gebhart/patrepeval huggingface dataset:
Cell‐type specific activation of p38 and ERK mediates calcitonin gene‐related peptide involvement in tolerance to morphine‐induced analgesia (2009)

Tolerance to morphine-induced analgesia is a well-established phenomenon, often limiting its usefulness in the long-term treatment of pain. The mechanisms underlying tolerance are not well understood. We previously suggested a possible role for spinal calcitonin gene-related peptide (CGRP) in the development of tolerance to morphine-induced analgesia. In the present study, we demonstrate that CGRP is involved in morphine tolerance by differentially regulating the ERK-dependent up-regulation of IL-1beta, TNF-alpha, and microsomal prostaglandin E synthase-1 (mPGES-1) in astrocytes and p38-dependent up-regulation of IL-6 in microglia in the rat spinal cord. A 7-d treatment with morphine induced tolerance to the antinociceptive effect and increased phosphorylated ERK localized in astrocytes and phosphorylated p38 enriched in microglia, both effects being inhibited by blocking CGRP receptors. Interestingly, the inhibition of the ERK pathway suppressed the development of tolerance and morphine-induced up-regulation of IL-1beta, TNF-alpha, and mPGES-1. Blockade of p38 activity also inhibited the development of tolerance and morphine-induced IL-6 up-regulation. Taken together, these data suggest that chronic morphine induces the synthesis of CGRP, which in turn acts on CGRP receptors located on astrocytes and microglia to stimulate ERK and p38, respectively, leading to increased synthesis and release of proinflammatory mediators resulting in tolerance to morphine-induced analgesia.
RNAi therapeutics: an update on delivery. (2008)

RNA interference (RNAi) has rapidly advanced from a laboratory observation into a major area of research within biology and medicine. RNAi is triggered by short interfering RNAs (siRNAs) of between 19 and 21 nucleotides in length, which induces the targeted cleavage of mRNA with sequences of homology to the siRNA. Because of its high degree of specificity and efficacy, the potential for RNAi-based therapeutics was recognized at an early stage. However, development of RNAi-based agents has been hindered because siRNAs are unstable in serum and delivery across the cell membrane is highly inefficient. Numerous methods have been developed to facilitate delivery of RNAi in animals and patients, each with their own set of advantages and disadvantages. This review discusses publications between 2005 to 2007 in the area of RNAi delivery, with a particular focus on in vivo application and clinical trials.
Kininogen-kallikrein-kinin system in plasma and saliva of patients with Sjögren's syndrome. (1998)

Comparisons between the total and the active tissue kallikrein in saliva of patients with SS showed that most of the tissue kallikrein was in its active form. In addition, we observed a concomitant increase of the tissue kallikrein-like activity in plasma. These results suggest increased activation of the KKKS in plasma and saliva of patients with SS.
Liquid Morphologies on Structured Surfaces: From Microchannels to Microchips (1999)

Liquid microchannels on structured surfaces are built up using a wettability pattern consisting of hydrophilic stripes on a hydrophobic substrate. These channels undergo a shape instability at a certain amount of adsorbed volume, from a homogeneous state with a spatially constant cross section to a state with a single bulge. This instability is quite different from the classical Rayleigh Plateau instability and represents a bifurcation between two different morphologies of constant mean curvature. The bulge state can be used to construct channel networks that could be used as fluid microchips or microreactors.
Iron Regulatory Element and Internal Loop/Bulge Structure for Ferritin mRNA Studied by Cobalt(III) Hexammine Binding, Molecular Modeling, and NMR Spectroscopy (1998)

