bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interplay between synaptic endocannabinoid signaling and metaplasticity in neuronal circuit function and dysfunction
Authors: Melis Miriam , Greco Barbara , Tonini Raffaella 
Published: April 2014

AbstractSynaptic neuromodulation acts across different functional domains to regulate cognitive processing and behavior. Recent challenges are related to elucidating the molecular and cellular mechanisms through which neuromodulatory pathways act on multiple time scales to signal state‐dependent contingencies at the synaptic level or to stabilise synaptic connections during behavior. Here, we present a framework with the synaptic neuromodulators endocannabinoids (eCBs) as key players in dynamic synaptic changes. Modulation of various molecular components of the eCB pathway yields interconnected functional activation states of eCB signaling (prior, tonic, and persistent), which may contribute to metaplastic control of synaptic and behavioral functions in health and disease. The emerging picture supports aberrant metaplasticity as a contributor to cognitive dysfunction associated with several pathological states in which eCB signaling, or other neuromodulatory pathways, are deregulated.
Tau acts as a mediator for Alzheimer's disease‐related synaptic deficits
Authors: Liao Dezhi , Miller Eric C. , Teravskis Peter J. 
Published: April 2014

AbstractThe two histopathological hallmarks of Alzheimer's disease (AD) are amyloid plaques containing multiple forms of amyloid beta (Aβ) and neurofibrillary tangles containing phosphorylated tau proteins. As mild cognitive impairment frequently occurs long before the clinical diagnosis of AD, the scientific community has been increasingly interested in the roles of Aβ and tau in earlier cellular changes that lead to functional deficits. Therefore, great progress has recently been made in understanding how Aβ or tau causes synaptic dysfunction. However, the interaction between the Aβ and tau‐initiated intracellular cascades that lead to synaptic dysfunction remains elusive. The cornerstone of the two‐decade‐old hypothetical amyloid cascade model is that amyloid pathologies precede tau pathologies. Although the premise of Aβ‐tau pathway remains valid, the model keeps evolving as new signaling events are discovered that lead to functional deficits and neurodegeneration. Recent progress has been made in understanding Aβ‐PrPC‐Fyn‐mediated neurotoxicity and synaptic deficits. Although still elusive, many novel upstream and downstream signaling molecules have been found to modulate tau mislocalization and tau hyperphosphorylation. Here we will discuss the mechanistic interactions between Aβ‐PrPC‐mediated neurotoxicity and tau‐mediated synaptic deficits in an updated amyloid cascade model with calcium and tau as the central mediators.
Fluorescence‐activated sorting of fixed nuclei: a general method for studying nuclei from specific cell populations that preserves post‐translational modifications
Authors: Marion‐Poll Lucile , Montalban Enrica , Munier Annie , Hervé Denis , Girault Jean‐Antoine 
Published: April 2014

AbstractLong‐lasting brain alterations that underlie learning and memory are triggered by synaptic activity. How activity can exert long‐lasting effects on neurons is a major question in neuroscience. Signalling pathways from cytoplasm to nucleus and the resulting changes in transcription and epigenetic modifications are particularly relevant in this context. However, a major difficulty in their study comes from the cellular heterogeneity of brain tissue. A promising approach is to directly purify identified nuclei. Using mouse striatum we have developed a rapid and efficient method for isolating cell type‐specific nuclei from fixed adult brain (fluorescence‐activated sorting of fixed nuclei; FAST‐FIN). Animals are quickly perfused with a formaldehyde fixative that stops enzymatic reactions and maintains the tissue in the state it was at the time of death, including nuclear localisation of soluble proteins such as GFP and differences in nuclear size between cell types. Tissue is subsequently dissociated with a Dounce homogeniser and nuclei prepared by centrifugation in an iodixanol density gradient. The purified fixed nuclei can then be immunostained with specific antibodies and analysed or sorted by flow cytometry. Simple criteria allow distinction of neurons and non‐neuronal cells. Immunolabelling and transgenic mice that express fluorescent proteins can be used to identify specific cell populations, and the nuclei from these populations can be efficiently isolated, even rare cell types such as parvalbumin‐expressing interneurons. FAST‐FIN allows the preservation and study of dynamic and labile post‐translational protein modifications. It should be applicable to other tissues and species, and allow study of DNA and its modifications.
Auxiliary proteins promote modal gating of AMPA‐ and kainate‐type glutamate receptors
Authors: Zhang Wei , Devi Suma Priya Sudarsana , Tomita Susumu , Howe James R. 
Published: April 2014

