gebhart/patrepeval huggingface dataset:
Regulation of parathyroid hormone-related peptide (PTHrP) gene transcription: cell- and tissue-specific promoter utilization mediated by multiple positive and negative cis-acting DNA elements. (1992)

The gene encoding PTH-related peptide (PTHrP) is expressed in a wide variety of normal and neoplastic tissues. Increased PTHrP gene expression in and secretion of PTHrP by specific tumors directly contributes to the development of malignancy-associated hypercalcemia in vivo. To define the genetic elements important for the control of PTHrP gene transcription, we used the reverse transcription polymerase chain reaction to delineate the control of promoter utilization and the splicing patterns of the exons encoding 5'-untranslated sequences. The majority of normal and neoplastic human tissues contained PTHrP mRNA transcripts initiating from both the up-stream (P1) and down-stream (P2) human PTHrP promoters. Furthermore, the downstream promoter was preferentially used by a factor of more than 30-fold. P1-initiated transcripts contained RNA species both with and without exon 2 (E2) sequences, except in the pancreas, adrenal, and stomach, where E2-containing sequences predominated. The transcriptional activities of P1, P2, and P1 + P2 were assessed by transfection of the corresponding PTHrP-chloramphenicol acetyltransferase (CAT) fusion genes into heterologous cell lines. Fusion genes containing P2 sequences were more transcriptionally active than fusion genes containing P1 sequences. The transcriptional activities of P1 + P2 in their natural tandem orientation were additive in rat keratinocytes and human JEG choriocarcinoma cells. In contrast, the activity of P1 + P2 was less than that of P2 alone in hamster BHK fibroblasts and InR1-G9 cells, and human HeLa cells. Analysis of the transcriptional properties of 5'-deleted human PTHrP-CAT constructs revealed the presence of multiple positive and negative DNA sequences (within both P1 and P2) functionally important for human PTHrP gene transcription. Distinct positive and negative DNA elements were also identified from analysis of 5'-deleted rat PTHrP-CAT fusion genes. The results of these experiments provide evidence for cell- and tissue-specific utilization of 1) distinct human PTHrP transcription start sites and specific patterns of 5'-exon splicing and 2) multiple positive and negative DNA control elements, important for the regulation of human and rat PTHrP gene transcription.
Spermine Inhibits Proinflammatory Cytokine Synthesis in Human Mononuclear Cells: A Counterregulatory Mechanism that Restrains the Immune Response (1997)

The local production of proinflammatory cytokines mediates the host response to inflammation, infection, and injury, whereas an overexpression of these mediators can injure or kill the host. Recently, we identified a class of multivalent guanylhydrazone compounds that are effective inhibitors of proinflammatory cytokine synthesis in monocytes/macrophages. The structure of one such cationic molecule suggested a molecular mimicry with spermine, a ubiquitous endogenous biogenic amine that increases significantly at sites of inflammation and infection. Here, we addressed the hypothesis that spermine might counterregulate the innate immune response by downregulating the synthesis of potentially injurious cytokines. When spermine was added to cultures of human peripheral blood mononuclear cells stimulated with lipopolysaccharide (LPS), it effectively inhibited the synthesis of the proinflammatory cytokines tumor necrosis factor (TNF), interleukin-1 (IL-1), IL-6, MIP-1alpha, and MIP-1beta. The inhibition of cytokine synthesis was specific and reversible, with significant inhibition of TNF synthesis occurring even when spermine was added after LPS. The mechanism of spermine-mediated cytokine suppression was posttranscriptional and independent of polyamine oxidase activity. Local administration of spermine in vivo protected mice against the development of acute footpad inflammation induced by carrageenan. These results identify a distinct molecular counterregulatory role for spermine in downregulating the monocyte proinflammatory cytokine response.
Disruption of the estrogen receptor β gene in mice causes myeloproliferative disease resembling chronic myeloid leukemia with lymphoid blast crisis (2003)

