Miracle-dz/UniFAR-FTUs huggingface dataset:
Drug Development at the Portfolio Level Is Important for Policy, Care Decisions and Human Protections

The development of a new drug is often portrayed as a series of increasingly demanding clinical trials, performed in patients with a single target condition, as the development program advances toward drug approval. However, rarely does drug development involve a single approach to using a drug. Instead, drugs are tested in multiple clinical trials—many pursued after initial drug approval and licensure—involving different clinical indications or drug combinations. This family of trials could be referred to as a drug development “portfolio. ” For example, the portfolio of the anticancer drug sorafenib included 203 clinical trials conducted over 13.2 years, spanning 26 different malignancies and 67 drug combinations.1 A portfolio can be enormous if defined in terms of drug classes. For instance, at least 803 trials are testing checkpoint inhibitors for the treatment of different malignancies.2 Drugs are not tested for randomly selected indications but, in contrast, are tested for diseases thought to share some common features (eg, metabolic pathways, pathophysiology, pathogens). The result is that trials in portfolios test hypotheses that are correlated with each other; if the drug is truly effective in one tested disease state, that generally increases the chance it is truly effective in another, and vice versa. Although results from these related trials are correlated, they can also differ from each other because of true differences in efficacy in different disease states, populations, and settings, as well as random variation in observed data sets. The fact that drug testing often involves multiple and related trials has unappreciated implications for clinical decision making, human protections, and policy.
Estimating Uncertainty in Global Mercury Emission Source and Deposition Receptor Relationships

Establishing mercury (Hg) source-receptor (SR) relationship matrices provides a tool to improve the understanding of the geographic relationship between regions of Hg release and its eventual deposition. SR relationship matrices are therefore a useful starting point for the development of policies aimed at reducing the impact of Hg emissions from anthropogenic activities (Hganthr) on sensitive ecosystems and areas potentially at risk of Hg contamination. A global Chemical Transport Model (CTM) has been used to simulate the emission, transport and fate of Hganthr from 12 source regions, considering a range of uncertainty in the modelled chemical and physical processes. This ensemble of simulations gives an estimate of the Hg deposition which derives from each source region, as well as an estimate of the uncertainty of the calculated deposition flux. The uncertainty has been calculated using the bootstrap method to estimate this uncertainty in terms of the normalised confidence interval amplitude of the mean (NCIAM). Within the calculated confidence ranges, for almost all regions the contribution to the Hg deposition flux from remote sources is greater than that from domestic sources. Europe and South Asia, where the contributions are statistically indistinguishable, are exceptions, as is East Asia, with local sources dominating the Hg deposition flux. East Asia is the single most important remote source region for most receptor regions. The results yield such high uncertainties in the deposition flux for many receptor regions that the results are unlikely to be taken into consideration by policy makers. This uncertainty is particularly relevant when considering the “domestic” contribution to regional deposition, highlighting the need for more studies to resolve remaining uncertainties in the atmospheric Hg cycle, and Hganthr emission inventories.
Dégradation de l'habitat et réponse au stress : de la physiologie a la biologie de la conservation

L'anthropisation croissante et les changements globaux entrainent de nombreuses perturbations dans l'environnement conduisant a la degradation, et meme a la destruction d'habitat. Le modele allostatique propose par McEwen et Wingfield en 2003 permet de mieux apprehender les relations entre physiologie et reponses demographique dans le cadre de la physiologie de la conservation. A travers des approches experimentales en milieux controle et semi-naturel nous avons teste l'effet de d'un stress chronique sur les changements des traits d'histoires de vie et les parametres physiologique chez le lezard vivipare (Zootoca vivipara). Nous discutons de la caracterisation de la charge allostatique et des effets a court terme et long terme d'un stress chronique et l'utilisation de la charge allostatique comme indicateur de la degradation de l'habitat. Ce travail pourra etre utilise afin de mieux comprendre et predire la dynamique des populations naturelles soumises aux changements globaux.
Linearized embedding: A new metric matrix algorithm for calculating molecular conformations subject to geometric constraints

