gebhart/patrepeval huggingface dataset:
Algorithm 659 (1988)

We compare empirically accuracy and speed of low-discrepancy sequence generators of Sobol' and Faure. These generators are useful for multidimensional integration and global optimization. We discuss our implementation of the Sobol' generator.
Genetically meaningful phenotypic subgroups in autism spectrum disorders (2013)

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with strong evidence for genetic susceptibility. However, the effect sizes for implicated chromosomal loci are small, hard to replicate and current evidence does not explain the majority of the estimated heritability. Phenotypic heterogeneity could be one phenomenon complicating identification of genetic factors. We used data from the Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Schedule, Vineland Adaptive Behavior Scales, head circumferences, and ages at exams as classifying variables to identify more clinically similar subgroups of individuals with ASD. We identified two distinct subgroups of cases within the Autism Genetic Resource Exchange dataset, primarily defined by the overall severity of evaluated traits. In addition, there was significant familial clustering within subgroups (odds ratio, OR ≈ 1.38-1.42, P < 0.00001), and genotypes were more similar within subgroups compared to the unsubgrouped dataset (Fst = 0.17 ± 0.0.0009). These results suggest that the subgroups recapitulate genetic etiology. Using the same approach in an independent dataset from the Autism Genome Project, we similarly identified two distinct subgroups of cases and confirmed this severity-based dichotomy. We also observed evidence for genetic contributions to subgroups identified in the replication dataset. Our results provide more effective methods of phenotype definition that should increase power to detect genetic factors influencing risk for ASD.
Human T-cell leukemia-lymphoma virus (HTLV): cloning of an integrated defective provirus and flanking cellular sequences. (1983)

Human T-cell leukemia-lymphoma virus (HTLV) is the first unequivocal human retrovirus. Seroepidemiological and virus isolation studies indicate that HTLV is etiologically associated with a subtype of adult T-cell malignancy. We have molecularly cloned approximately 1 kilobase of sequences derived from the 5' and 3' termini of the HTLV genome. Use of these clones as probes allowed isolation of a 9.8-kilobase EcoRI fragment from a genomic DNA library of an HTLV-infected neoplastic T-cell line (CR). Analysis of this clone revealed the presence of cellular sequences flanking approximately 5 kilobases of viral sequences including one long terminal repeat sequence. The 5' and 3' clones, as well as subclones derived from different regions of the genomic clone, were used as probes to compare integrated proviruses and viral RNA expression in different HLTV-infected neoplastic T cell lines. The results indicate that the infected cells are of clonal origin with respect to the virus integration sites and they express multiple viral mRNA species including a 35S RNA.
Possible creation of net circular polarization and not only depolarization of spectral lines by isotropic collisions (2008)

We will show that isotropic collisions of electrons and protons with neutral hydrogen can lead to creation of net orientation of the atomic levels in the presence of a magnetic field. Consequently, the emitted Stokes-V profile of the spectral lines can be almost symmetric in contrast to the typical antisymmetric signature of the Zeeman effect. Moreover, the amplitude of the symmetric lobe can be significantly higher than the amplitude of the antisymmetric components. This mechanism is caused by a ±M symmetry breaking of the collisional transitions between different Zeeman sublevels. We will show an example of our first results for the Hα line. This new mechanism could perhaps explain the net circular polarization of spectral lines observed in some solar limb observations and which are currently not understood. However, our results are very preliminary and more developments are needed for going further on.
Molecular mechanisms of compartmentalization and biomineralization in magnetotactic bacteria (2011)

Magnetotactic bacteria (MB) are remarkable organisms with the ability to exploit the earth's magnetic field for navigational purposes. To do this, they build specialized compartments called magnetosomes that consist of a lipid membrane and a crystalline magnetic mineral. These organisms have the potential to serve as models for the study of compartmentalization as well as biomineralization in bacteria. Additionally, they offer the opportunity to design applications that take advantage of the particular properties of magnetosomes. In recent years, a sustained effort to identify the molecular basis of this process has resulted in a clearer understanding of the magnetosome formation and biomineralization. Here, I present an overview of MB and explore the possible molecular mechanisms of membrane remodeling, protein sorting, cytoskeletal organization, iron transport, and biomineralization that lead to the formation of a functional magnetosome organelle.
Visualizing real estate property information on the Web (2003)

We have designed and are implementing a system called ReV (Real estate Visualiser) for exploring real estate property listings on the World-Wide Web. Given the large number of different Web sites providing listings, each with its own presentation format, and the high dimensionality of the property space itself, it is difficult to obtain a comprehensive single view of property data on the Web. ReV addresses this problem by using grammar induction techniques to automatically learn to parse pages from new Web sites and collate all of their listings together. It them visualizes this listing data using a map based color coding technique. This work draws together a number of strands from the fields of information visualization, machine learning, and database integration. We also hypothesize that ReV will be adaptable to inducing structures from other types of Web data.
Major role for neuronal NO synthase in curtailing choroidal blood flow autoregulation in newborn pig (2001)

