Miracle-dz/UniFAR-FTUs huggingface dataset:
Triathlon for energy functions: Who is the winner for design of protein–protein interactions?

Computational prediction of stabilizing mutations into monomeric proteins has become an almost ordinary task. Yet, computational stabilization of protein–protein complexes remains a challenge. Design of protein–protein interactions (PPIs) is impeded by the absence of an energy function that could reliably reproduce all favorable interactions between the binding partners. In this work, we present three energy functions: one function that was trained on monomeric proteins, while the other two were optimized by different techniques to predict side‐chain conformations in a dataset of PPIs. The performances of these energy functions are evaluated in three different tasks related to design of PPIs: predicting side‐chain conformations in PPIs, recovering native binding‐interface sequences, and predicting changes in free energy of binding due to mutations. Our findings show that both functions optimized on side‐chain repacking in PPIs are more suitable for PPI design compared to the function trained on monomeric proteins. Yet, no function performs best at all three tasks. Comparison of the three energy functions and their performances revealed that (1) burial of polar atoms should not be penalized significantly in PPI design as in single‐protein design and (2) contribution of electrostatic interactions should be increased several‐fold when switching from single‐protein to PPI design. In addition, the use of a softer van der Waals potential is beneficial in cases when backbone flexibility is important. All things considered, we define an energy function that captures most of the nuances of the binding energetics and hence, should be used in future for design of PPIs. Proteins 2011; © 2011 Wiley‐Liss, Inc.
Review article: exploring the link between Helicobacter pylori and gastric cancer

Cancer of the distal stomach, both of the intestinal and diffuse type, is strongly associated with Helicobacter pylori colonization. This bacterium causes chronic active inflammation of the gastric mucosa in the majority of colonized subjects. In a considerable number of them, this will eventually lead to a loss of gastric glands, and thus the establishment of atrophic gastritis, which is associated with the development of intestinal metaplasia and dysplasia. Development of atrophy and metaplasia of the gastric mucosa are thus strongly associated with H. pylori infection, instead of a direct and inevitable consequence of ageing. Approximately 40–50% of infected subjects develop these conditions, but they are rare in non‐infected subjects.
On the Mechanism of Hyperacidification in Lemon

Lemon fruit vacuoles acidify their lumens to pH 2.5, 3 pH units lower than typical plant vacuoles. To study the mechanism of hyperacidification, the kinetics of ATP-driven proton pumping by tonoplast vesicles from lemon fruits and epicotyls were compared. Fruit vacuolar membranes were less permeable to protons than epicotyl membranes. H pumping by epicotyl membranes was chloride-dependent, stimulated by sulfate, and inhibited by the classical vacuolar ATPase (V-ATPase) inhibitors nitrate, bafilomycin, N-ethylmaleimide, and N,N′-dicyclohexylcarbodiimide. In addition, the epicotyl H pumping activity was inactivated by oxidation at room temperature, and oxidation was reversed by dithiothreitol. Cold inactivation of the epicotyl V-ATPase by nitrate (≥100 mM) was correlated with the release of V complexes from the membrane. In contrast, H pumping by the fruit tonoplast-enriched membranes was chloride-independent, largely insensitive to the V-ATPase inhibitors, and resistant to oxidation. Unlike the epicotyl H-ATPase, the fruit H-ATPase activity was partially inhibited by 200 μM vanadate. Cold inactivation treatment failed to inhibit H pumping activity of the fruit membranes, even though immunoblots showed that V complexes were released from the membrane. However, cold inactivation doubled the percent inhibition by 200 μM vanadate from 30% to 60%. These results suggest the presence of two H-ATPases in the fruit preparation: a V-ATPase and an unidentified vanadate-sensitive H-ATPase. Attempts to separate the two activities in their native membranes on linear sucrose density gradients were unsuccessful. However, following detergent-solubilization and centrifugation on a glycerol density gradient, the two ATPase activities were resolved: a nitrate-sensitive V-type ATPase that is also partially inhibited by 200 μM vanadate, and an apparently novel vanadate-sensitive ATPase that is also partially inhibited by nitrate.
A customizable mobile tool for supporting health behavior interventions

