Miracle-dz/UniFAR-FTUs huggingface dataset:
Membrane dynamics of Notch-bound γ-secretase produces two distinct Notch conformations

Cleavage of Notch by the major intramembrane aspartyl protease complex γ-secretase is a central event in cell regulation and is also important to Alzheimer’s disease, with more than 200 mutations in the catalytic subunit of γ-secretase (PS1) causing severe early-onset forms of the disease. Recently, cryogenic electron microscopy (cryo-EM) has revealed the electron density of the protein-Notch complex in frozen solution, indicating major changes upon substrate binding and a possible helix unwinding to expose peptide bonds. In order understand the all-atom dynamics that cause this process, and to test the Notch binding in a membrane protein rather than solution, we developed an all-atom model of mature wild-type γ-secretase bound to Notch in a complete membrane-water system and studied the system using three independent 500-nanosecond molecular dynamics simulations. Our ensembles are in essential agreement with known cryo-EM data. As in previous simulations we find unusual β-strand transitions in exposed parts of PS1. We also observe the atomic helix motions that cause loss of helicity in bound Notch by direct comparison to corresponding 500 ns simulations of free Notch, in particular five residues to the N-terminal site of the primary cleavage site. Most importantly, we identify three conformation states, with two of them differing in the Notch-bound catalytic site. These dynamics produce a ping-pong relationship of positioning the S3 cleavage sites of Notch relative to the aspartates. These conformation states are not visible in the cryo-EM data; probably the density is an average snapshot of the two states. Our identified conformation states rationalize how Notch cleavage can be imprecise and yield multiple products. Our identified conformation states may aid efforts to develop conformation-selective drugs that target C99 and Notch cleavage differently. Statement of Significance The atomic dynamics underlying cleavage of Notch by γ-secretase in the membrane is of major biological importance. Electron microscopy has revealed the protein-Notch complex in frozen solution, showing major changes upon substrate binding and helix unwinding to expose peptide bonds, but does not explain why substrate cleavage is imprecise and produces several products. Our model of wild-type γ-secretase bound to Notch in a complete membrane-water system equilibrated by 3 × 500 nanoseconds of molecular dynamics strongly complements the electron microscopy data: We identify the specific loop and helix motions that cause the β-strand transitions in PS1 and the loss of helicity in specific residues of bound Notch. We identify different conformations of Notch, which importantly affect the S3 cleavage site; the open state may cause the imprecise cleavage with earlier release of products. Our identified states can aid development of conformation-selective drugs that target C99 and Notch cleavage differently.
Differences between cancers in terms of therapeutic responses.

The report I have been asked to prepare, to quote Dr. Weaver, â€œis not so much to document progressâ€• (not a review, in other words) â€œas it is to point up problems that must yet be solved and to re-evaluate concepts which may or may not be entirely valid. â€• I am forced to note at the outset the profound inadequacies in information and thought which I bring to this enormous problem. Members of this committee have reviewed the cancer problem from one end to another; they have constructed theories; they have appropriated information from many scientific disciplines; and they have wrestled with the problems of cancer in solitude, in the laboratory, at the hospital bed, and in committees. Yet all are still waiting for the con cept, the experiment, the clue, which can vitalize and orient the vast machinery of cancer research toward purposeful, productive, and practical ends. The signal for this activation cannot be provided by any presently known combination of words. This committee is seeking for something that con tinues to elude us, no matter how many the cor ners that have been swept, the drawers opened, the memories searched. Nevertheless, the search must go on, and somehow, from the experiments of the laboratory scientist and the experiences of the clinician, ideas extracted which, in Dr. Weav er's words, â€œmighteffect a practical solution of the cancer problem. â€• Because of the specific title of my assignment, I shall try to adhere closely to the subject. To cover the area it is necessary to make some general observation. , and then to turn to the responses of cancer to therapeutie agents.
Clock Skew Analysis via Vector Fitting in Frequency Domain

