Miracle-dz/UniFAR-FTUs huggingface dataset:
Burial of the Polymorphic Residue 129 in Amyloid Fibrils of Prion Stop Mutants*

Background: In human prion diseases, the phenotype is modified by a methionine/valine polymorphism at codon 129. Results: Prion stop mutants have a conserved amyloid core comprising residue 129. Conclusion: The polymorphic residue 129 is buried in the amyloid core structure. Significance: The data support a critical role of the methionine/valine 129 polymorphism in human prion diseases. Misfolding of the natively α-helical prion protein into a β-sheet rich isoform is related to various human diseases such as Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker syndrome. In humans, the disease phenotype is modified by a methionine/valine polymorphism at codon 129 of the prion protein gene. Using a combination of hydrogen/deuterium exchange coupled to NMR spectroscopy, hydroxyl radical probing detected by mass spectrometry, and site-directed mutagenesis, we demonstrate that stop mutants of the human prion protein have a conserved amyloid core. The 129 residue is deeply buried in the amyloid core structure, and its mutation strongly impacts aggregation. Taken together the data support a critical role of the polymorphic residue 129 of the human prion protein in aggregation and disease.
Rationale for Poly(ADP-ribose) Polymerase (PARP) Inhibitors in Combination Therapy with Camptothecins or Temozolomide Based on PARP Trapping versus Catalytic Inhibition

We recently showed that poly(ADP-ribose) polymerase (PARP) inhibitors exert their cytotoxicity primarily by trapping PARP-DNA complexes in addition to their NAD+-competitive catalytic inhibitory mechanism. PARP trapping is drug-specific, with olaparib exhibiting a greater ability than veliparib, whereas both compounds are potent catalytic PARP inhibitors. Here, we evaluated the combination of olaparib or veliparib with therapeutically relevant DNA-targeted drugs, including the topoisomerase I inhibitor camptothecin, the alkylating agent temozolomide, the cross-linking agent cisplatin, and the topoisomerase II inhibitor etoposide at the cellular and molecular levels. We determined PARP-DNA trapping and catalytic PARP inhibition in genetically modified chicken lymphoma DT40, human prostate DU145, and glioblastoma SF295 cancer cells. For camptothecin, both PARP inhibitors showed highly synergistic effects due to catalytic PARP inhibition, indicating the value of combining either veliparib or olaparib with topoisomerase I inhibitors. On the other hand, for temozolomide, PARP trapping was critical in addition to catalytic inhibition, consistent with the fact that olaparib was more effective than veliparib in combination with temozolomide. For cisplatin and etoposide, olaparib only showed no or a weak combination effect, which is consistent with the lack of involvement of PARP in the repair of cisplatin- and etoposide-induced lesions. Hence, we conclude that catalytic PARP inhibitors are highly effective in combination with camptothecins, whereas PARP inhibitors capable of PARP trapping are more effective with temozolomide. Our study provides insights in combination treatment rationales for different PARP inhibitors.
Unemployment in TB Patients – Ten-Year Observation at Regional Center of Pulmonology in Bydgoszcz, Poland

Background Tuberculosis (TB) affects the poorest of the poor and is an example of a disease that can contribute to the “disease-poverty trap”. The variable epidemiological situation is associated with social risk factors, such as unemployment, which may favor the occurrence of this disease. The aim of this study was to analyze unemployment as a factor that can influence the incidence and course of the disease. Material/Methods We analyzed TB patients with confirmed status of employment or unemployment admitted to the Regional Center of Pulmonology in Bydgoszcz in during the years 2001 to 2010. Out of 1130 patients, 604 were unemployed and the other confirmed their employment. Results The unemployed patients were mostly single men over age 40, with a low level of education, and living in a city. We observed that the proportions of smokers and alcohol abusers were significantly higher among the unemployed patients. The advanced radiological lesions, smear-positive pulmonary TB, and extra-pulmonary sites were diagnosed significantly more often in this group. The rate of death in the course of hospitalization was significantly higher in the group of unemployed patients. Conclusions Unemployment among TB patients is a serious problem. We found that more advanced radiological lesions were associated with more frequent treatment interruptions and a higher rate of death in the course of hospitalization. Increased efforts are needed to reduce and eliminate the problem of unemployment among patients with TB. This may, indirectly, contribute to a decrease in notifications of TB cases and improve treatment outcomes.
Terminological Cycles in a Description Logic with Existential Restrictions

