gebhart/patrepeval huggingface dataset:
3′ IgH Enhancer Elements Shift Synergistic Interactions During B Cell Development (1998)

IgH gene expression is tightly controlled over the course of B cell development, B cell activation, and the subsequent differentiation of these cells into Ig-secreting plasmacytes. There are several transcriptional enhancers that map within and downstream of the IgH locus, and some of these have been clearly implicated in the developmental regulation of IgH gene assembly and expression. While some of the individual enhancers from this locus have been studied extensively, the functional interactions possible among this group of enhancers have been largely unexplored. In the present study, we have measured the transcriptional activities of combinations of enhancers introduced into B-lineage cell lines at several different developmental stages. We detected a developmental progression in which the 3' enhancers are initially inactive, then become strongly active through synergistic interactions, and finally achieve a strong level of activity with little interdependency. The relative contributions of E mu (the intron enhancer) and of the 3' enhancers also change as a function of developmental stage. We discuss these results in light of parallel studies of developmental changes in transcription factor requirements.
The functional role of long non-coding RNA in human carcinomas (2011)

Long non-coding RNAs (lncRNAs) are emerging as new players in the cancer paradigm demonstrating potential roles in both oncogenic and tumor suppressive pathways. These novel genes are frequently aberrantly expressed in a variety of human cancers, however the biological functions of the vast majority remain unknown. Recently, evidence has begun to accumulate describing the molecular mechanisms by which these RNA species function, providing insight into the functional roles they may play in tumorigenesis. In this review, we highlight the emerging functional role of lncRNAs in human cancer.
Gene Transfer for Neovascular Age-Related Macular Degeneration (2011)

Age-related macular degeneration (AMD) is a complex disease that has two phases: a degenerative phase often referred to as nonneovascular AMD (non-NVAMD) or dry AMD and a phase dominated by growth of new blood vessels in the subretinal space, referred to as NVAMD or wet AMD. Advances in the understanding of the molecular pathogenesis of NVAMD have led to new drug therapies that have provided major benefits to patients. However, those treatments require frequent intraocular injections that in many patients must be continued indefinitely to maintain visual benefits. Gene transfer to augment expression of endogenous antiangiogenic proteins is an alternative approach that has the potential to provide long-term stability in patients with NVAMD. Studies in animal models that mimic aspects of NVAMD have identified several possible transgenes, and a clinical trial in patients with advanced NVAMD has suggested that the approach may be feasible. Many important questions remain, but the rationale and preliminary data are compelling. The results of two ongoing clinical trials may answer several of the questions and help direct future research.
pH-Responsive Properties of Multilayered Poly(l-lysine)/Hyaluronic Acid Surfaces (2003)

Multilayer films have been prepared by the sequential electrostatic adsorption of poly(L-lysine) and hyaluronic acid onto charged silicon surfaces from dilute aqueous solutions under various pH conditions. Microelectrophoresis was used to examine the local acid-base equilibria of the polyelectrolytes within the films as a function of the total number of layers in the film and the assembly solution pH. The acid-base dissociation constants were observed to deviate significantly from dilute solution values upon adsorption, to be layer dependent only within the first 3-4 layers, and to show sensitivity to the assembly solution pH. As a result, some of the physicochemical properties of the films have also been found to exhibit pH-responsive behavior. For example, the thickest films result when at least one of the polyelectrolytes is only partially dissociated in solution. As well, the pH-dependent degree of dissociation of the surface functional groups can be used to vary the contact angle of a water droplet by as much as 25 degrees and the coefficient of friction by up to an order of magnitude. In addition, the extent to which PLL/HA films can be made to swell in solution can be varied by a factor of 7 depending on the assembly solution and swelling solution pH. The anomalies found in the dissociation constants account for the trends in these pH-dependent properties. Here, we demonstrate that knowledge of the acid-base dissociation behavior in multilayer films is key to understanding and controlling the physical properties of the films, particularly surface friction and wettability, which are fundamentally important factors for many biomaterials applications. For example, we outline a mechanism whereby biopolymer thin films can be electrostatically adsorbed under highly charged "sticky" conditions and then quickly transformed into stable low-friction films simply by altering the pH environment.
Diabetes Treatment, Part 2: Oral Agents for Glycemic Management (2007)