An efficient frequency-based clock analysis method: CSAV is proposed in this paper. It computes the circuit response by first solving the state equation in frequency domain, and derive the rational approximate with the help of vector fitting [9]. There are two aspects that contribute to the time efficiency of the method. One is CSAV solves the state equation only on selected frequency points, which significantly reduce the amount of time for equation solving. The other is CSAV performs vector fitting and waveform recovery only on user specified nodes, which save the unnecessary computation on the nodes which are not concerned by user. The complexity of our method is O( lceillg fmaxrceilNalpha + lceillg fmaxrceil 2NaNout), where fmax is proportional to the knee frequencyquency of input signal, N is the node number of the circuit, a is a constant around 1.3, Na is the order of approximation and Nout is the number of output nodes. Our experimental results show that compared with Hspice, CSAV achieves speed-up up to 35 times while the error is only 1%. Moreover, computational saving of CSAV grows with circuit size, which makes this method especially promising for large cases.
Reputation Bootstrapping for Trust Establishment among Web Services

Reputation systems rely on past information to establish trust among unknown participants. Reputation bootstrapping - that is, assessing the reputations of newly deployed Web services (newcomers) - is a major issue in service-oriented environments because historical information often isn't present regarding newcomer behaviors. The authors examine different techniques for fairly and accurately bootstrapping newcomers' reputations in a service-oriented environment. They also present experimental results that evaluate the proposed techniques.
Impact of iodination on thyroid pathology in Africa.

Thyroid disorders are common worldwide.1 In Africa, dietary iodine deficiency is the major determinant of thyroid pathology, resulting in a spectrum of iodine deficiency disorders, including goitres, hypothyroidism and mental retardation.2 Of these, mental retardation poses the most severe threat to socioeconomic wellbeing; thus, its prevention has been the focus of current global efforts towards sustainable iodine sufficiency.3 At least 350 million Africans are at risk of iodine deficiency.4 According to World Health Organization (WHO) estimates, goitres are present in 28.3% of the African population,4 and approximately 25% of the global burden of iodine deficiency as measured by disability-adjusted life years (DALYs) occurs in Africa.5 The demands of communicable diseases, coupled with the challenges of poverty, civil conflicts and fragile political structures, have in the past frustrated efforts at eliminating iodine deficiency in Africa.6 However, recent decades have seen remarkable improvements in iodine nutrition through salt iodination in the continent.7 The effect of these developments on the pattern of thyroid gland disease are beginning to unravel and will be relevant to the strategies for extending the present gains. In this article, I examine the impact of recent progress in iodine nutrition on the epidemiology of thyroid gland pathology in Africa.
HIV-AIDS transmission symbols.

24. Fischl, M. A. , et al.: Evaluation of heterosexual partners, children, and household contacts of adults with AIDS. JAMA 257: 640-744, Feb. 6, 1987. 25. Gomperts, E. D. , et al.: LAV/HTLV-III presence in peripheral blood lymphocytes of seropositive young hemophiliacs. Blood 65: 1549-1552, June 1985. 26. Salahuddin, S. Z. , et al.: Isolation of infectious human T-cell leukemia/lymphotropic virus type III (HTLV-III) from patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) and from health carriers: A study of risk groups and tissues sources. Proc Natl Acad Sci USA 82: 5530-5534, August 1985. 27. Levy, J. A. , and Shimaukaro, J.: Recovery of AIDSassociated retroviruses from patients with AIDS or AIDSrelated conditions and from clinically healthy individuals. J Infect Dis 152: 734-738, October 1985.
Nanoceria: A Rare-Earth Nanoparticle as a Novel Anti-Angiogenic Therapeutic Agent in Ovarian Cancer

