gebhart/patrepeval huggingface dataset:
Trapping of Inhibitor-Induced Conformational Changes in the Erythrocyte Membrane Anion Exchanger AE1 (1999)

AE1, the chloride/bicarbonate anion exchanger of the erythrocyte plasma membrane, is highly sensitive to inhibition by stilbene disulfonate compounds such as DIDS (4,4'-diisothiocyanostilbene-2, 2'-disulfonate) and DNDS (4,4'-dinitrostilbene-2,2'-disulfonate). Stilbene disulfonates recruit the anion binding site to an outward-facing conformation. We sought to identify the regions of AE1 that undergo conformational changes upon noncovalent binding of DNDS. Since conformational changes induced by stilbene disulfonate binding cause anion transport inhibition, identification of the DNDS binding regions may localize the substrate binding region of the protein. Cysteine residues were introduced into 27 sites in the extracellular loop regions of an otherwise cysteineless form of AE1, called AE1C(-). The ability to label these residues with biotin maleimide [3-(N-maleimidylpropionyl)biocytin] was then measured in the absence and presence of DNDS. DNDS reduced the ability to label residues in the regions around G565, S643-M663, and S731-S742. We interpret these regions either as (i) part of the DNDS binding site or (ii) distal to the binding site but undergoing a conformational change that sequesters the region from accessibility to biotin maleimide. DNDS alters the conformation of residues outside the plane of the bilayer since the S643-M663 region was previously shown to be extramembranous. Upon binding DNDS, AE1 undergoes conformational changes that can be detected in extracellular loops at least 20 residues away from the hydrophobic core of the lipid bilayer. We conclude that the TM7-10 region of AE1 is central to the stilbene disulfonate and substrate binding region of AE1.
MCP-1 overexpressed in tuberous sclerosis lesions acts as a paracrine factor for tumor development (2005)

Patients with tuberous sclerosis complex (TSC) develop hamartomatous tumors showing loss of function of the tumor suppressor TSC1 (hamartin) or TSC2 (tuberin) and increased angiogenesis, fibrosis, and abundant mononuclear phagocytes. To identify soluble factors with potential roles in TSC tumorigenesis, we screened TSC skin tumor-derived cells for altered gene and protein expression. Fibroblast-like cells from 10 angiofibromas and five periungual fibromas produced higher levels of monocyte chemoattractant protein-1 (MCP-1) mRNA and protein than did fibroblasts from the same patient's normal skin. Conditioned medium from angiofibroma cells stimulated chemotaxis of a human monocytic cell line to a greater extent than conditioned medium from TSC fibroblasts, an effect blocked by neutralizing MCP-1-specific antibody. Overexpression of MCP-1 seems to be caused by loss of tuberin function because Eker rat embryonic fibroblasts null for Tsc2 (EEF Tsc2(-/-)) produced 28 times as much MCP-1 protein as did EEF Tsc2(+/+) cells; transient expression of WT but not mutant human TSC2 by EEF Tsc2(-/-) cells inhibited MCP-1 production; and pharmacological inhibition of the Rheb-mTOR pathway, which is hyperactivated after loss of TSC2, decreased MCP-1 production by EEF Tsc2(-/-) cells. Together these findings suggest that MCP-1 is an important paracrine factor for TSC tumorigenesis and may be a new therapeutic target.
Discovery and SAR Studies of Orally Active Somatostatin Receptor Subtype-2 (SSTR2) Agonists for the Treatment of Acromegaly (2020)

Acromegaly is a disease caused by the oversecretion of growth hormone. It is currently treated by intravenous injection with cyclic peptide drugs that activate somatostatin receptor subtype 2 (SSTR2). Here, novel nonpeptidic, small-molecule, and orally active SSTR2 agonists were identified from a hit compound (<b>13</b>). Pharmacophore studies enabled scaffold hopping to obtain a unique 3,4,5-trisubstituted pyridine motif. Further optimization conferred potent SSTR2 agonistic activity and metabolic stability. Several compounds were evaluated and these showed good oral pharmacokinetic profiles in rats, and one representative compound (<b>25</b>) showed highly potent inhibition of growth hormone secretion induced by growth hormone-releasing hormone in rats. Based on these results, <b>25</b> was identified as a promising lead for further optimization. A structure-activity relationship (SAR) study and the metabolic stability data for this compound are also described.
Cytosolic Entry Controls CD8+-T-Cell Potency during Bacterial Infection (2006)

