gebhart/patrepeval huggingface dataset:
Functional parameters of Dicer-independent microRNA biogenesis (2012)

Until recently, a Dicer-class RNase III enzyme was believed to be essential for microRNA (miRNA) biogenesis in all animals. The conserved vertebrate locus mir-451 defies this expectation and instead matures by direct cleavage of its pre-miRNA hairpin via the Slicer activity of Argonaute2 (Ago2). In this study, we used structure-function analysis to define the functional parameters of Ago2-mediated miRNA biogenesis. These include (1) the requirement for base-pairing at most, but not all, positions within the pre-mir-451 stem; (2) surprisingly little influence of the 5'-nucleotide on Ago sorting; (3) substantial influence of Ago protein stoichiometry on mir-451 maturation; (4) strong influence of G:C content in the distal stem on 3' resection of cleaved mir-451 substrates; and (5) the influence of hairpin length on substrate utilization by Ago2 and Dicer. Unexpectedly, we find that certain hairpin lengths confer competence to mature via both Dicer-mediated and Ago2-mediated pathways, and we show, in fact, that a conventional shRNA can traverse the Dicer-independent pathway. Altogether, these data inform the design of effective Dicer-independent substrates for gene silencing and reveal novel aspects of substrate handling by Ago proteins.
Dynamics of Early T Cells: Prothymocyte Migration and Proliferation in the Adult Mouse Thymus (1986)

The object of this review has been to consider precursor cell migration into the normal adult thymus, using the mouse model. We have presented a series of experiments and discussed them in the context of other relevant experiments in the literature. The conclusions, qualified in the text, can be summarized as follows: There is a continual input of precursor cells into the normal undepleted adult thymus. The daily input of precursors under normal circumstances is very low (e.g. several per day). Once a precursor enters the pool of proliferating cells inside the thymus, its proliferation is limited to only several weeks. There is no permanent endogenous stem cell. There are a number of different precursor microenvironments in the thymus with different controls, since the kinetics of early (bone marrow-derived) and late (thymus-derived) precursors is quite different. All of these points require further analysis, and we have presented a minimal model as a basis for further experiment.
Structure and functional properties of Norrin mimic Wnt for signalling with Frizzled4, Lrp5/6, and proteoglycan (2015)

Wnt signalling regulates multiple processes including angiogenesis, inflammation, and tumorigenesis. Norrin (Norrie Disease Protein) is a cystine-knot like growth factor. Although unrelated to Wnt, Norrin activates the Wnt/β-catenin pathway. Signal complex formation involves Frizzled4 (Fz4), low-density lipoprotein receptor related protein 5/6 (Lrp5/6), Tetraspanin-12 and glycosaminoglycans (GAGs). Here, we report crystallographic and small-angle X-ray scattering analyses of Norrin in complex with Fz4 cysteine-rich domain (Fz4CRD), of this complex bound with GAG analogues, and of unliganded Norrin and Fz4CRD. Our structural, biophysical and cellular data, map Fz4 and putative Lrp5/6 binding sites to distinct patches on Norrin, and reveal a GAG binding site spanning Norrin and Fz4CRD. These results explain numerous disease-associated mutations. Comparison with the Xenopus Wnt8-mouse Fz8CRD complex reveals Norrin mimics Wnt for Frizzled recognition. The production and characterization of wild-type and mutant Norrins reported here open new avenues for the development of therapeutics to combat abnormal Norrin/Wnt signalling.
Some) computer vision based interfaces for interactive art and entertainment installations (2001)

This paper presents a brief summary of body tracking tools and interfaces the author developed, and explains how they have been applied to a variety of interactive art and entertainment projects. The purpose of such grouping of techniques and related applications is to provide the reader with information on some of the tools available today for computer vision based body tracking, how they can be selected and applied to achieve the desired artistic goal, and their limitations. What these computer vision interfaces have in common is low cost, and ease of implementation, as they require means which are commonly available today to most individuals/institutions, such as computers and small cameras. They have the additional advantage that they do not require special calibration procedures, they do not limit body movements with cables or tethers, nor do they require wearing special suites with markers for tracking.
Rapid feature extraction for Bangla handwritten digit recognition (2011)

