Miracle-dz/UniFAR-FTUs huggingface dataset:
Outcomes of CLL patients treated with sequential kinase inhibitor therapy: a real world experience.

B-cell receptor kinase inhibitor (KI) therapy represents a paradigm shift in chronic lymphocytic leukemia (CLL) management, but data on practice patterns after KI discontinuation and optimal sequencing are limited. We conducted a multicenter, retrospective, comprehensive analysis on 178 patients with CLL (ibrutinib = 143; idelalisib = 35) who discontinued KI therapy. We examined responses, toxicity, post-KI therapies, and overall survival (OS). Patients had a median of 3 prior therapies (range 0-11); del17p (34%), p53 mutation (27%), del11q (33%), and complex karyotype (29%). Overall response rate (ORR) to first KI was 62% (complete response 14%). The most common reasons for KI discontinuation were toxicity (51%), CLL progression (29%), and Richter transformation (RT) (8%). Median progression-free survival (PFS) and OS from KI initiation were 10.5 and 29 months, respectively. Notably, initial KI choice did not impact PFS or OS; however, RT portended significantly inferior OS (P = .0007). One hundred fourteen patients received subsequent salvage therapy following KI discontinuation with an ORR to subsequent KI at 50% and a median PFS of 11.9 months. Median PFS in KI-intolerant patients treated with an alternate KI was not reached vs 7 months for patients with CLL progression. In summary, these data demonstrate that toxicity was the most common reason for KI discontinuation, that patients who discontinue KI due to toxicity can respond to an alternate KI, and that these responses may be durable. This trial was registered at www.clinicaltrials. gov as #NCT02717611 and #NCT02742090.
Atomic resolution analysis of the catalytic site of an aspartic proteinase and an unexpected mode of binding by short peptides

The X‐ray structures of native endothiapepsin and a complex with a hydroxyethylene transition state analog inhibitor (H261) have been determined at atomic resolution. Unrestrained refinement of the carboxyl groups of the enzyme by using the atomic resolution data indicates that both catalytic aspartates in the native enzyme share a single negative charge equally; that is, in the crystal, one half of the active sites have Asp 32 ionized and the other half have Asp 215 ionized. The electron density map of the native enzyme refined at 0.9 Å resolution demonstrates that there is a short peptide (probably Ser‐Thr) bound noncovalently in the active site cleft. The N‐terminal nitrogen of the dipeptide interacts with the aspartate diad of the enzyme by hydrogen bonds involving the carboxyl of Asp 215 and the catalytic water molecule. This is consistent with classical findings that the aspartic proteinases can be inhibited weakly by short peptides and that these enzymes can catalyze transpeptidation reactions. The dipeptide may originate from autolysis of the N‐terminal Ser‐Thr sequence of the enzyme during crystallization.
Nociceptin receptor coupling to a potassium conductance in rat locus coeruleus neurones in vitro

