gebhart/patrepeval huggingface dataset:
Regulation of Dendritic Cell Function by Histone Deacetylase Inhibitors. (2006)

Abstract Histone deacetylases (HDACs) modulate gene transcription and chromatin assembly by modifying histones at the post-transcriptional level. HDAC inhibitors have promising antitumor activity and are presently explored in clinical studies for malignancies of different histology. Preliminary evidence in animal models of immune disorders also suggests immunosuppressive properties for these small molecules, although the underlying mechanisms remain at present poorly understood. Here, we show that two HDAC inhibitors of clinical use, sodium valproate and MS-275, profoundly affect cytokine-induced differentiation of human monocytes to dendritic cells (DCs), and impair DC phenotypic maturation in response to the Toll-like receptor (TLR) ligand polyinosinic:polycytidylic acid (poly I:C) characterized by a reduced expression of HLA- and costimulatory molecules. HDAC inhibitors reduce cytokine secretion important for T-cell activation like IL-12 and immunostimulatory capacity in DCs and inhibit DC migratory capacity toward the chemoattractant CCL19/MIP-3β. The observed defects in DC function upon exposure to HDAC inhibitors were not due to an increased rate of apoptosis or production of IL-10. We finally investigated the effects of HDAC inhibition on intracellular signalling pathways that play a key role in controlling DC differentiation and function. HDAC inhibitors have been reported to cause a downregulation of the hematopoietic transcription factor PU.1, which contributes to the development of thymic and myeloid dendritic cells and of Langerhans cells in the mouse. We evaluated herein whether PU.1 expression was affected by VPA in monocyte-derived DCs, however, no significant reduction in protein levels could be detected. Therefore, our data rule out PU.1 shortening as a mechanism responsible for the functional defects observed in DCs that were exposed to HDAC inhibitors. Similarly, no significant effect of HDAC inhibitors was detected on Bcl-6, another known target of HDAC inhibitors that, besides its role in lymphomas, has also been linked to the regulation of cytokine and chemokine release in macrophages. In contrast, addition of VPA blocked RelB nuclear relocalization in response to poly I:C in a concentration-dependent manner. Interestingly, IRF-3 and IRF-8, which have been involved in DC differentiation, IL-12 production and DC migration, were also affected by HDAC inhibitors, since their nuclear levels were reduced by VPA in unstimulated as well as in poly I:C-activated DCs. On the other hand, IRAK-1 downregulation in response to poly I:C was not affected by VPA, suggesting that the effects of HDAC inhibition on RelB, IRF-3 and IRF-8 are probably mediated downstream of MyD88 and IRAK-1. In conclusion, HDAC inhibitors exhibit strong immunomodulatory properties on human DCs. Our results support the evaluation of HDAC inhibitors in inflammatory and autoimmune disorders.
Multilineage mesenchymal differentiation potential of human trabecular bone‐derived cells (2002)

Explant cultures of adult human trabecular bone fragments give rise to osteoblastic cells, that are known to express osteoblast-related genes and mineralize extracellular matrix. These osteoblastic cells have also been shown to undergo adipogenesis in vitro and chondrogenesis in vivo. Here we report the in vitro developmental potential of adult human osteoblastic cells (hOB) derived from explant cultures of collagenase-pretreated trabecular bone fragments. In addition to osteogenic and adipogenic differentiation, these cells are capable of chondrogenic differentiation in vitro in a manner similar to adult human bone marrow-derived mesenchymal progenitor cells. High-density pellet cultures of hOB maintained in chemically defined serum-free medium, supplemented with transforming growth factor-beta1, were composed of morphologically distinct, chondrocyte-like cells expressing mRNA transcripts of collagen types II, IX and X, and aggrecan. The cells within the high-density pellet cultures were surrounded by a sulfated proteoglycan-rich extracellular matrix that immunostained for collagen type II and proteoglycan link protein. Osteogenic differentiation of hOB was verified by an increased number of alkaline phosphatase-positive cells, that expressed osteoblast-related transcripts such as alkaline phosphatase, collagen type I, osteopontin and osteocalcin, and formed mineralized matrix in monolayer cultures treated with ascorbate, beta-glycerophosphate, and bone morphogenetic protein-2. Adipogenic differentiation of hOB was determined by the appearance of intracellular lipid droplets, and expression of adipocyte-specific genes, such as lipoprotein lipase and peroxisome proliferator-activated receptor gamma2, in monolayer cultures treated with dexamethasone, indomethacin, insulin and 3-isobutyl-1-methylxanthine. Taken together, these results show that cells derived from collagenase-treated adult human trabecular bone fragments have the potential to differentiate into multiple mesenchymal lineages in vitro, indicating their developmental plasticity and suggesting their mesenchymal progenitor nature.
Self-Annihilation of Antiphase Boundary in GaAs on Si(100) Grown by Molecular Beam Epitaxy (1987)

