Miracle-dz/UniFAR-FTUs huggingface dataset:
Bacillus anthracis Edema Factor Substrate Specificity: Evidence for New Modes of Action

Since the isolation of Bacillus anthracis exotoxins in the 1960s, the detrimental activity of edema factor (EF) was considered as adenylyl cyclase activity only. Yet the catalytic site of EF was recently shown to accomplish cyclization of cytidine 5′-triphosphate, uridine 5′-triphosphate and inosine 5′-triphosphate, in addition to adenosine 5′-triphosphate. This review discusses the broad EF substrate specificity and possible implications of intracellular accumulation of cyclic cytidine 3′:5′-monophosphate, cyclic uridine 3′:5′-monophosphate and cyclic inosine 3′:5′-monophosphate on cellular functions vital for host defense. In particular, cAMP-independent mechanisms of action of EF on host cell signaling via protein kinase A, protein kinase G, phosphodiesterases and CNG channels are discussed.
A hardware/software framework for supporting transactional memory in a MPSoC environment

Manufacturers are focusing on multiprocessor-system-on-a-chip (MPSoC) architectures in order to provide increased concurrency, rather than increased clock speed, for both large-scale as well as embedded systems. Traditionally lock-based synchronization is provided to support concurrency; however, managing locks can be very difficult and error prone. In addition, the performance and power cost of lock-based synchronization can be high. Transactional memories have been extensively investigated as an alternative to lock-based synchronization in general-purpose systems. It has been shown that transactional memory has advantages over locks in terms of ease of programming, performance and energy consumption. However, their applicability to embedded multi-core platforms has not been explored yet. In this paper, we demonstrate a complete hardware transactional memory solution for an embedded multi-core architecture, consisting of a cache-coherent ARM-based cluster, similar to ARM's MPCore. Using cycle accurate power and performance models for the transactional memory hardware, we evaluate our architectural framework over a set of different system and application settings, and show that transactional memory is a promising solution, even for resource-constrained embedded multiprocessors.
Use of telemedicine in the European penitentiaries: current scenario and best practices

Background: Telemedicine has demonstrated to improve access and quality of health services in underserved area, curtailing the costs, therefore its application to the delivery of health care in prison would be desirable. Little is known about its use across European penal institutions. Our study aimed to assess the state of telemedicine within the European jails. Methods: To maximize data availability, we used two different approaches. A bottom-up approach was used by gathering information directly from prison directors of every single penal establishment of the 28 European members. A top-down approach was used to collect information from persons involved in prison administration or project leaders at national level. In both approaches questions were sent by mail. Results: Information gathered directly by contacting prison directors and/or persons in charge come from all the 28 EU members. In total, we contacted 211 prison directors and 116 persons in charge, with a total response rate of 67%. We have found that telemedicine, as additional healthcare delivery model, is used only in 11 countries, especially among members of Northern and Western Europe. Only Romania showed to have a pilot project for a nationwide program of telemedicine. Conclusions: Telemedicine services among European penitentiaries appear still poorly developed. Given the numerous and demonstrated advantages of this technology, it would be desirable to implement its utilization in penal healthcare and to integrate it in the routine services, as benefit not only for prison environments but also for the whole community of each country.
Dornase alfa as postoperative therapy in cystic fibrosis sinonasal disease.

