Miracle-dz/UniFAR-FTUs huggingface dataset:
Telomerase down‐regulation does not mediate PC12 pheochromocytoma cell differentiation induced by NGF, but requires MAP kinase signalling

Telomerase is a ribonucleoprotein complex that maintains chromosomal telomere homeostasis and underlies continuous renewal of stem cells and immortalization of neoplastic cells. Telomerase is down‐regulated during cell differentiation, but the mechanisms of down‐regulation are largely unknown. Here, we examined roles of mitogen‐activated protein (MAP) kinase and phosphatidylinositol‐3 (PI3) kinase signalling pathways in telomerase down‐regulation triggered by nerve growth factor (NGF), and the role of telomerase down‐regulation in NGF‐induced neural differentiation in PC12 cells. We report that NGF‐induced telomerase down‐regulation requires MAP kinase signalling. While mutations of all putative Akt phosphorylation sites in telomerase reverse transcriptase (TERT) has no effect on telomerase activity, inhibition of MAP kinase signalling by PD98059 or U0126 abolishes NGF‐induced telomerase down‐regulation in a concentration‐dependent manner. Reversal of NGF‐induced telomerase down‐regulation by TERT overexpression does not prevent NGF‐induced neural differentiation. Down‐regulation of telomerase by silencing TERT gene expression does not trigger cell differentiation in the absence of NGF, nor enhances NGF‐induced differentiation. Thus, telomerase, withdraws by a mechanism at TERT gene transcription level involving MAP kinase signalling while cells cease proliferation and undergo differentiation. The withdrawal of telomerase is not required to mediate NGF‐induced PC12 cell differentiation and re‐establishment of telomerase activity at significant levels does not inhibit differentiation.
Autonomy or integration? Small-state responses to a changing European security landscape

ABSTRACT In this special issue, we examine whether there is a pattern in how small European states, inside and outside of the European Union (EU), adapt and adjust to EU foreign and security policy. We assess selected European small states’ room for manoeuvre within these fields, and within EU institutional structures more broadly, as part of everyday diplomatic interactions in Brussels and in the context of the rotating EU presidency. As the European integration process enters a new phase, possibly marked by a trend of more differentiated integration and flexibility of individual attachments, small states will continue to face the choice between formal autonomy and integration, and between de facto hesitance and adaptability. With Brexit, the remaining large states may become more influential, but small states will collectively have a majority of the votes and total population. Perhaps the coming era of European integration will become the era of small states.
Mutational analysis of the neurexin/neuroligin complex reveals essential and regulatory components

Neurexins are cell-surface molecules that bind neuroligins to form a heterophilic, Ca2+-dependent complex at central synapses. This transsynaptic complex is required for efficient neurotransmission and is involved in the formation of synaptic contacts. In addition, both molecules have been identified as candidate genes for autism. Here we performed mutagenesis experiments to probe for essential components of the neurexin/neuroligin binding interface at the single-amino acid level. We found that in neurexins the contact area is sharply delineated and consists of hydrophobic residues of the LNS domain that surround a Ca2+ binding pocket. Point mutations that changed electrostatic and shape properties leave Ca2+ coordination intact but completely inhibit neuroligin binding, whereas alternative splicing in α- and β-neurexins and in neuroligins has a weaker effect on complex formation. In neuroligins, the contact area appears less distinct because exchange of a more distant aspartate completely abolished binding to neurexin but many mutations of predicted interface residues had no strong effect on binding. Together with calculations of energy terms for presumed interface hot spots that complement and extend our mutagenesis and recent crystal structure data, this study presents a comprehensive structural basis for the complex formation of neurexins and neuroligins and their transsynaptic signaling between neurons.
Association of metabolic syndrome traits and severity of kidney stones: results from a nationwide survey on urolithiasis in Japan.

