Miracle-dz/UniFAR-FTUs huggingface dataset:
Reversing Melanoma Cross-Resistance to BRAF and MEK Inhibitors by Co-Targeting the AKT/mTOR Pathway

Background The sustained clinical activity of the BRAF inhibitor vemurafenib (PLX4032/RG7204) in patients with BRAFV600 mutant melanoma is limited primarily by the development of acquired resistance leading to tumor progression. Clinical trials are in progress using MEK inhibitors following disease progression in patients receiving BRAF inhibitors. However, the PI3K/AKT pathway can also induce resistance to the inhibitors of MAPK pathway. Methodology/Principal Findings The sensitivity to vemurafenib or the MEK inhibitor AZD6244 was tested in sensitive and resistant human melanoma cell lines exploring differences in activation-associated phosphorylation levels of major signaling molecules, leading to the testing of co-inhibition of the AKT/mTOR pathway genetically and pharmacologically. There was a high degree of cross-resistance to vemurafenib and AZD6244, except in two vemurafenib-resistant cell lines that acquired a secondary mutation in NRAS. In other cell lines, acquired resistance to both drugs was associated with persistence or increase in activity of AKT pathway. siRNA-mediated gene silencing and combination therapy with an AKT inhibitor or rapamycin partially or completely reversed the resistance. Conclusions/Significance Primary and acquired resistance to vemurafenib in these in vitro models results in frequent cross resistance to MEK inhibitors, except when the resistance is the result of a secondary NRAS mutation. Resistance to BRAF or MEK inhibitors is associated with the induction or persistence of activity within the AKT pathway in the presence of these drugs. This resistance can be potentially reversed by the combination of a RAF or MEK inhibitor with an AKT or mTOR inhibitor. These combinations should be available for clinical testing in patients progressing on BRAF inhibitors.
The Spin Periods and Rotational Profiles of Neutron Stars at Birth

We present results from an extensive set of one- and two-dimensional radiation-hydrodynamic simulations of the supernova core-collapse, bounce, and postbounce phases and focus on the proto-neutron star (PNS) spin periods and rotational profiles as a function of initial iron core angular velocity, degree of differential rotation, and progenitor mass. For the models considered, we find a roughly linear mapping between initial iron core rotation rate and PNS spin. The results indicate that the magnitude of the precollapse iron core angular velocities is the single most important factor in determining the PNS spin. Differences in progenitor mass and degree of differential rotation lead only to small variations in the PNS rotational period and profile. Based on our calculated PNS spins at ~200-300 ms after bounce and assuming angular momentum conservation, we estimate final neutron star rotation periods. We find periods of 1 ms and shorter for initial central iron core periods of ≲10 s. This is appreciably shorter than what previous studies have predicted and is in disagreement with current observational data from pulsar astronomy. After considering possible spin-down mechanisms that could lead to longer periods, we conclude that there is no mechanism that can robustly spin down a neutron star from ~1 ms periods to the "injection" periods of tens to hundreds of milliseconds observed for young pulsars. Our results indicate that, given current knowledge of the limitations of neutron star spin-down mechanisms, precollapse iron cores must rotate with periods of around 50-100 s to form neutron stars with periods generically near those inferred for the radio pulsar population.
Biochemical analysis of components of the pre-replication complex of Archaeoglobus fulgidus.

The eukaryotic pre-replication complex is assembled at replication origins in a reaction called licensing. Licensing involves the interactions of a variety of proteins including the origin recognition complex (ORC), Cdc6 and the Mcm2-7 helicase, homologues of which are also found in archaea. The euryarchaeote Archaeoglobus fulgidus encodes two genes with homology to Orc/Cdc6 and a single Mcm homologue. The A.fulgidus Mcm protein and one Orc/Cdc6 homologue have been purified and investigated in vitro. The Mcm protein is an ATP-dependent, hexameric helicase that can unwind between 200 and 400 bp of duplex DNA. Deletion of 112 amino acids from the N-terminus of A.f Mcm produced a protein, which was still capable of forming a hexamer, was competent in DNA binding and was able to unwind at least 1 kb of duplex DNA. The purified Orc/Cdc6 homologue was also able to bind DNA. Both Mcm and Orc/Cdc6 show a preference for specific DNA structures, namely molecules containing a single stranded bubble that mimics early replication intermediates. Nuclease protection showed that the binding sites for Mcm and Orc/Cdc6 overlap. The Orc/Cdc6 protein bound more tightly to these substrates and was able to displace pre-bound Mcm hexamer.
Uncertainty propagation in front end factor analysis for noise robust speaker recognition