Proliferation of pluripotent, bone marrow stem cells, which develop to lymphoid and myeloid progenitors, is negatively regulated by estrogen. Although in estrogen deficiency and in estrogen receptor knockout mice there is significant alteration in bone marrow hematopoiesis, the effects of aging on estrogen receptor deficiencies in mice have not been investigated yet. In this study we show that by 1.5 years of age, estrogen receptor beta knockout (ERbeta-/-) mice develop pronounced splenomegaly that is much more severe in females than in males. Further characterization of these mice revealed myelogenous hyperplasia in bone marrow, an increase in the number of granulocytes and B lymphocytes in blood, lymphadenopathy, and infiltration of leukocytes in the liver and lung. Analysis by flow cytometry of the bone marrow cells revealed that the percentage and total number of Gr-1hi/Mac-1hi-positive granulocytes were increased by 15-30% and 100%, respectively. The numbers of B cells in the bone marrow and spleen were significantly higher in ERbeta-/- mice than in WT littermates. Some of the ERbeta-/- mice also had a severe lymphoproliferative phenotype. Thus the absence of ERbeta results in a myeloproliferative disease resembling human chronic myeloid leukemia with lymphoid blast crisis. Our results indicate a previously unknown role for ERbeta in regulating the differentiation of pluripotent hematopoietic progenitor cells and suggest that the ERbeta-/- mouse is a potential model for myeloid and lymphoid leukemia. Furthermore, we suggest that ERbeta agonists might have clinical value in the treatment of leukemia.
CBWL: a new channel assignment and sharing method for cellular communication systems (1994)

A new scheme that allows cell gateways (base stations) to borrow channels from adjacent gateways in a cellular communication system is presented. Borrowed channels are used with reduced transmitted power to limit interference with cochannel cells. No channel locking is needed. The scheme, which can be used with various multiple access techniques, permits simple channel control management without requiring global information about channel usage throughout the system. It provides enhanced traffic performance in homogeneous environments and also can be used to relieve spatially localized traffic overloads (tele-traffic 'hot spots'). Co-channel interference analysis shows that the scheme can maintain the same SIR as nonborrowing schemes. Analytical models using multidimensional birth-death processes and decomposition methods are devised to characterize performance. The results which are also validated by simulation indicate that significantly increased traffic capacity can be achieved in comparison with nonborrowing schemes.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
In vivo ultrahigh-resolution optical coherence tomography (1999)

Ultrahigh-resolution optical coherence tomography (OCT) by use of state of the art broad-bandwidth femtosecond laser technology is demonstrated and applied to in vivo subcellular imaging. Imaging is performed with a Kerr-lens mode-locked Ti:sapphire laser with double-chirped mirrors that emits sub-two-cycle pulses with bandwidths of up to 350 nm, centered at 800 nm. Longitudinal resolutions of ~1mum and transverse resolution of 3mum, with a 110-dB dynamic range, are achieved in biological tissue. To overcome depth-of-field limitations we perform zone focusing and image fusion to construct a tomogram with high transverse resolution throughout the image depth. To our knowledge this is the highest longitudinal resolution demonstrated to date for in vivo OCT imaging.
Therapeutic Applications of Ribozymes (1998)

In Therapeutic Applications of Ribozymes, expert laboratory scientists describe in detail their methodologies for constructing ribozymes designed to elucidate the role of specific genes as key routes to the development of novel therapies for a wide variety of diseases. The authors review the many sites targeted with ribozymes in various diseases and provide specific accounts of the practical techniques required for the proper use of ribozymes in these systems. Their cutting-edge protocols demonstrate how to achieve ribozyme expression in distinct cellular systems, the preparation and use of high-efficiency ribozyme DNA or RNA delivery, and the studies required to prove the efficacy of ribozyme-mediated inhibition, with its concomitant effect on phenotypic parameters. Therapeutic Applications of Ribozymes contains all the practical detail necessary to realize the high promise of ribozyme technology as a significant, widely used methodology. Focused on ribozyme targets and the novel associated technology, the book immediately becomes the leading resource for all those seeking to transform this new category of therapeutic agent into efficacious clinical practice
From Prediction to Prescription: Evolutionary Optimization of Nonpharmaceutical Interventions in the COVID-19 Pandemic (2021)