1 In this study we have examined the effects of nociceptin, an endogenous ligand for the opioid‐like receptor ORL1, on the membrane properties of rat locus coeruleus (LC) neurones in vitro, using intracellular and whole cell patch clamp recording. 2 When locus coeruleus neurones were voltage clamped to −60 mV, application of nociceptin caused an outward current in all cells examined (n = 49), with an EC50 of 90 nM. Neither the potency nor the maximal effect of nociceptin was altered in the presence of the peptidase inhibitors, bestatin (20 μm) or thiorphan (2 μm). 3 The outward currents caused by nociceptin in 2.5 mM extracellular K+ reversed polarity at −123 mV, more negative than the predicted K+ reversal potential of −105 mV. Increasing extracellular K+ to 6.5 mM resulted in a shift of the reversal potential of +25 mV, a shift consistent with a K+ conductance. The conductance activated by nociceptin showed mild inward rectification. 4 Application of a high concentration of nociceptin (3 μm) occluded the current produced by simultaneous application of high concentrations of Met‐enkephalin (10 μm), (3 μm) somatostatin and UK 14304 (3 μm), indicating that nociceptin activated the same conductance as μ‐opioid and somatostatin receptors and α2‐adrenoceptors. 5 The actions of nociceptin were weakly antagonized by the opioid antagonist, naloxone, with pKb′s estimated from 2 cells of −4.23 and −4.33. The μ‐opioid antagonist, CTAP (D‐Phe‐Cys‐Tyr‐D‐Trp‐Arg‐Pen‐Thr‐NH2, 1 μm), the opioid antagonist, nalorphine (30 μm), or the somatostatin antagonist, CPP (cyclo(7‐aminoheptanoyl‐Phe‐D‐Tip‐Lys‐Thr[Bzl]) 3 μm) did not affect the nociceptin‐induced current. 6 Dynorphin A (3 μm), another putative endogenous ligand for ORL1, caused a robust outward current in locus coeruleus neurones that was, however, completely antagonized by moderate concentrations of naloxone (300 nM‐1 μm). 7 Continuous application of nociceptin (3 μm) resulted in a decrease of the outward current to a steady level of 70% of the maximum response with a t1/2 of 120s. Desensitization was largely homologous because simultaneous application of Met‐enkephalin (30 μm) during the desensitized period of the nociceptin response resulted in an outward current that was 92% of control responses to Met‐enkephalin in the same cells. Conversely, continuous application of Met‐enkephalin (30 μm) resulted in a decrease of Met‐enkephalin current to a steady level that was 54% of the initial current. During this desensitized period application of nociceptin (3 μm) resulted in a current that was 78% of the control responses to nociceptin in the same cells. 8 Thus nociceptin potently activates an inwardly rectifying K+ conductance in locus coeruleus neurones, with a pharmacological profile consistent with activation of the ORL1 receptor. Dynorphin A does not appear to be a ligand for ORL1 in rat locus coeruleus neurones.
A geometric approach to inspection

An exact solution is presented to the following inspection problem in two dimensions. A manufactured part is desired to have a polygonal shape E/sub d/. Tolerances are given in terms of two polygons, one, called E/sup -/ lying within E/sub d/, and the other, called E/sup +/, lying outside E/sub d/. A vision system yields a description of each manufactured part as a polygon I. It is desired to determine whether I can be translated and rotated to lie between the tolerance polygons E/sup -/ and E/sup +/, in which case the part is considered to conform to the desired tolerances. <<ETX>>
Universal Dependencies for Japanese

We present an attempt to port the international syntactic annotation scheme, Universal Dependencies, to the Japanese language in this paper. Since the Japanese syntactic structure is usually annotated on the basis of unique chunk-based dependencies, we first introduce word-based dependencies by using a word unit called the Short Unit Word, which usually corresponds to an entry in the lexicon UniDic. Porting is done by mapping the part-of-speech tagset in UniDic to the universal part-of-speech tagset, and converting a constituent-based treebank to a typed dependency tree. The conversion is not straightforward, and we discuss the problems that arose in the conversion and the current solutions. A treebank consisting of 10,000 sentences was built by converting the existent resources and currently released to the public.
Effects of Randomly Added Links on a Phase Transition in Data Network Traffic Models

We investigate how additional links added randomly to a network connection topology affect the phase transition from the free flow state to the congested state in packet-switching networks (PSNs). For the purpose of our study we have identified that the OSI Network Layer is the most important layer of the OSI reference model. For this layer we developed an abstraction for which we derived a time-discrete algo-ion for which we derived a time-discrete algorithmic simulation model. Using this simulation model we investigate the effects of various routing algorithms and connection topologies on the phase transition point. In this article we highlight the developed methodology and present some selected results.
Title Anti-smoking Educational Game Using Avatars as Visualized Possible Selves Anti-smoking Educational Game 1 Running Head: Anti-smoking Educational Game Anti-smoking Educational Game Using Avatars as Visualized Possible Selves Anti-smoking Educational Game 2 Anti-smoking Educational Game Using Av