Feature extraction is one of the fundamental problems of character recognition. The performance of character recognition system is largely depending on proper feature extraction and correct classifier selection. In this article, a rapid feature extraction method is proposed and named as Celled Projection (CP) that compute the projection of each section formed through partitioning an image. The recognition performance of the proposed method is compared with other widely used feature extraction methods that are intensively studied for many different scripts in literature. The experiments have been conducted using Bangla handwritten numerals along with three different well known classifiers which demonstrate comparable results including 94.12% recognition accuracy using celled-projection.
American Society of Clinical Oncology Clinical Practice Guideline for the Use of Larynx-Preservation Strategies in the Treatment of Laryngeal Cancer (2006)

All patients with T1 or T2 laryngeal cancer, with rare exception, should be treated initially with intent to preserve the larynx. For most patients with T3 or T4 disease without tumor invasion through cartilage into soft tissues, a larynx-preservation approach is an appropriate, standard treatment option, and concurrent chemoradiotherapy therapy is the most widely applicable approach. To ensure an optimum outcome, special expertise and a multidisciplinary team are necessary, and the team should fully discuss with the patient the advantages and disadvantages of larynx-preservation options compared with treatments that include total laryngectomy.
[Studies on synthesis and anticonvulsant activity of 3-GABA derivatives of 6-(substituted-phenyl) pyridazines]. (1991)

In recent years considerable emphasis has been placed on the hypothesis that enhancement of GABA transmission could be beneficial in some types of epilepsy. The alpha-(aryl)-4-morpholineacetonitrile obtained by the interaction of aryl aldehydes, morpholine and potassium cyanide, have been used to synthesize 3-(aroyl)-propionic acids and esters by 1,4-additions to acrylonitrile or acrylic ester. 3-(Aroyl) propionic acids reacting with hydrazine can yield 6-aryl-4,5-dihydro-3(2H) pyridazinones which are dehydrogenated by bromine (via bromination dehydrobromination) to give 6-aryl-3(2H) pyridazinones. The latter compounds were converted into 3-(N-GABA)-6-(substitutedphenyl) pyridazines and 3-(N-butyryllactamyl)-6-(substitutedphenyl) pyridazines by the chlorination (by means of phosphorus oxychloride) and then reaction with GABA. By this method seventeen 3-GABA derivatives of 6-(substituted-phenyl)pyridazines were synthesized. The anticonvulsant activity (MES) of these compounds were also tested. 3-(N-GABA)-6-(2',4'-dichloro)phenylpyridazine; potent anticonvulsant (ED50 = 21.05 mg/kg).
Access and Alignment of Data in an Array Processor (1975)

This paper discusses the design of a primary memory system for an array processor which allows parallel, conflict-free access to various slices of data (e.g., rows, columns, diagonals, etc.), and subsequent alignment of these data for processing. Memory access requirements for an array processor are discussed in general terms and a set of common requirements are defined. The ability to meet these requirements is shown to depend on the number of independent memory units and on the mapping of the data in these memories. Next, the need to align these data for processing is demonstrated and various alignment requirements are defined. Hardware which can perform this alignment function is discussed, e.g., permutation, indexing, switching or sorting networks, and a network (the omega network) based on Stone's shuffle-exchange operation [1] is presented. Construction of this network is described and many of its useful properties are proven. Finally, as an example of these ideas, an array processor is shown which allows conflict-free access and alignment of rows, columns, diagonals, backward diagonals, and square blocks in row or column major order, as well as certain other special operations.
Diffraction characteristics of photoresist surface-relief gratings (1984)

Theoretical results from rigorous coupled-wave analysis are compared with experimental diffraction characteristics for holographically formed dielectric photoresist surface-relief gratings with deep grooves (greater than a grating period) and high diffraction efficiency (&gt;85%). The angular selectivity (at a fixed wavelength) and the wavelength selectivity (at a fixed angle of incidence) are presented for both TE and TM incident polarizations. Modeling the gratings as a surface-relief modulated half-space and using rigorous coupled-wave analysis are shown to produce good general agreement with the experimentally measured diffraction characteristics.
Expanding the base editing scope in rice by using Cas9 variants (2018)