There are many methods in the literature for calculating conformations of a molecule subject to geometric constraints, such as those derived from two‐dimensional NMR experiments. One of the most general ones is the EMBED algorithm, based on distance geometry, where all constraints except chirality are converted into upper and lower bounds on interatomic distances. Here we propose a variation on this where the molecule is assumed to have fixed bond lengths, vicinal bond angles and chiral centers; and these holonomic constraints are enforced separately from the experimental constraints by being built into the mathematical structure of the problem. The advantages of this approach are: (1) for molecules having large rigid groups of atoms, there are substantially fewer variables in the problem than all the atomic coordinates; (2) rigid groups achieve in the end more accurate local geometry (e.g., planar aromatic rings are truly planar, chiral centers always have their correct absolute chirality); (3) it is easier to detect inconsistencies between the holonomic and the experimental constraints; and (4) when generating a random sampling of conformers consistent with all constraints, the probability of achieving satisfactory structures tends to be greater.
Hand-drawn animation with self-shaped canvas

Although 3D CG tools produce similar style animations with conventional 2D animation, conventional hand-drawn animation has advantages that cannot be substituted in animation produced by those tools. This paper introduces a new method to assist animators in creating 2D keyframe animation, which utilizes the self-shaped canvas hidden from the user. Drawing keyframes is the main input. Because the canvas has a three-dimensional shape deformed according to keyframes, inbetween animation with them mapped on it obtains depth-aware motion.
A tractable model for optimizing device-to-device communications in downlink cellular networks

In this paper, we develop a tractable and accurate framework for a Device-to-Device (D2D) enabled downlink cellular network with a dedicated spectrum approach, meaning that D2D links use a frequency band orthogonal to the cellular users. Using stochastic geometry, we provide accurate expressions for SINR distributions and average rates, under an assumption of interference randomization via time and/or frequency hopping. The obtained analytical results allow us to easily explore and optimize the impact of system parameters. For example, we find the optimal frequency hopping probability for the D2D users, i.e. how often they should randomly access a subband. We also propose an optimization approach for mode selection, i.e. when should potential D2D users transmit directly, and when should they fall back to the cellular mode. This can be viewed as an optimized lower bound to other more sophisticated scheduling schemes.
A NOVEL ITERATIVE OPTIMIZATION ALGORITHM BASED ON DYNAMIC RANDOM POPULATION

Original scientific paper Various heuristic optimization methods have been developed in artificial intelligence. These methods are mostly inspired by natural evolution or some applicable innovations, which seek good (near-optimal) solutions at a reasonable computational cost for search problems. A new iterative optimization algorithm is proposed in this paper. The algorithm is based on searching the most valuable part of the solution space, which is normally concentrated about a targeted bias vector (in the form of a dynamic random population). This algorithm greedily searches the solution space for global extremum. The comparison results between the proposed algorithm and some of the well-known heuristic search methods confirm the superiority of our proposed method in solving various non-linear optimization problems from the viewpoint of simplicity and accuracy.
News Bias Analysis Based on Stakeholder Mining

In this paper, we propose a novel stakeholder mining mechanism for analyzing bias in news articles by comparing descriptions of stakeholders. Our mechanism is based on the presumption that interests often induce bias of news agencies. As we use the term, a “stakeholder” is a participant in an event described in a news article who should have some relationships with other participants in the article. Our approach attempts to elucidate bias of articles from three aspects: stakeholders, interests of stakeholders, and the descriptive polarity of each stakeholder. Mining of stakeholders and their interests is achieved by analysis of sentence structure and the use of RelationshipWordNet, a lexical resource that we developed. For analyzing polarities of stakeholder descriptions, we propose an opinion mining method based on the lexical resource SentiWordNet. As a result of analysis, we construct a relations graph of stakeholders to group stakeholders sharing mutual interests and to represent the interests of stakeholders. We also describe an application system we developed for news comparison based on the mining mechanism. This paper presents some experimental results to validate the proposed methods.
ACTIVATED PROTEIN C CAN BE USED AS A PROPHYLACTIC AS WELL AS A THERAPEUTIC AGENT FOR HEAT STROKE IN RODENTS