T he epidemic of type 2 diabetes in the United States and the rest of the world continues to grow rapidly; as many as 20 million people in the United States may have the disease.1 The vast majority of people with diabetes have type 2 diabetes, caused by a relative insulin deficiency superimposed on a background of insulin resistance.2 Most patients begin treatment with diet and exercise or incorporate them into their treatment regimen, but, unfortunately, most patients are unsuccessful in controlling type 2 diabetes through lifestyle modification alone and require pharmacotherapy.

For several reasons, oral agents are typically the first medications used in the treatment of type 2 diabetes. Because of their wide range of efficacy, safety, and mechanisms of action, it is important for clinicians to gain a broad understanding of each class of oral agents to optimize diabetes control. This article reviews the major classes of oral agents used to treat type 2 diabetes, with an emphasis on the benefits and risks of each class. It is important to note that because type 1 diabetes results from an absolute deficiency of pancreatic β-cells, most oral agents are not indicated in the treatment of patients with type 1 diabetes. Oral agents are also largely not tested or approved for use in pregnancy.

Metformin is the sole member of the biguanide class of medications in the United States. It replaced another biguanide, fenformin, which was removed from the market because of a propensity for lactic acidosis in 1975.3,4 Available in short-acting and sustained-release formulations, it is one of the oldest, and indeed one of the safest, medications used in the treatment of type 2 diabetes.

Metformin exerts its effects primarily by decreasing hepatic glucose output and has a comparatively lesser effect increasing insulin sensitivity. …
Radiation Losses of Dielectric Waveguides in Terms of the Power Spectrum of the Wall Distortion Function (1969)

In an earlier paper I described a perturbation theory of the radiation losses of a dielectric slab waveguide. The statistical treatment of the radiation losses was based on the correlation function of the wall distortion. This paper discusses the results of the radiation loss theory in terms of the power spectrum of the function describing the thickness of the slab. We found that only those mechanical frequencies Θ of the power spectrum contribute to the radiation loss that fall into the range β <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">o</inf> - k < Θ < β <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">o</inf> + k. (β <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">o</inf> = propagation constant of guided mode, k = free space propagation constant.) The mechanical frequencies near both end points of this mechanical frequency range contribute more to the radiation loss than the region well inside of this range. We also discuss the far-field radiation pattern caused by a strictly sinusoidal wall distortion.
<title>Void-and-cluster method for dither array generation</title> (1993)

Halftoning to two or more levels by means of ordered dither has always been attractive because of its speed and simplicity. However, the so-called recursive tessellation arrays in wide use suffer from strong periodic structure that imparts an unnatural appearance to resulting images. A new method for generating homogeneous ordered dither arrays is presented. A dither array is built by looking for voids and clusters in the intermediate patterns and relaxing them to optimize isotropy. While the method can be used for strikingly high quality artifact-free dithering with relatively small arrays, it is quite general; with different initial conditions the familiar recursive tessellation arrays can be built. This paper presents the algorithm for generating such arrays. Example images are compared with other ordered dither and error diffusion-based techniques.
The relation between stimulus and response in olfactory receptor cells of the tiger salamander. (1993)

1. Olfactory receptor cells were isolated from the adult tiger salamander Ambystoma tigrinum and the current in response to odorant stimuli was measured with the whole-cell voltage-clamp technique while odorants at known concentrations were rapidly applied for controlled exposure times. 2. Three odorants, cineole, isoamyl acetate and acetophenone, were first applied at 5 x 10(-4) M. Out of forty-nine cells tested, 53% responded to one odorant only, 22% to two odorants and 25% to all three odorants. 3. The amplitude of the current in response to a given odorant concentration was found to be dependent on the duration of the odorant stimulus and reached a saturating peak value at 1.2 s of stimulus duration. 4. The current measured at the peak of the response for odorant steps of 1.2 s as a function of odorant concentration was well described by the Hill equation for the three odorants with Hill coefficients higher than 1 and K1/2 (odorant concentration needed to activate half the maximal current) ranging from 3 x 10(-6) to 9 x 10(-5) M. 5. It is concluded that olfactory receptor cells are broadly tuned and have a low apparent affinity for odorants, integrate stimulus information over time, and have a narrow dynamic range.
Clinical Pharmacokinetics of Cannabinoids (2003)