Ovarian cancer (OvCa) is the fifth most common cause of death from all cancers among women in United Sates and the leading cause of death from gynecological malignancies. While most OvCa patients initially respond to surgical debulking and chemotherapy, 75% of patients later succumb to the disease. Thus, there is an urgent need to test novel therapeutic agents to counteract the high mortality rate associated with OvCa. In this context, we have developed and engineered Nanoceria (NCe), nanoparticles of cerium oxide, possessing anti-oxidant properties, to be used as a therapeutic agent in OvCa. We show for the first time that NCe significantly inhibited production of reactive oxygen species (ROS) in A2780 cells, attenuated growth factor (SDF1, HB-EGF, VEGF165 and HGF) mediated cell migration and invasion of SKOV3 cells, without affecting the cell proliferation. NCe treatment also inhibited VEGF165 induced proliferation, capillary tube formation, activation of VEGFR2 and MMP2 in human umbilical vascular endothelial cells (HUVEC). NCe (0.1 mg/kg body weigh) treatment of A2780 ovarian cancer cells injected intra-peritoneally in nude mice showed significant reduction (p<0.002) in tumor growth accompanied by decreased tumor cell proliferation as evident from reduced tumor size and Ki67 staining. Accumulation of NCe was found in tumors isolated from treated group using transmission electron microscopy (TEM) and inductively coupled plasma mass spectroscopy (ICP-MS). Reduction of the tumor mass was accompanied by attenuation of angiogenesis, as observed by reduced CD31 staining and specific apoptosis of vascular endothelial cells. Collectively, these results indicate that cerium oxide based NCe is a novel nanoparticle that can potentially be used as an anti-angiogenic therapeutic agent in ovarian cancer.
Rapport de stage de premiere annee de Master Optimisation de cache d'instructions

Ce stage a ete effectue du 8 avril au 30 juin 2005 dans l’equipe Inria Compsys a l’E.N. S. de Lyon. L’objectif de l’equipe Compsys est le developpement de techniques d’optimisation pour les systemes embarques. Dans le cadre de ce stage, nous avons cherche une heuristique pour le placement des procedures minimisant les conflits. Une implementation en C de cette heuristique a ete implementee. Par ailleurs des resultats de complexite sur la minimisation des conflits dans le cache d’instructions ont ete trouvees.
Improving the Performance of Multithreaded Sparse Matrix-Vector Multiplication Using Index and Value Compression

The sparse matrix-vector multiplication kernel exhibits limited potential for taking advantage of modern shared memory architectures due to its large memory bandwidth requirements. To decrease memory contention and improve the performance of the kernel we propose two compression schemes. The first, called CSR-DU, targets the reduction of the matrix structural data by applying coarse grain delta encoding for the column indices. The second scheme, called CSR-VI, targets the reduction of the numerical values using indirect indexing and can only be applied to matrices which contain a small number of unique values. Evaluation of both methods on a rich matrix set showed that they can significantly improve the performance of the multithreaded version of the kernel and achieve good scalability for large matrices.
A QA-TSK fuzzy model vs evolutionary decision trees towards nonlinear action pattern recognition

A comparison among three linear methodologies, a novel auto-adjusted fuzzy quadruple TSK model (QA-TSK) and two evolutionary decision tree representations, is presented in this paper. The three architectures make use of a vast number of primitives1 utilised to reconfigure and evolve their internal structures of the classifier models so that to discriminate among spatial physical activities. Such primitives like statistical features employ a twofold role, initially to model the data set in a dimensionality reduction preprocessing and finally to exploit these attributes to recognise pattern actions. The performance statistics are being utilised for remote surveillance within a smart environment incorporating an ubiquitous 3D marker based tracker which acquires the timeseries data streams, whereas activity recognition statistics are being generated through an off-line process.
Pharmacogenetic differences and drug–drug interactions in immunosuppressive therapy

With the advent of new immunosuppressants and formulations, the elucidation of molecular targets and the evolution of therapeutic drug monitoring, the field of organ transplantation has witnessed significant reductions in acute rejection rates, prolonged graft survival and improved patient outcome. Nonetheless, challenges persist in the use of immunosuppressive medications. Marked interindividual variability remains in drug concentrations and drug response. As medications with narrow therapeutic indices, variations in immunosuppressant concentrations can result in acute toxicity or transplant rejection. Recent studies have begun to identify factors that contribute to this variability with the promise of tailoring immunosuppressive regimens to the individual patient. These advances have uncovered differences in genetic composition in drug-metabolising enzymes, drug transporters and drug targets. This review focuses on commonly used maintenance immunosuppressants (including cyclosporin, mycophenolate mofetil, tacrolimus, sirolimus, everolimus, azathioprine and corticosteroids), examines current studies on pharmacogenetic differences in drug-metabolising enzymes, drug transporters and drug targets and addresses common drug–drug interactions with immunosuppressant therapies. The potential role of drug-metabolising enzymes in contributing to these drug–drug interactions is briefly considered.
The Pregnane X Receptor Gene-Humanized Mouse: A Model for Investigating Drug-Drug Interactions Mediated by Cytochromes P450 3A