The present study was attempted to assess the prophylactic and the therapeutic effect of human recombinant activated protein C (APC; drotrecogin-&agr;, activated) in experimental heat stroke. Anesthetized rats were divided into two groups and given vehicle solution 1 h before the start or immediately after the termination of heat stress (isotonic sodium chloride solution, 2 mL kg−1 of body weight, i.v.) or APC (1-10 mg in 2 mL of isotonic sodium chloride solution per kilogram of body weight, i.v.). They were exposed to ambient temperature of 40°C for 100 min to induce heat stroke. When the vehicle-pretreated rats underwent heat stress, their survival time values were found to be 57 to 71 min. Pretreatment or treatment with APC significantly increased survival time (122-221 min). All vehicle-pretreated heat stroke animals displayed systemic inflammation (evidenced by increased TNF-&agr;, IL-1&agr;, and IL-6) and activated coagulation (evidenced by increased levels of activated partial thromboplastin time, prothrombin time, and D-dimer and decreased levels of both platelet count and protein C). Biochemical assay also revealed that both renal and hepatic dysfunction (e.g., increased plasma levels of blood urea nitrogen, creatinine, adenine aminotransferase, aspartate aminotransferase, and alkaline phosphatase) were noted during heat stroke. A significant decrease in both cerebral blood flow and partial pressure of oxygen in hypothalamus were also observed in vehicle-pretreated heat stroke animals. These heat stroke reactions were all significantly reduced by pretreatment or treatment with human recombinant APC. The results indicate that human recombinant APC can be used as a prophylactic and a therapeutic agent for experimental heat stroke by ameliorating systemic inflammation, hypercoagulable state, and multiple organ dysfunction.
High survivin expression is associated with favorable outcome in advanced primary oral squamous cell carcinoma after radiation therapy

Oral squamous cell carcinoma (OSCC) is a solid neoplasm exhibiting aggressive tumor phenotypes with unpredictable biological behavior. Recent studies suggested that high expression of the antiapoptotic protein survivin might be associated with adverse outcome in oral cancer patients. To investigate, whether increased copy numbers of the survivin‐encoding gene BIRC5 results in elevated survivin levels and whether BIRC5 and survivin could serve as progression markers in the clinical course of OSCC, tumor tissue microarray analysis was performed applying fluorescence in situ hybridization and immunohistochemistry to 296 OSCC specimens. Gene copy number gain of BIRC5 was detected in 33.9% (150/227) of cases, which correlated significantly with high UICC stage and the presence of lymph node metastases (p = 0.003 and p = 0.001, respectively), but not with unfavorable patients' outcome (p > 0.05) in multivariate analysis. High survivin expression was found in 67.3% (169/251) of cases to predict increased 5‐ and 10‐year overall survival of patients in a multivariate model including UICC stage and age as covariables (p = 0.035 and p = 0.026, respectively). Within a subgroup of patients, who received radiation therapy (n = 121), high survivin expression was found to be the only predictor of favorable 3‐, 5‐ and 10‐year overall survival in a multivariate cox regression analysis including UICC stage and age as covariables (p = 0.001, p = 0.004 and p = 0.006, respectively). In conclusion, high survivin expression might be useful to identify OSCC patients, who would benefit from radiotherapy. © 2006 Wiley‐Liss, Inc.
ICT and Ageing in Lebanese Public Hospitals - A Resource based View Perspective on Capabilities

This paper looks into the Lebanese healthcare system and its readiness to care for a growing elderly population and how ICT is used and how it is perceived by the stakeholders. The paper presents concerns on ageing population in Lebanon. It first addresses the status of hospital infrastructure in the country, and then discusses some interviews regarding ICT plans with six general managers of large public hospitals in different regions
Brood parasitism in the sand martin,Riparia riparia: evidence for two parasitic strategies in a colonial passerine