AbstractThe gating behavior of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) and kainate receptors is modulated by association with the auxiliary proteins: transmembrane AMPA receptor regulatory proteins (TARPs) and neuropilin tolloid‐like (Netos), respectively. Although the mechanisms underlying receptor modulation differ for both AMPA and kainate receptors, association with these auxiliary subunits results in the appearance of a slow component in the decay of ensemble responses to rapid applications of saturating concentrations of glutamate. We show here that these components arise from distinct gating behaviors, characterized by substantially higher open probability (Popen), which we only observe when core subunits are associated with their respective auxiliary partners. We refer to these behaviors as gating modes, because individual receptors switch between the low‐ and high‐Popen gating on a time‐scale of seconds. At any given time, association of AMPA and kainate receptors with their auxiliary subunits results in a heterogeneous receptor population, some of which are in the high‐Popen mode and others that display gating behavior similar to that seen for receptors formed from core subunits alone. While the switching between modes is infrequent, the presence of receptors displaying both types of gating has a large impact on both the kinetics and amplitude of ensemble currents similar to those seen at synapses.
Stoichiometric regulation of phytoplankton toxins
Authors: Van de Waal Dedmer B. , Smith Val H. , Declerck Steven A. J. , Stam Eva C. M. , Elser James J. 
Published: April 2014

AbstractEcological Stoichiometry theory predicts that the production, elemental structure and cellular content of biomolecules should depend on the relative availability of resources and the elemental composition of their producer organism. We review the extent to which carbon‐ and nitrogen‐rich phytoplankton toxins are regulated by nutrient limitation and cellular stoichiometry. Consistent with theory, we show that nitrogen limitation causes a reduction in the cellular quota of nitrogen‐rich toxins, while phosphorus limitation causes an increase in the most nitrogen‐rich paralytic shellfish poisoning toxin. In addition, we show that the cellular content of nitrogen‐rich toxins increases with increasing cellular N : P ratios. Also consistent with theory, limitation by either nitrogen or phosphorus promotes the C‐rich toxin cell quota or toxicity of phytoplankton cells. These observed relationships may assist in predicting and managing toxin‐producing phytoplankton blooms. Such a stoichiometric regulation of toxins is likely not restricted to phytoplankton, and may well apply to carbon‐ and nitrogen‐rich secondary metabolites produced by bacteria, fungi and plants.
Increased endothelial activation in recently symptomatic versus asymptomatic carotid artery stenosis and in cerebral microembolic‐signal‐negative patient subgroups
Authors: Kinsella J. A. , Tobin W. O. , Kavanagh G. F. , O'Donnell J. S. , McGrath R. T. , Tierney S. , Feeley T. M. , Egan B. , O'Neill D. , Collins R. D. , Coughlan T. , Harbison J. A. , Doherty C. P. , Madhavan P. , Moore D. J. , O'Neill S. M. , Colgan M.‐P. , Saqqur M. , Murphy R. P. , Moran N. , Hamilton G. , McCabe D. J. H. 
Published: April 2014

Background and purposevon Willebrand factor propeptide (VWF:Ag II) is potentially a more sensitive marker of acute endothelial activation than von Willebrand factor antigen (VWF:Ag). These biomarkers have not been simultaneously assessed in asymptomatic versus symptomatic carotid stenosis patients. The relationship between endothelial activation and cerebral microembolic signals (MESs) detected on transcranial Doppler ultrasound is unknown.MethodsIn this multicentre observational analytical study, plasma VWF:Ag and VWF:Ag II levels in patients with ≥50% asymptomatic carotid stenosis were compared with those from patients with ≥50% symptomatic carotid stenosis in the ‘early’ (≤4 weeks) and ‘late’ (≥3 months) phases after transient ischaemic attack or ischaemic stroke. Endothelial activation was also longitudinally assessed in symptomatic patients during follow‐up. Transcranial Doppler ultrasound monitoring classified patients as MES‐positive or MES‐negative.ResultsData from 31 asymptomatic patients were compared with those from 46 early symptomatic and 35 late phase symptomatic carotid stenosis patients, 23 of whom had undergone carotid intervention. VWF:Ag II levels were higher in early (12.8 μg/ml; P < 0.001), late (10.6 μg/ml; P = 0.01) and late post‐intervention (10.6 μg/ml; P = 0.038) symptomatic patients than asymptomatic patients (8.9 μg/ml). VWF:Ag levels decreased in symptomatic patients followed up from the early to late phase after symptom onset (P = 0.048). Early symptomatic MES‐negative patients had higher VWF: Ag II levels (13.3 vs. 9.0 μg/ml; P < 0.001) than asymptomatic MES‐negative patients.ConclusionsEndothelial activation is enhanced in symptomatic versus asymptomatic carotid stenosis patients, in early symptomatic versus asymptomatic MES‐negative patients, and decreases over time in symptomatic patients. VWF:Ag II levels are a more sensitive marker of endothelial activation than VWF:Ag levels in carotid stenosis. The potential value of endothelial biomarkers and concurrent cerebral MES detection at predicting stroke risk in carotid stenosis warrants further study.
Geographies of Pilgrimage: Meaningful Movements and Embodied Mobilities
Authors: Scriven Richard 
Published: April 2014