The most common clinical implication for the activation of the human pregnane X receptor (PXR) is the occurrence of drug-drug interactions mediated by up-regulated cytochromes P450 3A (CYP3A) isozymes. Typical rodent models do not predict drug-drug interactions mediated by human PXR because of species differences in response to PXR ligands. In the current study, a PXR-humanized mouse model was generated by bacterial artificial chromosome (BAC) transgenesis in Pxr-null mice using a BAC clone containing the complete human PXR gene and 5′- and 3′-flanking sequences. In this PXR-humanized mouse model, PXR is selectively expressed in the liver and intestine, the same tissue expression pattern as CYP3A. Treatment of PXR-humanized mice with the PXR ligands mimicked the human response, since both hepatic and intestinal CYP3As were strongly induced by rifampicin, a human-specific PXR ligand, but not by pregnenolone 16α-carbonitrile, a rodent-specific PXR ligand. In rifampicin-pretreated PXR-humanized mice, an ∼60% decrease was observed for both the maximal midazolam serum concentration (Cmax) and the area under the concentration-time curve, as a result of a 3-fold increase in midazolam 1′-hydroxylation. These results illustrate the potential utility of the PXR-humanized mice in the investigation of drug-drug interactions mediated by CYP3A and suggest that the PXR-humanized mouse model would be an appropriate in vivo tool for evaluation of the overall pharmacokinetic consequences of human PXR activation by drugs.
Somatosensory, multisensory, and task-related neurons in cortical area 7b (PF) of unanesthetized monkeys.

1. The goal of this study was to quantitatively characterize the response properties of somatosensory and multisensory neurons in cortical area 7b (or PF) of monkeys that were behaviorally trained to perform an appetitive tolerance-escape task. Particular emphasis was given to characterizing nociceptive thermal responses and correlating such responses to thermal pain tolerance as measured by escape frequency. 2. A total of 244 neurons that responded to somatosensory stimulation alone or to both somatosensory and visual stimulation (multisensory) were isolated and studied in the trigeminal region of cortical area 7b. Thirty neurons responded only to visual stimulation. Thermoreceptive neurons formed approximately 13% (31 of 244) of the neurons that had somatosensory response properties. Thermal nociceptive neurons made up approximately 9% (21 of 244) of the neurons that had somatosensory response properties or approximately 68% (21 of 31) of the neurons that had thermoreceptive response properties. Thermal nociceptive neurons responded either exclusively to noxious thermal stimuli (high-threshold thermoreceptive, HTT) or differentially to nonnoxious and noxious thermal stimuli (wide-range thermoreceptive, WRT). Multimodal HTT neurons had nonnociceptive (low-threshold mechanoreceptive, LTM) and/or nociceptive (nociceptive-specific, wide-dynamic-range) mechanical receptive fields, whereas multimodal WRT neurons had only nonnociceptive (LTM) mechanical receptive fields. Thermal nonnociceptive neurons (low-threshold thermoreceptive, LTT) made up approximately 3% (8 of 244) of the neurons that had somatosensory properties or approximately 26% (8 of 31) of the neurons that were thermoreceptive. The background discharge of two thermoreceptive neurons (6%, 2 of 31) was inhibited by innocuous thermal stimulation. 3. Thermal nociceptive neurons (HTT and WRT) were functionally differentiated by statistical analyses into subpopulations that did encode (HTT-EN, WRT-EN) and did not encode (HTT-NE, WRT-NE) the magnitude of noxious thermal stimulus intensities. The mean slopes and median regression coefficients for the stimulus-response (S-R) functions of HTT-EN and WRT-EN neurons, respectively, were significantly greater than those for the S-R functions of HTT-NE and WRT-NE neurons. In contrast to HTT-NE and WRT-NE neurons, HTT-EN and WRT-EN neurons reliably encoded the magnitude of noxious thermal intensity by grading their mean discharge frequency. 4. The S-R functions of HTT-EN and WRT-EN neurons, unlike those of HTT-NE and WRT-NE neurons, closely approximated stimulus intensity-escape frequency functions. (ABSTRACT TRUNCATED AT 400 WORDS)
Escherichia coli and Proteus mirabilis inhibit the perinuclear but not the circulating antineutrophil cytoplasmic antibody reaction.