Recorded self-observations on a regular basis is an important component in many health behavior interventions. Using information and communication technologies (ICT) and especially mobile eHealth applications is a promising way of improving user-friendliness and possibly the overall effectiveness of self-monitoring. Mobility as such brings the added value of continuous availability and timely information access. One additional benefit of ICT based solutions is the possibility for various types of customization, allowing support for a wider set of application requirements than was originally planned, and meeting changing needs and targets of individuals, groups or larger user segments. In this paper, we present a customizable mobile application for recording and managing health related self-observations, Wellness Diary, and the ideas and technical solutions for supporting tailoring of the application. The main idea is to allow end-users to freely change the data model in the application, and customize related data presentations. This work has been done in Nuadu ITEA project, as well as further work where the effectiveness of the mobile tool and other ICT technologies will be investigated in a controlled trial in Finland. We'll also present shortly a counterpart for the mobile application, a web service that should bring some added value for the end user.
Randomized Trial of Verubecestat for Mild‐to‐Moderate Alzheimer's Disease

BACKGROUND Alzheimer's disease is characterized by the deposition of amyloid‐beta (Aβ) plaques in the brain. Aβ is produced from the sequential cleavage of amyloid precursor protein by β‐site amyloid precursor protein–cleaving enzyme 1 (BACE‐1) followed by γ‐secretase. Verubecestat is an oral BACE‐1 inhibitor that reduces the Aβ level in the cerebrospinal fluid of patients with Alzheimer's disease. METHODS We conducted a randomized, double‐blind, placebo‐controlled, 78‐week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had a clinical diagnosis of mild‐to‐moderate Alzheimer's disease. The coprimary outcomes were the change from baseline to week 78 in the score on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS‐cog; scores range from 0 to 70, with higher scores indicating worse dementia) and in the score on the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS‐ADL; scores range from 0 to 78, with lower scores indicating worse function). RESULTS A total of 1958 patients underwent randomization; 653 were randomly assigned to receive verubecestat at a dose of 12 mg per day (the 12‐mg group), 652 to receive verubecestat at a dose of 40 mg per day (the 40‐mg group), and 653 to receive matching placebo. The trial was terminated early for futility 50 months after onset, which was within 5 months before its scheduled completion, and after enrollment of the planned 1958 patients was complete. The estimated mean change from baseline to week 78 in the ADAS‐cog score was 7.9 in the 12‐mg group, 8.0 in the 40‐mg group, and 7.7 in the placebo group (P=0.63 for the comparison between the 12‐mg group and the placebo group and P=0.46 for the comparison between the 40‐mg group and the placebo group). The estimated mean change from baseline to week 78 in the ADCS‐ADL score was ‐8.4 in the 12‐mg group, ‐8.2 in the 40‐mg group, and ‐8.9 in the placebo group (P=0.49 for the comparison between the 12‐mg group and the placebo group and P=0.32 for the comparison between the 40‐mg group and the placebo group). Adverse events, including rash, falls and injuries, sleep disturbance, suicidal ideation, weight loss, and hair‐color change, were more common in the verubecestat groups than in the placebo group. CONCLUSIONS Verubecestat did not reduce cognitive or functional decline in patients with mild‐to‐moderate Alzheimer's disease and was associated with treatment‐related adverse events. (Funded by Merck; ClinicalTrials.gov number, NCT01739348.)
Using machine learning, general regression, and cox proportional hazards regression to predict the effectiveness of treatment in patients with breast cancer

The objective of this feasibility study is to introduce machine learning algorithms in the combination of general regression and cox proportional hazards regression to predicate the outcome of disease management. By using the delay in the receipt of adjuvant chemotherapy and SEER-Medicare databases as proof-of-principle, we conclude that general regression and Cox proportional hazards regression following the feature selection could identify factors that predict the delay and the impact of delay on survival outcome.
Hypoxemia increases plasma catecholamine concentrations in exercising humans.