The ferritin IRE, a highly conserved (96-99% in vertebrates) mRNA translation regulatory element in animal mRNA, was studied by molecular modeling (using MC-SYM and DOCKING) and by NMR spectroscopy. Cobalt(III) hexammine was used to model hydrated Mg2+. IRE isoforms in other mRNAs regulate mRNA translation or stability; all IREs bind IRPs (iron regulatory proteins). A G.C base pair, conserved in ferritin IREs, spans an internal loop/bulge in the middle of an A-helix and, combined with a dynamic G.U base pair, formed a pocket suitable for Co(III) hexammine binding. On the basis of the effects of Co(III) hexammine on the 1H NMR spectrum and results of automatic docking into the IRE model, the IRE bound Co(III) hexammine at the pocket in the major groove; Mg2+ may bind to the IRE at the same site on the basis of an analogy to Co(III) hexammine and on the Mg2+ inhibition of Cu-(phen)2 cleavage at the site. Distortion of the IRE helix by the internal loop/bulge near a conserved unpaired C required for IRP binding and adjacent to an IRP cross-linking site suggests a role for the pocket in ferritin IRE/IRP interactions.
Origins of Serum Semicarbazide-Sensitive Amine Oxidase (2004)

Semicarbazide-sensitive amine oxidases (SSAO) are enzymes that are capable of deaminating primary amines to produce aldehyde, ammonia, and hydrogen peroxide. This activity has been associated with vascular adhesion protein-1 (VAP-1) and is found in the serum, endothelium, adipose, and smooth muscle of mammals. Circulating SSAO activity is increased in congestive heart failure, diabetes, and inflammatory liver diseases. To investigate the origin of circulating SSAO activity, two transgenic mouse models were created with full-length human VAP-1 (hVAP-1) expressed on either endothelial (mTIEhVAP-1) or adipose tissues (aP2hVAP-1), with tie-1 and adipocyte P2 promoters, respectively. Under normal conditions a circulating form of hVAP-1 was found at high levels in the serum of mice with endothelium-specific expression and at low levels in the serum of mice with adipose specific expression. The level of circulating hVAP-1 in the transgenic mice varied with gender, transgene zygosity, diabetes, and fasting. Serum SSAO activity was absent from VAP-1 knockout mice and endothelial cell-specific expression of human VAP-1 restored SSAO activity to the serum of VAP-1 knockout mice. Together, these experiments show that in the mouse VAP-1 is the only source of serum SSAO, that under physiological conditions vascular endothelial cells can be a major source of circulating VAP-1 protein and SSAO, and that serum VAP-1 can originate from both endothelial cells and adipocytes during experimental diabetes. An increased endothelial cell capacity for lymphocyte binding and altered expression of redox-sensitive proteins was also associated with the mTIEhVAP-1 transgene.
Medical Therapy for Obstructive Sleep Apnea: A Review by the Medical Therapy for Obstructive Sleep Apnea Task Force of the Standards of Practice Committee of the American Academy of Sleep Medicine (2006)

A significant number of patients with obstructive sleep apnea neither tolerate positive airway pressure (PAP) therapy nor achieve successful outcomes from either upper airway surgeries or use of an oral appliance. The purpose of this paper, therefore, was to systematically evaluate available peer-reviewed data on the effectiveness of adjunctive medical therapies and summarize findings from these studies. A review from 1985 to 2005 of the English literature reveals several practical findings. Weight loss has additional health benefits and should be routinely recommended to most overweight patients. Presently, there are no widely effective pharmacotherapies for individuals with sleep apnea, with the important exceptions of individuals with hypothyroidism or with acromegaly. Treating the underlying medical condition can have pronounced effects on the apnea/hypopnea index. Stimulant therapy leads to a small but statistically significant improvement in objective sleepiness. Nonetheless, residual sleepiness remains a significant health concern. Supplemental oxygen and positional therapy may benefit subsets of patients, but whether these therapies reduce morbidities as PAP therapy does will require rigorous randomized trials. PAP therapy has set the bar high for successful treatment of sleep apnea and its associated morbidities. Nonetheless, we should strive towards the development of universally effective pharmacotherapies for sleep apnea. To accomplish this, we require a greater knowledge of the neurochemical mechanisms underlying sleep apnea, and we must use this infrastructure of knowledge to design well-controlled, adequately powered studies that examine, not only effects on the apnea/hypopnea index, but also the effects of pharmacotherapies on all health related outcomes shown beneficial with PAP therapy.
Towards Sample Efficient Reinforcement Learning (2018)

