Miracle-dz/UniFAR-FTUs huggingface dataset:
A novel BH3 ligand that selectively targets Mcl-1 reveals that apoptosis can proceed without Mcl-1 degradation

Like Bcl-2, Mcl-1 is an important survival factor for many cancers, its expression contributing to chemoresistance and disease relapse. However, unlike other prosurvival Bcl-2–like proteins, Mcl-1 stability is acutely regulated. For example, the Bcl-2 homology 3 (BH3)–only protein Noxa, which preferentially binds to Mcl-1, also targets it for proteasomal degradation. In this paper, we describe the discovery and characterization of a novel BH3-like ligand derived from Bim, BimS2A, which is highly selective for Mcl-1. Unlike Noxa, BimS2A is unable to trigger Mcl-1 degradation, yet, like Noxa, BimS2A promotes cell killing only when Bcl-xL is absent or neutralized. Furthermore, killing by endogenous Bim is not associated with Mcl-1 degradation. Thus, functional inactivation of Mcl-1 does not always require its elimination. Rather, it can be efficiently antagonized by a BH3-like ligand tightly engaging its binding groove, which is confirmed here with a structural study. Our data have important implications for the discovery of compounds that might kill cells whose survival depends on Mcl-1.
Watermarking, Tamper-Proofing, and Obfuscation-Tools for Software Protection

We identify three types of attack on the intellectual property contained in software and three corresponding technical defenses. A defense against reverse engineering is obfuscation, a process that renders software unintelligible but still functional. A defense against software piracy is watermarking, a process that makes it possible to determine the origin of software. A defense against tampering is tamper-proofing, so that unauthorized modifications to software (for example, to remove a watermark) will result in nonfunctional code. We briefly survey the available technology for each type of defense.
The End of Optimism? An Asymptotic Analysis of Finite-Armed Linear Bandits

Stochastic linear bandits are a natural and simple generalisation of finite-armed bandits with numerous practical applications. Current approaches focus on generalising existing techniques for finite-armed bandits, notably the optimism principle and Thompson sampling. While prior work has mostly been in the worst-case setting, we analyse the asymptotic instance-dependent regret and show matching upper and lower bounds on what is achievable. Surprisingly, our results show that no algorithm based on optimism or Thompson sampling will ever achieve the optimal rate, and indeed, can be arbitrarily far from optimal, even in very simple cases. This is a disturbing result because these techniques are standard tools that are widely used for sequential optimisation. For example, for generalised linear bandits and reinforcement learning.
Fast particle smoothing: if I had a million particles

We propose efficient particle smoothing methods for generalized state-spaces models. Particle smoothing is an expensive O(N2) algorithm, where N is the number of particles. We overcome this problem by integrating dual tree recursions and fast multipole techniques with forward-backward smoothers, a new generalized two-filter smoother and a maximum a posteriori (MAP) smoother. Our experiments show that these improvements can substantially increase the practicality of particle smoothing.
A comparative study of network link emulators

Between discrete event simulation and evaluation within real networks, network emulation is a useful tool to study and evaluate the behaviour of applications. Using a real network as a basis to simulate another network's characteristics, it enables researchers to perform experiments in a wide range of conditions. After an overview of the various available network emulators, this paper focuses on three freely available and widely used network link emulators: Dummynet, NIST-Net, and the Linux Traffic Control subsystem. We start by comparing their features, then focus on the accuracy of their latency and bandwidth emulation, and discuss the way they are affected by the time source of the system. We expose several problems that cannot be ignored when using such tools. We also outline differences in their user interfaces, such as the interception point, and discuss possible solutions. This work aims at providing a complete overview of the different solutions for network emulation.
Adaptive smoothing in fMRI data processing neural networks