BACKGROUND Perinuclear antineutrophil cytoplasmic antibodies (P-ANCA) are found in 48%-83% of serum samples from patients with ulcerative colitis (UC). Their pathogenic role and initiating stimuli are unknown. In contrast to patients with vasculitides and ANCA reactivities, the antibodies in UC patients do not react with myeloperoxidase (MPO) or proteinase 3 (PR3). The aim of the present study was to investigate whether bacterial species of the intestinal tract and other sources could interfere with P-ANCA in sera from patients with UC. METHODS Seventeen P-ANCA-positive and anti-MPO-negative serum samples from patients with UC were tested with Escherichia coli 014 and Staphylococcus aureus Wood 46. Six of these serum samples with different P-ANCA titres were selected to test further the influence of 15 different gram-negative or gram-positive bacterial strains. Six anti-MPO positive P-ANCA, 5 anti-PR3 positive C-ANCA, and 10 antinuclear antibody (ANA)-positive serum samples were used as controls. The antineutrophil cytoplasmic antibodies (ANCAs) were analysed by an indirect immunofluorescence method (IIF) on ethanol-fixed neutrophils, and the ANAs were tested by IIF on HEp-2 cells or rat liver tissues. The bacteria used in the experiments were either live or killed by formalin or glutaraldehyde fixation or heated at 80 degrees C for 30 min. The test was first performed as a bacterial absorption test with sedimented organisms and then at various temperatures with the supernatant from suspension of live bacteria. RESULTS Both MPO-positive and MPO-negative P-ANCA reactivity was abolished by absorption of patient sera with live E. coli and Proteus mirabilis but not with bacteria representing members of 10 other species, suggesting that antibody reactivity was absorbed away. However, continued experiments indicated that the inhibition of P-ANCA was not due to classic antigen-antibody interactions but rather to decomposition of the antigenic substrate of the neutrophils by factors present in the supernatants of live E. coli and P. mirabilis. The activity of the supernatant was temperature-dependent, with strong activity at room temperature and 37 degrees C, no activity at 0 degrees C, and abolished by mild heat treatment (56 degrees or 60 degrees C). No activity was shown in the supernatants from bacteria treated with formaldehyde or glutaraldehyde. CONCLUSIONS Soluble material from live E. coli and P. mirabilis has the capacity to decompose the antigenic substrate of neutrophils responsible for both MPO-positive and MPO-negative P-ANCA, most probably brought about through enzymatic activity. Anti PR3-positive C-ANCA were not affected, which suggests substrate specificity of the proposed enzymatic activity.
Wrong-Site Surgery in California, 2007-2014

Objective The implementation of a universal surgical safety protocol in 2004 was intended to minimize the prevalence of wrong-site surgery (WSS). However, complete elimination of WSS in the operating room continues to be a challenge. The purpose of this study is to evaluate the prevalence and etiology of WSS in the state of California. Study Design A retrospective study of all WSS reports investigated by the California Department of Public Health between 2007 and 2014. Methods Prevalence of overall and specialty-specific WSS, causative factors, and recommendations on further improvement are discussed. Results A total of 95 cases resulted in incident reports to the California Department of Public Health and were included in our study. The most common errors were operating on the wrong side of the patient’s body (n = 60, 62%), performing the wrong procedure (n = 21, 21%), operating on the wrong body part (n = 12, 12%), and operating on the wrong patient (n = 2, 2%). WSS was most prevalent in orthopedic surgery (n = 33, 35%), followed by general surgery (n = 26, 27%) and neurosurgery (n = 16, 17%). All 3 otolaryngology WSS cases in California are associated with the ear. Conclusion WSS continues to surface despite national efforts to decrease its prevalence. Future research could establish best practices to avoid these “never events” in otolaryngology and other surgical specialties.
Micro-needle electrode array for electro tactile display

This paper describes electro tactile display with micro-needle electrodes that stimulate tactile receptors using electric stimulation. The needle length was designed to have approximately the same length as the stratum corneum so as not to injure nerve area. This device allowed subjects to feel tactile sensation with lower voltage than a flat electrode array with good repeatability. In addition, the tactile sensation was created in the vicinity of the needles, i.e., tactile display with a high spatial resolution was achieved.