bluuebunny/crossref_metadata_2025_split huggingface dataset:
F‐actin rearrangement is regulated by mTORC2/Akt/Girdin in mouse fertilized eggs
Authors: Wu Didi , Yu Dahai , Wang Xiuxia , Yu Bingzhi 
Published: September 2016

AbstractIn mouse fertilized eggs, correct assembly and distribution of the actin cytoskeleton are intimately related to cleavage in early‐stage embryos. However, in mouse fertilized eggs, mechanisms and involved factors responsible for regulating the actin cytoskeleton are poorly defined. In this study, mTORC2, PKB/Akt and Girdin were found to modulate division of mouse fertilized eggs by regulating distribution of the actin cytoskeleton. RNA interference (RNAi)‐mediated depletion of mTORC2, Akt1 or Girdin disrupted F‐actin rearrangement and strongly inhibited egg development. PKB/Akt has been proven to be a downstream target of the mTORC2 signalling pathway. Girdin, a newly found actin cross‐linker, has been proven to be a downstream target of the Akt signalling pathway. Furthermore, phosphorylation of both Akt1 and girdin was affected by knockdown of mTORC2. Akt1 positively regulated development of the mouse fertilized eggs by girdin‐mediated F‐actin rearrangement. Thus it seems that girdin could be a downstream target of the Akt1‐mediated signalling pathway. Collectively, this study aimed to prove participation of mTORC2/Akt in F‐actin assembly in early‐stage cleavage of mouse fertilized eggs via the function of girdin.ObjectivesIn mouse fertilized eggs, the proper assembly and distribution of actin cytoskeleton is intimately related with the cleavage of early‐stage embryo. However, in mammals, especially in mouse fertilized eggs, the mechanisms and involved factors responsible for regulating the actin cytoskeleton are poorly defined. The aim of this study was to determine the role of mTORC2,PKB/Akt and Girdin in early development of fertilized mouse eggs, via regulating the distribution of actin cytoskeleton.Materials and methodsChanges of F‐actin after treatting with mTORC2 shRNA, Akt siRNA or Girdin siRNA were observed by Immunofluorescence staining and laser‐scanning confocal microscopy. Levels of phosphorylated Girdin at Se1417 were detected by Western immunoblotting. Percentages of cells undergoing division were determined by counting, using a dissecting microscope.ResultsRNA interference (RNAi)‐mediated depletion of mTORC2, Akt1 or Girdin disrupts F‐actin rearrangement, and remarkably inhibited the development of mouse‐fertilized eggs. PKB/Akt has been proved to be a downstream target of the mTORC2 signaling pathway. Girdin, the newly found actin‐cross linker, has been proved to be a downstream target of the Akt signaling pathway. Furthermore phosphorylation of both Akt1 and Girdin were affected by knockdown of mTORC2. Akt1 positively regulates the development of mouse‐fertilized eggs by Girdin mediated F‐actin rearrangement. Girdin could be a downstream target of the Akt1‐mediated signaling pathway.ConclusionsCollectively, this study aimed to prove the participation of mTORC2/Akt in F‐actin assembling in early‐stage cleavage of mouse fertilized eggs via the function of Girdin.
p75 neurotrophin receptor regulates differential mineralization of rat ectomesenchymal stem cells
Authors: Yang Kun , Wang Yingying , Ju Yingxin , Li Gang , Liu Chang , Liu Junyu , Liu Qi , Wen Xiujie , Liu Lu Chuan 
Published: September 2016