We examined whether nitric oxide (NO) generated from neuronal NO synthase (nNOS) contributes to the reduced ability of the newborn to autoregulate retinal blood flow (RBF) and choroidal blood flow (ChBF) during acute rises in perfusion pressure. In newborn pigs (1-2 days old), RBF (measured by microsphere) is autoregulated over a narrow range of perfusion pressure, whereas ChBF is not autoregulated. N(G)-nitro-L-arginine methyl ester (L-NAME) or specific nNOS inhibitors 7-nitroindazole, 3-bromo-7-nitroindazole, and 1-(2-trifluoromethyl-phenyl)imidazole as well as ganglionic blocker hexamethonium, unveiled a ChBF autoregulation as observed in juvenile (4- to 6-wk old) animals, whereas autoregulation of RBF in the newborn was only enhanced by L-NAME. All NOS inhibitors and hexamethonium prevented the hypertension-induced increase in NO mediator cGMP in the choroid. nNOS mRNA expression and activity were three- to fourfold higher in the choroid of newborn pigs than in tissues of juvenile pigs. It is concluded that increased production of NO from nNOS curtails ChBF autoregulation in the newborn and suggests a role for the autonomic nervous system in this important hemodynamic function, whereas, for RBF autoregulation, endothelial NOS seems to exert a more important contribution in limiting autoregulation.
Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients (2017)

Preclinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti-programmed cell death 1 protein (PD-1) immunotherapy (<i>n</i> = 112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus nonresponders. Analysis of patient fecal microbiome samples (<i>n</i> = 43, 30 responders, 13 nonresponders) showed significantly higher alpha diversity (<i>P</i> < 0.01) and relative abundance of bacteria of the Ruminococcaceae family (<i>P</i> < 0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in responders, including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and antitumor immunity in responding patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors.
Virus Movements on the Plasma Membrane Support Infection and Transmission between Cells (2009)

How viruses are transmitted across the mucosal epithelia of the respiratory, digestive, or excretory tracts, and how they spread from cell to cell and cause systemic infections, is incompletely understood. Recent advances from single virus tracking experiments have revealed conserved patterns of virus movements on the plasma membrane, including diffusive motions, drifting motions depending on retrograde flow of actin filaments or actin tail formation by polymerization, and confinement to submicrometer areas. Here, we discuss how viruses take advantage of cellular mechanisms that normally drive the movements of proteins and lipids on the cell surface. A concept emerges where short periods of fast diffusive motions allow viruses to rapidly move over several micrometers. Coupling to actin flow supports directional transport of virus particles during entry and cell-cell transmission, and local confinement coincides with either nonproductive stalling or infectious endocytic uptake. These conserved features of virus-host interactions upstream of infectious entry offer new perspectives for anti-viral interference.
Clinical Approach to Progressive Supranuclear Palsy (2016)

Sixty years ago, Steele, Richardson and Olszewski designated progressive supranuclear palsy (PSP) as a new clinicopathological entity in their seminal paper. Since then, in addition to the classic Richardson's syndrome (RS), different clinical phenotypic presentations have been linked with this four-repeat tauopathy. The clinical heterogeneity is associated with variability of regional distribution and severity of abnormal tau accumulation and neuronal loss. In PSP subtypes, the presence of certain clinical pointers may be useful for antemortem prediction of the underlying PSP-tau pathology. Midbrain atrophy on conventional MRI correlates with the clinical phenotype of RS but is not predictive of PSP pathology. Cerebrospinal fluid biomarkers and tau ligand positron emission tomography are promising biomarkers of PSP. A multidisciplinary approach to meet the patients' complex needs is the current core treatment strategy for this devastating disorder.
<title>Polarization-based folded Sagnac fiber optic sensor array for acoustic waves</title> (2002)

The basic Sagnac acoustic sensor array consists of a set of fiber hydrophones placed asymmetrically in a long Sagnac loop. It uses time division multiplexing (TDM) to address individual sensors. A new Sagnac-based array is described that uses a folded loop to reduce acoustic pick-up along the loop. This configuration also enables the use of polarization biasing to provide every sensor in the array with a stable phase bias of arbitrary value (including +/- (pi) /2, for maximum sensitivity), thus eliminating signal fading. A further benefit is the use of balanced detection to eliminate the excess noise from the broadband Er-doped fiber source. These improvements are demonstrated experimentally, as well as a minimum detectable signal close to the shot-noise limit (~0.06 (mu) rad/(root)Hz).
Posttranscriptional Gene Silencing in Neurospora by a RecQ DNA Helicase (1999)