OBJECTIVE To determine the benefit of nasally inhaled dornase alfa in patients with cystic fibrosis and nasal symptoms. DESIGN Double-blind placebo-controlled trial. SETTING Cystic Fibrosis Regional Center of Campania at the University of Naples "Federico II. " PATIENTS A total of 24 patients with cystic fibrosis and chronic sinusitis. INTERVENTIONS Patients underwent sinonasal surgery during a 3-year period and received once-daily doses of either dornase alfa (2.5 mg) or hypotonic saline solution (5 mL) beginning 1 month after surgery and for a 12-month period. MAIN OUTCOME MEASURES Primary outcomes were nasal-related symptoms and nasal endoscopic appearance; secondary outcomes were forced expiratory volume in 1 second, nasal computed tomography findings, and saccharine clearance test results. Patients were evaluated before and after treatment. RESULTS After surgery, all outcomes were significantly improved for each treatment at 1 month (P<.05); primary outcomes were improved at 24 and 48 weeks in the group receiving dornase alfa (P<.05), and at 12 weeks in the group receiving placebo. Secondary outcomes were better in the dornase alfa group (P<.01) than in the placebo group at 12 months except for the saccharine clearance test results. In particular, median relative difference in forced expiratory volume in 1 second between dornase alfa and placebo was significantly improved in the dornase alfa group (P<.01). CONCLUSIONS Nasally inhaled dornase alfa can be effective in patients with cystic fibrosis and sinonasal disease who do not respond to conventional therapy after surgical treatment. Further studies should be carried out to determine the long-term effect on sinus disease, recurrence of polyps, and quality of life.
Synthesis of variable gain controllers based on LQ optimal control for a class of uncertain linear systems

This paper proposes a new variable gain controller for a class of uncertain linear systems. The proposed variable gain controller is based on optimal control for the nominal system and consists of the optimal feedback gain and a time-varying adjustable parameter which is designed so as to reduce the effect of uncertainties, i.e. the proposed variable gain controller can achieve good transient performance which is close to LQ optimal control for the nominal system. In this paper, we show sufficient conditions for the existence of the proposed variable gain controller for uncertain linear systems. Finally, numerical examples are presented.
The use of ion mobility mass spectrometry to probe modulation of the structure of p53 and of MDM2 by small molecule inhibitors

Developing drug-like molecules to inhibit the interactions formed by disordered proteins is desirable due to the high correlation of disorder with protein implicated in disease, but is challenging due in part to the lack of atomistically resolved and resolvable structures from conformationally dynamic systems. Ion mobility mass spectrometry (IM-MS) is well-positioned to assess protein ligand interactions along with the effect of a given inhibitor on conformation. Here we demonstrate the use of IM-MS to characterize the effect of two inhibitors RITA and Nutlin-3 on their respective binding partners: p53 and MDM2. RITA binds N-terminal transactivation domain of p53 (Np53) weakly, preventing direct observation of the complex in the gas phase. Nonetheless, upon incubation with RITA, we observe an alteration in the charge state distribution and in the conformational distributions adopted by Np53 in the gas phase. This finding supports the hypothesis that RITAs mode of action proceeds via a conformational change in p53. Circular dichroism corroborates our gas phase findings, showing a slight increase in secondary structure content on ligand incubation, and HDX-MS experiments also highlight the dynamic properties of this protein. Using the same approach we present data to show the effect of Nutlin-3 binding to the N-terminal domain of MDM2 (N-MDM2), N-MDM2 presents as at least two conformational families in the absence of Nutlin-3. Upon Nutlin-3 binding, the protein undergoes a compaction event similar to that exhibited by RITA on Np53. This multi-technique approach highlights the inherent disorder in these systems; and in particular exemplifies the power of IM-MS as a technique to study transient interactions between small molecule inhibitors and intrinsically disordered proteins.
The Myth of Mental Illness

Mental Illness. By Thomas S. Szasz. {Seeker & Warburg, ̂ s\t Over a century and a half ago Pinel removed the chains from the insane , Paris, John Conolly in England introduced more humane methods of treatment them, and since the days of Charcot, Kraepelin and Freud, mental illness has W' the subject of scientific enquiry like other illnesses. The author of The Myth of Mental Illness puts forward the view that pa*ie with mental disorders should, after all, not be regarded as ill, because they d? suffer from any demonstrable physico-chemical disorders of their bodies, but reg&r!
Severity of Hypoxemia and Other Factors That Influence the Response to Aerosolized Prostacyclin in ARDS