Functional Magnetic Resonance Imaging (fMRI) relies on multi-step data processing pipelines to accurately determine brain activity; among them, the crucial step of spatial smoothing. These pipelines are commonly suboptimal, given the local optimisation strategy they use, treating each step in isolation. With the advent of new tools for deep learning, recent work has proposed to turn these pipelines into end-to-end learning networks. This change of paradigm offers new avenues to improvement as it allows for a global optimisation. The current work aims at benefitting from this paradigm shift by defining a smoothing step as a layer in these networks able to adaptively modulate the degree of smoothing required by each brain volume to better accomplish a given data analysis task. The viability is evaluated on real fMRI data where subjects did alternate between left and right finger tapping tasks.
Opposing Effects of C-Reactive Protein Isoforms on Shear-Induced Neutrophil-Platelet Adhesion and Neutrophil Aggregation in Whole Blood

Background—Plasma C-reactive protein (CRP) level is a powerful predictor of cardiovascular events. However, it is not known whether CRP could affect neutrophil-platelet adhesion and neutrophil aggregation, key events in acute coronary syndromes. Emerging in vitro evidence suggests that some bioactivities of CRP are expressed on loss of the pentameric symmetry, resulting in formation of modified or monomeric CRP (mCRP). Methods and Results—We studied the impact of human native CRP and bioengineered mCRP that cannot rearrange into the pentameric structure on the kinetics of neutrophil-platelet adhesion and neutrophil aggregation in whole blood subjected to shear (≈100 s−1) using real-time flow cytometry. Shear resulted in upregulation of platelet P-selectin expression, leading to platelet capture of neutrophils and subsequent neutrophil aggregation, which was dependent on P-selectin, L-selectin, and CD18. Native CRP at clinically relevant concentrations markedly attenuated these changes. The residual amount of neutrophil adhesion was blocked with anti-CD18 or anti-CD11b antibody. By contrast, mCRP concentration-dependently enhanced shear-induced platelet P-selectin expression and increased the rate and extent of formation of both neutrophil-platelet and neutrophil-neutrophil aggregates. Complete abrogation of platelet-neutrophil adhesion and neutrophil aggregation required both anti–P-selectin and anti-CD18 antibodies but not anti–L-selectin antibody. The CRP action was markedly inhibited by an anti-CD32 antibody, whereas the mCRP effects were significantly attenuated by an anti-CD16 antibody. Conclusions—These results indicate that native CRP inhibits platelet activation and prevents platelet capture of neutrophils, whereas mCRP displays potent prothrombotic activities under low levels of shear. Thus, mCRP rather than native CRP may precipitate acute coronary syndromes.
Proto-value Functions: A Laplacian Framework for Learning Representation and Control in Markov Decision Processes

This paper introduces a novel spectral framework for solving Markov decision processes (MDPs) by jointly learning representations and optimal policies. The major components of the framework described in this paper include: (i) A general scheme for constructing representations or basis functions by diagonalizing symmetric diffusion operators (ii) A specific instantiation of this approach where global basis functions called proto-value functions (PVFs) are formed using the eigenvectors of the graph Laplacian on an undirected graph formed from state transitions induced by the MDP (iii) A three-phased procedure called representation policy iteration comprising of a sample collection phase, a representation learning phase that constructs basis functions from samples, and a final parameter estimation phase that determines an (approximately) optimal policy within the (linear) subspace spanned by the (current) basis functions. (iv) A specific instantiation of the RPI framework using least-squares policy iteration (LSPI) as the parameter estimation method (v) Several strategies for scaling the proposed approach to large discrete and continuous state spaces, including the Nystrom extension for out-of-sample interpolation of eigenfunctions, and the use of Kronecker sum factorization to construct compact eigenfunctions in product spaces such as factored MDPs (vi) Finally, a series of illustrative discrete and continuous control tasks, which both illustrate the concepts and provide a benchmark for evaluating the proposed approach. Many challenges remain to be addressed in scaling the proposed framework to large MDPs, and several elaboration of the proposed framework are briefly summarized at the end.
Motoneuronal Activity Movements of a Stick Insect Leg. II. Control of Pattern Generation for Walking and Searching