In this study, we explore the propagation of uncertainty in the state-of-the-art speaker recognition system. Specifically, we incorporate the uncertainty associated with observation features into the i-Vector extraction framework. To prove the concept, both the oracle and practically estimated uncertainty are used for evaluation. The oracle uncertainty is calculated assuming the knowledge of clean speech features, while the estimated uncertainties are obtained using SPLICE and joint-GMM based methods. We evaluate the proposed framework on both YOHO and NIST 2010 Speaker Recognition Evaluation (SRE) corpora by artificially introducing noise at different SNRs. In the speaker verification experiments, we confirmed that the proposed uncertainty based i-Vector extraction framework shows significant robustness against noise.
Bound energy masses of mesons containing the fourth generation and iso-singlet quarks

The fourth Standard Model (SM) family quarks and weak iso-singlet quarks predicted by E6 GUT are considered. The spin-average of the pseudoscalar η4(n1S0) and vector ψ4(n3S1) quarkonium binding masses of the new mesons formed by the fourth Standard Model (SM) family and iso-singlet E6 with their mixings to ordinary quarks are investigated. Further, the fine and hyperfine mass splittings of the these states are also calculated. We solved the Schrodinger equation with logarithmic and Martin potentials using the shifted large-N expansion technique. Our results are compared with other models to gauge the reliability of the predictions and point out differences.
Adaptive Digital Feedback Predistortion Technique for Linearizing Power Amplifiers

We have developed a new adaptive digital predistortion (DPD) linearization technique based on analog feedback predistortion (FBPD). The lookup-table-based feedback input can remove the bandwidth limitation of the feedback circuit related to the loop delay, and suppress feedback oscillation by accurate digital control of the feedback signal. Moreover, the predistortion (PD) signal can be extracted very efficiently. By combining the feedback linearization and DPD linearization techniques, the performance of the predistorter is enhanced significantly compared to the conventional DPD. To clearly visualize the characteristics of digital FBPD (DFBPD), we have compared it to the conventional DPD based on the recursive least square algorithm using Matlab simulation. The results clearly show that the new method is a good linearization algorithm, better than a conventional DPD. For the demonstration, a Doherty power amplifier with 180-W peak envelope power is linearized using the proposed DFBPD. For a 2.14-GHz forward-link wideband code-division multiple-access signal, the adjacent channel leakage ratio at 2.5-MHz offset is -58 dBc, which is improved by 15 dB at an average output power of 43 dBm
Emotion processing in children showing disordered behaviour referred into a crime prevention programme: Identifying impairments and developing and evaluating an emotion recognition training

Early childhood behaviour problems have been linked to later antisocial and criminal behaviour. Emotion recognition impairments are hypothesised to contribute to these negative behaviours. However, before now, no study has looked at the nature and extent of emotion recognition impairments in children with disordered behaviour and whether they can be improved. We hypothesised that whilst some children with disordered behaviour would show negative emotion recognition impairments, others would not, and that emotion recognition would improve after completing the specifically developed Cardiff Emotion Recognition Training (CERT). Secondary aims and hypotheses are included within the thesis. Ninety-two children with disordered behaviour (DB; 64 male), confirmed by their teacher using the Strengths and Difficulties Questionnaire, and who were participating in a crime prevention programme, took part. A typically developing group of 58 children (45 male) formed a comparison group. All children initially completed a Facial Emotion Recognition (FER) test. An accuracy threshold was then applied to the DB children’s FER scores, further categorising them into those with (DB+) and without (DB-) emotion recognition impairments. Only DB+ children completed the three-session CERT. All DB children then repeated the FER test. 59% of the DB children were impaired in negative and neutral emotion recognition (DB+). Completion of the CERT led to a significant improvement in fear, sadness, anger and neutral emotion recognition. This thesis has extended knowledge; up until now, no study has investigated the extent of emotion recognition impairments and whether they can be improved in the same sample of children showing disordered behaviour. This has valuable implications for practitioners; we have shown that interventions should be delivered early and target individual children’s impairments. Emotion recognition training is a viable option in case of emotion recognition problems. Research should now investigate if the improvement in emotion recognition is related to an improvement in behaviour.
Line broadening analysis using integral breadth methods: a critical review