To determine whether plasma catecholamine concentrations (a measure of sympathetic nervous activity [SNA]) rise above normoxic levels during exercise with hypoxemia, we exercised seven men for 15 min at three loads that required from 40 to 88% of maximal O2 uptake (VO2max). Subjects breathed room air on one day and 11-12% O2 on another with relative work loads corrected for the 24% fall in VO2max during hypoxemia. Hypoxemia caused large increments in norepinephrine (NE) concentration (radioenzyme technique) to 1.21 +/- 0.20 ng/ml (mean +/- SE), 2.79 +/- 0.38, and up to 5.90 +/- 0.75 (hypoxemia) compared with 0.89 +/- 0.06, 1.66 +/- 0.16, and 3.95 +/- 0.39 in normoxia at the three loads, respectively (P less than 0.001). Epinephrine (E) concentration approximately doubled (P less than 0.001) in hypoxemia at each load when compared with normoxic levels (i.e., 0.10 +/- 0.01 ng/ml, 0.23 +/- 0.03, and 0.46 +/- 0.06 in normoxia). However, hypoxemia did not significantly alter linear relationships between log plasma NE concentration and either heart rate (HR) or percent VO2max utilized, or between HR and percent VO2max. Thus NE concentration, like HR, appeared to reflect relative severity of exercise and overall SNA in both hypoxemia and normoxia. Above 40% VO2max during hypoxemia, circulating NE and E far exceeded levels known to have direct vasoconstrictor and metabolic effects in normoxic humans, but hypoxemia may blunt vasoconstriction in some regions.
CMOS analog power meter and delay line for automatic efficiency optimization in medical power transmitters

Inductive powering is an efficient method to wire-lessly transfer power to an implant. On the transmitter side, a power amplifier (class-D or class-E) is used to convert DC power, from a supply unit, into AC power, which can be transferred across the inductive link. At frequencies conventionally used for powering implants, the efficiency of a Class-D power amplifier is highly dependent on the dead time between the switching of the low-side and the high-side switches. Closed-loop techniques can then be adopted to automatically set the appropriate dead time. This paper addresses this issue by presenting the conceptual design of an analog CMOS closed-loop automatic efficiency optimization circuit for class-D PAs, consisting of an analog power meter and a 13-bit programmable delay line. The circuits have been designed in a 0. 18μm CMOS technology and simulated using Cadence Spectre.
Some Statistical Implications of Dose Uncertainty in Radiation Dose–Response Analyses

Abstract Schafer, D. W. and Gilbert, E. S. Some Statistical Implications of Dose Uncertainty in Radiation Dose–Response Analyses. Radiat. Res. 166, 303–312 (2006). Statistical dose–response analyses in radiation epidemiology can produce misleading results if they fail to account for radiation dose uncertainties. While dosimetries may differ substantially depending on the ways in which the subjects were exposed, the statistical problems typically involve a predominantly linear dose–response curve, multiple sources of uncertainty, and uncertainty magnitudes that are best characterized as proportional rather than additive. We discuss some basic statistical issues in this setting, including the bias and shape distortion induced by classical and Berkson uncertainties, the effect of uncertain dose-prediction model parameters on estimated dose–response curves, and some notes on statistical methods for dose–response estimation in the presence of radiation dose uncertainties.
Experimental validation of a tactile sensor model for a robotic hand

We describe a tactile sensor for a robotic hand, based on the mechanoreceptors in the glabrous skin of the human hand to replicate the sensory function of both slow adapting and fast adapting receptors. Strain gauges are used for the slow adapting receptors, and polyvinylidene fluoride (PVDF) film was used to replicate the function of the fast adapting receptors. One unit sensor consisted of four strain gauges and a single PVDF film, embedded beneath a square protrusion. The protrusion helped localize the applied force onto the region or ‘receptive field’ of the sensing unit. Strain gauges were orientated to enable the unit sensor to identify the tri-axial force components. Multiple linear regression was used to predict the components of force. The regression model with interaction terms gave good prediction with mean percentage errors of less than 15% for each force component.
Prevalence and risk factors for sexually transmitted infections in a high-risk occupational group: the case of fishermen along Lake Victoria in Kisumu, Kenya