Base editing is a novel genome editing strategy that enables irreversible base conversion at target loci without the need for double stranded break induction or homology-directed repair. Here, we developed new adenine and cytosine base editors with engineered SpCas9 and SaCas9 variants that substantially expand the targetable sites in the rice genome. These new base editors can edit endogenous genes in the rice genome with various efficiencies. Moreover, we show that adenine and cytosine base editing can be simultaneously executed in rice. The new base editors described here will be useful in rice functional genomics research and will advance precision molecular breeding in crops.
The orphan receptors NGFI-B and steroidogenic factor 1 establish monomer binding as a third paradigm of nuclear receptor-DNA interaction. (1993)

We examined in detail the DNA interaction of the nuclear receptors NGFI-B and steroidogenic factor 1 (SF-1) by using a series of gain-of-function domain swaps. NGFI-B bound with high affinity as a monomer to a nearly linear DNA molecule. The prototypic zinc modules interacted with a half-site of the estrogen receptor class, and a distinct protein motif carboxy terminal to the zinc modules (the A box) interacted with two A/T base pairs 5' to the half-site. SF-1 bound in the same manner as NGFI-B, with an overlapping but distinct sequence requirement 5' to the half-site. The key features that distinguished the NGFI-B and SF-1 interactions were an amino group in the minor groove of the SF-1 binding sequence and an asparagine in the SF-1 A box. These results define a common mechanism of NGFI-B and SF-1 DNA binding, which may underlie a competitive mechanism of gene regulation in steroidogenic tissues that express these proteins. This monomer-DNA interaction represents a third paradigm of DNA binding by nuclear receptors in addition to direct and inverted dimerization.
IGF-I and IGF-II protect cultured hippocampal and septal neurons against calcium-mediated hypoglycemic damage (1992)

Insulin and insulin-like growth factors I and II (IGF-I and IGF-II) have recently been shown to have biological activity in central neurons, but their normal functions and mechanisms of action in the brain are unknown. Since central neurons are particularly vulnerable to hypoglycemia that results from ischemia or other insults, we tested the hypothesis that growth factors can protect central neurons against hypoglycemic damage in vitro. IGF-I and IGF-II (3-100 ng/ml) each prevented glucose deprivation-induced neuronal damage in a dose-dependent manner in rat hippocampal and septal cell cultures. High concentrations of insulin (greater than 1 microgram/ml) also protected neurons against hypoglycemic damage. Epidermal growth factor did not protect against hypoglycemic damage. Both IGFs and insulin were effective when administered 24 hr before or immediately following the onset of glucose deprivation. Direct measurements of intraneuronal calcium levels and manipulations of calcium influx demonstrated that calcium influx and sustained elevations in intraneuronal calcium levels mediated the hypoglycemic damage. IGF-I and IGF-II each prevented the hypoglycemia-induced elevations of intraneuronal free calcium. Studies with excitatory amino acid receptor antagonists and calcium channel blockers indicated that NMDA receptors did, and L-type calcium channels did not, play a major role in hypoglycemic damage. Taken together, these findings indicate that IGFs can stabilize neuronal calcium homeostasis and thereby protect against hypoglycemic damage.
Synthesis of biotin conjugates of the antifungal compound cymoxanil (2002)

Biotin conjugates are of considerable value in investigating the mode of action of biologically active compounds. Two biotin conjugates related to the antifungal compound cymoxanil [1-(2-cyano-2-methoximinoacetyl)-3-ethyl urea] were prepared as the first step in an effort to employ display cloning to identify the compound's target site. In the first conjugate, prepared in five steps, the biotin moiety was attached at the position occupied by the ethyl group in cymoxanil. In the second conjugate, prepared in four steps, the biotin moiety was attached through the oxime functional group.
Dronedarone: An antiarrhythmic agent for the management of atrial fibrillation and atrial flutter (2009)