Few social smokers envision themselves being affected by the negative consequences of smoking despite well-known facts that smoking causes serious illnesses and death. However, as smoking habits quickly develop, social smokers cannot be free from the negative consequences of smoking. In this study, we pose the following question: “Would showing social smokers’ possible future as a consequence of smoking help them alter their current smoking behaviors? ” Thus, using the theoretical concept of possible selves, an anti-smoking educational game was created in which players could see changes to the appearance of their future selves as a consequence of smoking. We used a 2 (Future face: Showing vs. Not showing) x 2 (Self avatar: Self-avatar vs. Other-avatar) between-subjects design for the experiment. Results indicated that participants who viewed the future face, compared to who did not, reported more negative attitudes toward social smoking and greater intention to quit smoking. The main effect of the self avatar was insignificant; however, seeing the future face in the self-avatar condition led to an increase in perceived risks compared to other-avatar condition. The implications of using avatars as visualized possible selves in health promotion are discussed.
Simulation Model of Wind Turbine 3p Torque Oscillations due to Wind Shear and Tower Shadow

To determine control structures and possible power quality issues, the dynamic torque generated by the blades of a wind turbine must be represented. This paper presents an analytical formulation of the generated aerodynamic torque of a three bladed wind turbine including effects of wind shear and tower shadow. The comprehensive model includes turbine specific parameters such as radius, height, and tower dimensions, as well as the site specific parameter, the wind shear exponent. The model proves the existence of a 3p pulsation due to wind shear and explains why it cannot be easily identified in field measurements. The proportionality constant between torque and wind speed is determined allowing direct aerodynamic torque calculation from an equivalent wind speed. It is shown that the tower shadow effect is more dominant than the wind shear effect in determining the dynamic torque, although there is a small DC reduction in the torque oscillation due to wind shear. The model is suitable for real-time wind turbine simulation or other time domain simulation of wind turbines in power systems
Improving GGH cryptosystem for large error vector

This paper analyzes the first lattice-based encryption scheme proposed by Goldreich, Goldwasser and Halevi and proposed a variant of the schemes to improve resistance against lattice reductions. In practice, lattice reductions such as LLL reduction are able to break the specific CVP with small dimension that was applied to the GGH cryptosystem; the scheme with representative dimensions such as 400 dimension was broken. This paper proposes an improvement of GGH cryptosystem based on a variant of lattice problem, which is expected to be harder than the previous problem of CVP. For given lattice basis B, a vector v, sets of integers I1 and I2, and an integer k, the problem is to find a vector e such that k coordinates of b-v are in I1 and others are in I2 with some lattice vector b. Furthermore, unlike the original GGH cryptosystem sacrificed from an ineligible probability of decryption error, the proposal solves the decryption error problem and decrypts ciphertext with probability 1.
Low complexity language recognition exploiting ensemble of random subspace

The current approaches for spoken language recognition (LR) are predominantly based on GMM mean supervector as the representation of the utterances. It is assumed that the language information lies in a linear manifold of low dimensional spaces. Exploiting that a low dimensional projections of the GMM mean supervectors, known as i-vectors, are derived using a total variability matrix. The i-vector representation followed by LDA/WCCN based session/channel compensation forms the state-of-the-art. The major drawback of the i-vector approach lies in its computational complexity and storage requirements. Motivated by these constraints, in this work we explore ensemble of random subspaces of supervector based LR approach which includes LDA/WCCN based session/channel compensation in the subspace. The proposed approach does not require any learning for creating the subspaces and has very low storage requirements. In typical LR applications, the number of languages involved is not very large. As a result of that the complexity of joint factor analysis (JFA) based system turns out to be lower than that of the i-vector based one. Exploiting this fact, the combination of the proposed ensemble approach with JFA is also explored. The effectiveness of the proposed ensemble approach is demonstrated on the NIST 2007 language recognition evaluation task.
Understanding disk failure rates: What does an MTTF of 1,000,000 hours mean to you?