The aim of this study was to assess prevalence and risk factors for sexually transmitted infections (STIs) among fishermen along Lake Victoria, Kenya. This cross-sectional study surveyed 250 fishermen from beaches in Kisumu District using proportional-to-size sampling based on the number of registered boats per beach. Participants provided demographic and sexual behaviour information, blood for HIV-1 herpes simplex virus type 2 (HSV-2) and syphilis serological tests urine for transcription-mediated amplification assays for Neisseria gonorrhoeae and Chlamydia trachomatis and penile and scrotal swabs for human papillomavirus (HPV) DNA assay. Consistent condom use with the three most recent sexual partners was reported by 30%; 38% reported concurrent sexual partnerships and 65% reported ever having transactional sex. HIV seroprevalence was 26%, HSV-2 seroprevalence by Western blot assay was 58% and 9.5% were rapid plasma reagin and Treponema pallidum particle agglutination assay positive. Genital HPV DNA of any type was detected in 57.2% with 74% of these having two or more HPV types. C. trachomatis and N. gonorrhoeae were detected in 3.2% and 1.2% respectively. Risk factors for syphilis seropositivity included working on multiple beaches during the past year (adjusted odds ratio [AOR] 3.81; 95% confidence interval [CI] 1.29–11.28). HPV infection was associated with owning a radio which is a marker for higher socioeconomic status (AOR 6.33; 95% CI 2.94–7.14) and reporting transactional sex with the most recent sexual partner (AOR 3.03; 95% CI 1.23–7.69). In conclusion, 90% of fishermen had evidence of one or more STIs. This exceptionally high-risk occupational group represents a high priority for preventive interventions.
Decreasing trends of suspended particulate matter and PM2.5 concentrations in Tokyo, 1990–2010

In Tokyo, the annual average suspended particulate matter (SPM) and PM2.5 concentrations have decreased in the past two decades. The present study quantitatively evaluated these decreasing trends using data from air-pollution monitoring stations. Annual SPM and PM2.5 levels at 83 monitoring stations and hourly SPM and PM2.5 levels at four monitoring stations in Tokyo, operated by the Tokyo Metropolitan Government, were used for analysis, together with levels of co-pollutants and meteorological conditions. Traffic volume in Tokyo was calculated from the total traveling distance of vehicles as reported by the Ministry of Land, Infrastructure, Transport, and Tourism. High positive correlations between SPM levels and nitrogen oxide levels, sulfur dioxide levels, and traffic volume were determined. The annual average SPM concentration declined by 62.6% from 59.4 µg/m3 in 1994 to 22.2 µg/m3 in 2010, and PM2.5 concentration also declined by 49.8% from 29.3 µg/m3 in 2001 to 14.7 µg/m3 in 2010. Likewise, the frequencies of hourly average SPM and PM2.5 concentrations exceeding the daily guideline values have significantly decreased since 2001 and the hourly average SPM or PM2.5 concentrations per traffic volume for each time period have also significantly decreased since 2001. However, SPM and PM2.5 concentrations increased at some monitoring stations between 2004 and 2006 and from 2009 despite strengthened environmental regulations and improvements in vehicle engine performance. The annual average SPM and PM2.5 concentrations were positively correlated with traffic volumes and in particular with the volume of diesel trucks. These results suggest that the decreasing levels of SPM and PM2.5 in Tokyo may be attributable to decreased traffic volumes, along with the effects of stricter governmental regulation and improvements to vehicle engine performance, including the fitting of devices for exhaust emission reduction. Implications: In Tokyo, the annual average SPM concentration declined by 62.6% from 59.4 μg/m3 in 1994 to 22.2 μg/m3 in 2010, and the concentration of PM2.5 declined by 49.8% from 29.3 μg/m3 in 2001 to 14.7 μg/m3 in 2010. Significant positive correlations were found between traffic volumes and SPM or PM2.5, but the average concentrations of SPM and PM2.5 concentration per traffic volume have also decreased over the decade studied. These results suggest that reductions in traffic volumes as well as improvements in engine design and the installation of exhaust gas treatment systems may have improved air quality.
Modéliser l'insertion territoriale du Miscanthus x giganteus à partir des décisions des agriculteurs : une approche exploitant le modèle du raisonnement à partir de cas