[PDF] [Full Text] [Abstract] , January 1, 2001; 85 (1): 341-353. J Neurophysiol H. Fischer, J. Schmidt, R. Haas and A. Buschges Coordination of Motor Activity Pattern Generation for Walking and Searching Movements of a Stick Insect Leg. I. [PDF] [Abstract] , March 1, 2003; 22 (3-4): 151-167. The International Journal of Robotics Research V. Durr, A. F. Krause, J. Schmitz and H. Cruse Neuroethological Concepts and their Transfer to Walking Machines [PDF] [Full Text] [Abstract] , July 2, 2003; 23 (13): 5953-5962. J. Neurosci. B. Mulloney Swimmeret Motor Neurons During Fictive Locomotion, Graded Synaptic Currents Drive Bursts of Impulses in [PDF] [Full Text] [Abstract] , March 1, 2005; 93 (3): 1255-1265. J Neurophysiol B. Ch. Ludwar, M. L. Goritz and J. Schmidt Intersegmental Coordination of Walking Movements in Stick Insects [PDF] [Full Text] [Abstract] , October 1, 2005; 94 (4): 2772-2784. J Neurophysiol B. Ch. Ludwar, S. Westmark, A. Buschges and J. Schmidt Insect Front-Leg Walking Modulation of Membrane Potential in Mesothoracic Motoand Interneurons During Stick
CLINICAL ANATOMY OF THE NORTH AMERICAN RIVER OTTER (LONTRA CANADENSIS)

Abstract Published anatomic studies of North American river otters (Lontra canadensis) include only comparative reviews of single anatomic systems, but this paper includes multiple clinically relevant anatomic features. Both captive and free-ranging North American river otters were studied by gross dissection of nine specimens, radiography of 18 live otters, and physical examination of 170 otters. Body fat in North American river otters is stored primarily subcutaneously at the base of the tail and in the axillae, so lack of visceral detail on abdominal radiographs is due to a lack of coelomic fat. The heart and great vessels are oriented as in the dog. The cardiac radiographic silhouette measures three intercostal spaces laterally between the fourth and sixth ribs and 4–4.5 intercostal spaces between the seventh through 11th ribs on the ventrodorsal projection. Subjective estimation of age by evaluation of tooth wear is confirmed by histologic examination of cementum annuli. Structures of the feet were imaged by high-resolution mammographic technique. The adult thymus was prominent, but the gland was small in the one juvenile animal studied. The spleen was unexpectedly large but consistent with findings in European otters (Lutra lutra). As in other otters and mammals, kidneys are reniculated.
The Power of Gene-Based Rare Variant Methods to Detect Disease-Associated Variation and Test Hypotheses About Complex Disease

Genome and exome sequencing in large cohorts enables characterization of the role of rare variation in complex diseases. Success in this endeavor, however, requires investigators to test a diverse array of genetic hypotheses which differ in the number, frequency and effect sizes of underlying causal variants. In this study, we evaluated the power of gene-based association methods to interrogate such hypotheses, and examined the implications for study design. We developed a flexible simulation approach, using 1000 Genomes data, to (a) generate sequence variation at human genes in up to 10K case-control samples, and (b) quantify the statistical power of a panel of widely used gene-based association tests under a variety of allelic architectures, locus effect sizes, and significance thresholds. For loci explaining ~1% of phenotypic variance underlying a common dichotomous trait, we find that all methods have low absolute power to achieve exome-wide significance (~5-20% power at α=2.5×10-6) in 3K individuals; even in 10K samples, power is modest (~60%). The combined application of multiple methods increases sensitivity, but does so at the expense of a higher false positive rate. MiST, SKAT-O, and KBAC have the highest individual mean power across simulated datasets, but we observe wide architecture-dependent variability in the individual loci detected by each test, suggesting that inferences about disease architecture from analysis of sequencing studies can differ depending on which methods are used. Our results imply that tens of thousands of individuals, extensive functional annotation, or highly targeted hypothesis testing will be required to confidently detect or exclude rare variant signals at complex disease loci.
Gingival zenith positions and levels of the maxillary anterior dentition.