The phenomenon of posttranscriptional gene silencing (PTGS), which occurs when a transgene is introduced into a cell, is poorly understood. Here, the qde-3 gene, which is required for the activation and maintenance of gene silencing in the fungus Neurospora crassa, was isolated. Sequence analysis revealed that the qde-3 gene belongs to the RecQ DNA helicase family. The QDE3 protein may function in the DNA-DNA interaction between introduced transgenes or with an endogenous gene required for gene-silencing activation. In animals, genes that are homologous to RecQ protein, such as the human genes for Bloom's syndrome and Werner's syndrome, may also function in PTGS.
High Performance Thin-Film Composite Forward Osmosis Hollow Fiber Membranes with Macrovoid-Free and Highly Porous Structure for Sustainable Water Production (2012)

The development of high-performance and well-constructed thin-film composite (TFC) hollow fiber membranes for forward osmosis (FO) applications is presented in this study. The newly developed membranes consist of a functional selective polyamide layer formed by highly reproducible interfacial polymerization on a polyethersulfone (PES) hollow fiber support. Using dual-layer coextrusion technology to design and effectively control the phase inversion during membrane formation, the support was designed to possess desirable macrovoid-free and fully sponge-like morphology. Such morphology not only provides excellent membrane strength, but it has been proven to minimize internal concentration polarization in a FO process, thus leading to the water flux enhancement. The fabricated membranes exhibited relatively high water fluxes of 32-34 LMH and up to 57-65 LMH against a pure water feed using 2 M NaCl as the draw solution tested under the FO and pressure retarded osmosis (PRO) modes, respectively, while consistently maintaining relatively low salt leakages below 13 gMH for all cases. With model seawater solution as the feed, the membranes could display a high water flux up to 15-18 LMH, which is comparable to the best value reported for seawater desalination applications.
PAM identification by CRISPR-Cas effector complexes: diversified mechanisms and structures (2018)

Adaptive immunity of prokaryotes is mediated by CRISPR-Cas systems that employ a large variety of Cas protein effectors to identify and destroy foreign genetic material. The different targeting mechanisms of Cas proteins rely on the proper protection of the host genome sequence while allowing for efficient detection of target sequences, termed protospacers. A short DNA sequence, the protospacer-adjacent motif (PAM), is frequently used to mark proper target sites. Cas proteins have evolved a multitude of PAM-interacting domains, which enables them to cope with viral anti-CRISPR measures that alter the sequence or accessibility of PAM elements. In this review, we summarize known PAM recognition strategies for all CRISPR-Cas types. Available structures of target bound Cas protein effector complexes highlight the diversity of mechanisms and domain architectures that are employed to guarantee target specificity.
Mechanisms of Resistance to NTRK Inhibitors and Therapeutic Strategies in NTRK1-Rearranged Cancers (2017)

<i>Neurotrophic receptor tyrosine kinase 1</i> (<i>NTRK1</i>) gene rearrangement leads to constitutive activation of NTRK1, which induces high-transforming ability. NTRK-rearranged cancers have been identified in several cancer types, such as glioblastoma, non-small cell lung cancer, and colorectal cancer. Although there are currently no clinically approved inhibitors that target NTRK1, several tyrosine kinase inhibitors (TKI), such as entrectinib and LOXO-101, are in clinical trials. The purpose of this study was to identify potential mechanisms of resistance to NTRK inhibitors and find potential therapeutic strategies to overcome the resistance. We examined the sensitivity of TPM3-NTRK1-transformed Ba/F3 cells and TPM3-NTRK1-harboring KM12 cells to multiple NTRK inhibitors. Acquired NTRK inhibitor-resistant mutations were screened by N-ethyl-N-nitrosourea mutagenesis with Ba/F3-TPM3-NTRK1 cells or by the establishment of NTRK-TKI-resistant cells from KM12 cells continuously treated with NTRK-TKIs. We identified multiple novel NTRK-TKI resistance mutations in the NTRK1 kinase domain, including G595R, and insulin growth factor receptor type 1 (IGF1R) bypass pathway-mediated resistance. After identifying the resistance mechanisms, we performed drug screening with small-molecule inhibitors to overcome the resistance. As a result, we found that ponatinib and nintedanib effectively inhibited the survival of TPM3-NTRK1-G667C but not G595R mutants, both of which showed resistance to entrectinib or larotrectinib (LOXO-101). Furthermore, cabozantinib with an IGF1R inhibitor such as OSI-906 could overcome bypass pathway-mediated resistance. We developed a comprehensive model of acquired resistance to NTRK inhibitors in cancer with NTRK1 rearrangement and identified cabozantinib as a therapeutic strategy to overcome the resistance. <i>Mol Cancer Ther; 16(10); 2130-43. ©2017 AACR</i>.
The FSN challenge: large-scale interactive TV (1995)