BACKGROUND: ARDS is characterized by decreased functional residual capacity (FRC), heterogeneous lung injury, and severe hypoxemia. Tidal ventilation is preferentially distributed to ventilated alveoli. Aerosolized prostaglandin I2 exploits this pathophysiology by inducing local vasodilation, thereby increasing ventilation-perfusion matching and reducing hypoxemia. Therefore, aerosolized prostaglandin I2 efficacy may depend upon FRC. Both PaO2/FIO2 and compliance of the respiratory system (CRS) are indirect signifiers of FRC and thus may partly determine the response to aerosolized prostaglandin I2. METHODS: We reviewed the records of 208 ARDS subjects who received aerosolized prostaglandin I2 and had arterial blood gases done before and after the initiation of therapy, without other ventilator manipulations. Subjects were grouped according to baseline PaO2/FIO2 (lowest: < 60, intermediate: 60–90, highest: > 90 mm Hg) and CRS (< 20, 20–29, 30–39, and ≥ 40 mL/cm H2O) and by other factors, such as sepsis. Comparisons were analyzed by paired t tests, or Kruskal-Wallis and Dunn post-tests. Multivariate logistic regression modeling was done to determine which of 18 clinically relevant factors were most predictive for responding to aerosolized prostaglandin I2. α was set at . 05. RESULTS: Mean PaO2/FIO2 increased by 33 mm Hg (42%) upon initiation of prostaglandin I2, with a responder rate of 62%. PaO2/FIO2 increased significantly in all oxygenation groups. The highest baseline PaO2/FIO2 group had the greatest improvement and responder rate (51 ± 63 mm Hg, and 82%). In addition, those with sepsis had a smaller improvement in PaO2/FIO2 compared with those without sepsis (18 ± 35 vs 40 ± 55 mm Hg, P = .002). Both PaO2/FIO2 and responder rate increased as CRS improved, but between-group improvements were not as consistent. In the final model, the only factors that predicted a positive response to aerosolized prostaglandin I2 were baseline PaO2/FIO2 (odds ratio 1.10 [1.004–1.205], P = .042) and CRS (odds ratio 1.04 [1.01–1.08], P = .02). CONCLUSIONS: Aerosolized prostaglandin I2 improves oxygenation in approximately 60% of ARDS cases. A favorable response was most strongly associated with baseline PaO2/FIO2 and CRS.
Direct observation of the enhancement of noncooperative protein self-assembly by macromolecular crowding: Indefinite linear self-association of bacterial cell division protein FtsZ

Recent measurements of sedimentation equilibrium and sedimentation velocity have shown that the bacterial cell division protein FtsZ self-associates to form indefinitely long rod-like linear aggregates in the presence of GDP and Mg2+. In the present study, the newly developed technique of non-ideal tracer sedimentation equilibrium was used to measure the effect of high concentrations—up to 150 g/liter—of each of two inert “crowder” proteins, cyanmethemoglobin or BSA, on the thermodynamic activity and state of association of dilute FtsZ under conditions inhibiting (−Mg2+) and promoting (+Mg2+) FtsZ self-association. Analysis of equilibrium gradients of both FtsZ and crowder proteins indicates that, under the conditions of the present experiment, FtsZ interacts with each of the two crowder proteins essentially entirely via steric repulsion, which may be accounted for quantitatively by a simple model in which hemoglobin, albumin, and monomeric FtsZ are modeled as effective spherical hard particles, and each oligomeric species of FtsZ is modeled as an effective hard spherocylinder. The functional dependence of the sedimentation of FtsZ on the concentrations of FtsZ and either crowder indicates that, in the presence of high concentrations of crowder, both the weight-average degree of FtsZ self-association and the range of FtsZ oligomer sizes present in significant abundance are increased substantially.
Improving Students’ Long-Term Knowledge Retention Through Personalized Review

Human memory is imperfect; thus, periodic review is required for the long-term preservation of knowledge and skills. However, students at every educational level are challenged by an ever-growing amount of material to review and an ongoing imperative to master new material. We developed a method for efficient, systematic, personalized review that combines statistical techniques for inferring individual differences with a psychological theory of memory. The method was integrated into a semester-long middle-school foreign-language course via retrieval-practice software. Using a cumulative exam administered after the semester’s end, we compared time-matched review strategies and found that personalized review yielded a 16.5% boost in course retention over current educational practice (massed study) and a 10.0% improvement over a one-size-fits-all strategy for spaced study.
Anorexia nervosa versus hyperinsulinism: therapeutic effects of neuropharmacological manipulation