It has been shown that single domain GaAs can be grown on Si(100) which consists of two domains. A mechanism for self-annihilation of the antiphase boundary in the process of GaAs growth has been proposed to explain the experimental result.
Observation of the collapse and revival of a Rydberg electronic wave packet (1990)

We report an observation of the long-term evolution of a radially localized electronic wave packet formed by the coherent superposition of Rydberg states of atomic potassium. Initially, the wave packet can be described classically. Subsequent dephasing of the discrete states in the superposition leads to a loss of spatial localization so that the evolution can no longer be described classically. However, the wave packet revives at a later time. Theory and experiment show good agreement including an accurate measurement of the phase shift of the wave packet on revival.
Automatic step-size adaptation in incremental supervised learning (2010)

Performance and stability of many iterative algorithms such as stochastic gradient descent largely depend on a fixed and scalar step-size parameter. Use of a fixed and scalar step-size value may lead to limited performance in many problems. We study several existing step-size adaptation algorithms in nonstationary, supervised learning problems using simulated and real-world data. We discover that effectiveness of the existing step-size adaptation algorithms requires tuning of a meta parameter across problems. We introduce a new algorithm - Autostep - by combining several new techniques with an existing algorithm, and demonstrate that it can effectively adapt a vector step-size parameter on all of our training and test problems without tuning its meta parameter across them. Autostep is the first step-size adaptation algorithm that can be used in widely different problems with the same setting of all of its parameters.
Melanoma Treatments: Advances and Mechanisms (2015)

Advances in the understanding of the molecular pathogenesis of melanoma and in cancer immunology have led to the rational design and recent clinical implementation of a variety of novel therapies for metastatic melanoma. BRAF and MEK inhibitors that target the MAPK pathway have high rates of clinical response in BRAF-mutant melanoma. Therapies that modulate the immune response to melanoma, including monoclonal antibodies that interfere with pathways that inhibit T-cell function, have been shown to be effective in melanoma. Lessons learned from these encouraging results are driving the development of new treatments for melanoma and other cancers. This review will focus on the science and clinical findings related to targeted therapies that inhibit BRAF or MEK as well as the immunotherapies that block the CTLA-4 or PD-1 pathways. Other experimental and combinatorial therapeutic approaches will also be discussed.
Prevalence of <i>Helicobacter pylori</i> infection among Egyptian children: impact of social background and effect on growth (2007)

The results demonstrate not only that the prevalence of H. pylori infection is extremely high among Egyptian schoolchildren, but also that the adverse effects of the infection reach far beyond the stomach. Evidence of the burden of infection on growth failure is presented.
Identification of Small-Molecule Positive Modulators of Calcitonin-like Receptor-Based Receptors (2020)

Class B G protein-coupled receptors are highly therapeutically relevant but challenges remain in identifying suitable small-molecule drugs. The calcitonin-like receptor (CLR) in particular is linked to conditions such as migraine, cardiovascular disease, and inflammatory bowel disease. The CLR cannot act as a cell-surface receptor alone but rather must couple to one of three receptor activity-modifying proteins (RAMPs), forming heterodimeric receptors for the peptides adrenomedullin and calcitonin gene-related peptide. These peptides have extended binding sites across their receptors. This is one reason why there are few small-molecule ligands that can modulate these receptors. Here we describe small molecules that are able to positively modulate the signaling of the CLR with all three RAMPs but are not active at the related calcitonin receptor. These compounds were selected from a β-arrestin recruitment screen, coupled with rounds of medicinal chemistry to improve their activity. Translational potential is shown as the compounds can positively modulate cAMP signaling in a vascular cell line model. Binding experiments do not support an extracellular domain binding site; however, molecular modeling reveals potential allosteric binding sites in multiple receptor regions. These are the first small-molecule positive modulators described for the CLR:RAMP complexes.
Identification of valproic acid metabolites in human serum and urine using hexadeuterated valproic acid and gas chromatographic mass spectrometric analysis (1983)