The Myerson-Satterthwaite theorem is a foundational impossibility result in mechanism design which states that no mechanism can be Bayes-Nash incentive compatible, individually rational, and not run a deficit. It holds universally for priors that are continuous, gapless, and overlapping. Using automated mechanism design, we investigate how often the impossibility occurs over discrete valuation domains. While the impossibility appears to hold generally for settings with large numbers of possible valuations (approaching the continuous case), domains with realistic valuation structure circumvent the impossibility with surprising frequency. Even if the impossibility applies, the amount of subsidy required to achieve individual rationality and incentive compatibility is relatively small, even over large unstructured domains.
Tracking multiple objects in complex scenes

Automatic video surveillance-based security is one of the most dynamically developing segment of the security industry. There has been a large progress of related vision hardware in the recent years, however, methods used to detect and monitor moving objects still lack the robustness to handle specific events occurring in complex scenes. In this paper we propose an algorithm to resolve occlusion events based on the smoothness constraint of kinematic and color features. The methods are tested using two images sequences and qualitative results are presented in terms of the accuracy and stability of obtained trajectories.
Energy is just another resource: energy accounting and energy pricing in the Nemesis OS

In this paper, we argue that, with an appropriate operating system structure, energy in mobile computers can be treated and managed as just another resource. In particular, we investigate how energy management could be added to the Nemesis OS which provides detailed and accurate resource accounting capabilities in order to provide Quality of Service (QoS) guarantees for all resources to applications. We argue that, with such an operating system, accounting of energy to individual processes can be achieved. Furthermore, we investigate how an economic model, proposed for congestion avoidance in computer network, and recently applied to CPU resource management, can be used as a dynamic, decentralised energy management system, forming a collaborative environment between operating system and applications.
Trimipramine pharmacokinetics after intravenous and oral administration in carriers of CYP2D6 genotypes predicting poor, extensive and ultrahigh activity.

OBJECTIVE The tricyclic antidepressant trimipramine is one of the drugs with the most pronounced differences in pharmacokinetics caused by the CYP2D6 genetic polymorphism. However, the effect of CYP2D6 genotype on steady state kinetics and on bioavailability has not been studied so far. In addition, we were interested in trimipramine pharmacokinetics in genetically defined ultra rapid metabolizers. METHODS We studied intravenous and multiple dose oral application of 50 mg trimipramine in five, seven, and three healthy volunteers with CYP2D6 genotypes predicting deficient, highly active and ultrarapid metabolism. The latter group included carriers of one wild-type and one duplication allele. Trimipramine and desmethyltrimipramine concentrations were measured by HPLC over a time interval of 72 h after intravenous and after one oral application. RESULTS Both bioavailability and systemic clearance significantly depended on CYP2D6 genotype with a linear gene dose relationship. Mean bioavailability was 44, 16 and 12% in carriers of zero, two and three active genes of CYP2D6, respectively, and the corresponding data for systemic clearance were 12.0, 24.2, and 30.3 l/h. Consequently, the mean total oral clearances were 27.3, 151, and 253 l/h in poor, extensive and ultrarapid metabolizers. CONCLUSIONS High bioavailability combined with low systemic clearance of trimipramine in poor metabolizers of CYP2D6 substrates results in a very high exposure to trimipramine with the risk of adverse drug reactions. On the other hand, the extremely high systemic and presystemic elimination may result in sub-therapeutic drug concentrations in carriers of CYP2D6 gene duplications with a high risk of poor therapeutic response.
Carbon Stocks of Tropical Coastal Wetlands within the Karstic Landscape of the Mexican Caribbean