Dronedarone, an investigational antiarrhythmic agent being studied for the management of AF and atrial flutter, has a pharmacologic mechanism of action that is similar to that of amiodarone, but dronedarone lacks an iodine moiety, which may result in less thyroid and pulmonary toxicity. Dronedarone is currently pending FDA approval; the agent was granted priority review in August 2008.
Activation of human prothrombin by highly purified human factors V and X-a in presence of human antithrombin. (1975)

In this communication we describe the first method for isolating human Factor V. The final product contains no other coagulation components as judged by functional assays and is physically homogeneous as shown by isofocusing gel electrophoresis. In addition, we present a means for obtaining intrinsically activated human Factor X-a. This preparation is usually homogeneous as judged by isofocusing gel electrophoresis. However, on occasion, an additional minor electrophoretic species with Factor X-a activity is observed. Furthermore, we describe the use of isoelectric focusing in sucrose density gradients to free human prothrombin from contamination by coagulation factors and other components. These homogeneous human proteins are employed to examine the conversion of prothrombin to thrombin in the presence and absence of human antithrombin. The latter component is responsible for virtually all of the plasm's capacity to neutralize Factor X-a and thrombin. In the absence of antithrombin, prothrombin (67,800) is converted to the precursor P-2 (51,600) and the fragment F-a (19,500). Subsquently, P-2 is cleaved to form the precursor P-3 (37,000), and the fragment F-b (11,500). Finally, P3 IS proteolyzed to form the heavy chain T-h (29,500) and the light chain T-L (6,500) of active thrombin. In the presence of antithrombin, an additional prothrombin conversion pathway is observed in which the zymogen is directly cleaved to form P-3 and F-A + B (30,000) prior to thrombin generation. Trace amounts of free thrombin remain uninhibited by antithrombin and could bias the zymogen activation pathway. Hirudin is known to neutralized thrombin instantaneoulsly. We demonstrate that the purified leech protein also binds to P-3 and prevents thrombin formation. When hirudin is added to activation mixtures at concentrations sufficient to virtually suppress P-3 conversion to thrombin, molecular species from both activation pathways are observed. Thus two human prothrombin conversion sequences appear to be initiated by Factor X-3 and may be of physiological significance.
Design and Synthesis of Fast‐Degrading Poly(anhydride‐esters) (2009)

Fast-degrading, salicylate-based poly(anhydride-esters) were designed to degrade and release the active component, salicylic acid (SA), within 1 week. The polymer degradation was enhanced by using shorter or oxygen-containing aliphatic chains. A copolymer of diglycolic acid was also made with a salicylate-based diacid for comparison of polymer properties, including SA release. Both methods resulted in polyanhydrides with molecular weights ranging from 14 500 to 27 800 Da and displayed glass transition temperatures near physiological conditions, namely 33-40 degrees C. the homo- and copolymers completely degraded within one week releasing the chemically incorporated SA.
Population Genetic and Phylogenetic Evidence for Positive Selection on Regulatory Mutations at the Factor VII Locus in HumansSequence data from this article have been deposited with the EMBL/GenBank Data Libraries under accession nos. AY493422, AY493423, AY493424, AY493425, AY493426, AY493427, AY493428, AY493429, AY493430, AY493431, AY493432, AY493433. (2004)

The abundance of cis-regulatory polymorphisms in humans suggests that many may have been important in human evolution, but evidence for their role is relatively rare. Four common polymorphisms in the 5' promoter region of factor VII (F7), a coagulation factor, have been shown to affect its transcription and protein abundance both in vitro and in vivo. Three of these polymorphisms have low-frequency alleles that decrease expression of F7 and may provide protection against myocardial infarction (heart attacks). The fourth polymorphism has a minor allele that increases the level of transcription. To look for evidence of natural selection on the cis-regulatory variants flanking F7, we genotyped three of the polymorphisms in six Old World populations for which we also have data from a group of putatively neutral SNPs. Our population genetic analysis shows evidence for selection within humans; surprisingly, the strongest evidence is due to a large increase in frequency of the high-expression variant in Singaporean Chinese. Further characterization of a Japanese population shows that at least part of the increase in frequency of the high-expression allele is found in other East Asian populations. In addition, to examine interspecific patterns of selection we sequenced the homologous 5' noncoding region in chimpanzees, bonobos, a gorilla, an orangutan, and a baboon. Analysis of these data reveals an excess of fixed differences within transcription factor binding sites along the human lineage. Our results thus further support the hypothesis that regulatory mutations have been important in human evolution.
Anthropometric, metabolic, and immunological effects of recombinant human growth hormone in AIDS and AIDS-related complex. (1993)