AbstractObjectivesThe aim of this study was to investigate whether p75NTR (p75 neurotrophin receptor) regulates differential mineralization capacity of rEMSCs (rat ectomesenchymal stem cells) and underlying mechanisms associated with Mage‐D1 (melanoma‐associated antigens‐D1).Materials and methodsImmunohistochemical staining of p75NTR in developing tooth germs was performed on E12.5d (embryonic 12.5 days) and E19.5d (embryonic 19.5 days). E12.5d EMSCs and E19.5d EMSCs were isolated in the same pregnant Sprague‐Dawley rats from embryonic maxillofacial processes and tooth germs. p75NTR small‐interfering RNA, p75NTR overexpression plasmid, Mage‐D1 small‐interfering RNA and recombined rat NGF were used to transfect cells.Resultsp75NTR was expressed in epithelial‐mesenchymal interaction areas at E12.5d and E19.5d tooth germ development stages. E19.5d EMSCs had higher p75NTR expression levels and differential mineralization capacity but lower levels of cell proliferation. Under induction by mineralized culture medium, the potential of differential mineralization had identical trends in regulation of p75NTR in EMSCs; Mage‐D1 did not fluctuate and TrkA was not expressed. Binding of p75NTR and Mage‐D1 were detected. Mage‐D1 knockdown significantly down‐regulated expression of related genes, which NGF could not rescue.Conclusionp75NTR participated in tooth germ development stages and mediated differential mineralization of EMSCs. p75NTR played a critical role in regulating the potential of differential mineralization of EMSCs. Mage‐D1 seemed to act as a bridge in the underlying mechanism of effects of p75NTR.
The JAK/STAT3 signalling pathway regulated angiogenesis in an endothelial cell/adipose‐derived stromal cell co‐culture, 3D gel model
Authors: Xue Changyue , Xie Jiamin , Zhao Dan , Lin Shiyu , Zhou Tengfei , Shi Sirong , Shao Xiaoru , Lin Yunfeng , Zhu Bofeng , Cai Xiaoxiao 
Published: September 2016

AbstractObjectivesThe aim of the study was to investigate the role of the JAK/STAT3 signalling pathway in angiogenesis.Materials and methodsThe model established in vitro, involved a 3D collagen gel being implanted with endothelial cells (ECs) from red fluorescent protein‐labelled mice, and adipose‐derived stromal cells (ASCs) from green fluorescent protein‐labelled mice. Phenomena of angiogenesis, after treatment by the inhibitor and the activator of JAK/STAT3 pathway respectively, were observed using confocal laser scanning microscopy. Transwell co‐culture of ECs and ASCs was used to elucidate mechanisms.ResultsStattic, inhibitor of JAK/STAT3 pathway, attenuated angiogenesis in the model. In contrast, angiogenesis was promoted after treatment of Olanzapine, an activator. We found that protein levels of VEGFA and cyclin D1 were regulated by the JAK/STAT3 pathway, and flow cytometry further confirmed variations in cell cycle parameters of ECs and ASCs. Genes VEGFA/B, VEGFR2, MMP‐2, MMP‐9, IGF‐1 and b‐FGF were down‐regulated by Stattic in ECs, while Olanzapine significantly up‐regulated mRNA levels of these genes. As for ASCs, genes VEGFA, MMP‐2, MMP‐9, IGF‐1 and b‐FGF were modulated by the JAK/STAT3 pathway.ConclusionsAngiogenesis in the 3D collagen gel was regulated by the JAK/STAT3 pathway which involved changes in vessel length, vessel diameter and sprout number. The underlying mechanism was that the JAK/STAT3 signalling pathway regulated angiogenesis by modulation of numbers of angiogenesis‐related growth factors and by direct regulation of cell cycle.
Optimizing neuronal differentiation of human pluripotent NT2 stem cells in monolayer cultures
Authors: Abolpour Mofrad Sepideh , Kuenzel Katharina , Friedrich Oliver , Gilbert Daniel F. 
Published: September 2016

Human pluripotent embryonal carcinoma (NT2) cells are increasingly considered as a suitable model for in vitro developmental toxicity and neurotoxicity (DT/DNT) studies as they undergo neuronal differentiation upon stimulation with retinoic acid (RA) and allow toxicity testing at different stages of maturation. However, differentiation of NT2 cells is not straightforward. There are different protocols available in the literature reporting varying results with regard to differentiation efficiency, expression of neuronal markers and morphological characteristics of differentiated cells. Yet, the efficiency of available protocols has not been systematically compared. To address this question, we quantified the number and size of cell cluster formed during differentiation using published and modified protocols and analyzed the abundance of neuronal and non‐neuronal expression markers using immunocytochemistry. In the course of the experiments we observed that differentiation results strongly depend on the cell density at differentiation‐initiation as well as on the type of used cell culture plastic ware. Based on those observations and the results from our comparative analysis, we created our own optimized and robust protocol that reproducibly reveals differentiated cells with high yield. We conclude that our method may be superior to differentiation of NT2 cells for systematic in vitro‐based primary screening for developmental toxicants and neurotoxicants at different stages of maturation over previous protocols used. Our approach will also contribute to reduce animal testing in the context of the 3Rs.
Participation restriction in childhood phenotype of myotonic dystrophy type 1: a systematic retrospective chart review
Authors: Gagnon Cynthia , Kierkegaard Marie , Blackburn Catherine , Chrestian Nicolas , Lavoie Mélissa , Bouchard Marie‐Frédéric , Mathieu Jean 
Published: September 2016