ABSTRACT Absorption and metabolism of tetrahydrocannabinol (THC) vary as a function of route of administration. Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes, while psychotropic effects start within seconds to a few minutes, reach a maximum after 15 to 30 minutes, and taper off within 2 to 3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30 to 90 minutes, reach their maximum after 2 to 3 hours, and last for about 4 to 12 hours, depending on dose and specific effect. The initial volume of distribution of THC is small for a lipophilic drug, equivalent to the plasma volume of about 2.5–3 L, reflecting high protein binding of 95–99%. The steady state volume of distribution has been estimated to be about 100 times larger, in the range of about 3.5 L per kg of body weight. The lipophility of THC with high binding to tissue and in particular to fat, the major long-term storage site, causes a change of distribution pattern over time. Only about 1% of THC administered IV is found in the brain at the time of peak psychoactivity. THC crosses the placenta and small amounts penetrate into the breast milk. Metabolism of THC occurs mainly in the liver by microsomal hydroxylation and oxidation catalyzed by enzymes of the cytochrome P-450 complex. In man, the C-11 carbon is the major site attacked. Hydroxylation results in 11-hydroxy-THC (11-OH-THC) and further oxidation to 11-nor-9-carboxy-THC (THC-COOH), which may be glucuronated to THC-COOH beta-glucuronide. Pharmacologically, 11-OH-THC shows a similar profile as THC while THC-COOH is devoid of psycho-tropic effects. With oral administration higher amounts of 11-OH-THC are formed than with inhalation, reaching similar plasma levels as its parent drug, and contributing significantly to the overall effects of THC. Metabolic interaction between THC and the non-psychotropic cannabidiol (CBD) is based on inhibition of the cytochrome P-450-3A enzyme by CBD. Repeated administration of all cannabinoids causes induction of some cytochrome P-450 isoenzymes which may result in interactions with other medical and non-medical drugs that are using the same enzymes for metabolism.
Gradient methods for the optimization of dynamical systems containing neural networks (1991)

An extension of the backpropagation method, termed dynamic backpropagation, which can be applied in a straightforward manner for the optimization of the weights (parameters) of multilayer neural networks is discussed. The method is based on the fact that gradient methods used in linear dynamical systems can be combined with backpropagation methods for neural networks to obtain the gradient of a performance index of nonlinear dynamical systems. The method can be applied to any complex system which can be expressed as the interconnection of linear dynamical systems and multilayer neural networks. To facilitate the practical implementation of the proposed method, emphasis is placed on the diagrammatic representation of the system which generates the gradient of the performance function.
Teratogen-Mediated Inhibition of Target Tissue Response to Shh Signaling (1998)

Veratrum alkaloids and distal inhibitors of cholesterol biosynthesis have been studied for more than 30 years as potent teratogens capable of inducing cyclopia and other birth defects. Here, it is shown that these compounds specifically block the Sonic hedgehog (Shh) signaling pathway. These teratogens did not prevent the sterol modification of Shh during autoprocessing but rather inhibited the response of target tissues to Shh, possibly acting through the sterol sensing domain within the Patched protein regulator of Shh response.
Carcinoma in situ. (1992)

