single intravitreal microinjection of mAbFzd7 or CRD significantly attenuated retinal neovascularization (NV) in mice with OIR. Molecular analysis revealed that Fzd7 may act through the activation of Wnt/β‐catenin and Jagged1 expression to control EC proliferation in extra‐retinal neovessels. We identified Fzd7/β‐catenin signaling as new regulator of pathological retinal NV. Fzd7 appears to be a potent pharmacological target to prevent or treat aberrant angiogenesis of ischemic retinopathies.
Grb2 binding induces phosphorylation-independent activation of Shp2
Authors: Lin Chi-Chuan , Wieteska Lukasz , Suen Kin Man , Kalverda Arnout , Ahmed Zamal , Ladbury John E. 
Published: November 2019

AbstractThe regulation of phosphatase activity is fundamental to the control of intracellular signalling and in particular the tyrosine kinase-mediated mitogen-activated protein kinase (MAPK) pathway. Shp2 is a ubiquitously expressed protein tyrosine phosphatase and its kinase-induced hyperactivity is associated with many cancer types. In non-stimulated cells we find that binding of the adaptor protein, Grb2, in its monomeric state initiates Shp2 activity independent of phosphatase phosphorylation. Grb2 forms a bidentate interaction with both the N-terminal SH2 and the catalytic domains of Shp2, releasing the phosphatase from its auto-inhibited conformation. Grb2 typically exists as a dimer in the cytoplasm. However, its monomeric state prevails under basal conditions when it is expressed at low concentration, or when it is constitutively phosphorylated on a specific tyrosine residue (Y160). Thus, Grb2 can activate Shp2 and downstream signal transduction, in the absence of extracellular growth factor stimulation or kinase-activating mutations, in response to defined cellular conditions. We identify a polypeptide biotool capable of blocking the Grb2-Shp2 interaction. This peptide down-regulates Shp2 activityin vitroand MAPK signalling in a cancer cell line.
Cell Tracking Profiler: a user-driven analysis framework for evaluating 4D live cell imaging data
Authors: Mitchell Claire , Caroff Lauryanne , Vigilante Alessandra , Solis-Lemus Jose Alonso , Reyes-Aldasoro Constantino Carlos , de Chaumont Fabrice , Dufour Alexandre , Dallongeville Stephane , Olivo-Marin Jean-Christophe , Knight Robert 
Published: November 2019

AbstractAccurate measurements of cell morphology and behaviour are fundamentally important for understanding how disease, molecules and drugs affect cell function in vivo. Using muscle stem cell (muSC) responses to injury in zebrafish as our biological paradigm we have established a ground truth for muSC cell behaviour. This revealed that variability in segmentation and tracking algorithms from commonly used programs are error-prone, leading us to develop a fast semi-automated image analysis pipeline that allows user defined parameters for segmentation and correction of cell tracking. Cell Tracking Profiler (CTP) operates through the freely available Icy platform, and allows user-managed cell tracking from 3D time-lapsed datasets to provide measures of cell shape and movement. Using dimensionality reduction methods, multiple correlation and regression analyses we identify myosin II-dependent parameters of muSC behaviour during regeneration. CTP and the associated statistical tools we have developed thus provide a powerful framework for analysing complex cell behaviour in vivo from 4D datasets.SummaryAnalysis of cell shape and movement from 3D time-lapsed datasets is currently very challenging. We therefore designed Cell Tracking Profiler for analysing cell behaviour from complex datasets and demonstrate its effectiveness by analysing stem cell behaviour during muscle regeneration in zebrafish.
Optimizing assembly sequence planning using precedence graph-based assembly subsets prediction method
Authors: Zhang Nan , Liu Zhenyu , Qiu Chan , Hu Weifei , Tan Jianrong 
Published: November 2019

Purpose
Assembly sequence planning (ASP) plays a vital role in assembly process because it directly influences the feasibility, cost and time of the assembly process. The purpose of this study is to solve ASP problem more efficiently than current algorithms.

Design/methodology/approach
A novel assembly subsets prediction method based on precedence graph is proposed to solve the ASP problem. The proposed method adopts the idea of local to whole and integrates a simplified firework algorithm. First, assembly subsets are generated as initial fireworks. Then, each firework explodes to several sparks with higher-level assembly subsets and new fireworks are selected for next generation according to selection strategy. Finally, iterating the algorithm until complete and feasible solutions are generated.

Findings
The proposed method performs better in comparison with state-of-the-art algorithms because of the balance of exploration (fireworks) and exploitation (sparks). The size of initial fireworks population determines the diversity of the solution, so assembly subsets prediction method based on precedence graph (ASPM-PG) can explore the solution space. The size of sparks controls the exploitation ability of ASPM-PG; with more sparks, the direction of a specific firework can be adequately exploited.

Practical implications
The proposed method is with simple structure and high efficiency. It is anticipated that using the proposed method can effectively improve the efficiency of ASP and reduce computing cost for industrial applications.

Originality/value
The proposed method finds the optimal sequence in the construction process of assembly sequence rather than adjusting order of a complete assembly sequence in traditional methods. Moreover, a simplified firework algorithm with new operators is introduced. Two basic size parameters are also analyzed to explain the proposed method.