Coastal wetlands can have exceptionally large carbon (C) stocks and their protection and restoration would constitute an effective mitigation strategy to climate change. Inclusion of coastal ecosystems in mitigation strategies requires quantification of carbon stocks in order to calculate emissions or sequestration through time. In this study, we quantified the ecosystem C stocks of coastal wetlands of the Sian Ka'an Biosphere Reserve (SKBR) in the Yucatan Peninsula, Mexico. We stratified the SKBR into different vegetation types (tall, medium and dwarf mangroves, and marshes), and examined relationships of environmental variables with C stocks. At nine sites within SKBR, we quantified ecosystem C stocks through measurement of above and belowground biomass, downed wood, and soil C. Additionally, we measured nitrogen (N) and phosphorus (P) from the soil and interstitial salinity. Tall mangroves had the highest C stocks (987±338 Mg ha−1) followed by medium mangroves (623±41 Mg ha−1), dwarf mangroves (381±52 Mg ha−1) and marshes (177±73 Mg ha−1). At all sites, soil C comprised the majority of the ecosystem C stocks (78–99%). Highest C stocks were measured in soils that were relatively low in salinity, high in P and low in N∶P, suggesting that P limits C sequestration and accumulation potential. In this karstic area, coastal wetlands, especially mangroves, are important C stocks. At the landscape scale, the coastal wetlands of Sian Ka'an covering ≈172,176 ha may store 43.2 to 58.0 million Mg of C.
RAPID ADAPTATION TO SOCIAL CHANGE IN CENTRAL EUROPE: CHANGES IN LOCUS OF CONTROL, ATTRIBUTION, SUBJECTIVE WELL-BEING, SELF-DIRECTION, AND TRUST

Rapid Adaptation to Social Change in Central Europe: Changes in Locus of Control, Attribution, Subjective Well-Being, Self-Direction, and Trust. This paper reviews research examining the impact of political and economic transition in post-communist Central European countries on social psychological processes. While other aspects of democratization in Central Europe have been well documented, only recently have social psychologists turned their attention to this event. Since the collapse of communism, Central Europeans have a more internal sense of control and make more dispositional attributions for others’ behaviour. After initial declines in subjective well-being during the first decade of the post-communist period, Central Europeans now have higher levels of well-being then they did at the beginning of the post-communist period. Central Europeans have also become more self-directed and have higher levels of general trust since the end of communism. Taken together these findings suggest that Central Europeans are unique in how quickly and successfully they have adapted to the rapid and massive institutional, political, economic, and social changes that accompanied democratization. Sociológia 2008, Vol. 40 (No. 3: 215-235)
Predicting Acute Ischaemic Stroke Outcome Using Clinical and Temporal Thresholds

Background. Few studies have analysed the natural course of cerebral ischaemia for predicting outcome. We aimed to determine the early clinical findings and the thresholds for deficit severity and symptom duration that make it possible to stratify outcome. Methods. We included 154 patients with transient ischaemic attack or ischaemic stroke. Stroke profiles and neurological status were assessed from onset to 24 hrs, on admission, at 48 hrs, and at discharge. Outcomes were evaluated using the modified Rankin Scale. Positive and negative predictive values were calculated for the different thresholds. The model was subsequently evaluated on a new prospective cohort of 157 patients. Results. Initial National Institute of Health Stroke Scale (NIHSS) score <5 and symptoms regressing within 135 min were predictive of good outcome. Initial NIHSS score >22 and symptom stability after 1,230 min were predictive of physical dependency or death. Conclusions. Low and high NIHSS cut-off points are effective positive predictive values for good and poor outcomes. Thresholds for symptom duration are less conclusive.
Eosinophilic inflammation in COPD: prevalence and clinical characteristics