Several models have been developed to predict how the COVID-19 pandemic spreads, and how it could be contained with nonpharmaceutical interventions, such as social distancing restrictions and school and business closures. This article demonstrates how evolutionary AI can be used to facilitate the next step, i.e., determining most effective intervention strategies automatically. Through evolutionary surrogate-assisted prescription, it is possible to generate a large number of candidate strategies and evaluate them with predictive models. In principle, strategies can be customized for different countries and locales, and balance the need to contain the pandemic and the need to minimize their economic impact. Early experiments suggest that workplace and school restrictions are the most important and need to be designed carefully. They also demonstrate that results of lifting restrictions can be unreliable, and suggest creative ways in which restrictions can be implemented softly, e.g., by alternating them over time. As more data becomes available, the approach can be increasingly useful in dealing with COVID-19 as well as possible future pandemics.
Contributions of symptoms, signs, erythrocyte sedimentation rate, and C-reactive protein to a diagnosis of pneumonia in acute lower respiratory tract infection. (2003)

Most symptoms and signs traditionally associated with pneumonia are not predictive of pneumonia in general practice. The prediction rule for low-risk patients presented here, including a CRP of < 20, can considerably reduce unjustified antibiotic prescribing.
Nonradical Mechanisms for the Uncatalyzed Thermal Functionalization of Silicon Surfaces by Alkenes and Alkynes:  A Density Functional Study (2006)

We propose a new concerted mechanism for the uncatalyzed hydrosilylation of terminal alkenes and alkynes, alternative to the conventional radical-based mechanism. Density functional calculations have been carried out on these and on previously proposed alternative mechanisms for the hydrosilylation of ethylene and acetylene by suitable finite size clusters as models of the thermal functionalization of -SiH3, =SiH2, and [triple bound] SiH groups in flat Si(100) and Si(111) and porous silicon surfaces by alkenes and alkynes. For each step involved in the considered hydrosilylation pathways, we optimized the geometries of reactants and products and located the corresponding transition states. The calculated activation energies for the concerted pathways of ethylene and acetylene are, respectively, 57.6 and 60.9 kcal mol(-1) on -SiH3 and in the ranges 62-63 and 58-61 kcal mol-1 on =SiH2 and 64-66 and 56-61 kcal mol(-1) on SiH. These values are much lower than the activation energies calculated for the corresponding homolytic dissociation of the Si-H bond, which is the preliminary step in the radical path, 85.6, 82-83, and 79-81 kcal mol(-1), respectively, for -SiH3, =SiH2, and [triple bound] SiH groups. Our results thus suggest that the thermal hydrosilylation of alkenes and alkynes on silicon surfaces, for which a radical-based mechanism is currently accepted, may occur through a concerted mechanism.
Identification of the site on IgG Fc for interaction with streptococci of groups A, C and G. (1987)

The interaction between living groups A, C and G streptococci and IgG Fc was studied using human IgG, IgG Fc and IgG Fc-intermediate (Fci) fragments, chemically modified human IgG and fragment D of staphylococcal protein A (SPA). Diethylpyrocarbonate modification of His or N-acetylimidazole modification of Tyr of human IgG resulted in the loss of its capacity to inhibit the binding of radiolabelled human IgG Fc to the group A streptococci types M1 and M55, and to the group C strain SC-1, indicating that the amino acids His and Tyr are involved in the binding. Lys seems not to participate in the binding of IgG to these bacteria, however, since reductive methylation of Lys did not reduce its inhibitory capacity. Fragment D of SPA also inhibited the binding of radiolabelled human IgG Fc to strains M1, M55 and SC-1. We have previously shown that these bacteria do not bind to IgG fragments consisting of only the C gamma 2 or C gamma 3 domains. On the basis of these results, and the known relative positions in space of the His and Tyr residues on IgG Fc, it is speculated whether streptococci with IgG Fc receptors, like SPA and rheumatoid factors, interact with IgG in the interface between the C gamma 2 and C gamma 3 domains and involve His 435 and one or more of Tyr 436, His 433 and His 310. The similarities in binding sites on IgG for RFs and these bacterial Fc binding proteins suggest structural similarities between them that may be relevant to the production of rheumatoid factors in rheumatoid arthritis.
Diabetes mellitus and the risk of dementia (1999)

The diabetes attributable risk for dementia of 8.8% suggests that diabetes may have contributed to the clinical syndrome in a substantial proportion of all dementia patients.
Atomic Resolution Insights into Curli Fiber Biogenesis (2011)