Reinforcement learning is a major tool to realize intelligent agents that can be autonomously adaptive to the environment. With deep models, reinforcement learning has shown great potential in complex tasks such as playing games from pixels. However, current reinforcement learning techniques are still suffer from requiring a huge amount of interaction data, which could result in unbearable cost in real-world applications. In this article, we share our understanding of the problem, and discuss possible ways to alleviate the sample cost of reinforcement learning, from the aspects of exploration, optimization, environment modeling, experience transfer, and abstraction. We also discuss some challenges in real-world applications, with the hope of inspiring future researches.
Septic arthritis (1990)

We report herein that cartilage proteolytic activity increased in bovine and rabbit articular cartilage after treatment with a purified staphylococcal culture medium or intraarticular infection with Staphylococcus aureus. Staphylococcal culture medium increased the release of gelatinolytic, collagenolytic, and caseinolytic activity into the medium of isolated chondrocytes or cartilage organ culture. The proteolytic activities were determined in assays using radiolabeled substrate and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Staphylococcal culture medium was proteolytically inactive by both assay techniques. RNA synthesis of isolated chondrocytes was unaffected by staphylococcal culture medium, whereas overall protein synthesis was inhibited by 84%. An analysis of extracts of Staphylococcus aureus-infected rabbit knee cartilage by substrate gels showed increased gelatinolytic and caseinolytic activity compared with extracts of uninfected knee cartilage. Our data suggest that the rapid loss of proteoglycan and persistent degradation of cartilage in staphylococcal septic arthritis is due to the production and activation of chondrocyte proteases.
THE ROLE OF ALKALINE PHOSPHATASE IN OSTEOGENESIS (1951)

The role of alkaline phosphatase in osteogenesis has been investigated by histochemical techniques with particular attention to its relationship to phosphate metabolism and matrix elaboration. The upper tibial epiphysis mainly, and other epiphyses as well of growing rabbits, and the costochondral junctions of newborn human beings were studied, as were bone grafts in growing rabbits. The findings in the newborn human beings were identical with those in the rabbits. Phosphatase activity and free phosphate localization do not universally coincide. The enzyme appears to be intimately related to preosseous cellular metabolism and to the elaboration of a bone matrix that is chemically calcifiable. It remains possible, however, that phosphatase may be in some way involved in making inorganic salts available to the calcifiable matrix. If this function does exist it is a secondary one, since the elaboration of bone matrix, which is always associated with phosphatase activity, can and does occur in the absence of calcification. Calcification may occur later, in the absence of the enzyme. There is evidence to suggest that cartilage matrix is utilized in the formation of bone matrix. Phosphatase is physiologically active only in the presence of living cells. Where it is demonstrable in the absence of living cells, as in the cartilage remnants of the metaphysis, it appears to be physiologically inactive. Since phosphatase is temporarily inactivated in weakly acid media, and readily reactivated by alkaline solutions it is possible that the enzyme might survive in a physiologically inactive state in weakly acid tissues, and yet remain capable of histochemical demonstration in vitro in an alkaline medium. Phosphatase is not related to the disappearance of chondroitin sulfate.
Development of a Large-Scale Functional Brain Network during Human Non-Rapid Eye Movement Sleep (2010)

Graph theoretical analysis of functional magnetic resonance imaging (fMRI) time series has revealed a small-world organization of slow-frequency blood oxygen level-dependent (BOLD) signal fluctuations during wakeful resting. In this study, we used graph theoretical measures to explore how physiological changes during sleep are reflected in functional connectivity and small-world network properties of a large-scale, low-frequency functional brain network. Twenty-five young and healthy participants fell asleep during a 26.7 min fMRI scan with simultaneous polysomnography. A maximum overlap discrete wavelet transformation was applied to fMRI time series extracted from 90 cortical and subcortical regions in normalized space after residualization of the raw signal against unspecific sources of signal fluctuations; functional connectivity analysis focused on the slow-frequency BOLD signal fluctuations between 0.03 and 0.06 Hz. We observed that in the transition from wakefulness to light sleep, thalamocortical connectivity was sharply reduced, whereas corticocortical connectivity increased; corticocortical connectivity subsequently broke down in slow-wave sleep. Local clustering values were closest to random values in light sleep, whereas slow-wave sleep was characterized by the highest clustering ratio (gamma). Our findings support the hypothesis that changes in consciousness in the descent to sleep are subserved by reduced thalamocortical connectivity at sleep onset and a breakdown of general connectivity in slow-wave sleep, with both processes limiting the capacity of the brain to integrate information across functional modules.
MUTATION OF REGNASE-1 CAUSES PRIMARY IMMUNODEFICIENCY ASSOCIATED WITH AUTO-INFLAMMATORY DISEASE (2017)