Interaction with host immunoreceptors during microbial infection directly impacts the magnitude of the ensuing innate immune response. How these signals affect the quality of the adaptive T-cell response remains poorly understood. Utilizing an engineered strain of the intracellular pathogen Listeria monocytogenes that infects cells but fails to escape from the phagosome, we demonstrate the induction of long-lived memory T cells that are capable of secondary expansion and effector function but are incapable of providing protective immunity. We demonstrate that microbial invasion of the cytosol is required for dendritic cell activation and integration of CD40 signaling, ultimately determining the ability of the elicited CD8+-T-cell pool to protect against lethal wild-type L. monocytogenes challenge. These results reveal a crucial role for phagosomal escape, not for delivery of antigen to the class I major histocompatibility complex pathway but for establishing the appropriate cellular context during CD8+-T-cell priming.
The multics system: an examination of its structure (1972)

This volume provides an overview of the Multics system developed at M.I.T.--a time-shared, general purpose utility like system with third-generation software. The advantage that this new system has over its predecessors lies in its expanded capacity manipulate and file information on several levels and police and control access data in its various files. On the invitation of M.I.T.'s Project MAC, Elliott Organick developed over a period of years an explanation of the workings, concepts, and mechanisms of the Multics system. This book is a result of that effort, and is approved by the Computer Systems Research Group of Project MAC.

In keeping with his reputation as a writer able explain technical ideas in the computer field clearly and precisely, the author develops an exceptionally lucid description of the Multics system, particularly in the area of it works. His stated purpose is serve the expected needs of designers, and help them to gain confidence that they are really able exploit the system fully, as they design increasingly larger programs and subsystems.

The chapter sequence was planned build an understanding of increasingly larger entities. From segments and the addressing of segments, the discussion extends ways in which procedure segments may link dynamically one another and data segments. Subsequent chapters are devoted how Multics provides for the solution of problems, the file system organization and services, and the segment management functions of the Multics file system and how the user may employ these facilities advantage. Ultimately, the author builds a picture of the life of a process in coexistence with other processes, and suggests ways model or construct subsystems that are far more complex than could be implemented using predecessor computer facilities.

This volume is intended for the moderately well informed computer user accustomed predecessor systems and familiar with some of the Multics overview literature. While not intended as a definitive work on this living, ever-changing system, the book nevertheless reflects Multics as it has been first implemented, and should reveal its flavor, structure and power for some time come.
Schwann Cell Differentiation in vitro: Extracellular Matrix Deposition and Interaction (1986)

Neonatal rat Schwann cells isolated in culture proliferate slowly and do not form a basement membrane although they express laminin continuously. We demonstrate here that isolated Schwann cells express other basement membrane components, including entactin and heparan sulfate proteoglycan. Treatment with ascorbate, and to a lesser extent with cyclic adenosine 3',5'-monophosphate, modulates the synthesis of extracellular matrix components by cultured Schwann cells. After this treatment, fibronectin and collagen type IV are detected on the Schwann cell surface, which form, with the other components, a membrane-bound extracellular matrix. Electron microscopy shows that these elements are organized in a filamentous matrix which resembles a basement membrane and may be a precursor form of a basement membrane. We also show the effect of complete basement membrane matrices on Schwann cell behavior in culture. These matrices support Schwann cell proliferation in both serum-containing and serum-free media. The extracellular matrix from endothelial cells mimics fibronectin and induces a flat phenotype whereas the reconstituted basement membrane gel from the EHS tumor mimics laminin and allows an elongated phenotype. Thus, the basement membrane matrices interact with Schwann cells in vitro and may play an important role in Schwann cell proliferation in vivo.
Antibody-dependent enhancement of dengue virus infection mediated by bispecific antibodies against cell surface molecules other than Fc gamma receptors (1991)