Bacteria produce functional amyloid fibers called curli in a controlled, noncytotoxic manner. These extracellular fimbriae enable biofilm formation and promote pathogenicity. Understanding curli biogenesis is important for appreciating microbial lifestyles and will offer clues as to how disease-associated human amyloid formation might be ameliorated. Proteins encoded by the curli specific genes (csgA-G) are required for curli production. We have determined the structure of CsgC and derived the first structural model of the outer-membrane subunit translocator CsgG. Unexpectedly, CsgC is related to the N-terminal domain of DsbD, both in structure and oxido-reductase capability. Furthermore, we show that CsgG belongs to the nascent class of helical outer-membrane macromolecular exporters. A cysteine in a CsgG transmembrane helix is a potential target of CsgC, and mutation of this residue influences curli assembly. Our study provides the first high-resolution structural insights into curli biogenesis.
Megawatt, Pulsed Ultraviolet Photon Sources for Microbial Inactivation (2004)

The University of Missouri-Columbia (UMC) has developed pulsed ultraviolet (UV) photon sources commensurate with enhanced ultraviolet inactivation of hazardous microbials on surfaces or in a water matrix. Pulsed xenon flashlamps have been optimized to produce a high ultraviolet photon yield in the 180-320 nm range that is lethal to microbials and has a high cross-sectional interaction with photosensitizer chemicals to synergistically enhance microbial inactivation. Electrical models have been derived to predict the time-dependent plasma discharge impedance profiles of the flashlamp UV source.
A High-Affinity Metal-Binding Peptide from Escherichia coli HypB (2008)

The high-affinity nickel-binding site of the Escherichia coli [NiFe]-hydrogenase accessory protein HypB was localized to residues at the immediate N-terminus of the protein. Modification of a metal-binding fusion protein, site-directed mutagenesis experiments, and DFT calculations were used to identify the N-terminal amine as a ligand as well as the three cysteine residues in the CXXCGCXXX motif. This sequence can be removed from the protein and both a synthesized peptide and a protein fusion bind nickel with a similar affinity and the same structure as the parent metalloprotein, indicating the self-sufficiency of this high-affinity nickel-binding sequence.
Transforming growth factor-beta activity is potentiated by heparin via dissociation of the transforming growth factor-beta/alpha 2-macroglobulin inactive complex. (1989)

The control of smooth muscle cell (SMC) proliferation is determined by the combined actions of mitogens, such as platelet-derived growth factor, and the opposing action of growth inhibitory agents, such as heparin and transforming growth factor-beta (TGF-beta). The present studies identify an interaction between heparin and TGF-beta in which heparin potentiates the biological action of TGF-beta. Using a neutralizing antibody to TGF-beta, we observed that the short term antiproliferative effect of heparin depended upon the presence of biologically active TGF-beta. This effect was observed in rat and bovine aortic SMC and in CCL64 cells, but not in human saphenous vein SMC. Binding studies demonstrated that the addition of heparin (100 micrograms/ml) to medium containing 10% plasma-derived serum resulted in a 45% increase in the specific binding of 125I-TGF-beta to cells. Likewise, heparin induced a twofold increase in the growth inhibitory action of TGF-beta at concentrations of TGF-beta near its apparent dissociation constant. Using 125I-labeled TGF-beta, we demonstrated that TGF-beta complexes with the plasma component alpha 2-macroglobulin, but not with fibronectin. Heparin increases the electrophoretic mobility of TGF-beta apparently by freeing TGF-beta from its complex with alpha 2-macroglobulin. Dextran sulfate, another highly charged antiproliferative molecule, but not chondroitin sulfate or dermatan sulfate, similarly modified TGF-beta's mobility. Relatively high, antiproliferative concentrations of heparin (1-100 micrograms/ml) were required to dissociate the TGF-beta/alpha 2-macroglobulin complex. Thus, it appears that the antiproliferative effect of heparin may be partially attributed to its ability to potentiate the biological activity of TGF-beta by dissociating it from alpha 2-macroglobulin, which normally renders it inactive. We suggest that heparin-like agents may be important regulators of TGF-beta's biological activity.
[ras p21-like small MW GTP-binding proteins in transmembrane signaling]. (1989)