Carcinoma in situ is a high-grade and aggressive manifestation of transitional-cell carcinoma of the bladder that has a highly variable course. The treatment of CIS has undergone dramatic changes since this malignancy was first recognized. While cystectomy was once recommended as the initial treatment of choice, recognition of the highly variable prognosis and the uniformly high response rate to intravesical BCG has prompted a more conservative approach to management. While it is recommended that patients be offered the option of radical cystectomy, data do not currently exist to confirm that cystectomy provides a superior survival or quality of life compared with an initial trial of BCG immunotherapy followed by salvage cystectomy if needed. With current optimal BCG immunotherapy regimens, which consist of a 6-week course of BCG followed by three weekly instillations at 3 months, 6 months, and every 6 months for 3 years, the complete response rate is 82%; and it is estimated that more than 75% of patients having a complete response will remain continuously disease free for 5 or more years. Patients who fail BCG immunotherapy without evidence of progression may yet be candidates for intravesical chemotherapy, photodynamic therapy, or alternative immunotherapies such as alpha-2b interferon, bropirimine, or keyhole limpet hemocyanin.
舆论研究向行为研究的过渡 “青年生活方式和消费模式”国际讨论会总结报告 (1992)

青春不局限于年龄,换言之,青春是多么美好,但并非对所有年轻人而言。在后现代化社会里,青年时代(青春)是具有重大价值的,人们都应年轻。年轻人享有充分空余时光、意味着幸福,意味着个性充分发挥,意味着自由以及性别上的平等。这样描绘的结果必然对
Channeling of developing rat corticospinal tract axons by myelin-associated neurite growth inhibitors. (1991)

CNS myelin contains 2 membrane proteins that are potent inhibitors of neurite growth (NI-35 and NI-250). Because myelin formation starts at different times in different regions and tracts of the CNS, this inhibitory property of myelin could serve boundary and guidance functions for late-growing fiber tracts. In the rat, the corticospinal tract (CST) grows into and down the spinal cord during the first 10 postnatal days, in close proximity to the sensory tracts fasciculus cuneatus and gracilis. Immunofluorescence for myelin constituents showed that, in the rostral half of the spinal cord, the myelinating tissue of these ascending tracts surrounds the growing, myelin-free CST in a channellike fashion. Elimination of oligodendrocytes by x-irradiation of the newborn rats, or application of antibody IN-1, which neutralizes the inhibitory substrate property of CNS myelin, resulted in significant anatomical aberration of CST fibers. In particular, the tract was larger in cross-section, and aberrant CST fibers and fascicles intermixed with the neighboring sensory ascending tracts. These results assign an important channeling and "guard-rail" function to the oligodendrocyte-associated neurite growth inhibitors for the developing CST in the rat spinal cord.
Sparse partial least squares for on-line variable selection in multivariate data streams (2009)

In this paper we propose a computationally efficient algorithm for on-line variable selection in multivariate regression problems involving high dimensional data streams. The algorithm recursively extracts all the latent factors of a partial least squares solution and selects the most important variables for each factor. This is achieved by means of only one sparse singular value decomposition which can be efficiently updated on-line and in an adaptive fashion. Simulation results based on artificial data streams demonstrate that the algorithm is able to select important variables in dynamic settings where the correlation structure among the observed streams is governed by a few hidden components and the importance of each variable changes over time. We also report on an application of our algorithm to a multivariate version of the "enhanced index tracking" problem using financial data streams. The application consists of performing on-line asset allocation with the objective of overperforming two benchmark indices simultaneously.
Production of the Antibiotic Phenazine-1-Carboxylic Acid by Fluorescent Pseudomonas Species in the Rhizosphere of Wheat (1990)

Pseudomonas fluorescens 2-79 and P. aureofaciens 30-84 produce the antibiotic phenazine-1-carboxylic acid and suppress take-all, an important root disease of wheat caused by Gaeumannomyces graminis var. tritici. To determine whether the antibiotic is produced in situ, wheat seeds were treated with strain 2-79 or 30-84 or with phenazine-nonproducing mutants or were left untreated and then were sown in natural or steamed soil in the field or growth chamber. The antibiotic was isolated only from roots of wheat colonized by strain 2-79 or 30-84 in both growth chamber and field studies. No antibiotic was recovered from the roots of seedlings grown from seeds treated with phenazine-nonproducing mutants or left untreated. In natural soils, comparable amounts of antibiotic (27 to 43 ng/g of root with adhering soil) were recovered from roots colonized by strain 2-79 whether or not the pathogen was present. Roots of plants grown in steamed soil yielded larger bacterial populations and more antibiotic than roots from natural soils. In steamed and natural soils, roots from which the antibiotic was recovered had significantly less disease than roots with no antibiotic, indicating that suppression of take-all is related directly to the presence of the antibiotic in the rhizosphere.
Measuring and Modeling the Kinetics of Individual DNA–DNA Polymerase Complexes on a Nanopore (2013)