To the Editor: Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, with patients displaying varying clinical and pathophysiological features. The identification of COPD phenotypes with distinct characteristics may allow targeted treatment strategies directed towards specific biological pathways. Eosinophilic inflammation is thought to be a characteristic feature of asthma rather than COPD. However, studies have shown that a subset of COPD patients with eosinophilic airway inflammation exists, even after the careful exclusion of patients with any features of asthma, such as β-agonist reversibility, bronchial hyperresponsiveness, atopy or a childhood history of asthma [1–4]. Interestingly, these patients exhibit the greatest response to corticosteroid treatment [1–4]. Likewise, sputum eosinophil numbers are increased in a subset of COPD exacerbations [5, 6], and titrating corticosteroid therapy according to sputum eosinophil counts reduces exacerbation rates [7]. Furthermore, there are similar increases in sputum and blood eosinophil numbers during COPD exacerbations [5]; using blood eosinophils as a surrogate maker for airway eosinophils to direct oral corticosteroid therapy for the treatment of COPD exacerbations enhances clinical recovery [8]. Taken together, these observations suggest that eosinophilic airway inflammation in COPD is a predictive biomarker of corticosteroid responsiveness during clinical stability and exacerbations. The prevalence of eosinophilic inflammation in COPD patients is unknown. We do not know whether patients with sputum or blood eosinophilia represent a stable COPD phenotype over time and, apart from corticosteroid responsiveness, little is known about the other clinical characteristics of this subset of patients. We analysed samples from the ECLIPSE (Evaluation of COPD Longitudinally to Identify …
PARABLE: A PArallel RAndom-partition Based HierarchicaL ClustEring Algorithm for the MapReduce Framework

Large datasets, of the order of petaand terabytes, are becoming prevalent in many scientific domains including astronomy, physical sciences, bioinformatics and medicine. To effectively store, query and analyze these gigantic repositories, parallel and distributed architectures have become popular. Apache Hadoop is one such framework for supporting data-intensive applications. It provides an open source implementation of the MapReduce programming paradigm which can be used to build scalable algorithms for pattern analysis and data mining. In this paper, we present a PArallel, RAndom-partition Based hierarchicaL clustEring algorithm (PARABLE) for the MapReduce framework. It proceeds in two main steps – local hierarchical clustering on nodes using mappers and reducers and integration of results by a novel dendrogram alignment technique. Empirical results on two large data sets (High Energy Particle Physics and Intrusion Detection) from the KDDCup competition on a large cluster indicates that significant scalability benefits can be obtained by using the parallel hierarchical clustering algorithm in addition to maintaining good cluster quality.
Implementation of epidural analgesia for labor: is the standard of effective analgesia reachable in all women? An audit of two years.

BACKGROUND Social and cultural factors combined with little information may prevent the diffusion of epidural analgesia for pain relief during childbirth. The present study was launched contemporarily to the implementation of analgesia for labor in our Department in order to perform a 2 years audit on its use. The goal is to evaluate the epidural acceptance and penetration into hospital practice by women and care givers and safety and efficacy during childbirth. PATIENTS AND METHODS This audit cycle measured epidural analgesia performance against 4 standards: (1) Implementation of epidural analgesia for labor to all patients; (2) Acceptance and good satisfaction level reported by patients and caregivers. (3) Effectiveness of labor analgesia; (4) No maternal or fetal side effects. RESULTS During the audit period epidural analgesia increased from 15.5% of all labors in the first trimester of the study to 51% in the last trimester (p < 0.005). Satisfaction levels reported by patients and care givers were good. A hierarchical clustering analysis identified two clusters based on VAS (Visual Analogue Scale) time course: in 226 patients (cluster 1) VAS decreased from 8.5±1.4 before to 4.1±1.3 after epidural analgesia; in 1002 patients (cluster 2) VAS decreased from 8.12±1.7 before (NS vs cluster 1), to 0.76±0.79 after (p < 0.001 vs before and vs cluster 2 after). No other differences between clusters were observed. CONCLUSIONS Present audit shows that the process of implementation of labor analgesia was quick, successful and safe, notwithstanding the identification of one cluster of women with suboptimal response to epidural analgesia that need to be further studies, overall pregnant womens'adhesion to labor analgesia was satisfactory.
Criminal behavior in frontotemporal dementia and Alzheimer disease.