PURPOSE The location of the gingival zenith in a medial-lateral position relative to the vertical tooth axis of the maxillary anterior teeth remains to be clearly defined. In addition, the apex of the free gingival margin of the lateral incisor teeth relative to the gingival zeniths of the adjacent proximal teeth remains undetermined. Therefore, this investigation evaluated two clinical parameters: (1) the gingival zenith position (GZP) from the vertical bisected midline (VBM) along the long axis of each individual maxillary anterior tooth; and (2) the gingival zenith level (GZL) of the lateral incisors in an apical-coronal direction relative to the gingival line joining the tangents of the GZP of the adjacent central incisor and canine teeth under healthy conditions. MATERIALS AND METHODS A total of 240 sites in 20 healthy patients (13 females, 7 males) with an average age of 27.7 years were evaluated. The inclusion patient criteria were absence of periodontal disease, gingival recession, or gingival hypertrophy as well as teeth without loss of interdental papillae, spacing, crowding, existing restorations, and incisal attrition. GZP dimensions were measured with calibrated digital calipers for each individual tooth and within each tooth group in a medial-lateral direction from the VBM. GZLs were measured in an apical-coronal direction from a tangent line drawn on the diagnostic casts from the GZPs of the adjacent teeth. RESULTS This study demonstrated that all central incisors displayed a distal GZP from the VBM, with a mean average of 1 mm. Lateral incisors showed a deviation of the gingival zenith by a mean of 0.4 mm. In 97.5% of the canine population, the GZP was centralized along the long axis of the canine. The mean distance of the contour of the gingival margin in an apical-coronal direction of the lateral incisors (GZL) relative to gingival line joining the tangent of the adjacent central and canine GZPs was approximately 1 mm. CONCLUSION This investigation revealed a GZP mean value of 1 mm distal from the VBM for the central incisor tooth group. The lateral incisors showed a mean average of 0.4 mm. The canine tooth group demonstrated almost no deviations of the GZP from the VBM. The GZL of the lateral incisors relative to the adjacent central incisor and canine teeth were more coronal by approximately 1 mm. These data could be used as reference points during esthetic anterior oral rehabilitation. CLINICAL SIGNIFICANCE The information presented in this article can be clinically applied to reestablish the proper intratooth GZPs of the maxillary anterior teeth during periodontal crown lengthening or root coverage procedures. In addition, the intra-arch gingival level of the lateral incisor gingival zenith relative to the adjacent central and canine teeth can be appropriately established.
Buffer Space Allocation for Real-Time Priority-Aware Networks

In this work, we address the challenge of incorporating buffer space constraints in worst-case latency analysis for priority-aware networks. A priority-aware network is a wormhole-switched network-on-chip with distinct virtual channels per priority. Prior worst-case latency analyses assume that the routers have infinite buffer space allocated to the virtual channels. This assumption renders these analyses impractical when considering actual deployments. This is because an implementation of the priority-aware network imposes buffer constraints on the application. These constraints can result in back pressure on the communication, which the analyses must incorporate. Consequently, we extend a worst- case latency analysis for priority-aware networks to include buffer space constraints. We provide the theory for these extensions and prove their correctness. We experiment on a large set of synthetic benchmarks, and show that we can deploy applications on priority-aware networks with virtual channels of sizes as small as two flits. In addition, we propose a polynomial time buffer space allocation algorithm. This algorithm minimizes the buffer space required at the virtual channels while scheduling the application sets on the target priority-aware network. Our empirical evaluation shows that the proposed algorithm reduces buffer space requirements in the virtual channels by approximately 85% on average.
VISUAL WORD RECOGNITION IN SERBO-CROATIAN IS NECESSARILY PHONOLOGICAL

In a naming task conducted with bi-alphabetic readers of Serbo-Croatian. it was shown that letter strings that can be assigned both a Roman and a Cyrillic alphabet reading incur longer latencies than the unique alphabet transcription of the same word. and that the magnitude of the difference depended on the number of ambiguous characters in the ambiguous letter string. While this wi thin-word phonological ambiguity effect obtained for both wprds and pseudowords. it was more consistent with words. The same pattern of results occurred in a lexical decision task. and the correlation between latencies (for words and pseudowords) in the two tasks was significant. It was concluded that both lexical decision and naming in Serbo-Croatian necessarily involve a phonological strategy.
Effects of Si and Cr on Bainite Microstructure of Medium Carbon Steels