Primary immunodeficiencies (PIDs) are a heterogeneous group of disorders causing immune dysfunction that manifest with increased susceptibility to infection. Some PID patients may also have autoimmune and autoinflammatory manifestations. In many cases, PIDs are monogenic disorders that follow Mendelian inheritance and mutations in more than 250 genes have been shown to cause PIDs. However, in the majority of PID patients the causative mutations remain unknown. Here I report a study of a patient from a consanguineous family who presented in infancy with colitis, autoimmune hepatitis, autoimmune anemia and thrombocytopenia. The patient also suffered recurrent respiratory infections leading to bronchiectasis and had several episodes of severe varicella zoster virus (VZV) infections, including pneumonia and meningitis. Immunologically, the patient had increased IgM and IgG levels, absent IgA, low specific antibodies and multiple auto-antibodies, including anti-Interferon- antibodies. Whole blood stimulation assays identified an increased production of the pro-inflammatory cytokine IL-6. Throughout his life the patient received immunosuppressive therapy. Whole exome sequencing of the patient discovered a homozygous frameshift mutation in the ZC3H12A gene that encodes the Regnase-1 protein also known as MCPIP1. Regnase-1 is a regulatory RNase that directly degrades mRNAs of several pro-inflammatory genes, e.g. mRNA of cytokine IL-6, thus curbing the immune activation. The presentation of the patient resembled the phenotype of the Regnase-1-knockout mice that developed spontaneous systemic inflammation, disorganisation of lymphoid organs, severe anaemia and hyperimmunoglobulinemia, with the increased production of IL-6. I studied expression of the mutant Regnase-1 protein using commercial antibodies; also a new custom-made antibody that detects the truncated mutant Regnase-1 protein was developed. Analysis of the patient-derived cells demonstrated absence of the full-length Regnase-1 protein. Cloning and forced expression of the truncated mutant protein showed that it is mislocalized inside the cells and is functionally impaired. Studies of the iPSC-derived macrophages, EBV-transformed B cells and primary fibroblasts of the patient demonstrated increased levels of the IL-6 mRNA in the resting cells. They also showed impaired regulation of the truncated mutant Regnase-1 protein and IL-6 mRNA levels after cell stimulation. Mutations in Regnase-1 have never been associated with human diseases previously. Therefore, this study describes a novel PID caused by the Regnase-1 deficiency.
Direct Synthesis of Hybrid Organic−Inorganic Nanoporous Silica by a Neutral Amine Assembly Route:  Structure−Function Control by Stoichiometric Incorporation of Organosiloxane Molecules (1999)

The co-condensation of tetraethoxysilane (TEOS) and organotrialkoxysilane molecules by neutral alkylamine surfactant assembly (S0I0) is a convenient synthesis methodology for the one-step preparation of organically functionalized mesostructured materials. Two distinct approaches were considered for the formation of such hybrid inorganic−organic compounds, denoted as the template substitution and direct addition pathways. The template substitution pathway, involving the replacement of both surfactant and TEOS by an equivalent amount of organosilane (up to 11% substitution), was convenient for the functionalization of mesostructures with moieties whose size is comparable to that of the structure-directing amine surfactant. The direct addition method, involving the equimolar replacement of TEOS with organosilane (up to 9% of total silicon) while keeping the surfactant amount constant in the reaction mixture, was successful for the incorporation of organic groups whose sizes were smaller than that of the templating amine surfactant. Thus, the functionalization of mesostructured silica was demonstrated using a wide range of organosilane species, including octyltriethoxysilane, mercaptopropyltrimethoxysilane, phenyltriethoxysilane, butyltrimethoxysilane, and propyltrimethoxysilane. Short-chain functional groups such as ethyltriethoxysilane, however, appeared to become occluded within the framework walls of HMS silica, resulting in a lowering of the framework order and the porosity of the hybrid materials. A sufficiently long carbon chain (at least three methylene units) in the functional group of the organosilane allows an interaction with the hydrophobic core of the structure-directing micelle, thereby permitting the successful incorporation of the organosilane into the pore walls of the mesostructure.
The major peripheral myelin protein zero gene: structure and localization in the cluster of Fcγ receptor genes on human chromosome 1q21.3 – q23 (1993)