It is known that antibodies to dengue viruses at subneutralizing concentrations enhance dengue virus infection of Fc gamma R+ cells. This phenomenon called antibody-dependent enhancement (ADE) occurs when virus-antibody complexes bind to the Fc gamma R via the Fc portion of the Ig. It has been hypothesized that ADE may be responsible for the pathogenesis of the severe manifestations of dengue virus infection including dengue hemorrhagic fever/dengue shock syndrome. To further analyze the mechanisms of ADE, we prepared bispecific antibodies by chemically cross-linking antidengue virus antibodies to antibodies specific for Fc gamma RI or Fc gamma RII and the non-Fc R molecules beta2 microglobulin, CD15 or CD33 and examined whether these bispecific antibodies could enhance infection. Bispecific antibodies targeting dengue virus to Fc gamma RI or Fc gamma RII enhanced dengue virus infection, consistent with previous reports using conventional antibodies. Furthermore, bispecific antibodies targeting dengue virus to beta2 microglobulin, CD15 or CD33 also enhanced dengue virus infection. Bispecific antibody mediated ADE was inhibited by pretreating the cells with the appropriate blocking mAb. These results indicate that cell surface molecules other than Fc gamma R can mediate ADE and suggest that the Fc gamma R does not provide a unique signal necessary for enhanced infection. We hypothesize that directing dengue virus to the cell surface by a bispecific antibody facilitates the interaction between dengue virus and its receptor, thereby increasing its infectivity.
A null mutation of ROS1a for DNA demethylation in rice is not transmittable to progeny (2012)

Genes that promote DNA methylation and demethylation in plants have been characterized mainly in Arabidopsis. Arabidopsis DNA demethylation is mediated by bi-functional DNA enzymes with glycosylase activity that removes 5-methylcytosine and lyase activity that nicks double-stranded DNA at an abasic site. Homologous recombination-promoted knock-in targeting of the ROS1a gene, the longest of six putative DNA demethylase genes in the rice genome, by fusing its endogenous promoter to the GUS reporter gene, led to reproducibly disrupted ROS1a in primary (T(0)) transgenic plants in the heterozygous condition. These T(0) plants exhibited no overt morphological phenotypes during the vegetative phase, and GUS staining showed ROS1a expression in pollen, unfertilized ovules and meristematic cells. Interestingly, neither the maternal nor paternal knock-in null allele, ros1a-GUS1, was virtually detected in the progeny; such an intransmittable null mutation is difficult to isolate by conventional mutagenesis techniques that are usually used to identify and isolate mutants in the progeny population. Even in the presence of the wild-type paternal ROS1a allele, the maternal ros1a-GUS1 allele caused failure of early-stage endosperm development, resulting in incomplete embryo development, with embryogenesis producing irregular but viable embryos that failed to complete seed dormancy, implying non-equivalent maternal and paternal contribution of ROS1a in endosperm development. The paternal ros1a-GUS1 allele was not transmitted to progeny, presumably because of a male gametophytic defect(s) prior to fertilization. Thus, ROS1a is indispensable in both male and female gametophytes, and DNA demethylation must plays important roles in both gametophytes.
Rethinking Indoor Wireless Mesh Design: Low Power, Low Frequency, Full-Duplex (2010)

Existing indoor WiFi networks in the 2.5 GHz and 5 GHz use too much transmit power, needed because the high carrier frequency limits signal penetration and connectivity. Instead, we propose a novel indoor wireless mesh design paradigm, based on Low Frequency, using the newly freed white spaces previously used as analogue TV bands, and Low Power-100 times less power than currently used. Preliminary experiments show that this maintains a similar level of connectivity and performance to existing networks. It also yields more uniform connectivity, thus simplifies MAC and routing protocol design. We also advocate full-duplex networking in a single band, which becomes possible in this setting (because we operate at low frequencies). It potentially doubles the throughput of each link and eliminates hidden terminals.
Vgr-1, a mammalian gene related to Xenopus Vg-1, is a member of the transforming growth factor beta gene superfamily. (1989)

The transforming growth factor beta (TGF-beta)-related products of the Xenopus Vg-1 and Drosophila decapentaplegic (DPP) genes have been implicated in the control of growth and differentiation during embryogenesis. We have isolated a mouse cDNA, Vgr-1, that encodes a polypeptide structurally related to Xenopus Vg-1. Sequence comparisons indicate that the Vgr-1 protein belongs to a family of DPP-like gene products within the TGF-beta superfamily. The levels of Vgr-1 RNA were determined in embryos and tissues isolated at various stages of development. A 3.5-kilobase mRNA increases throughout development and into adulthood in many tissues and in F9 teratocarcinoma cells differentiating into endoderm in response to retinoic acid and cAMP. The amino acid homologies and patterns of expression suggest that, like the DPP gene product, Vgr-1 plays a role at various stages of development.
Viral interleukin 10 is critical for the induction of B cell growth transformation by Epstein-Barr virus. (1993)