Valproic acid, an antiepileptic drug, is extensively metabolized in humans. A hexadeuterated valproic acid was used in this study to aid the identification of metabolites and their artifacts in serum and urine extracts. A 600 mg oral dose of hexadeuterated valproic acid was administered to a human volunteer at steady state serum concentrations of unlabelled valproic acid. By using gas chromatography mass spectrometry, metabolites were characterized as their methyl, tert-butyldimethylsilyl, or trimethylsilyl derivatives. A di-unsaturated metabolite with concentrations comparable to 2-ene valproic acid was identified in serum and urine. The presence of a molecular ion doublet in the mass spectrum corresponding to the unlabelled and hexadeuterated dienes reduces the possible structures for this metabolite. A new metabolite, 2-propyl-4-ketopentanoic acid was also identified in serum and in urine. The dicarboxylic acids, 2-propylsuccinic and 2-propylmalonic were identified in the urine extract as metabolites. Identification of isolated metabolites was aided by comparison of the retention times and mass spectra to those of synthesized reference compounds. Diagnostic fragment ions and ion doublets in the mass spectra of the derivatives of newly identified metabolites were compared to those of known metabolites.
An electron microscopic method for studying nucleic acid–protein complexes. Visualization of RNA polymerase bound to the DNA of bacteriophages T7 and T3 (1974)

Abstract Double‐stranded DNA can be readily adsorbed on mica or directly on carbon coated grids from the surface of solutions containing ethidium bromide, actinomine, or propidium diiodide. The DNA molecules are unfolded, well separated, and show a length distribution similar to molecules prepared by protein monolayer techniques. Since the intercalating dyes tested do not lead to an increased apparent diameter of the nucleic acid the method is useful for the study of nucleic acid–protein complexes. As a model, the binding of E. coli RNA polymerase to phage T7 and T3 DNA was examined under different conditions. The enzyme can easily be identified and its position along the DNA molecule can be mapped.
Measurement and analysis of sarcomere length in rat cardiomyocytes in situ and in vitro (2010)

Sarcomere length (SL) is an important determinant and indicator of cardiac mechanical function; however, techniques for measuring SL in living, intact tissue are limited. Here, we present a technique that uses two-photon microscopy to directly image striations of living cells in cardioplegic conditions, both in situ (Langendorff-perfused rat hearts and ventricular tissue slices, stained with the fluorescent marker di-4-ANEPPS) and in vitro (acutely isolated rat ventricular myocytes). Software was developed to extract SL from two-photon fluorescence image sets while accounting for measurement errors associated with motion artifact in raster-scanned images and uncertainty of the cell angle relative to the imaging plane. Monte-Carlo simulations were used to guide analysis of SL measurements by determining error bounds as a function of measurement path length. The mode of the distribution of SL measurements in resting Langendorff-perfused heart is 1.95 mum (n = 167 measurements from N = 11 hearts) after correction for tissue orientation, which was significantly greater than that in isolated cells (1.71 mum, n = 346, N = 9 isolations) or ventricular slice preparations (1.79 mum, n = 79, N = 3 hearts) under our experimental conditions. Furthermore, we find that edema in arrested Langendorff-perfused heart is associated with a mean SL increase; this occurs as a function of time ex vivo and correlates with tissue volume changes determined by magnetic resonance imaging. Our results highlight that the proposed method can be used to monitor SL in living cells and that different experimental models from the same species may display significantly different SL values under otherwise comparable conditions, which has implications for experiment design, as well as comparison and interpretation of data.
DEVELOPMENT OF EXTERNALLY POWERED UPPER EXTREMITY ORTHOTIC SYSTEMS (1965)

1. Orthotic systems for the upper limb are described. 2. Two patients are described to illustrate the value of the systems.
PDTM-27. DIANHYDROGALACTITOL (VAL-083) OVERCOMES CHEMORESISTANCE IN PEDIATRIC MALIGNANT BRAIN TUMORS AND DISPLAYS SYNERGY WITH TOPOISOMERASE INHIBITORS (2017)