BACKGROUND Although metabolic syndrome and its individual components have been associated with kidney stone disease, whether the clustering of metabolic syndrome traits increases the severity of kidney stone disease has not been examined in a large-scale study. STUDY DESIGN Cross-sectional analysis. SETTING & PARTICIPANTS Data were obtained from 30,448 patients enrolled in the 6th Nationwide Survey on Urolithiasis in Japan conducted in 2005. Patients with lower urinary tract stones, struvite stones, cystine stones, or hyperparathyroidism and those younger than 15 years were excluded. PREDICTOR Number of metabolic syndrome traits (obesity [body mass index ≥25 kg/m(2)], diabetes, hypertension, and dyslipidemia). OUTCOMES Severe form of kidney stone disease, defined as recurrent and/or multiple stones, and abnormalities in urine constituents (hypercalciuria, hyperuricosuria, hyperoxaluria, and hypocitraturia). RESULTS 11,555 patients were included in the final analyses. Proportions of patients with recurrent and/or multiple stones were 57.7%, 61.7%, 65.2%, 69.3%, and 73.3% with 0, 1, 2, 3, and 4 metabolic syndrome traits, respectively (P < 0.001). There was a significant and stepwise increase in the odds of recurrent and/or multiple stones after adjustment for age and sex. In patients with 4 metabolic syndrome traits, the odds was 1.8-fold greater compared with patients with 0 traits (OR, 1.78; 95% CI, 1.22-2.66). In addition, the presence of metabolic syndrome traits was associated with significantly increased odds of having hypercalciuria, hyperuricosuria, hyperoxaluria, and hypocitraturia after adjustment for age and sex. LIMITATIONS Cross-sectional design, absence of dietary data, ill-defined diagnostic criteria for metabolic syndrome traits, and missing data for the majority of participants. CONCLUSIONS Metabolic syndrome trait clustering is associated with greater severity of kidney stone disease; increased urinary calcium, uric acid, and oxalate excretion; and decreased urinary citrate excretion. These results suggest that kidney stone disease should be regarded as a systemic disorder linked to metabolic syndrome.
The coming community. The politics of alternative food networks in Southern Italy

ABSTRACT Sociologists and political scientists suggest that community is increasingly lacking in contemporary life. At the same time, consumer researchers have long suggested that brands and commodities can act as a source of community and ethics. In recent years a number of communitarian productive networks have emerged in sectors like food, software, fashion, design and social enterprise. Such communities of commons-based peer production have transformed the role of consumer communities by making communitarian relations count also in the material production of goods and services. In this paper we examine the ‘neorural’ communitarian networks located in Southern Italy. We suggest that the creation of community around high quality, ‘authentic’ agricultural produce serves a dual role. On the one hand such communities singularise agricultural products and enable them to acquire market value as goods. At the same time, communities provide space for a new politics of things oriented towards pragmatic social transformation and the creation of ontological security in a world understood to be highly contingent.
The changing context of energy generation and supply : the case study of Georgia

There is now extensive academic and policy literature on pressures to rethink prevailing logics of energy governance in response to a range of, challenges and opportunities from factors including, carbon reduction, concerns about the security of imported oil and gas, the exploitation of new fuel reserves, continued opposition to nuclear energy and new agendas of decentralised energy generation. Decarbonisation is a key element of those debates about a new energy governance reflecting the influence of carbon policy in the present and the future. The new energy governance is affecting many countries. This thesis focuses on the changing context for energy governance, and especially electricity generation and supply in the USA. Electricity generation is selected as the primary focus in order to explore factors such as new models of decentralised energy generation. The thesis presents an in-depth case study of the state of Georgia, and especially the changing strategies for the state energy provider, Georgia Power in response to changing economic and environmental imperatives in electricity generation and supply and lobbying from a range of key stakeholders. The case study is based on 25 interviews with key stakeholders, including Georgia Power officials, state energy regulators (public service commissioners), federal, regional and state agency representatives, industrial associations, clean energy businesses, environmental and consumer advocates and political organisations. The case study focuses on a range of key issues that mark tensions in the transition from the prevailing mode of energy governance, notably developing federal regulations, pressure for decentralisation and new nuclear development. The thesis makes a number of key contributions to literature and debate on energy governance. By providing in-depth investigation of a context for energy transition/new energy governance that has not previously been researched, revealing new bottom up coalitions for decentralised supply and the importance of electricity pricing in influencing policy decisions.
Prediction of Short-Term Cardiovascular Events Using Quantification of Global Myocardial Flow Reserve in Patients Referred for Clinical 82Rb PET Perfusion Imaging