Developers at Time Warner Cable's Full Service Network in Orlando are quickly learning about the challenges of sending megabytes of video information across miles of fibre optic cables. Although the pilot project's video- and shopping-on-demand are up and running, the software developers must now determine how to send different news-on-demand requests to 4,000 homes by the end of the year.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Immunotherapy and other novel therapies (1991)

Although no true breakthroughs occurred, publications during the 12-month period of this review added substantial definition to certain novel immunotherapies potentially applicable to the treatment of rheumatoid arthritis. Overall, this period witnessed maturation in the field of biologic interventions. Clinical trials provided further data needed to assess the efficacy of high-dose intravenous gamma-globulin therapy in patients with systemic juvenile rheumatoid arthritis, and extended uncontrolled experience with interferon-gamma in adult rheumatoid arthritis was obtained. An intriguing immunostimulant and antiviral drug, isoprinosine (inosine pranobex), failed in a scientifically rigorous trial in rheumatoid arthritis. Provocative insights into totally new approaches surfaced in additional reports from a variety of immunologic areas. Although seemingly distal to rheumatoid arthritis, these papers are cited because their further development or adaptations could reach a stage where clinical trials in rheumatoid arthritis are warranted.
Coumarin and Chromen-4-one Analogues as Tautomerase Inhibitors of Macrophage Migration Inhibitory Factor: Discovery and X-ray Crystallography (2000)

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine released from T-cells and macrophages. Although a detailed understanding of the biological functions of MIF has not yet been clarified, it is known that MIF catalyzes the tautomerization of a nonphysiological molecule, D-dopachrome. Using a structure-based computer-assisted search of two databases of commercially available compounds, we have found 14 novel tautomerase inhibitors of MIF whose K(i) values are in the range of 0.038-7.4 microM. We also have determined the crystal structure of MIF complexed with the hit compound 1. It showed that the hit compound is located in the active site of MIF containing the N-terminal proline which plays an important role in the tautomerase reaction and forms several hydrogen bonds and undergoes hydrophobic interactions. A crystallographic study also revealed that there is a hydrophobic surface which consists of Pro-33, Tyr-36, Trp-108, and Phe-113 at the rim of the active site of MIF, and molecular modeling studies indicated that several more potent hit compounds have the aromatic rings which can interact with this hydrophobic surface. To our knowledge, our compounds are the most potent tautomerase inhibitors of MIF. One of these small, drug-like molecules has been cocrystallized with MIF and binds to the active site for tautomerase activity. Molecular modeling also suggests that the other hit compounds can bind in a similar fashion.
Fluid Shear Regulates the Kinetics and Receptor Specificity of Staphylococcus aureus Binding to Activated Platelets (2004)

The interaction between surface components on the invading pathogen and host cells such as platelets plays a key role in the regulation of endovascular infections. However, the mechanisms mediating Staphylococcus aureus binding to platelets under shear remain largely unknown. This study was designed to investigate the kinetics and molecular requirements of platelet-S. aureus interactions in bulk suspensions subjected to a uniform shear field. Hydrodynamic shear-induced collisions augment platelet-S. aureus binding, which is further potentiated by platelet activation with stromal derived factor-1beta. Peak adhesion efficiency occurs at low shear (100 s(-1)) and decreases with increasing shear. The molecular interaction of platelet alpha(IIb)beta(3) with bacterial clumping factor A through fibrinogen bridging is necessary for stable bacterial binding to activated platelets under shear. Although this pathway is sufficient at low shear (</=400 s(-1)), the involvement of platelet gpIb and staphylococcal protein A through von Willebrand factor bridging is essential for optimal recruitment of S. aureus cells by platelets in the high shear regime. IgG plays an inhibitory role in the adhesion process, presumably by interfering with the binding of von Willebrand factor to staphylococcal protein A. This study demonstrates that platelet activation and a fluid-mechanical environment representative of the vasculature affect platelet-S. aureus cell-adhesive interactions pertinent to the process of S. aureus-induced bloodstream infections.
Genetic heterogeneity of the immunogenic viral capsid protein region of human parvovirus B19 isolates obtained from an outbreak in a pediatric ward (1999)

Whereas human parvovirus B19 commonly infects children and causes erythema infectiosum, it causes more severe diseases when it infects adults. In order to examine whether different clinical outcomes of B19 infection can be ascribed to the viral genetic heterogeneity, we have determined the nucleotide sequence of highly immunogenic portions of the B19 genome obtained from six patients with various clinical manifestations in a single outbreak. Our observations demonstrated that although the B19 sequences showed a significant heterogeneity, it was not correlated with the clinical manifestation. It was thus suggested that the host immune response to B19 infection may be a major determinant of clinical presentations associated with acute B19 infection.