More children die from brain cancer than from any other disease. Medulloblastoma (MB) and pediatric high-grade gliomas (pHGG) are the most common malignant brain cancers in children. Children with pHGG have few therapeutic options and 5-year survival is less than 20%. Treatment includes surgery, radiotherapy and various chemotherapeutic combinations often including topoisomerase inhibitors and/or temozolomide (TMZ). The expression of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is strongly correlated with TMZ-resistance and is highly expressed in many pHGG, and deficient DNA mismatch repair (MMR) (25% of pHGG) confers a secondary mechanism of TMZ-resistance. VAL-083 is a novel bi-functional DNA targeting agent that readily crosses the blood-brain barrier and accumulates in brain tumor tissue. In prior NCI-sponsored clinical trials, VAL-083 was well-tolerated and demonstrated activity against pediatric brain tumors, including pHGG and MB. VAL-083 induces interstrand cross-links at N7-guanine, DNA double-strand breaks and irreversible S/G2-phase cell cycle arrest leading to persistent activation of the homologous recombination (HR) DNA repair pathway and cancer cell death. VAL-083 overcomes MGMT-related resistance mechanisms and is equally active against HGG cancer stem cells and non-stem cells, in vitro. Here, we report strong VAL-083 activity against pHGG (SF188), MB (Med8a) and adult HGG (T98G) cancer cells known to be radio- and chemoresistant, independent of p53 and MGMT status. Further, VAL-083 cytotoxicity was shown to be MMR-independent in two colorectal cancer cell lines. We also report strong synergy between VAL-083 and inhibitors of both topoisomerase I and II (camptothecin and etoposide) in A549 and PC3 cancer cell lines. Our results suggest a distinct anti-cancer mechanism for VAL-083 compared to standard MB/pHGG chemotherapy, resulting in the ability to overcome MGMT- and MMR-related chemoresistance and exhibiting synergy with topoisomerase inhibitors.
An ideographic language front end processor for accessing English language computer systems (1981)

A scheme is described which enables users to interact with a timesharing computer in an ideographic language such as Chinese. The host computer runs a completely unmodified English-based operating system, the necessary translation being performed by a preprocessing microcomputer which constitutes the ideographic terminal. The two systems communicate through a serial line, and the host sees the preprocessor as an ordinary (English) terminal. After brief consideration of the terminal's keyboard and display, we examine the software problems of translation for five examples subsystems – an interpreted programming language, text editor, document preparation software, interactive data base management system, and the command level of the operating system itself.
Externally Triggered Dual Function of Complex Microcapsules (2013)

By introducing UV-sensitive chemical groups causing different potential response as building blocks, fabricated LbL capsules can be endowed with dual UV-responsive properties in specific layers. One block is responsible for fast capsule sealing and the other for longer term capsule swelling and rupture. Therefore, the multifunction of these capsules could be activated selectively when exposed to external UV light with suitable wavelengths. In this work, dual-functional complex microcapsules (PDADMAC/PAZO)4-(DAR/Nafion)2 containing both diazonium and aozbenzene groups were proposed as clear examples to realize a time-dependent UV response for successive encapsulation and release. Upon exposure to UV light, the DAR/Nafion layers underwent a rapid in situ cross-linking and hence to seal the capsule shells through diazonium-related photolysis. Then further gradual shell swelling was followed by realignment of azobenzene molecules in PDADMAC/PAZO layers. Fluorescent polymers were consequently studied as cargo substances. Results indicated that continuous UV light triggered rapid cargo encapsulation over minutes time scale and gradual release with continuous irradiation over hours.
Quantitative molecular analysis with molecular bands emission using laser-induced breakdown spectroscopy and chemometrics (2008)