Sand martin parentage was studied at a large breeding colony in central Scotland. Multilocus DNA fingerprinting was used during the 3-year study to exclude some social parents as true parents, and thereby determine the frequency of monogamy, quasiparasitism (QP), intraspecific brood parasitism (ISBP) and extrapair fertilization (EPF) amongst 45 broods and 167 nestlings. Monogamous parentage characterized the majority of broods (60%), so most chicks were the offspring of their social parents (81%). QP (involving a male's extrapair mate laying in his nest) was found in 9% of broods and 2.4% of chicks and ISBP (or 'egg dumping') in 4% of broods and 1.8% of chicks. A substantial proportion of offspring arose from EPFs, affecting 36% of broods and 14% of chicks. On present evidence, the relatively high frequency of QP found in sand martins is unusual. We propose that its observed frequency is unlikely to be due to chance events and may represent a female-driven strategy. (c)1998 The Association for the Study of Animal Behaviour.
Local anaesthesia efficacy: discrepancies between in vitro and in vivo studies

Electrophysiological studies on isolated nerves have been used extensively in the past to assess the comparative efficiency of local anaesthetics as agents of peripheral nerve blockade. It is shown here that three closely related amide local anaesthetics behave differently in vitro and in vivo. In terms of onset of action and of maximum suppression of the evoked action potential, mepivacaine proved a less efficient anaesthetic than lidocaine or prilocaine on isolated nerves, but in parallel studies on the sciatic nerve of live animals and in the absence of vasoconstrictors: (a) mepivacaine's potency was superior to that of the other two agents, (b) its speed of onset of anaesthetic action was at least as good and (c) its duration of action was found to be considerably longer. These results, in combination with the physical properties of the anaesthetics examined, favour differential ionization as the cause of the reduced performance of mepivacaine in the nerve bath. Thus, studies on isolated nerves, which are often quoted in the pharmacological literature, can be poor guides to the in vivo comparative efficacy of local anaesthetics.
Abnormal Neural Basis of Emotional Conflict Control in Treatment-Resistant Depression

Emotional conflict has received increased attention as a research topic. The objective of this study is to confirm that the processing of emotional conflict is impaired in treatment-resistant depression (TRD). We compared the event-related potentials of 17 patients with TRD and 17 healthy controls during the face-word Stroop task, which is an effective way of assessing the effects of emotional conflict directly. Compared with healthy controls, the accuracy scores of the TRD patients were lower in both “congruent stimuli” and “incongruent stimuli” conditions, and their response times were longer. The TRD patients also had larger N2 amplitudes over the frontal region, regardless of stimulus condition, which might reflect that TRD patients pay more attention to emotional information. A larger P3 amplitude over the frontal region for “incongruent stimuli minus congruent stimuli” was also found among patients with TRD, which indicates interference effects in the Stroop task. The results of this study provide novel behavioral and neurophysiological evidence of anomalies in cognitive inhibition among patients with TRD using the word-face task. These findings not only improve our understanding of deficient inhibition in TRD, but also pave the way for a cognitive neuropsychiatric model of depression.
Competing Through Cooperation: The Organization of Standard Setting in Wireless Telecommunications

This study examines cooperative standard setting in wireless telecommunications. Focusing on the competition among firms to influence formal standardization, the roles of standard-setting committees, private alliances, and industry consortia are highlighted. The empirical context is Third Generation Partnership Project (3GPP), an international standards-development organization in the wireless telecommunication industry. Panel data analyses exploiting natural experiments caused by a consortium merger and entry of Asian firms suggest that participation in industry consortia increases firms' contributions to the development of new technical specifications in 3GPP committees. Moreover, connections to standard-setting peers formed in consortia facilitate change requests to ongoing specifications. These results suggest that if firms in network technology industries want to influence the evolution of their industry, they should identify both formal standard-setting committees and industry consortia in which they can discuss, negotiate, and align positions on technical features with their peers. For policymakers, these results suggest that it is important to ensure that technical consortia remain open for all industry actors and that membership fees do not become prohibitive to small and resource-constrained players.
Visualization of Grasping Operations based on Hand Kinematics measured through Data Glove