Component failure in large-scale IT installations is becoming an ever-larger problem as the number of components in a single cluster approaches a million. This article is an extension of our previous study on disk failures [Schroeder and Gibson 2007] and presents and analyzes field-gathered disk replacement data from a number of large production systems, including high-performance computing sites and internet services sites. More than 110,000 disks are covered by this data, some for an entire lifetime of five years. The data includes drives with SCSI and FC, as well as SATA interfaces. The mean time-to-failure (MTTF) of those drives, as specified in their datasheets, ranges from 1,000,000 to 1,500,000 hours, suggesting a nominal annual failure rate of at most 0.88%. We find that in the field, annual disk replacement rates typically exceed 1%, with 2--4% common and up to 13% observed on some systems. This suggests that field replacement is a fairly different process than one might predict based on datasheet MTTF. We also find evidence, based on records of disk replacements in the field, that failure rate is not constant with age, and that rather than a significant infant mortality effect, we see a significant early onset of wear-out degradation. In other words, the replacement rates in our data grew constantly with age, an effect often assumed not to set in until after a nominal lifetime of 5 years. Interestingly, we observe little difference in replacement rates between SCSI, FC, and SATA drives, potentially an indication that disk-independent factors such as operating conditions affect replacement rates more than component-specific ones. On the other hand, we see only one instance of a customer rejecting an entire population of disks as a bad batch, in this case because of media error rates, and this instance involved SATA disks. Time between replacement, a proxy for time between failure, is not well modeled by an exponential distribution and exhibits significant levels of correlation, including autocorrelation and long-range dependence.
Change in protein flexibility upon complex formation: Analysis of Ras‐Raf using molecular dynamics and a molecular framework approach

Changes in flexibility upon protein–protein complex formation of H‐Ras and the Ras‐binding domain of C‐Raf1 have been investigated using the molecular framework approach FIRST (Floppy Inclusion and Rigid Substructure Topology) and molecular dynamics simulations (MD) of in total ∼35 ns length. In a computational time of about one second, FIRST identifies flexible and rigid regions in a single, static three‐dimensional molecular framework, whose vertices represent protein atoms and whose edges represent covalent and non‐covalent (hydrogen bond and hydrophobic) constraints and fixed bond angles within the protein. The two methods show a very good agreement with respect to the identification of changes in flexibility in both binding partners on a local scale. This implies that flexibility can be successfully predicted by identifying which bonds limit motion within a molecule and how they are coupled. In particular, as identified by MD, the β‐sheet in Raf shows considerably more pronounced orientational correlations in the bound state compared to the unbound state. Similarly, FIRST assigns the β‐sheet to the largest rigid cluster of the complex. Interestingly, FIRST allows us to identify that interactions across the interface (but not conformational changes upon complex formation) result in the observed rigidification. Since regions of the β‐sheet of Raf that do not interact directly with Ras become rigidified, this also demonstrates the long‐range aspect to rigidity percolation. Possible implications of the change of flexibility of the Ras‐binding domain of Raf on the activation of Raf upon complex formation are discussed. Finally, the sensitivity of FIRST results with respect to the representation of non‐covalent interactions used as constraints is probed. Proteins 2004. © 2004 Wiley‐Liss, Inc.
Quantifying Bias in Randomized Controlled Trials in Child Health: A Meta-Epidemiological Study

Objective To quantify bias related to specific methodological characteristics in child-relevant randomized controlled trials (RCTs). Design Meta-epidemiological study. Data Sources We identified systematic reviews containing a meta-analysis with 10–40 RCTs that were relevant to child health in the Cochrane Database of Systematic Reviews. Data Extraction Two reviewers independently assessed RCTs using items in the Cochrane Risk of Bias tool and other study factors. We used meta-epidemiological methods to assess for differences in effect estimates between studies classified as high/unclear vs. low risk of bias. Results We included 287 RCTs from 17 meta-analyses. The proportion of studies at high/unclear risk of bias was: 79% sequence generation, 83% allocation concealment, 67% blinding of participants, 47% blinding of outcome assessment, 49% incomplete outcome data, 32% selective outcome reporting, 44% other sources of bias, 97% overall risk of bias, 56% funding, 35% baseline imbalance, 13% blocked randomization in unblinded trials, and 1% early stopping for benefit. We found no significant differences in effect estimates for studies that were high/unclear vs. low risk of bias for any of the risk of bias domains, overall risk of bias, or other study factors. Conclusions We found no differences in effect estimates between studies based on risk of bias. A potential explanation is the number of trials included, in particular the small number of studies with low risk of bias. Until further evidence is available, reviewers should not exclude RCTs from systematic reviews and meta-analyses based solely on risk of bias particularly in the area of child health.
Ketamine activation of experimental corticoreticular epilepsy