We have separated multiple GTP-binding proteins (G proteins) having Mr values of about 20,000 (small MW G proteins) from bovine brain membranes, purified to near homogeneity and characterized two novel G proteins designated as smg p25A and smg p21, c-Ki-ras p21 and rho p20. smg p25A is specifically found in neural tissue and adrenal medulla. This G protein is also found in rat pheochromocytoma PC-12 cells, and its mRNA level increases after differentiation of the cells into neuron-like cells in response to nerve growth factor or dibutyryl cyclic AMP. These results suggest that smg p25A plays an important role in the regulation of neural functions. In contrast, smg p21 is found in most tissues. This G protein has the same putative effector domain as ras p21s, suggesting that smg p21 exerts actions similar and/or antagonistic to those of ras p21s. In fact, smg p21 has been found to be identical with the ras-suppressor gene, designated as Krev-1, recently isolated by Noda's group. On the other hand, rho p20 is ADP-ribosylated by botulinum toxin. This toxin, known to be a neurotoxin, has recently been shown to induce the morphological changes similar to those induced by ras p21 in fibroblasts. Thus, ras p21-like small Mr G proteins are part of a huge network of intracellular regulatory systems and play important roles in the regulation of various cell functions including cell transformation, proliferation and differentiation.
Membrane-Associated DNA in the Cytoplasm of Diploid Human Lymphocytes (1971)

A species of DNA that is apparently associated with the plasma membrane of diploid human lymphocytes that are continously growing is described. This DNA differes from nuclear or mitochondrial DNA by virtue of its location in the cell, time of synthesis in the cell cycle, and various physical properties. At present, the role of this DNA is unknown.
Multiple functions of let-23, a Caenorhabditis elegans receptor tyrosine kinase gene required for vulval induction. (1991)

The let-23 gene, which encodes a putative tyrosine kinase of the epidermal growth factor (EGF) receptor subfamily, has multiple functions during Caenorhabditis elegans development. We show that let-23 function is required for vulval precursor cells (VPCs) to respond to the signal that induces vulval differentiation: a complete loss of let-23 function results in no induction. However, some let-23 mutations that genetically reduce but do not eliminate let-23 function result in VPCs apparently hypersensitive to inductive signal: as many as five of six VPCs can adopt vulval fates, in contrast to the three that normally do. These results suggest that the let-23 receptor tyrosine kinase controls two opposing pathways, one that stimulates vulval differentiation and another that negatively regulates vulval differentiation. Furthermore, analysis of 16 new let-23 mutations indicates that the let-23 kinase functions in at least five tissues. Since various let-23 mutant phenotypes can be obtained independently, the let-23 gene is likely to have tissue-specific functions.
Bispecific T cell engager (BiTE®) antibody constructs can mediate bystander tumor cell killing (2017)

For targets that are homogenously expressed, such as CD19 on cells of the B lymphocyte lineage, immunotherapies can be highly effective. Targeting CD19 with blinatumomab, a CD19/CD3 bispecific antibody construct (BiTE®), or with chimeric antigen receptor T cells (CAR-T) has shown great promise for treating certain CD19-positive hematological malignancies. In contrast, solid tumors with heterogeneous expression of the tumor-associated antigen (TAA) may present a challenge for targeted therapies. To prevent escape of TAA-negative cancer cells, immunotherapies with a local bystander effect would be beneficial. As a model to investigate BiTE®-mediated bystander killing in the solid tumor setting, we used epidermal growth factor receptor (EGFR) as a target. We measured lysis of EGFR-negative populations in vitro and in vivo when co-cultured with EGFR-positive cells, human T cells and an EGFR/CD3 BiTE® antibody construct. Bystander EGFR-negative cells were efficiently lysed by BiTE®-activated T cells only when proximal to EGFR-positive cells. Our mechanistic analysis suggests that cytokines released by BiTE®-activated T-cells induced upregulation of ICAM-1 and FAS on EGFR-negative bystander cells, contributing to T cell-induced bystander cell lysis.
A 1.4psrms-period-jitter TDC-less fractional-N digital PLL with digitally controlled ring oscillator in 65nm CMOS (2010)

State of the art digital PLLs can be divided in two categories, depending on the implementation of the digital phase detector. Digital clocking and wireline applications mostly use a Bang-Bang detector (BBPLLs) [1–3], offering very low jitter values in integer-N mode but not supporting fractional-N synthesis, which is desirable to implement, i.e., spread spectrum clocking (SSC) for EMI reductions. Wireless applications implement time to digital converters (TDC) [4–6] which allow fractional-N synthesis, but require high architecture complexity, need calibration routines for period normalization, and introduce analog limitations that a digital PLL should be intended to eliminate.