Current noninvasive tests for coronary artery disease detect atherosclerosis or regional ischemia. Global myocardial flow reserve is not routinely identified, although it may be an additional marker of disease development and progression. Methods: For the clinical work-up of suspected or known stable coronary artery disease, 275 individuals had undergone rest–dipyridamole 82Rb myocardial perfusion imaging using PET. In addition to clinical measures of regional perfusion and function, an experimentally validated approach to quantify global myocardial flow reserve was used. Follow-up was obtained for 362 ± 277 d. Results: Myocardial blood flow and flow reserve showed significant correlation to systemic and cardiac hemodynamics and a weak association with risk factors such as age and history of hyperlipidemia. Flow reserve was expectedly lower in subjects with regional ischemia (1.70 ± 0.65 vs. 2.31 ± 0.97 in those without; P < 0.0001), but a wide range was observed in those without regional perfusion abnormalities. We used a composite endpoint of hard and soft events to determine that flow reserve below the median was predictive of adverse outcome in the overall population (P = 0.001) and in subjects with normal regional perfusion (n = 178; P = 0.036), whereas stress flow was predictive only in the overall population (P = 0.001). Age-adjusted multivariate analysis confirmed regional perfusion defects (relative hazard, 2.51; 95% confidence interval, 1.24–5.10; P = 0.009) and low global flow reserve (relative hazard, 2.93; 95% confidence interval, 1.30–6.65; P = 0.011) as independent predictors of cardiac events. Conclusion: In clinical cardiac 82Rb PET, globally impaired flow reserve is a relevant marker for predicting short-term cardiovascular events. It may be used for integration with currently established functional and morphologic test results and for guidance of preventive measures, especially in the absence of regional flow–limiting disease.
Dentatorubral‐pallidoluysian atrophy in three generations, with clinical courses from nearly asymptomatic elderly to severe juvenile, in an Australian family of Macedonian descent

We report a three‐generation Caucasian family of Macedonian origin with dentatorubral‐pallidoluysian atrophy (DRPLA), manifesting as very mild elderly onset, severe young adult onset, and severe childhood onset presentations in the three generations. The grandparental trinucleotide expansion size (52 repeats) is the smallest overtly pathogenic mutation yet reported. This 67‐year‐old man displayed only subtle neurological and cognitive deficits on formal examination and very slight signs on MRI. His son had developed a choreiform disorder at age 32 years, and by his 40s suffered severe dementia and motor decline. The grandson, the proband, presented as a teenager with progressive myoclonic epilepsy, dysarthria, ataxia, and cognitive decline, having manifesting learning difficulties from the age 5 years. Atrophin‐1 expansion sizes of 52, 57, and 66 repeats were demonstrated in the three patients, respectively. Given an absence of any other indicative history in the family, we speculate that the mutation may have expanded from a ‘high‐end’ normal allele to a pathogenic size at the grandfather's conception, or that one of his parents may have had a pathogenic mutation at the lowest end of the expanded range. © 2005 Wiley‐Liss, Inc.
Insights from recent positron emission tomographic studies of drug abuse and dependence