Generalized corticoreticular epilepsy was established in adult cats by parenteral penicillin, and electroencephalographic monitoring was carried out. Ketamine HCI was injected intravenously in doses of 2.5 to 20 mg per kilogram. If doses of penicillin were inadequate to establish typical spike-wave activity, ketamine induced the spike-wave pattern typical of much higher doses of penicillin. At doses of penicillin that established the spike-wave pattern, ketamine potentiated the spike-wave activity and sometimes induced spike-and-wave status. These findings suggest caution in the clinical use of ketamine in patients with corticoreticular epilepsy. Because analogous effects have been observed upon administration of GABA-mimetic agents, GABA systems may play a role in ketamine anesthesia and corticoreticular epilepsy. Precollicular brain transections failed to modify ketamine effects, excluding a possible influence of mesencephalic centers on the observed potentiation.
Multispace KL for Pattern Representation and Classification

This work introduces the multispace Karhunen-Loeve (MKL) as a new approach to unsupervised dimensionality reduction for pattern representation and classification. The training set is automatically partitioned into disjoint subsets, according to an optimality criterion; each subset then determines a different KL subspace which is specialized in representing a particular group of patterns. The extension of the classical KL operators and the definition of ad hoc distances allow MKL to be effectively used where KL is commonly employed. The limits of the standard KL transform are pointed out, in particular, MKL is shown to outperform KL when the data distribution is far from a multidimensional Gaussian and to better cope with large sets of patterns, which could cause a severe performance drop in KL.
Lymphotoxin Induces Secretion of Granule Proteins From Adherent Neutrophils: Possible Role of Intracellular Free Calcium

Lymphotoxin (LT) can activate human neutrophils. Using a hemolytic plaque assay to detect secretion of lactoferrin and myeloperoxidase (MPO) from single adherent neutrophils, we showed that LT induced secretion from both primary and secondary granules. Incubation of cells with cytochalasin B was required for MPO secretion, and it enhanced lactoferrin secretion. Pertussis toxin, which blocks a G‐protein in the plasma membrane, inhibited LT‐induced exocytosis of MPO, but not of lactoferrin. Incubation with LT did not induce any detectable changes of the cytoplasmic free [Ca2+] in neutrophils. On the other hand, secretion of granule proteins from adherent neutrophils in response to LT was blocked by loading neutrophils with quin‐2 in order to increase the intracellular calcium buffering capacity. This was achieved at a concentration of quin‐2, at which the secretion induced by the phorbol ester PMA and the chemotactic peptide FMLP was unaffected. Trifluoroperazine (TFP), a dual protein kinase C and calmodulin inhibitor, significantly inhibited the LT‐mediated secretion of lactoferrin from adherent granulocytes. The PMA effect was unaltered by TFP under these conditions, suggesting that the inhibitory effect was on a calcium‐calmodulin dependent step. The secretion induced by TNF and GM‐CSF was also blocked by buffering changes in the intracellular ICa2+] and inhibited to a similar extent by TFP. Our results suggest that calmodulin and minute changes in the cytoplasmic free [Ca2+] may be involved in a common signal transduction pathway engaged in activation of adherent neutrophils by several cytokines.
Psychiatric characteristics in transsexual individuals: multicentre study in four European countries.

BACKGROUND Research into the relationship between gender identity disorder and psychiatric problems has shown contradictory results. AIMS To investigate psychiatric problems in adults fulfilling DSM-IV-TR criteria for a diagnosis of gender identity disorder. METHOD Data were collected within the European Network for the Investigation of Gender Incongruence using the Mini International Neuropsychiatric Interview - Plus and the Structured Clinical Interview for DSM-IV Axis II Disorders (n = 305). RESULTS In 38% of the individuals with gender identity disorder a current DSM-IV-TR Axis I diagnosis was found, mainly affective disorders and anxiety disorders. Furthermore, almost 70% had a current and lifetime diagnosis. All four countries showed a similar prevalence, except for affective and anxiety disorders, and no difference was found between individuals with early-onset and late-onset disorder. An Axis II diagnosis was found in 15% of all individuals with gender identity disorder, which is comparable to the general population. CONCLUSIONS People with gender identity disorder show more psychiatric problems than the general population; mostly affective and anxiety problems are found.