We have used an efficient cDNA subtraction library procedure to identify newly induced genes in human B lymphocytes infected for 6 h with Epstein-Barr virus (EBV). Among the genes identified by automated sequencing of a random subset of clones from this library, one coded the EBV BCRF1 open reading frame, which specifies the viral interleukin 10 gene (vIL-10). This molecule is highly homologous to human (h)IL-10 and was previously thought to represent a "late" viral gene expressed only during the lytic phase of virus replication. Using gene amplification by reverse transcriptase polymerase chain reaction of B cell RNA obtained at varying times after infection, we detected vIL-10 expression within a few hours of EBV infection, followed, 20-30 h later by expression of hIL-10. Expression of both genes continued beyond the initial transformation phase (5-10 d) and was present in all transformed cell lines tested. When added at the time of viral infection, antisense (but not sense) oligonucleotides for vIL-10 mRNA (cytosolic half-life, approximately 6 h) prevented subsequent B cell transformation. The antisense effect was highly specific, leaving the expression levels of other transformation-related genes intact. Addition of exogenous (h)IL-10 rescued the transformation process in antisense-treated cells. Our observations establish vIL-10 as a new latency gene with a directly transformation-prerequisite function.
New approaches for cooperative use of multiple antennas in ad hoc wireless networks (2005)

The paper explores the interaction between cooperative diversity techniques, in the physical layer, and routing, in the network layer. Three approaches are proposed: relay-by-flooding; relay-assisted routing; relay-enhanced routing. In relay-by-flooding, the tradeoff between achieved rate and required power is studied for three selective decode-and-forward schemes: simple relay; space-time-coded relay; best-select relay. In relay-enhanced routing, cooperation is applied to each link of an existing route. Two relay selection approaches are proposed: best-select in the neighbor set; best-select in the decoded set. Best-select in the decoded set is shown to improve the performance significantly.
A PARALLEL DYNAMIC-MESH LAGRANGIAN METHOD FOR SIMULATION OF FLOWS WITH DYNAMIC INTERFACES (2000)

Many important phenomena in science and engineering, including our motivating problem of microstructural blood flow, can be modeled as flows with dynamic interfaces. The major challenge faced in simulating such flows is resolving the interfacial motion. Lagrangian methods are ideally suited for such problems, since interfaces are naturally represented and propagated. However, the material description of motion results in dynamic meshes, which become hopelessly distorted unless they are regularly regenerated. Lagrangian methods are particularly challenging on parallel computers, because scalable dynamic mesh methods remain elusive. Here, we present a parallel dynamic mesh Lagrangian method for flows with dynamic interfaces. We take an aggressive approach to dynamic meshing by triangulating the propagating grid points at every timestep using a scalable parallel Delaunay algorithm. Contrary to conventional wisdom, we show that the costs of the dynamic mesh components (triangulation, coarsening, refinement, and partitioning) can be made small relative to the flow solver.
Automated monitoring of apoptosis in suspension cell cultures. (1996)