Le Miscanthus x giganteus est une culture perenne, nouvellement produite en Europe et presentant un interet fort pour son usage energetique. Son implantation presage donc une reorganisation territoriale perenne. Pour anticiper cette reorganisation, de nombreuses etudes modelisent les dynamiques spatialement explicites de son insertion. Notre these se positionne dans ce courant de recherche. Celle-ci vise a proposer un nouveau cadre de modelisation des processus de decision des agriculteurs, permettant la dissemination horizontale (scaling out) de ces processus issus d’etudes de cas, vers des territoires elargis. Pour cela, la these exploite le modele du raisonnement a partir de cas. Elle articule (i) une demarche d’acquisition de connaissances sur les processus de decision des agriculteurs relatifs a l’insertion territoriale du miscanthus et (ii) la conception et evaluation d’un prototype ad hoc de raisonnement a partir de cas. La phase d’acquisition des connaissances montre que le processus d’insertion territoriale du miscanthus est complexe : celui-ci est etroitement lie aux contraintes parcellaires du territoire. Ces connaissances nous conduisent alors a discuter du choix des variables biophysiques et humaines integrees a ce jour dans les modeles spatialement explicites. La phase de conception et d’evaluation du prototype de raisonnement a partir de cas montre que le modele du raisonnement a partir de cas est particulierement bien adapte pour modeliser un phenomene contextualise. Evalues sur nos donnees d’enquetes, ces resultats nous conduisent a discuter des modalites d’application du prototype sur d’autres bassins de production de miscanthus
Melanocortin 4 Receptor Pathway Dysfunction in Obesity: Patient Stratification Aimed at MC4R Agonist Treatment

Abstract Context The hypothalamic melanocortin 4 receptor (MC4R) pathway serves a critical role in regulating body weight. Loss of function (LoF) mutations in the MC4R pathway, including mutations in the pro-opiomelanocortin (POMC), prohormone convertase 1 (PCSK1), leptin receptor (LEPR), orMC4R genes, have been shown to cause early-onset severe obesity. Methods Through a comprehensive epidemiological analysis of known and predicted LoF variants in thePOMC, PCSK1, andLEPR genes, we sought to estimate the number of US individuals with biallelic MC4R pathway LoF variants. Results We predict ~650α-melanocyte-stimulating hormone (MSH)/POMC, 8500PCSK1, and 3600LEPR homozygous and compound heterozygous individuals in the United States, cumulatively enumerating >12,800 MC4R pathway–deficient obese patients. Few of these variants have been genetically diagnosed to date. These estimates increase when we include a small subset of less rare variants:β-MSH/POMC,PCSK1 N221D, and aPCSK1 LoF variant (T640A). To further define the MC4R pathway and its potential impact on obesity, we tested associations between body mass index (BMI) and LoF mutation burden in thePOMC, PCSK1, andLEPR genes in various populations. We show that the cumulative allele burden in individuals with two or more LoF alleles in one or more genes in the MC4R pathway are predisposed to a higher BMI than noncarriers or heterozygous LoF carriers with a defect in only one gene. Conclusions Our analysis represents a genetically rationalized study of the hypothalamic MC4R pathway aimed at genetic patient stratification to determine which obese subpopulations should be studied to elucidate MC4R agonist (e.g., setmelanotide) treatment responsiveness.
Externalities and Financial Reporting

REFERENCES TO THE EXISTENCE of externalities in financial reporting are being made increasingly in the literature. For instance, a committee of the American Accounting Association [1977] observed that "financial accounting information shares much in common with the more traditional examples of externalities" and that "without intervention, too little information will be produced. This is one of the standard arguments for . disclosure policies" (p. 24). 1 This paper will discuss (a) the various ways that externalities may arise in financial reporting, and (b) how the traditional economic approaches to "controlling" for externalities apply in that context. One purpose of the discussion is to guide future empirical research on the significance of and problems in "controlling" externalities in financial reporting. There is far from unanimity about the meaning of the externality term in the economics literature.2 The definition adopted here stresses the interdependence notion and has antecedents dating back to at least 1962-see Buchanan and Stubblebine [1962]. An externality will be said to exist when the utility of individual m(Um) is a function not only of his action choices (am) and the state occurrence (sn), but also of the action choices of individuals x, y . i.e.,
Government SME intervention policy: perception is 9/10ths of the truth?

The Small and Medium Enterprise (SME) sector plays a pivotal role in creating innovation, wealth, employment and economic growth in industrialised and developing countries (Robson and Bennett, 2000). Specifically, Jutla et al. (2002) estimated that SMEs accounted for 80% of global economic growth, driven partly by their numerical significance (Birchall and Giambona, 2007). In the UK context SMEs account for over 4.5 million entities (99.8%), and 52.4% of employment, whilst Europe’s population of SMEs accounts for 99.8% of all businesses and 66.2% of employment (SBS, 2008). Support for SMEs has, therefore, become an important component of many economic policies to promote sustainable competitive advantage (see for example Greene et al., 2008).