Integral breadth methods for line profile analysis are reviewed, including modifications of the Williamson–Hall method recently proposed for the specific case of dislocation strain broadening. Two cases of study, supported by the results of a TEM investigation, are considered in detail: nanocrystalline ceria crystallized from amorphous precursors and highly deformed nickel powder produced by extensive ball milling. A further application concerns a series of Fe–Mo powder specimens that were ball milled for increasing time. Traditional and modified Williamson–Hall methods confirm their merits for a rapid overview of the line broadening effects and possible understanding of the main causes. However, quantitative results are generally not reliable. Limits in the applicability of integral breadth methods and reliability of the results are discussed in detail.
Unique word prefix in SC/FDE and OFDM: A comparison

The concept of using unique word (UW) prefixes instead of cyclic prefixes (CPs) is already well investigated for single carrier systems with frequency domain equalization (SC/FDE). In OFDM (orthogonal frequency division multiplexing), where the data symbols are specified in frequency domain, the introduction of UWs — which are specified in time domain — is not that straight forward. In this paper we show how unique words can also be introduced in OFDM symbols. In OFDM our proposed method introduces correlations between subcarrier symbols. This allows to apply a highly efficient LMMSE (linear minimum mean square error) receiver. Throughout this paper we discuss the similarities and differences of UW-SC/FDE and UW-OFDM transmitter/receiver processing, and we present simulation results in indoor multipath environments.
Essential fatty acids in early life: structural and functional role

Essential fatty acids (EFA) are structural components of all tissues and are indispensable for cell membrane synthesis; the brain, retina and other neural tissues are particularly rich in long-chain polyunsaturated fatty acids (LCPUFA). These fatty acids serve as specific precursors for eicosanoids that regulate numerous cell and organ functions. Results from animal and recent human studies support the essential nature of n-3 EFA in addition to the well-established role of n-6 EFA for human subjects, particularly in early life. The most significant effects relate to neural development and maturation of sensory systems. Recent studies using stable-isotope-labelled tracers demonstrate that even preterm infants are able to form arachidonic acid (AA) and docosahexaenoic acid (DHA), but that synthesis is extremely low. Intracellular fatty acids or their metabolites regulate transcriptional activation of gene expression during adipocyte differentiation, and retinal and nervous system development. Regulation of gene expression by LCPUFA occurs at the transcriptional level and is mediated by nuclear transcription factors activated by fatty acids. These nuclear receptors are part of the steroid hormone receptor family. Two types of polyunsaturated fatty acid responsive transcription factors have been characterized, the peroxisome proliferator-activated receptor (PPAR) and the hepatic nuclear factor 4α. DHA also has significant effects on photoreceptor membranes involved in the signal transduction process, rhodopsin activation, and rod and cone development. Comprehensive clinical studies have shown that dietary supplementation with marine oil or single-cell oils, sources of LCPUFA, results in increased blood levels of DHA and AA, as well as an associated improvement in visual function in formula-fed premature infants to match that of human milk-fed infant. Recent clinical trials convincingly support LCPUFA supplementation of preterm infant formulations and possibly term formula to mimic human milk composition.
Formalizing Opacity and Transparency in Belief ContextsMassimo