Effects of Si and Cr contents on bainite microstructure of medium carbon steels have been examined in order to obtain important information for good strength–ductility balanced spring steel. Four practical medium carbon steels, JIS-S55C, SUP9, SUP7 and SUP12 were isothermally transformed at temperatures between 300°C and 500°C after austenitized at 1000°C. The microstructure was observed by means of scanning electron microscopy and transmission electron microscopy. While carbide was formed from the early stage of bainite transformation in S55C without Si and Cr, carbide precipitation was suppressed by the increase of Si particularly in SUP7 and SUP12. The fraction of retained austenite was increased with increasing of Si and Cr at the intermediate stage of bainite transformation because of the increase of C concentration in retained austenite. Particularly, Si addition promoted carbide-free bainitic ferrite and leading to larger amounts of retained austenite by carbon enrichment.
Protamine 2 precursors, protamine 1/protamine 2 ratio, DNA integrity and other sperm parameters in infertile patients.

BACKGROUND The protamine 1-to-protamine 2 ratio (P1/P2) is altered in the sperm cells of some infertile patients. Also, evidence for increased protamine 2 precursors (pre-P2) in a few patients has been reported. But so far, there have been no studies measuring simultaneously these two variables in a large number of patients. METHODS We measured the P1/P2 ratio and the presence of pre-P2 using, for the first time, an antibody specific to the precursor pre-P2, together with other sperm parameters in 224 infertile patients. Additionally, the DNA integrity was assessed by terminal transferase dUTP nick-end labelling (TUNEL) in a subset of the samples. RESULTS Pre-P2 levels show a significant positive correlation with the P1/P2 ratio, with the presence of other proteins and, at low pre-P2 levels, with TUNEL-positive sperm. An inverse correlation with sperm count, normal morphology and motility was detected. CONCLUSIONS The levels of pre-P2 may provide clues into the pathogenic mechanisms of infertility. The increased proportion of pre-P2 in some patients with increased P1/P2 ratio suggests an involvement of pre-P2 processing. The positive correlation between TUNEL-positive sperm and pre-P2 at low pre-P2/P2 ratios also suggests a link between deficient protamine processing and decreased DNA integrity.
Spacetime Forests with Complementary Features for Dynamic Scene Recognition

This paper presents spacetime forests defined over complementary spatial and temporal features for recognition of naturally occurring dynamic scenes. The approach improves on the previous state-of-the-art in both classification and execution rates. A particular improvement is with increased robustness to camera motion, where previous approaches have experienced difficulty. There are three key novelties in the approach. First, a novel spacetime descriptor is employed that exploits the complementary nature of spatial and temporal information, as inspired by previous research on the role of orientation features in scene classification. Second, a forest-based classifier is used to learn a multi-class representation of the feature distributions. Third, the video is processed in temporal slices with scale matched preferentially to scene dynamics over camera motion. Slicing allows for temporal alignment to be handled as latent information in the classifier and for efficient, incremental processing. The integrated approach is evaluated empirically on two publically available datasets to document its outstanding performance.
Molecular Features of Wheat Endosperm Arabinoxylan Inclusion in Functional Bread

Arabinoxylan (AX) is a major dietary fibre component found in a variety of cereals. Numerous health benefits of arabinoxylans have been reported to be associated with their solubility and molecular features. The current study reports the development of a functional bread using a combination of AX-enriched material (AEM) and optimal commercial endoxylanase. The total AX content of bread was increased to 8.2 g per 100 g available carbohydrates. The extractability of AX in breads with and without endoxylanase was determined. The results demonstrate that water-extractable AX (WE-AX) increased progressively through the bread making process. The application of endoxylanase also increased WE-AX content. The presence of 360 ppm of endoxylanase had positive effects on the bread characteristics in terms of bread volume and firmness by converting the water unextractable (WU)-AX to WE-AX. In addition, the molecular weight (Mw) distribution of the WE-AX of bread with and without endoxylanase was characterized by size-exclusion chromatography. The results show that as the portion of WE-AX increased, the amount of high Mw WE-AX (higher than 100 kDa) decreased, whereas the amount of low Mw WE-AX (lower than 100 kDa) increased from 33.2% to 44.2% through the baking process. The low Mw WE-AX further increased to 75.5% with the application of the optimal endoxylanase (360 ppm).