Metabolic and anthropometric changes induced by "pharmacological" versus "physiological" doses (5.0 vs. 2.5 mg, every other day) of recombinant human growth hormone (rhGH) were compared in 10 human immunodeficiency virus-positive patients with AIDS or AIDS-related complex. Five patients were randomly assigned to each treatment schedule in a 3-month prospective, double-blind clinical trial. Three of the 10 patients, none taking zidovudine and all with low initial CD4 counts, were withdrawn during the study due to acute opportunistic infections. During treatment, insulin-like growth factor-1 (IGF-1) levels increased significantly (p < 0.05) in the pharmacological hGH treatment group, whereas no significant change was observed in IGF-1 in the physiological dose rhGH group. In the pharmacological hGH treatment group, weight loss preceding the study was reversed (p < 0.05) in each of the four patients who completed the study. This weight gain was associated with increases (p < 0.05) in lean body mass and total body water, with concomitant decreases in fat mass (p < 0.05) and urinary nitrogen excretion. Muscle power and endurance, as assessed by standardized omnikinetic dynamometry, also improved. All four patients lost weight again (p < 0.05) 6 weeks after completion of the study and termination of rhGH treatment. Minor positive changes in body composition were also observed in the physiologic-dose hGH group. The pharmacological dose of hGH was associated with minor increments (p < 0.05) in fasting plasma glucose, insulin, and C-peptide concentrations, which were of negligible clinical significance.(ABSTRACT TRUNCATED AT 250 WORDS)
Internalization of Antibodies (2002)

The selective delivery of drugs to tumors is a major goal in cancer chemotherapy. To achieve this goal, various strategies have been proposed: 1) encapsulation of drugs in organ-seeking liposomes (1); 2) incorporation of toxin genes into tumor-infiltrating lymphocytes; 3) activation of inert prodrugs (i.e., drugs modified chemically to prevent their uptake or their cytotoxic action) by tumor-elaborated or tumor-targeted enzymes (2–4); and 4) conjugation of drugs, toxins, or radionuclides to monoclonal antibodies (MAbs) specific for tumor-associated antigens or to growth factors directed towards receptors on tumors (5). In an attempt to demonstrate this concept, drugs and proteins are chemically linked to increase stability during transport of the drug conjugate in extracellular fluids and liberation of the drug in an active form within the cells (6). MAbs recognizing human tumor-associated antigens have been used to target antigens in various cancer cells (7–9) with minimal effects on adjacent normal cells (10). Promising results have been obtained in both animal and human tumor models using unmodified and modified MAbs (10). A recent example is given by the HER-2/neu-specific humanized antibody, Herceptin, which enhanced the chemosensitivity of tumor cells and extended remission periods in patients with refractory metastatic breast cancer (11–14)
Enhancing antibody: a novel component of the immune response. (1982)

Current descriptions of the immune response identify two classes of antigenic stimuli that result in the production of specific antibody: (i) exogenous antigens and (ii) endogenous variable-region determinants of the immune system. We expand this scheme to include a third class of antigenic stimulus--new determinants created by the binding of antibody to antigen. This paper describes a set of monoclonal antibodies which arose after repeated immunization with antigen alone but which bound antibody--antigen complexes. These antibodies recognize determinants on the antibody portion of the complexes that were expressed as a consequence of antigen binding. Antibodies of this general type, "enhancing antibodies," which can strengthen antibody--antigen and idiotypic-anti-idiotypic antibody interactions, may play important regulatory and effector roles in the immune response. We suggest a model that predicts the occurrence and specificity of different classes of such antibodies and provides a conceptual framework that gives a straightforward explanation of the appearance in the immune response of rheumatoid antibodies and of antibodies that bind cooperatively to antigen.