One of the most interesting puzzles in formalizing belief contexts is the fact that many belief reports can be given both an opaque and a transparent reading. A traditional explanation is that the two readings are related to the failure and success of the principle of substitutivity respectively, and this in turn is explained with the de re/de dicto distinction. We propose an alternative analysis, based on the idea that another agent's beliefs can just be quoted (preserving opaqueness) or translated into the reporter's language (allowing transparency). We show that MultiContext systems allow the formalization of these two phenomena at the same time, thanks to their multi-language feature. 1 Beliefs and substitutivity A very important capability is reasoning about our own and other people's beliefs. We have beliefs about our beliefs; we learn from other people's beliefs; we accept (don't accept) other people's beliefs among our beliefs; we share our beliefs with other people; we report other people's beliefs; we infer new information by combining diierent people's beliefs; we make decisions based on conjectures about other people's beliefs; many communication conventions are based on what we believe other people believe; and so on. Despite the pervasiveness of the notion of belief and the apparent easiness for humans to deal with it, representing beliefs and formalizing reasoning with and about beliefs has raised very diicult problems. From a logical point of view, a well-known problem is that a very general and intuitive logical principle, the principle of substitutivity, fails in its unrestricted version 1. Intuitively, the unrestricted principle of substitutivity (UPS) states that whenever two terms (two sentences) have the same meaning 2 , they can be substituted one for the other in any sentence salva veritate. More formally, let be a sentence and ; 0 two terms (sentences). If = 0 (0), then == 0 ], where == 0 ] is the result of replacing some occurrences of with 0. But UPS is not sound (validity preserving) when applied in belief contexts (namely within the scope of an operator of the form X-believes-that. . ], where. . ] stands for any sentence). Consider the following instance of UPS: Mr. A believes that the president of the local football team is a corruptor The president of the local football team is Mr. C Mr. A believes that Mr. C is a corruptor It is easy to see that the conclusion is …
Pedestrian flows and non‐classical shocks

We present a model for the flow of pedestrians that describes features typical of this flow, such as the fall due to panic in the outflow of people through a door. The mathematical techniques essentially depend on the use of non‐classical shocks in scalar conservation laws. Copyright © 2005 John Wiley & Sons, Ltd.
The organization of computer resources into a packet radio network

In this paper, we describe the use of packet radio communication for organizing computer resources into a computer communications network. A system to demonstrate the packet radio concept is being developed by the Advanced Research Projects Agency with initial testing in the San Francisco area beginning in 1975. The attributes of this system are presented and its application to mobile radio communications and computer architecture is briefly discussed.
Brain-Derived Neurotrophic Factor Increases in the Uninjured Dorsal Root Ganglion Neurons in Selective Spinal Nerve Ligation Model

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are two major members of the neurotrophin family. Using immunohistochemistry and in situ hybridization histochemistry, we examined the effect of L5 spinal nerve ligation (SPNL), a neuropathic pain model, on the expression of BDNF in the uninjured L4 dorsal root ganglion (DRG). After L5 SPNL, both immunoreactivity for BDNF and the hybridization intensity for BDNF mRNA increased mainly in the small- and medium-sized neurons. The percentage of BDNF mRNA-expressing neurons increased in the ipsilateral L4 DRG compared with the contralateral DRG from the third to 28th day after ligation. A significantly greater number of BDNF-immunoreactive neurons were observed in the ipsilateral L4 DRG than contralateral side 14 d after ligation. To test the contribution of BDNF to the thermal hyperalgesia produced in this model, we intrathecally injected anti-BDNF antibody at third day after ligation. This treatment clearly attenuated thermal hyperalgesia for a few hours. Almost all BDNF mRNA-expressing neurons coexpressed trkA, a high-affinity NGF receptor, mRNA. The percentage of BDNF mRNA-expressing cells of trkA cells significantly increased in the ipsilateral L4 DRG 14 d after ligation. Furthermore, we examined the contribution of NGF on this phenotypic change using ELISA, Northern blot analysis, and anti-NGF antibody. NGF content in the ipsilateral L4 DRG linearly increased and reached a statistical significant level 14 d after L5 SPNL. Moreover, at this time point, the increase in NGF mRNA was observed in the ipsilateral L5 DRG and sciatic nerve, but not in the ipsilateral L4 DRG or L4 spinal nerve. Local application of anti-NGF antibody to the L4 spinal nerve beside the L5 spinal nerve-ligation site prevented the development of thermal hyperalgesia for 5 d after ligation. Our data suggest that BDNF, which increased in the uninjured L4 DRG neurons, acts as a sensory neuromodulator in the dorsal horn and contributes to thermal hyperalgesia in this neuropathic pain model. The contribution of locally synthesized NGF to thermal hyperalgesia was also demonstrated. These dynamic alterations in the expression and content of BDNF and NGF in the uninjured DRG neurons might be involved in the pathomechanisms of neuropathic pain.
Rapid Molecular Cloud and Star Formation: Mechanisms and Movies