AbstractThis article argues for the importance of geographic engagements with pilgrimage and its analysis through the lenses, considerations and sympathies of the mobilities turn. Pilgrimage is being increasingly recognised as a multifaceted sociocultural spatial practice that plays a significant role in the lives of millions of people and in numerous sites across the world. The geographies of mobilities' emphasis on movement and practices in shaping the world enable the formation of new understandings of pilgrimage. This article builds on the links being forged between the study of pilgrimage and the mobility field, by showing how pilgrimage, as an activity that is focused on performances in specific places, can be analysed as an embodied mobility. Pilgrimage is explored as a meaningful journey in which the performance entwines the outer physical and inner spiritual/emotion journey in a process that defines and shapes the people and places involved.
Preparation of High‐Strength Ti3AlC2 by Spark Plasma Sintering
Authors: Wang Wenjuan , Li Cuiwei , Zhai Hongxiang , Wang Changan 
Published: April 2014

Ti3AlC2 bulk materials with high mechanical properties have been fabricated by spark plasma sintering using Ti3AlC2 powders as starting material. Effects of sintering temperature on the microstructure and mechanical properties of Ti3AlC2 were investigated. Nearly full‐dense Ti3AlC2 samples could be obtained after sintering the powders in the 1300–1400°C temperature range for 3 min under a pressure of 20 MPa. The as‐prepared Ti3AlC2 samples have finer grains, which results in higher mechanical properties. The Ti3AlC2 samples prepared at 1350°C show a higher hardness of 3.84 ± 0.06 GPa and flexural strength of 746.8 ± 6 MPa.
Sub-Cortical Infarcts and the Risk of Falls in Older People: Combined Results of TASCOG and Sydney MAS Studies
Authors: Callisaya Michele L. , Srikanth Velandai K. , Lord Stephen R. , Close Jacqueline C. , Brodaty Henry , Sachdev Perminder S. , Phan Thanh , Beare Richard , Trollor Julian , Wen Wei , Zheng Jacqueline J. , Delbaere Kim 
Published: April 2014

Background White matter hyperintensities increase the risk of multiple falls in older people, but the effect of sub-cortical infarcts is unknown. Aims By pooling data from two Australian population-based studies, we aimed to investigate the association between subcortical infarcts and multiple falls and whether this relationship, and that of white matter hyperintensities, is mediated or modified by cognitive or sensorimotor factors. Methods Participants underwent structural magnetic resonance imaging and cognitive and sensorimotor assessments. Falls were prospectively measured over 12 months. Subcortical infarcts were detected visually. Total white matter hyperintensity volume was quantified using automated segmentation methods. Generalized linear models were used to examine if sub-cortical infarcts and white matter hyperintensities predicted falls. Results The mean age of the sample ( n = 655) was 74·5 (standard deviation 6·7) years, 336 (51·3%) males. Overall, 114 (17·4%) had multiple falls. The majority had no sub-cortical infarcts ( n = 491, 75·0%), while 90 had one (13·7%), 41 had two (6·3%), and 33 had more than or equal to three sub-cortical infarcts (5·0%). The risk of multiple falls was elevated in people with more than or equal to three sub-cortical infarcts (adjusted relative risk 1·89, 95% confidence interval 1·03, 3·46) and in the highest quarter of white matter hyperintensity volume (adjusted relative risk 1·46, 95% confidence interval 1·00, 2·13). The effect of sub-cortical infarcts on falls was amplified by poorer vision ( P = 0·03). The effect of white matter hyperintensities was amplified by poorer vision ( P = 0·008), proprioception ( P = 0·03), and muscle strength ( P = 0·008). There was no modifying effect of cognitive function. Conclusions Increasing burdens of sub-cortical infarcts and white matter hyperintensities are associated with a risk of falling. Interventions targeting sensorimotor factors along with strategies to prevent sub-cortical infarcts and white matter hyperintensities may reduce the risk of falls.
Cytoreductive nephrectomy for metastatic renal cell carcinoma: A population‐based analysis of perioperative outcomes according to clinical stage
Authors: Takagi Toshio , Sugihara Toru , Yasunaga Hideo , Horiguchi Hiromasa , Fushimi Kiyohide , Kondo Tsunenori , Homma Yukio , Tanabe Kazunari 
Published: April 2014