Background: We have demonstrated that anorexia nervosa is underpinned by overwhelming adrenal sympathetic activity which abolishes the neural sympathetic branch of the peripheral autonomic nervous system. This physiological disorder is responsible for gastrointestinal hypomotility, hyperglycemia, raised systolic blood pressure, raised heart rate, and other neuroendocrine disorders. Therefore, we prescribed neuropharmacological therapy to reverse this central and autonomic nervous system disorder, in order to normalize the clinical and neuroendocrine profile. Methods: The study included 22 female patients with anorexia nervosa (10 restricted type, 12 binge-eating type) who received three months of treatment with amantadine 100 mg/day. We measured blood pressure, heart rate, and circulating neurotransmitters, (noradrenaline, adrenaline, dopamine, platelet serotonin, free plasma serotonin) during supine resting, one minute of orthostasis, and a five-minute exercise test before and after one, two, and three months of treatment with amantadine, a drug which abrogates adrenal sympathetic activity by acting at the C1(Ad) medullary nuclei responsible for this branch of the peripheral sympathetic activity. Results: We found the amantadine abolished symptoms of anorexia nervosa from the first oral dose onwards. Normalization of autonomic and cardiovascular parameters was demonstrated within the early days of therapy. Abrupt and sustained increases in the plasma noradrenaline:adrenaline ratio and disappearance of abnormal plasma glucose elevation were registered throughout the three-month duration of the trial. Significant and sustained increases in body weight were documented in all cases. No relapses were observed. Conclusion: We have confirmed our previously published findings showing that the anorexia nervosa syndrome depends on the hypomotility of the gastrointestinal tract plus hyperglycemia, both of which are triggered by adrenal sympathetic hyperactivity. The above neuroendocrine plus neuroautonomic and clinical disorders which underpinned anorexia nervosa were abruptly suppressed since the first oral dose of amantadine, a drug able to revert the C1(Ad) over A5(NA) pontomedullary predominance responsible for adrenal and neural sympathetic activity, respectively.
Decision Theoretic Approaches to Experiment Design and External Validity

A modern, decision-theoretic framework can help clarify important practical questions of experimental design. Building on our recent work, this chapter begins by summarizing our framework for understanding the goals of experimenters, and applying this to re-randomization. We then use this framework to shed light on questions related to experimental registries, pre-analysis plans, and most importantly, external validity. Our framework implies that even when large samples can be collected, external decision-making remains inherently subjective. We embrace this conclusion, and argue that in order to improve external validity, experimental research needs to create a space for structured speculation.
Golgi-derived vesicles from developing epithelial cells bind actin filaments and possess myosin-I as a cytoplasmically oriented peripheral membrane protein

In the intestinal brush border, the mechanoenzyme myosin-I links the microvillus core actin filaments with the plasma membrane. Previous immunolocalization shows that myosin-I is associated with vesicles in mature enterocytes (Drenckhahn, D., and R. Dermietzel. 1988. J. Cell Biol. 107:1037-1048) suggesting a potential role mediating vesicle motility. We now report that myosin-I is associated with Golgi-derived vesicles isolated from cells that are rapidly assembling brush borders in intestinal crypts. Crypt cells were isolated in hyperosmotic buffer, homogenized, and fractionated using differential- and equilibrium- density centrifugation. Fractions containing 50-100-nm vesicles, a similar size to those observed in situ, were identified by EM and were shown to contain myosin-I as demonstrated by immunoblotting and immunolabel negative staining. Galactosyltransferase, a marker enzyme for trans-Golgi membranes was present in these fractions, as was alkaline phosphatase, which is an apical membrane targeted enzyme. Galactosyltransferase was also present in vesicles immuno-purified with antibodies to myosin-I. Villin, a marker for potential contamination from fragmented microvilli, was absent. Myosin-I was found to reside on the vesicle "outer" or cytoplasmic surface for it was accessible to exogenous proteases and intact vesicles could be immunolabeled with myosin-I antibodies in solution. The bound myosin-I could be extracted from the vesicles using NaCl, KI and Na2CO3, suggesting that it is a vesicle peripheral membrane protein. These vesicles were shown to bundle actin filaments in an ATP-dependent manner. These results are consistent with a role for myosin-I as an apically targeted motor for vesicle translocation in epithelial cells.
Enhancing Learning in Introductory Computer Science Courses Through SCALE: An Empirical Study