The assembly of a DNA-DNA polymerase binary complex is the precursory step in genome replication, in which the enzyme binds to the 3' junction created when a primer binds to its complementary substrate. In this study, we use an active control method for observing the binding interaction between Klenow fragment (exo-) (KF) in the bulk-phase chamber above an α-hemolysin (α-HL) nanopore and a single DNA molecule tethered noncovalently in the nanopore. Specifically, the control method regulates the temporal availability of the primer-template DNA to KF binding and unbinding above the nanopore, on millisecond-to-second time scales. Our nanopore measurements support a model that incorporates two mutually exclusive binding states of KF to DNA at the primer-template junction site, termed "weakly bound" and "strongly bound" states. The composite binding affinity constant, the equilibrium constant between the weak and strong states, and the unbound-to-strong association rate are quantified from the data using derived modeling analysis. The results support that the strong state is in the nucleotide incorporation pathway, consistent with other nanopore assays. Surprisingly, the measured unbound-to-strong association process does not fit a model that admits binding of only free (unbound) KF to the tethered DNA but does fit an association rate that is proportional to the total (unbound and DNA-bound) KF concentration in the chamber above the nanopore. Our method provides a tool for measuring pre-equilibrium kinetics one molecule at a time, serially and for tens of thousands of single-molecule events, and can be used for other polynucleotide-binding enzymes.
Irradiated sporozoite vaccine induces HLA-B8-restricted cytotoxic T lymphocyte responses against two overlapping epitopes of the Plasmodium falciparum sporozoite surface protein 2. (1995)

Vaccines designed to protect against malaria by inducing CD8+ cytotoxic T lymphocytes (CTL) in individuals of diverse HLA backgrounds must contain multiple conserved epitopes from various preerythrocytic-stage antigens. Plasmodium falciparum sporozoite surface protein 2 (PfSSP2) is considered an important antigen for inclusion in such vaccines, because CD8+ CTL against the P. yoelii SSP2 protect mice against malaria by eliminating infected hepatocytes. To develop PfSSP2 as a component of malaria vaccines, we investigated the presence of anti-PfSSP2 CTL in two HLA-B8+ volunteers immunized with irradiated P. falciparum sporozoites and characterized their CTL responses using PfSSP2-derived 15-amino acid peptides bearing the HLA-B8-binding motif. Peripheral blood mononuclear cells from both volunteers stimulated with recombinant vaccinia expressing PfSSP2 displayed antigen-specific, genetically restricted, CD8+ T cell-dependent CTL activity against autologous target cells expressing PfSSP2. Of the five HLA-B8 motif-bearing 15-mers identified in the PfSSP2 sequence, two peptides sharing a 10-amino acid overlap sensitized HLA-B8-matched target cells from both volunteers for lysis by peptide-stimulated effectors. The CTL activity was HLA-B8 restricted and dependent on CD8+ T cells. Analysis of the three shorter peptides representing HLA-B8 motif-bearing sequences within the two positive peptides for their ability to bind to HLA-B8 in vitro, and to sensitize target cells for lysis by effectors stimulated with the 15-mers, identified two overlapping HLA-B8-restricted CTL epitopes. Available data indicate that the sequence of one CTL epitope is conserved and the other is variant among P. falciparum isolates. Circulating activated CTL against the conserved epitope could be directly identified in one of the two volunteers. The identification of two HLA-B8-restricted CTL epitopes on PfSSP2 provides data critical to developing an epitope-based anti-liver stage malaria vaccine.