ObjectivesTo investigate the perioperative outcomes of cytoreductive nephrectomy according to clinical T stage, and to analyze factors affecting these outcomes.MethodsThe Japanese Diagnosis Procedure Combination database from 2007 to 2012 was used to evaluate perioperative outcomes including in‐hospital mortality, complications, blood transfusion, anesthesia time, postoperative length of stay and total cost in patients who underwent cytoreductive nephrectomy for metastatic renal cell carcinoma, according to clinical T stage. Multivariable regression analyses including sex, age, clinical N stage, hospital volume, type of hospital, Charlson Comorbidity Index and clinical T stage were carried out to identify outcome predictors.ResultsThe present study enrolled 1074 patients including 270 with T1, 215 with T2, 479 with T3 and 110 with T4. Age, sex and Charlson Comorbidity Index were not significantly different among the four stages. A low clinical T stage was associated with minimally‐invasive surgery (P < 0.001). The blood transfusion rate, anesthesia time, postoperative length of stay and total cost increased significantly with increasing clinical T stage (all P < 0.001). Multivariable regression analyses showed that increasing clinical T stage was significantly associated with unfavorable perioperative outcomes except in‐hospital mortality (T4/T1: postoperative complications OR 2.34; blood transfusion OR 5.27; anesthesia time +14%; postoperative length of stay +13.2%; total cost +13.4%; all P < 0.05). Clinical N stage was the only significant predictive factor for in‐hospital mortality (N1/N0: OR 3.34, P = 0.004; N2/N0: OR 3.48, P = 0.008).ConclusionsClinical T stage is significantly associated with perioperative outcomes, other than in‐hospital mortality, in patients with metastatic renal call carcinoma undergoing cytoreductive nephrectomy. Clinical N stage is significantly associated with in‐hospital mortality.
Prevalence of antimicrobial resistance in normal rectal flora of patients undergoing transrectal ultrasonography‐guided prostate biopsy in Korea
Authors: Lee Jea Whan , Park Seung Chol , Kim Myung Ki , Cheon Min Woo , Kim Ga Young , Cho Ji‐Hyun 
Published: April 2014

ObjectivesTo determine the prevalence of antimicrobial resistance in the normal rectal flora of patients undergoing transrectal ultrasonography‐guided prostate biopsy in Korea.MethodsBetween May 2010 and October 2010, rectal swabs were cultured from patients before transrectal ultrasonography‐guided prostate biopsy in three tertiary referral centers of Jeonbuk Province, Korea. Rectal swabs were collected using cotton‐tipped culture swabs in a standard collection system immediately before prostate biopsy. The swabs were cultured on eosin methylene blue and McConkey agar at 37°C. Antimicrobial sensitivity tests were carried out according to National Committee for Clinical Laboratory Standards guidelines.ResultsOf the 160 patients who had a rectal swab taken before prostate biopsy, microorganisms were isolated in 125 patients. Escherichia coli was isolated from the rectal swabs of 95 patients. The mean age was 68.1 years, the median serum prostate specific antigen was 5.6 ng/mL and the mean prostate volume measured by transrectal ultrasonography was 43.8 mL. Of the E. coli, 33.7%, 29.1%, 26.7%, 23.3%, 12.8%, 9.3%, 5.8%, 1.2% and 0% were resistant to ampicillin, piperacillin, levofloxacin, trimethoprim sulfamethoxazole, gentamicin, cephalothin, cefotaxim, amikacin and meropenem, respectively.ConclusionsThere is a high level of resistance to ciprofloxacin and ampicillin, and a very low level of resistance to amikacin in the E. coli in the bowel flora. The prevalence of resistance to ciprofloxacin in Korea is significantly higher than that reported in Western countries.
Relationship between plasma melatonin levels and the efficacy of selective serotonin reuptake inhibitors treatment on premature ejaculation
Authors: Kirecci Sinan Levent , Simsek Abdulmuttalip , Gurbuz Zafer Gokhan , Mimaroglu Saban , Yuksel Alpaslan , Vural Pervin , Degirmencioglu Suzan 
Published: April 2014