Cell death by apoptosis is often accompanied by extensive DNA cleavage at internucleosomal linker sites. Thus, the foremost techniques for estimating apoptosis are based on biochemical, electrophoretic, or flow cytometry analysis of nuclear DNA. However, apoptosis is also associated with a chain of morphologic changes in the nuclear and cytoplasmic structures that are easily recognizable using light microscopy. We suggest that changes in morphology of cells undergoing apoptosis might cause characteristic changes in their optical properties. It follows that continuous measuring of the OD of cells undergoing apoptosis would enable the study of the kinetics of cell death. We recently described an automated microculture kinetic (MiCK) assay that provides multiple OD measurements in nondisrupted cell cultures. In the present study the MiCK assay was employed to follow OD changes in HL-60 and OCI/AML-3 myelogenous leukemia cells and murine thymocytes exposed to ethanol, hydrogen peroxide, etoposide, cisplatin, doxorubicin, or hyperthermia; i.e., divers stimuli known to induce cell death via apoptosis or necrosis. The MiCK assay revealed prominent differences between the optical properties of the cells undergoing the two different modes of death. Plotting the OD data accumulated during the assay period against time betrayed characteristic patterns of either "apoptotic" or "necrotic" OD curves. The best fit slope of the indicative of apoptosis steep rising component of the apoptotic curve, correlated directly with the percentage of morphologically apoptotic cells in the culture. Criteria for graphical estimate of apoptosis were suggested and used to study apoptosis induced in HL-60 cells by the chemotherapy compounds etoposide and cisplatin. The MiCK assay demonstrated markedly varying time courses of the cell apoptotic response to these two drugs. In both cases, however, the time of graphically predicted peaks of apoptosis correlated with the time of morphologically and electrophoretically recognized peaks of apoptosis. Adaptability of the MiCK assay to a 96-well microplate format opens the way for large-scale studying of cell apoptotic response to various stimuli. An important technical advantage of the automated MiCK assay of apoptosis is that it does not require additional laboratory procedures after microcultures are initiated.
[Inhibitory effect of AG490 on invasion and metastasis of human pancreatic cancer cells in vitro]. (2006)

Blocking STAT3 activation with AG490 can inhibit the invasion and metastasis ability of pancreatic cancer cells in vitro through down-regulation of MMP-2 and VEGF expression. Blocking STAT3 signaling pathway may provide a novel strategy in prevention of invasion and metastasis of pancreatic cancer.
Setting Reaction and Hardening of an Apatitic Calcium Phosphate Cement (1997)

The combination of self-setting and biocompatibility makes calcium phosphate cements potentially useful materials for a variety of dental applications. The objective of this study was to investigate the setting and hardening mechanisms of a cement-type reaction leading to the formation of calcium-deficient hydroxyapatite at low temperature. Reactants used were alpha-tricalcium phosphate containing 17 wt% beta-tricalcium phosphate, and 2 wt% of precipitated hydroxyapatite as solid phase and an aqueous solution 2.5 wt% of disodium hydrogen phosphate as liquid phase. The transformation of the mixture was stopped at selected times by a freeze-drying techniques, so that the cement properties at various stages could be studied by means of x-ray diffraction, infrared spectroscopy, and scanning electron microscopy. Also, the compressive strength of the cement was measured as a function of time. The results showed that: (1) the cement setting was the result of the alpha-tricalcium phosphate hydrolysis, giving as a product calcium-deficient hydroxyapatite, while beta-tricalcium phosphate did not participate in the reaction; (2) the extent of conversion of alpha-TCP was nearly 80% after 24 hr; (3) both the extent of conversion and the compressive strength increased initially linearly with time, subsequently reaching a saturation level, with a strong correlation observed between them, indicating that the microstructural changes taking place as the setting reaction proceeded were responsible for the mechanical behavior of the cement; and (4) the microstructure of the set cement consisted of clusters of big plates with radial or parallel orientations in a matrix of small plate-like crystals.
Glucocorticoids Suppress Tumor Angiogenesis and In vivo Growth of Prostate Cancer Cells (2006)

Glucocorticoids suppressed androgen-independent prostate cancer growth possibly due to the inhibition of tumor-associated angiogenesis by decreasing VEGF and IL-8 production directly through glucocorticoid receptor in vivo.
Autologous Dendritic Cell Vaccines for Non–Small-Cell Lung Cancer (2004)

Vaccines were well tolerated and had biologic activity in a variety of NSCLC patients. Establishing an optimal approach will require comparative studies in well-defined NSCLC patient groups.
Frequent inactivation of the retinoblastoma anti-oncogene is restricted to a subset of human tumor cells. (1990)

We have used polyclonal anti-synthetic peptide serum to study the role of retinoblastoma gene (RB) inactivation in a variety of human tumor cell lines. Our analysis indicates that inactivation of the RB protein, p105-Rb, is universal in retinoblastoma cells, vindicating the predictions of the Knudson "two-hit" hypothesis. In addition, our analysis has shown that inactivations of the RB gene are nearly as frequent in a more common human tumor, small cell lung carcinoma. One-third of bladder carcinomas surveyed also carry altered or absent p105-Rb. Other human tumors by contrast demonstrate only infrequent inactivation of the RB gene. These results suggest that inactivation of the RB gene is a critical step in the pathogenesis of a subset of human tumors.