IMPORTANCE Neurodegenerative diseases can cause dysfunction of neural structures involved in judgment, executive function, emotional processing, sexual behavior, violence, and self-awareness. Such dysfunctions can lead to antisocial and criminal behavior that appears for the first time in the adult or middle-aged individual or even later in life. OBJECTIVE To investigate the frequency and type of criminal behavior among patients with a diagnosed dementing disorder. DESIGN, SETTING, AND PARTICIPANTS We conducted a retrospective medical record review of 2397 patients who were seen at the University of California, San Francisco, Memory and Aging Center between 1999 and 2012, including 545 patients with Alzheimer disease (AD), 171 patients with behavioral variant of frontotemporal dementia (bvFTD), 89 patients with semantic variant of primary progressive aphasia, and 30 patients with Huntington disease. Patient notes containing specific keywords denoting criminal behavior were reviewed. Data were stratified by criminal behavior type and diagnostic groups. MAIN OUTCOMES AND MEASURES Frequencies of criminal behavior and χ² statistics were calculated. RESULTS Of the 2397 patients studied, 204 (8.5%) had a history of criminal behavior that emerged during their illness. Of the major diagnostic groups, 42 of 545 patients (7.7%) with AD, 64 of 171 patients (37.4%) with bvFTD, 24 of 89 patients (27.0%) with semantic variant of primary progressive aphasia, and 6 of 30 patients (20%) with Huntington disease exhibited criminal behavior. A total of 14% of patients with bvFTD were statistically significantly more likely to present with criminal behavior compared with 2% of patients with AD (P < .001) and 6.4% were statistically significantly more likely to exhibit violence compared with 2% of patients with AD (P = .003). Common manifestations of criminal behavior in the bvFTD group included theft, traffic violations, sexual advances, trespassing, and public urination in contrast with those in the AD group, who commonly committed traffic violations, often related to cognitive impairment. CONCLUSIONS AND RELEVANCE Criminal behavior is more common in patients with bvFTD and semantic variant of primary progressive aphasia than in those with AD and is more likely to be an early manifestation of the disorder. Judicial evaluations of criminality in the demented individual might require different criteria than the classic "insanity defense" used in the American legal system; these individuals should be treated differently by the law. The appearance of new-onset criminal behavior in an adult should elicit a search for frontal and anterior temporal brain disease and for dementing disorders.
Lithospheric structure under the western African‐European plate boundary: A transect across the Atlas Mountains and the Gulf of Cadiz

We present a two‐dimensional lithospheric thermal and density model along a transect running from the southwestern Iberian Peninsula to the northwestern Sahara. The main goal is to investigate the lithosphere structure underneath the Gulf of Cadiz and the Atlas Mountains. The model is based on the assumption of topography in local isostatic equilibrium and is constrained by surface heat flow, gravity anomalies, geoid, and topography data. The crustal structure has been constrained by seismic and geological data where available. Mantle density is supposed to vary linearly with temperature, providing the link between thermal and density‐related data. The lithospheric thickness varies strongly along the profile, going from near 100 km under the Iberian Peninsula to at least 160–190 km under the Gulf of Cadiz and the Gharb foreland basin in Morocco and to 70 km underneath the Atlas Mountains, coinciding with a region of Neogene volcanism. The thickening of the lithosphere is interpreted as a SW trending lithospheric slab extending from the western Betics to the Gulf of Cadiz and the Gharb Basin, whereas the thin lithosphere underneath the Atlas may be interpreted as plume‐like asthenospheric upwelling similar to those observed in the west European Alpine foreland or as a side effect of a slab penetrating the less viscous asthenosphere.