We have characterized the human gene encoding the major peripheral myelin protein zero (P0) and assigned it, by in situ hybridization, to the q21.3-q23 region of human chromosome 1. This region is known to contain a cluster of interspersed genes coding for the related human leukocyte receptors of the Fc portion of the immunoglobulin G (Fc gamma RI, II, III). This colocalization was refined by the finding of a yeast artificial chromosome (YAC) of the Centre d'Etude du Polymorphisme Humain (CEPH) library, hybridizing to the P0 and Fc gamma RIIA genes, demonstrating their physical linkage. These data may have important implications in demyelinating diseases studies like Charcot-Marie-Tooth disease type 1B (CMT1B).
Beta-Adrenergic Blockade in Chronic Heart Failure (1998)

In summary, beta-blockade is currently the most promising "new" treatment undergoing Phase III testing in chronic heart failure. Multiple studies on the effects of these agents on LV function and chamber characteristics as well as limited survival data strongly suggest that these agents produce a beneficial effect on the natural history of heart failure. If this promise is borne out in the currently active or planned large-scale clinical trials, this form of therapy will emerge as the most valuable treatment available for chronic heart failure.
The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis (2005)

PTEN is an important tumor suppressor gene. Hereditary mutation of PTEN causes tumor-susceptibility diseases such as Cowden disease. We used the Cre-loxP system to generate an endothelial cell-specific mutation of Pten (Tie2CrePten) in mice. Tie2CrePten(flox/+) mice displayed enhanced tumorigenesis due to an increase in angiogenesis driven by vascular growth factors. This effect was partially dependent on the PI3K subunits p85alpha and p110gamma. In vitro, Tie2CrePten(flox/+) endothelial cells showed enhanced proliferation/migration. Tie2CrePten(flox/flox) mice died before embryonic day 11.5 (E11.5) due to bleeding and cardiac failure caused by impaired recruitment of pericytes and vascular smooth muscle cells to blood vessels, and of cardiomyocytes to the endocardium. These phenotypes depend strongly on p110gamma rather than on p85alpha and were associated with decreased expression of Ang-1, VCAM-1, connexin 40, and ephrinB2 but increased expression of Ang-2, VEGF-A, VEGFR1, and VEGFR2. Pten is thus indispensable for normal cardiovascular morphogenesis and post-natal angiogenesis, including tumor angiogenesis.
Allyl Sulfides Are Privileged Substrates in Aqueous Cross-Metathesis: Application to Site-Selective Protein Modification (2008)

Allyl sulfides undergo efficient cross-metathesis in aqueous media with Hoveyda-Grubbs second generation catalyst 1. The high reactivity of allyl sulfides in cross-metathesis was exploited in the first examples of cross-metathesis on a protein surface. S-Allylcysteine was incorporated chemically into the protein, providing the requisite allyl sulfide handle. Preliminary efforts to genetically incorporate S-allylcysteine into proteins are also reported.
Variation Study and Implications for BJT-Based Thin-Body Capacitorless DRAM (2012)

Variability in back-gated thin-body capacitorless DRAM cell performance is investigated via TCAD simulation. Sources of variability considered include variations in front gate oxide thickness, body thickness, buried oxide thickness, and gate-sidewall spacer width, as well as random dopant fluctuations. Bipolar junction transistor-based cell operation is most sensitive to variations in body thickness and buried oxide thickness. Retention time for an optimized 22 nm-node cell design is predicted to be reduced by approximately 63% due to process-induced variations.