AimMyotonic dystrophy type 1 (DM1), a neuromuscular disorder, is divided into four clinical phenotypes: congenital; childhood; adult‐onset, and late‐onset. Publications about the childhood phenotype, especially the long‐term outcome, are scarce. The aims of this study were to assess and describe participation outcomes in adults with the childhood phenotype.MethodA retrospective chart methodology. Data were extracted from health records for 63 adults with childhoodDM1 (32 males, 31 females; mean age 34y, standard deviation [SD] 11y 6mo; range 18–54y) who had attended the Saguenay Neuromuscular Clinic, Canada.ResultsThirty‐four adults (54%) lived with their parents or in foster homes, and most patients needed services or help to live independently. A significant proportion (22%) were isolated in regard to friendship. Very few adults had children, although 33% lived with a spouse. The majority of patients (86%) relied on social security and only one person was currently working. Financial responsibilities were often an issue and 13 (21%) were under legal guardianship.InterpretationThis study showed that patients with the childhood phenotype present a guarded prognosis regarding long‐term social participation. These participation restrictions could be related to behavioural, cognitive, and social stigma problems in childhood. This study illustrates the absolute necessity to pursue an interdisciplinary follow‐up of these patients when they are reaching adulthood.
Turkey and the Palestinian Question: The Shift of Roles in Foreign Policy
Authors: Ertosun Erkan 
Published: September 2016

AbstractFor Turkey, which was seeking a leading role in the Middle East, the Palestinian Question became a priority in its foreign policy during the late 1990s. In this article, it is argued that the role Turkey primarily espoused in the resolution of the Palestinian Question in the period 2000–2009 has mainly been that of a communicator. Nonetheless, in times of crises between Palestine and Israel, Ankara lost its neutrality and credibility to some extent, as it shifted to the role of guardian of Palestinians and proponent of Palestine, thereby undermining its communicator role. Finally, this dilemma in Turkish foreign policy in the Palestinian Question was the fundamental impediment to Turkey's sustainable and constructive contribution to the settlement of the problem in the examined period.
Regulatory B10 cells display an altered homoeostasis in acute graft‐versus‐host disease
Authors: Chakupurakal Geothy , Garcia‐Marquez María Alejandra , Shimabukuro‐Vornhagen Alexander , Kluth Sandra , Schlosser Hans , Theurich Sebastian , Scheid Christof , Hallek Michael , Holtick Udo , von Bergwelt‐Baildon Michael 
Published: September 2016

AbstractObjectiveThe role of B cells and the subgroup of IL‐10 producing B cells, known to have a regulatory function, in patients following a haematopoietic stem cell transplant (alloSCT) has not been clearly understood to date.MethodsWe prospectively recruited 95 patients following an alloSCT and studied the B‐cell reconstitution on days 30, 90 and 150. Regulatory B10 cells could be analysed in 22 consecutively recruited patients on day 30 post‐transplant.ResultsThe total B‐cell percentages in transplant recipients (median 0.33; range 0.01–5.9) were significantly reduced than the controls (P = 0.0001) and constituted predominantly of transitional CD24high CD38high B cells. Regulatory B10 cells could be analysed in 22 consecutively recruited patients on day 30 post‐transplant. The percentages of B10 cells (median 1.35; 0.0–4.5) were significantly reduced in the transplant recipients in comparison with the control cohort (P < 0.0001). Interestingly, the percentages of B10 cells in patients with acute GvHD (median 1.7; 0.33–4.5) were significantly higher than those without GvHD (median 0.7; 0–1.9) (P = 0.0003).ConclusionThis is the first report demonstrating B10 cells in stem cell transplant recipients in the early post‐alloSCT (30 d) period. Our data suggest a possible role for B10 cells in the pathophysiology of acute GvHD. Further longitudinal studies are warranted to understand the implications of our findings.
Activation of cannabinoid receptor 2 attenuates mechanical allodynia and neuroinflammatory responses in a chronic post‐ischemic pain model of complex regional pain syndrome type I in rats
Authors: Xu Jijun , Tang Yuying , Xie Mian , Bie Bihua , Wu Jiang , Yang Hui , Foss Joseph F. , Yang Bin , Rosenquist Richard W. , Naguib Mohamed 
Published: September 2016