The work presented in this paper aims to support and promote the learning process in introductory computer science courses through the Web-based, adaptive, activity-oriented learning environment known as Supporting Collaboration and Adaptation in a Learning Environment (SCALE). The environment engages students actively in the learning process and supports them with multiple informative and tutoring feedback components. The exploitation of appropriately developed educational material, which was provided through SCALE, showed that SCALE can be a valuable tool for supporting the learning process in introductory computer science courses.
Sediment-associated nutrient transport in UK rivers

Monitoring programmes established to document river nutrient loads have commonly focused on quantifying total loads, without distinguishing between the dissolved and particulate components. There is now a growing recognition of the need to distinguish these two components which may exhibit contrasting behaviour and reflect different sources and controls. Few reliable data are currently available with which to assess the role of sediment-asso ciated transport in nutrient transport by British rivers and this contribution reports the results of a study aimed at assessing this role for four contrasting river basins in Britain. The study rivers were selected to embrace a range of basin characteristics and include the River Severn, the Warwickshire Avon, the River Exe and its tributary the River Dart. Detailed monitoring of the N and P loads transported by these four rivers was undertaken during the period January to December 1995, and the dissolved and sediment-associated components of the total N and P flux were determined with a view to assessing the significance of the latter component. Significant differences existed between the four rivers in terms of both specific N and P yields and the relative contribution of the particulate component. These contrasts reflected variations in the magnitude of the specific suspended sediment yields and in the relative importance of point and non-point sources as well as other basin characteristics. In the case of phosphorus, sediment-associated transport accounted for between 26.3% and 75.4% of the annual total P load of the study rivers, whereas for N the sediment-associated contribution was much less and ranged between 3.3% and 8.0%. The magnitude of the sediment-associated contribution varied through the year in response to a number of controls, including the seasonal pattern of suspended sediment transport.
Cocaine-related sudden death: a prospective investigation in south-west Spain.

AIMS With an estimated 12 million consumers in Europe, cocaine (COC) is the illicit drug leading to the most emergency department visits. The aim of this study was to examine a consecutive series of sudden deaths (SDs) to focus on the prevalence, the toxicological characteristics, and the causes of death in COC-related fatalities. METHODS AND RESULTS Prospective case-control study of forensic autopsies was carried out in the time interval November 2003 to June 2006 at the Institute of Legal Medicine, Seville, south-west Spain, with a reference population of 1 875 462 inhabitants. Toxicology included blood ethanol analysis and blood and urine investigation for drugs of abuse and medical drugs. Autopsy was performed according to the European standardized protocol. Ten age- and sex-matched patients who died of violent causes with no antecedents of COC consumption and negative toxicology served as controls. During the study period, 2477 forensic autopsies were performed, including 1114 natural deaths. Among the latter, 668 fulfilled the criteria of SD and 21 (all males, mean age 34.6 +/- 7.3 years) resulted to be COC-related (3.1%). Cocaine was detected in 67.1% of the blood (median 0.17 mg/L, interquartile range 0.08-0.42) and in 83.0% of the urine samples (median 1.15 mg/L, interquartile range 0.37-17.34). A concomitant use of ethanol was found in 76.0% and cigarette smoking in 81.0%. Causes of SD were cardiovascular in 62.0%, cerebrovascular in 14.0%, excited delirium in 14.0%, respiratory and metabolic in 5.0% each. Left ventricular hypertrophy was observed in 57.0%, small vessels disease in 42.9%, severe atherosclerotic coronary artery disease in 28.6%, and coronary thrombosis in 14.3%. CONCLUSION Systematic toxicology investigation indicates that 3.1% of SDs are COC-related and are mainly due to cardio-cerebrovascular causes. Left ventricular hypertrophy, small vessel disease, and premature coronary artery atherosclerosis, with or without lumen thrombosis, are frequent findings that may account for myocardial ischaemia at risk of cardiac arrest in COC addicts.