Purpose of review Recent positron emission tomographic studies demonstrate a variety of abnormalities in the brains of addicted individuals. This review aims to discuss and highlight these findings. Recent findings The recent findings are as follows: (a) the reward response to an addictive substance is associated with increased dopamine release in the striatum. (b) Activation of the orbitofrontal region is involved in the reinforcing properties of a drug. (c) Behavioral, cognitive and affective abnormalities are associated with alterations in specific brain networks and regions (e.g., prefrontal cortices) in drug abusers. (d) Personality traits may play a role in the susceptibility to addiction and the brain's responses to drugs. (e) Sex-differences exist for cue-induced craving. (f) Several studies have confirmed decreased D2 receptors in drug users, which is associated with increased salience to drug cues. (g) Serotonergic transporters are decreased in the current users of 3,4-methylene-deoxy-methamphetamine but found normal in the past users of 3,4-methylene-deoxy-methamphetamine. Summary Abnormalities in the dopaminergic, opioid, and serotonergic systems in drug abusers are seen in positron emission tomography scans. Decreased D2 receptor densities in drug users, whether premorbid or the consequence of substance misuse, imply a source of the susceptibility to relapse of this population. Insights from these studies could lead to better treatment approaches targeting specific neurotransmitter systems.
Thermodynamic consequences of disrupting a water‐mediated hydrogen bond network in a protein:pheromone complex

The mouse pheromones (±)‐2‐sec‐butyl‐4,5‐dihydrothiazole (SBT) and 6‐hydroxy‐6‐methyl‐3‐heptanone (HMH) bind into an occluded hydrophobic cavity in the mouse major urinary protein (MUP‐1). Although the ligands are structurally unrelated, in both cases binding is accompanied by formation of a similar buried, water‐mediated hydrogen bond network between the ligand and several backbone and side chain groups on the protein. To investigate the energetic contribution of this hydrogen bond network to ligand binding, we have applied isothermal titration calorimetry to measure the binding thermodynamics using several MUP mutants and ligand analogs. Mutation of Tyr‐120 to Phe, which disrupts a hydrogen bond from the phenolic hydroxyl group of Tyr‐120 to one of the bound water molecules, results in a substantial loss of favorable binding enthalpy, which is partially compensated by a favorable change in binding entropy. A similar thermodynamic effect was observed when the hydrogen bonded nitrogen atom of the heterocyclic ligand was replaced by a methyne group. Several other modifications of the protein or ligand had smaller effects on the binding thermodynamics. The data provide supporting evidence for the role of the hydrogen bond network in stabilizing the complex.
Twelve weeks of treadmill exercise does not alter age‐dependent chronic kidney disease in the Fisher 344 male rat

Non‐technical summary In older people, the function of the kidney deteriorates, and one possible way to slow this process down is through exercise. Exercise increases the abundance of important enzymes that are needed for optimal vessel health and kidney function, for instance the nitric oxide synthase and superoxide dismutase (SOD) enzymes. It also reduces oxidative stress, a type of cellular injury caused by highly reactive molecules. When we compared young and old sedentary rats to young and old exercise‐trained (12 weeks treadmill) rats, we found that exercise was not effective in reversing the age‐related kidney changes. In old rats, renal function declined as did the abundance of the protective SOD enzymes, and oxidative stress increased; interestingly, exercise did not influence these changes. Our results suggest that the cardiovascular benefits of exercise do not necessarily extend to the kidney.
Gastrointestinal Hemorrhage after Acute Ischemic Stroke and Its Risk Factors in Asians

Background: The aim of this study was to examine the frequency and risk factors of gastrointestinal (GI) hemorrhage in acute ischemic stroke patients in Taiwan. Method: 920 patients admitted for acute ischemic stroke from January 2001 to October 2005 were included in the study. We reviewed the available medical records for any episode of GI hemorrhage, possible precipitating factors and administration of ulcer prophylaxis. Results: Seventy-two patients (7.8%) experienced GI hemorrhage; these patients were of an older age (74.7 vs. 69.0 years, p < 0.001), had a longer acute ward stay (30.4 vs. 12.9 days, p < 0.001) and higher mortality rate (odds ratio 9.61, CI 4.53–20.42) than patients without GI hemorrhage. In multivariate logistic regression analysis, the important risk factors of GI hemorrhage included sepsis, previous history of GI hemorrhage, severe stroke, renal insufficiency and abnormal liver function. Of the 779 patients who had a 0–1 risk factor, 26 (3.3%) experienced GI hemorrhage; of the 27 patients with more than 2 risk factors, 17 (63%) suffered GI hemorrhage. Conclusion: This study of Asians revealed a higher frequency of GI hemorrhage after acute ischemic stroke than that reported in previous studies, and the frequency of GI hemorrhage was positively correlated with the number of risk factors present. We suggest that identifying stroke patients with a high risk of hemorrhage may allow clinicians to set up ulcer prophylactic protocols for the patients most likely to benefit, especially in an Asian population.
Characterization of Nuclear Localization Signals (NLSs) and Function of NLSs and Phosphorylation of Serine Residues in Subcellular and Subnuclear Localization of Transformer-2β (Tra2β)*