ObjectivesTo examine the relationship between premature ejaculation and plasma melatonin levels, and assess the efficacy of selective serotonin reuptake inhibitors in treating premature ejaculation.MethodsA total of 60 men with lifelong premature ejaculation and 40 healthy male controls were included in the present study. For each participant, a medical history was obtained, a physical examination was carried out, and intravaginal ejaculation latency time and melatonin levels were measured. Premature ejaculation patients were randomly categorized into three treatment groups: group 1 received fluoxetine (20 mg/day), group 2 received paroxetine (20 mg/day) and group 3 received sertraline (50 mg/day).ResultsThe mean baseline plasma melatonin levels in men with premature ejaculation were significantly lower than in the healthy controls (5.34 vs 14.84 pg/mL). After 4 weeks of treatment, the mean intravaginal ejaculation latency time scores for all of the premature ejaculation treatment groups showed a significant improvement from the baseline values. The plasma melatonin levels were also significantly increased (P < 0.05) from baseline (5.34 pg/mL) to 9.50 pg/mL, 10.24 pg/mL or 13.30 pg/mL for groups 1, 2 and 3, respectively.ConclusionsOur findings show that premature ejaculation is associated with decreased plasma melatonin levels. After treatment with selective serotonin reuptake inhibitors, an increased plasma melatonin level can retard ejaculation, presumably by both central and peripheral mechanisms. This is the first study to evaluate the possible role of serotoninergic interactions on the melatoninergic system in premature ejaculation.
The importance of regulatory T‐cell heterogeneity in maintaining self‐tolerance
Authors: Yuan Xiaomei , Cheng Guoyan , Malek Thomas R. 
Published: April 2014

SummaryCD4+ Forkhead box protein 3 (Foxp3)+ regulatory T cells (Tregs) are the major cell type that mediates dominant tolerance in the periphery. Over the past decade, extensive study of Tregs has revealed that these cells express substantial heterogeneity to maintain tolerance and regulate immune responses. Tregs possess heterogeneity with respect to their origin and processes for development, functional activity, migratory pattern, and activation status. Some of the same environmental cues and molecular pathways utilized to generate specialized T‐effector cells are also integrated by Tregs to colocalize and fine‐tune suppressive mechanisms to optimally regulate and restrain distinctive self and antigen‐specific T‐cell responses. Here, we review our current understanding and significance of Treg heterogeneity in maintaining peripheral immune tolerance. We also highlight recent work from our laboratory that has studied the extent phenotypically distinct Treg subsets are related to each other and expand in an ordered fashion to give rise to highly activated short‐lived Klrg1+ suppressor cells to optimize immune regulation and maintain homeostasis of the Treg compartment.
Homeostasis and function of regulatory T cells (Tregs) in vivo: lessons from TCR‐transgenic Tregs
Authors: Attridge Kesley , Walker Lucy S. K. 
Published: April 2014

SummaryThe identification of CD25 and subsequently Forkhead box protein 3 (Foxp3) as markers for regulatory T cells (Tregs) has revolutionized our ability to explore this population experimentally. In a similar vein, our understanding of antigen‐specific Treg responses in vivo owes much to the fortuitous generation of T‐cell receptor (TCR)‐transgenic Tregs. This has permitted tracking of Tregs with a defined specificity in vivo, facilitating analysis of how encounter with cognate antigen shapes Treg homeostasis and function. Here, we review the key lessons learned from a decade of analysis of TCR‐transgenic Tregs and set this in the broader context of general progress in the field. Use of TCR‐transgenic Tregs has led to an appreciation that Tregs are a highly dynamic proliferative population in vivo, rather than an anergic population as they were initially portrayed. It is now clear that Treg homeostasis is positively regulated by encounter with self‐antigen expressed on peripheral tissues, which is likely to be relevant to the phenomenon of peripheral repertoire reshaping that has been described for Tregs and the observation that the Treg TCR specificities vary by anatomical location. Substantial evidence has also accumulated to support the role of CD28 costimulation and interleukin‐2 in Treg homeostasis. The availability of TCR‐transgenic Tregs has enabled analysis of Treg populations that are sufficient or deficient in particular genes, without the comparison being confounded by repertoire alterations. This approach has yielded insights into genes required for Treg function in vivo, with particular progress being made on the role of ctla‐4 in this context. As the prospect of manipulating Treg populations in the clinic becomes reality, a full appreciation of the rules governing their homeostasis will prove increasingly important.