AbstractComplex regional pain syndrome type 1 (CRPS‐I) remains one of the most clinically challenging neuropathic pain syndromes and its mechanism has not been fully characterized. Cannabinoid receptor 2 (CB2) has emerged as a promising target for treating different neuropathic pain syndromes. In neuropathic pain models, activated microglia expressing CB2 receptors are seen in the spinal cord. Chemokine fractalkine receptor (CX3CR1) plays a substantial role in microglial activation and neuroinflammation. We hypothesized that a CB2 agonist could modulate neuroinflammation and neuropathic pain in an ischemia model of CRPS by regulating CB2 and CX3CR1 signaling. We used chronic post‐ischemia pain (CPIP) as a model of CRPS‐I. Rats in the CPIP group exhibited significant hyperemia and edema of the ischemic hindpaw and spontaneous pain behaviors (hindpaw shaking and licking). Intraperitoneal administration of MDA7 (a selective CB2 agonist) attenuated mechanical allodynia induced by CPIP. MDA7 treatment was found to interfere with early events in the CRPS‐I neuroinflammatory response by suppressing peripheral edema, spinal microglial activation and expression of CX3CR1 and CB2 receptors on the microglia in the spinal cord. MDA7 also mitigated the loss of intraepidermal nerve fibers induced by CPIP. Neuroprotective effects of MDA7 were blocked by a CB2 antagonist, AM630. Our findings suggest that MDA7, a novel CB2 agonist, may offer an innovative therapeutic approach for treating neuropathic symptoms and neuroinflammatory responses induced by CRPS‐I in the setting of ischemia and reperfusion injury.
The brain‐derived neurotrophic factor Val66Met polymorphism affects encoding of object locations during active navigation
Authors: Wegman Joost , Tyborowska Anna , Hoogman Martine , Arias Vásquez Alejandro , Janzen Gabriele 
Published: September 2016

AbstractThe brain‐derived neurotrophic factor (BDNF) was shown to be involved in spatial memory and spatial strategy preference. A naturally occurring single nucleotide polymorphism of the BDNF gene (Val66Met) affects activity‐dependent secretion of BDNF. The current event‐related fMRI study on preselected groups of ‘Met’ carriers and homozygotes of the ‘Val’ allele investigated the role of this polymorphism on encoding and retrieval in a virtual navigation task in 37 healthy volunteers. In each trial, participants navigated toward a target object. During encoding, three positional cues (columns) with directional cues (shadows) were available. During retrieval, the invisible target had to be replaced while either two objects without shadows (objects trial) or one object with a shadow (shadow trial) were available. The experiment consisted of blocks, informing participants of which trial type would be most likely to occur during retrieval. We observed no differences between genetic groups in task performance or time to complete the navigation tasks. The imaging results show that Met carriers compared to Val homozygotes activate the left hippocampus more during successful object location memory encoding. The observed effects were independent of non‐significant performance differences or volumetric differences in the hippocampus. These results indicate that variations of the BDNF gene affect memory encoding during spatial navigation, suggesting that lower levels of BDNF in the hippocampus results in less efficient spatial memory processing.
The change in the sex ratio in multiple sclerosis is driven by birth cohort effects
Authors: Ajdacic‐Gross V. , Schmid M. , Mutsch M. , Steinemann N. , von Wyl V. , Bopp M. 
Published: September 2016

Background and purposeBirth cohort effects have greatly shaped long‐term trends in multiple sclerosis (MS). This study examined whether birth cohort effects have also determined trends in the sex ratio.MethodsAge−period−cohort analyses were applied to Swiss mortality data, 1901−2010, using logit models. Sex was introduced as an additional main effect (overall effect) and in interaction terms with A, P and C.ResultsBirth cohort effects strongly impacted the trends of MS risk in Switzerland, with a peak in cohorts born in the 1910s and 1920s. Similarly, birth cohort effects accounted for the change in the sex ratios during the 20th century. The balanced sex ratio at the beginning of the 20th century has been superseded by a ratio with a preponderance of women. Despite similarities in timing, the patterns of overall and sex‐specific birth cohort estimates were not congruent.ConclusionThe change in the sex ratio in MS is driven by birth cohort related factors. Overall and sex‐specific trends indicate that the appearance of MS has changed dramatically in the 20th century. The driving force behind these trends is related to yet unknown environmental factors.
Fatigue in early Parkinson's disease: the Norwegian ParkWest study
Authors: Ongre S. O. , Larsen J. P. , Tysnes O. B. , Herlofson K. 
Published: September 2016