Background: Subcellular localization of splicing factor Tra2β is closely related to its function. Results: NLSs in RS domains are required for Tra2β nuclear localization, while serine phosphorylation of the NLSs promotes Tra2β cytoplasmic accumulation. Conclusion: Serine phosphorylation has a competitive effect against the NLS directed-nuclear location of Tra2β. Significance: New insight into the molecular basis for phosphorylation-regulated Tra2β subcellular localization. The serine/arginine-rich (SR) proteins are one type of major actors in regulation of pre-mRNA splicing. Their functions are closely related to the intracellular spatial organization. The RS domain and phosphorylation status of SR proteins are two critical factors in determining the subcellular distribution. Mammalian Transformer-2β (Tra2β) protein, a member of SR proteins, is known to play multiple important roles in development and diseases. In the present study, we characterized the subcellular and subnuclear localization of Tra2β protein and its related mechanisms. The results demonstrated that in the brain the nuclear and cytoplasmic localization of Tra2β were correlated with its phosphorylation status. Using deletional mutation analysis, we showed that the nuclear localization of Tra2β was determined by multiple nuclear localization signals (NLSs) in the RS domains. The point-mutation analysis disclosed that phosphorylation of serine residues in the NLSs inhibited the function of NLS in directing Tra2β to the nucleus. In addition, we identified at least two nuclear speckle localization signals within the RS1 domain, but not in the RS2 domain. The nuclear speckle localization signals determined the localization of RS1 domain-contained proteins to the nuclear speckle. The function of the signals did not depend on the presence of serine residues. The results provide new insight into the mechanisms by which the subcellular and subnuclear localization of Tra2β proteins are regulated.
Comparison of the Fullerton Advanced Balance Scale, Mini-BESTest, and Berg Balance Scale to Predict Falls in Parkinson Disease

Background The correct identification of patients with Parkinson disease (PD) at risk for falling is important to initiate appropriate treatment early. Objective This study compared the Fullerton Advanced Balance (FAB) scale with the Mini-Balance Evaluation Systems Test (Mini-BESTest) and Berg Balance Scale (BBS) to identify individuals with PD at risk for falls and to analyze which of the items of the scales best predict future falls. Design This was a prospective study to assess predictive criterion-related validity. Setting The study was conducted at a university hospital in an urban community. Patients Eighty-five patients with idiopathic PD (Hoehn and Yahr stages: 1–4) participated in the study. Measurements Measures were number of falls (assessed prospectively over 6 months), FAB scale, Mini-BESTest, BBS, and Unified Parkinson's Disease Rating Scale. Results The FAB scale, Mini-BESTest, and BBS showed similar accuracy to predict future falls, with values for area under the curve (AUC) of the receiver operating characteristic (ROC) curve of 0.68, 0.65, and 0.69, respectively. A model combining the items “tandem stance,” “rise to toes,” “one-leg stance,” “compensatory stepping backward,” “turning,” and “placing alternate foot on stool” had an AUC of 0.84 of the ROC curve. Limitations There was a dropout rate of 19/85 participants. Conclusions The FAB scale, Mini-BESTest, and BBS provide moderate capacity to predict “fallers” (people with one or more falls) from “nonfallers. ” Only some items of the 3 scales contribute to the detection of future falls. Clinicians should particularly focus on the item “tandem stance” along with the items “one-leg stance,” “rise to toes,” “compensatory stepping backward,” “turning 360°,” and “placing foot on stool” when analyzing postural control deficits related to fall risk. Future research should analyze whether balance training including the aforementioned items is effective in reducing fall risk.