Although a number of prosthetic hands have been reported, anthropomorphic control is still a challenge. Precise determination of human hand kinematics will certainly enhance the control for prosthetic hands. One of the ways to push the research forward is to measure and visualize the human hand kinematics in real-time during grasping operations. This paper reports the development of a data glove that can measure human hand finger joint kinematics. The measured hand kinematics is visualized for 16 grasp types, adopted from Cutkosky's grasps taxonomy, in SynGrasp MATLAB toolbox. The glove can measure the finger joint angles with an accuracy±standard deviation for metacarpophalangeal (MCP)±4°, proximal inter phalangeal (PIP)±2° and distal inter phalangeal (DIP)±2° during flexion/ extension and abduction/ adduction.
Is 25 Gb/s On-Board Signaling Viable?

What package improvements are required for dense, high-aggregate bandwidth buses running at data rates beyond 10 Gb/s per channel, and when might optical interconnects on the board be required? We present a study of distance and speed limits for electrical on-board module-to-module links with an eye to answering these questions. Hardware-validated models of advanced organic modules and printed circuit boards were used to explore these limits. Simulations of link performance performed with an internal link modeling tool allowed us to explore the effect of equalization and modulation formats at different data rates on link bit error rate and eye opening. Our link models have been validated with active, high-speed differential bus measurements utilizing a 16-channel link chip with programmable equalization and a per-channel data rate of up to 11 Gb/s. Electrical signaling limits were then determined by extrapolating these hardware-correlated models to higher speeds, and these limits were compared to the results of recent work on on-board optical interconnects.
Conserved vertebrate mir-451 provides a platform for Dicer-independent, Ago2-mediated microRNA biogenesis

Canonical animal microRNAs (miRNAs) are generated by sequential cleavage of precursor substrates by the Drosha and Dicer RNase III enzymes. Several variant pathways exploit other RNA metabolic activities to generate functional miRNAs. However, all of these pathways culminate in Dicer cleavage, suggesting that this is a unifying feature of miRNA biogenesis. Here, we show that maturation of miR-451, a functional miRNA that is perfectly conserved among vertebrates, is independent of Dicer. Instead, structure-function and knockdown studies indicate that Drosha generates a short pre-mir-451 hairpin that is directly cleaved by Ago2 and followed by resection of its 3′ terminus. We provide stringent evidence for this model by showing that Dicer knockout cells can generate mature miR-451 but not other miRNAs, whereas Ago2 knockout cells reconstituted with wild-type Ago2, but not Slicer-deficient Ago2, can process miR-451. Finally, we show that the mir-451 backbone is amenable to reprogramming, permitting vector-driven expression of diverse functional miRNAs in the absence of Dicer. Beyond the demonstration of an alternative strategy to direct gene silencing, these observations open the way for transgenic rescue of Dicer conditional knockouts.
Prioritizing Areas of the Conasauga River Sub-basin in Georgia and Tennessee for Preservation and Restoration

Land preservation and restoration are important tools for managing imperiled aquatic species, but they are often applied in the absence of a transparent scheme of geographic prioritization. To help guide preservation and restoration efforts in the Conasauga River Basin in Georgia and Tennessee, we used the “Zonation” algorithm to prioritize sub-watersheds. Zonation is a prioritization system that uses species occurrence to identify localities of highest biodiversity, greatest interconnectivity, and (optionally) lowest cost. We based the prioritization on known and predicted distributions of 10 imperiled fish species and 12 imperiled invertebrate species, with predicted distributions derived from maximum entropy niche modeling. In the resulting prioritization scheme, highly ranked areas included the Conasauga River mainstem, the Conasauga headwaters, and the Holly Creek tributary system. We propose that a prioritization such as this should be conducted prior to any major program of land preservation or restoration.