Background and purposeFatigue is a common and disabling non‐motor symptom in Parkinson's disease (PD). The pathogenesis is unknown, and the treatment options are limited. The aim of the present study was to investigate the development of fatigue during the first year after diagnosis.MethodsThe study design was a prospective, controlled population‐based longitudinal cohort study, comprising 181 de novo, drug‐naïve patients with PD and 162 control participants. PD was diagnosed according to the Gelb criteria. Fatigue was assessed by the Fatigue Severity Scale (FSS). Both groups were assessed for fatigue at baseline and after 1 year.ResultsPatients reported more fatigue than the control subjects at baseline and at the 1‐year follow‐up evaluation. The FSS scores in the patient group improved from a mean score of 4.4 (SD 1.6) to 4.0 (SD 1.6). Patients with fatigue at baseline received higher doses of dopaminergic medication during follow‐up. Patients who received dopamine agonists improved slightly more than patients who received levodopa. A regression analysis did not show a correlation between an improvement in fatigue and a change in disease severity, depressive symptoms, sleep problems, apathy or cognitive impairment.ConclusionFatigue is a common symptom in PD, also in early, untreated patients. During the first year of observation, an improvement in the fatigue scores was found. The improvement could not be attributed to a change in disease severity or depressive symptoms. The results indicate a better effect of dopamine agonists than of levodopa. This may have implications for treatment in patients with PD‐associated fatigue.
The molecular and phenotypic spectrum of IQSEC2‐related epilepsy
Authors: Zerem Ayelet , Haginoya Kazuhiro , Lev Dorit , Blumkin Lubov , Kivity Sara , Linder Ilan , Shoubridge Cheryl , Palmer Elizabeth Emma , Field Michael , Boyle Jackie , Chitayat David , Gaillard William D. , Kossoff Eric H. , Willems Marjolaine , Geneviève David , Tran‐Mau‐Them Frederic , Epstein Orna , Heyman Eli , Dugan Sarah , Masurel‐Paulet Alice , Piton Ame'lie , Kleefstra Tjitske , Pfundt Rolph , Sato Ryo , Tzschach Andreas , Matsumoto Naomichi , Saitsu Hirotomo , Leshinsky‐Silver Esther , Lerman‐Sagie Tally 
Published: September 2016

SummaryObjectiveIQSEC2 is an X‐linked gene associated with intellectual disability (ID) and epilepsy. Herein we characterize the epilepsy/epileptic encephalopathy of patients with IQSEC2 pathogenic variants.MethodsForty‐eight patients with IQSEC2 variants were identified worldwide through Medline search. Two patients were recruited from our early onset epileptic encephalopathy cohort and one patient from personal communication. The 18 patients who have epilepsy in addition to ID are the subject of this study. Information regarding the 18 patients was ascertained by questionnaire provided to the treating clinicians.ResultsSix affected individuals had an inherited IQSEC2 variant and 12 had a de novo one (male‐to‐female ratio, 12:6). The pathogenic variant types were as follows: missense (8), nonsense (5), frameshift (1), intragenic duplications (2), translocation (1), and insertion (1). An epileptic encephalopathy was diagnosed in 9 (50%) of 18 patients. Seizure onset ranged from 8 months to 4 years; seizure types included spasms, atonic, myoclonic, tonic, absence, focal seizures, and generalized tonic–clonic (GTC) seizures. The electroclinical syndromes could be defined in five patients: late‐onset epileptic spasms (three) and Lennox‐Gastaut or Lennox‐Gastaut–like syndrome (two). Seizures were pharmacoresistant in all affected individuals with epileptic encephalopathy. The epilepsy in the other nine patients had a variable age at onset from infancy to 18 years; seizure types included GTC and absence seizures in the hereditary cases and GTC and focal seizures in de novo cases. Seizures were responsive to medical treatment in most cases. All 18 patients had moderate to profound intellectual disability. Developmental regression, autistic features, hypotonia, strabismus, and white matter changes on brain magnetic resonance imaging (MRI) were prominent features.SignificanceThe phenotypic spectrum of IQSEC2 disorders includes epilepsy and epileptic encephalopathy. Epileptic encephalopathy is a main clinical feature in sporadic cases. IQSEC2 should be evaluated in both male and female patients with an epileptic encephalopathy.