We demonstrate that the observationally inferred rapid onset of star formation after parental molecular clouds have assembled can be achieved by flow-driven cloud formation of atomic gas, using our previous three-dimensional numerical simulations. We postprocess these simulations to approximate CO formation, which allows us to investigate the times at which CO becomes abundant relative to the onset of cloud collapse. We find that global gravity in a finite cloud has two crucial effects on cloud evolution. (1) Lateral collapse (perpendicular to the flows sweeping up the cloud) leads to rapidly increasing column densities above the accumulation from the one-dimensional flow. This in turn allows fast formation of CO, allowing the molecular cloud to “appear” rapidly. (2) Global gravity is required to drive the dense gas to the high pressures necessary to form solar-mass cores, in support of recent analytical models of cloud fragmentation. While the clouds still appear “supersonically turbulent,” this turbulence is relegated to playing a secondary role, in that it is to some extent a consequence of gravitational forces.
A 610 Mbin/s CABAC decoder for H.265/HEVC level 6.1 applications

This paper presents a high-throughput decoder of HEVC context-based adaptive binary arithmetic coding (CABAC). A multi-sub-engine arithmetic decoder (MSE-AD) design is proposed to increase the average number of bins delivered per clock cycle by adaptively processing different patterns of upcoming bins with balanced critical path delay. A syntax element (SE) grouping scheme is proposed to maximize the utilization of MSE-AD under the SE parsing order specified in the standard. We also employ a prediction-based pipeline to alleviate the data hazard problem. The proposed CABAC decoder delivers 2.36 bins per clock cycle and achieves a maximum clock frequency of 258MHz in 90nm technology. The resulting performance is 610 Mbin/s which is enough for H.265/HEVC level 6.1 (8K×4K@60fps) applications.
Wiring space and length estimation in two-dimensional arrays

We propose a new global routing area estimation approach for high-performance very large scale integration and multichip modules (MCMs). The objective is to route nets with minimum density of global cells, producing a four-bend routing for each two-terminal net. We propose an approximate upper bound on global cell d/sub H//spl les/2d/sub 0/log(m/(2d/sub 0/)), in an m/spl times/m two-dimensional array, where d/sub 0/ is the estimated lower-bound density. The total wirelength is (2/spl alpha/+/spl beta/)4m/sup 2/d/sub 0//3, where /spl alpha/+/spl beta/=1 and /spl alpha/ is the percentage of diagonal combinations and /spl beta/ is the percentage of adjacent combinations of nets. If /spl alpha//spl les//spl beta/ (this assumption holds since a good placement minimizes the longer wires), then the total wirelength is at most 2m/sup 2/d/sub 0/. By counting on the adjacent and diagonal combinations separately in the cost function, d/sub R//spl les/[4d/sub 0//3]/spl times/log([m/(4d/sub 0//3)]). We verified that the bound obtained are realistic in the worst case. A solution to this problem can be used for quick estimation of necessary wiring space (for standard cell array designs) and difficulty of routing (for gate array designs) in the early design planning stage.