The present work describes the first quantitative molecular prediction using laser-induced molecular bands along with chemometrics. In addition, this spectroscopic procedure has demonstrated the first complete quantitative analysis utilizing traditionally insensitive elements for pharmaceutical formulations. Atomic LIBS requires certain sensitive elements, such as Cl, F, Br, S and P, in order to quantitate a specific organic compound in a complex matrix. Molecular LIBS has been demonstrated to be the first successful approach using atomic spectroscopy to evaluate a complex organic matrix. This procedure is also the first quantitative analysis using laser-induced molecular bands and chemometrics. We have successfully applied chemometrics to predict the formulation excipients and active pharmaceutical ingredient (API) in a complex pharmaceutical formulation. Using such an approach, we demonstrate that the accuracy for the API and a formulation lubricant, magnesium stearate, have less than 4% relative bias. The other formulation excipients such as Avicel® and lactose have been accurately predicted to have less than a 15% relative bias. Molecular LIBS and chemometrics have provided a novel approach for the quantitative analysis of several molecules that was not technically possible with the traditional atomic LIBS procedure, that required sensitive elements to be present in both API and formulation excipients.
Formation of Highly Conductive p-Type ZnSe Using Li<sub>3</sub>N Diffusion (1996)

We have achieved high concentration p-type doping of ZnSe grown by metalorganic vapor phase epitaxy using a Li 3 N diffusion technique. The average hole concentration in the ZnSe : (Li, N) layer formed at a diffusion temperature of 470° C was as high as 1×10 18 cm -3 , and the layer exhibited a resistivity of ρ=0.3 Ω· cm and a hole mobility of µ p =18 cm 2 /V·s.
Selective spin inversion in nuclear magnetic resonance and coherent optics through an exact solution of the Bloch-Riccati equation (1985)

An analytical solution of the Bloch equations is presented using as a driving function a complex hyperbolic secant pulse. The solution indicates that, under the appropriate conditions, the use of such a pulse creates a highly selective population inversion which, above a critical threshold, is independent of pulse (irradiating ${B}_{1}$ field) amplitude and hence ${B}_{1}$ field homogeneity. This result is shown to be in excellent agreement with experiment, and as an aid to comprehension, analogies to adiabatic rapid passage and self-induced transparency are drawn.
The emerging chemistry of blood product disinfection (2002)

Given the importance and limitations of the blood supply worldwide, widely applicable procedures for the inactivation of pathogens (viruses, bacteria, protozoa etc.) in donated blood and blood products are now required. Conventional treatments such as ultraviolet irradiation cause damage to therapeutic components in the blood, so more targeted approaches are being sought. These include targeted chemotherapy, photochemotherapy and photodynamic antimicrobial chemotherapy (PACT).
Strontium calcium aluminate glasses (1996)

Glasses containing (mol%) 0-17SrO, 45-70CaO and 30-40 Al 2 O 3 were produced by conventional melting techniques. The addition of SrO markedly improves the glass forming tendency up to the limits of glass formation. The density and refractive index increase and the glass transformation temperature decreases as SrO replaces CaO. The infrared transmission is not significantly influenced by substituting strontium for calcium even at the limits of glass formation. No insight into the ease of glass formation was gained by examination of T x -T g values. Trends observed in the physical data are consistent with the current understanding of the structure of other aluminate glasses.
Synapsin IIa Controls the Reserve Pool of Glutamatergic Synaptic Vesicles (2008)

Synapsins regulate synaptic transmission by controlling the reserve pool of synaptic vesicles. Each of the three mammalian synapsin genes is subject to alternative splicing, yielding several isoforms whose roles are unknown. To investigate the function of these isoforms, we examined the synaptic effects of introducing each isoform into glutamatergic cultured hippocampal neurons from synapsin triple knock-out mice. Remarkably, we found that synapsin IIa was the only isoform that could rescue the synaptic depression phenotype of the triple knock-out mice; other isoforms examined, including the well-studied synapsin Ia isoform, had no significant effect on the kinetics of synaptic depression. The slowing of synaptic depression by synapsin IIa was quantitatively paralleled by an increase in the density of reserve pool synaptic vesicles, as measured either by fluorescent tagging of the vesicle protein synaptobrevin-2 or by staining with the styryl dye FM4-64 [N-(3-triethylammoniumpropyl)-4-(6-(4-diethylamino)phenyl)-hexatrienyl)pyridinium dibromide]. Our results provide further support for the hypothesis that synapsins define the kinetics of synaptic depression at glutamatergic synapses by controlling the size of the vesicular reserve pool and identify synapsin IIa as the isoform primarily responsible for this task.