gebhart/patrepeval huggingface dataset:
Enhancing versus Suppressive Effects of Stress on Immune Function: Implications for Immunoprotection and Immunopathology (2009)

Stress is known to suppress immune function and increase susceptibility to infections and cancer. Paradoxically, stress is also known to exacerbate asthma, and allergic, autoimmune and inflammatory diseases, although such diseases should be ameliorated by immunosuppression. Moreover, the short-term fight-or-flight stress response is one of nature's fundamental defense mechanisms that enables the cardiovascular and musculoskeletal systems to promote survival, and it is unlikely that this response would suppress immune function at a time when it is most required for survival (e.g. in response to wounding and infection by a predator or aggressor). These observations suggest that stress may suppress immune function under some conditions while enhancing it under others. The effects of stress are likely to be beneficial or harmful depending on the type (immunoprotective, immunoregulatory/inhibitory, or immunopathological) of immune response that is affected. Studies have shown that several critical factors influence the direction (enhancing vs. suppressive) of the effects of stress or stress hormones on immune function: (1) Duration (acute vs. chronic) of stress: Acute or short-term stress experienced at the time of immune activation can enhance innate and adaptive immune responses. Chronic or long-term stress can suppress immunity by decreasing immune cell numbers and function and/or increasing active immunosuppressive mechanisms (e.g. regulatory T cells). Chronic stress can also dysregulate immune function by promoting proinflammatory and type-2 cytokine-driven responses. (2) Effects of stress on leukocyte distribution: Compartments that are enriched with immune cells during acute stress show immunoenhancement, while those that are depleted of leukocytes, show immunosuppression. (3) The differential effects of physiologic versus pharmacologic concentrations of glucocorticoids, and the differential effects of endogenous versus synthetic glucocorticoids: Endogenous hormones in physiological concentrations can have immunoenhancing effects. Endogenous hormones at pharmacologic concentrations, and synthetic hormones, are immunosuppressive. (4) The timing of stressor or stress hormone exposure relative to the time of activation and time course of the immune response: Immunoenhancement is observed when acute stress is experienced at early stages of immune activation, while immunosuppression may be observed at late stages of the immune response. We propose that it is important to study and, if possible, to clinically harness the immunoenhancing effects of the acute stress response, that evolution has finely sculpted as a survival mechanism, just as we study its maladaptive ramifications (chronic stress) that evolution has yet to resolve. In view of the ubiquitous nature of stress and its significant effects on immunoprotection as well as immunopathology, it is important to further elucidate the mechanisms mediating stress-immune interactions and to meaningfully translate findings from bench to bedside.
Regulation of PI3K/Akt/GSK‐3 pathway by cannabinoids in the brain (2007)

Delta9-tetrahydrocannabinol (THC), the main psychoactive component in Cannabis sativa preparations, exerts its central effects mainly through the G-protein coupled receptor CB1, a component of the endocannabinoid system. Several in vitro and in vivo studies have reported neuroprotective effects of cannabinoids in excitotoxicity and neurodegeneration models. However, the intraneuronal signaling pathways activated in vivo by THC underlying its central effects remain poorly understood. We report that THC acute administration (10 mg/kg, i.p.) increases the phosphorylation of Akt in mouse hippocampus, striatum, and cerebellum. This phosphorylation was mediated by CB1 receptors as it was blocked by the selective CB1 antagonist rimonabant. Moreover, PI3K inhibition by wortmannin abrogated THC-induced phosphorylation of Akt, but blockade of extracellular signal-regulated protein kinases by SL327 did not modify this activation/phosphorylation of Akt. Moreover, administration of the dopaminergic D1 (SCH 23390) and D2 (raclopride) receptor antagonists did not block the activation of PI3K/Akt pathway induced in the striatum by cannabinoid receptor stimulation, suggesting that this effect is independent of the dopaminergic system. In addition, THC increased the phosphorylation of glycogen synthase kinase 3 beta. Therefore, activation of the PI3K/Akt/GSK-3 signaling pathway may be related to the in vivo neuroprotective properties attributed to cannabinoids.
TOR2 is required for organization of the actin cytoskeleton in yeast (1996)

The Saccharomyces cerevisiae gene TOR2 encodes a putative phosphatidylinositol kinase that has two essential functions. One function is redundant with TOR1, a TOR2 homolog, and is required for signaling translation initiation and early G1 progression. The second essential function is unique to TOR2. Here we report that loss of the TOR2-unique function disrupts polarized distribution of the actin cytoskeleton. A screen for dosage suppressors of a dominant negative TOR2 allele identified TCP20/CCT6, encoding a subunit of the cytosolic chaperonin TCP-1 that is involved in the biogenesis of actin structures. Overexpression of TCP20 restores growth and polarized distribution of the actin cytoskeleton in a tor2 mutant. TCP20 overexpression does not restore growth in a tor1 tor2 double mutant. We suggest that the unique function of the phosphatidylinositol kinase homolog TOR2 is required for signaling organization of the actin cytoskeleton during the cell cycle. TOR2, via its two functions, may thus integrate temporal and spatial control of cell growth.
A Non-Precious Electrocatalyst for Oxygen Reduction Based on Simple Heat-Treated Precursors (2008)

An active, non-precious catalyst for electrochemical oxygen reduction was made by heat-treating simple precursors. The current density obtained in an H2/O2 PEM fuel cell was as high as 0.34 A/cm2MEA at 0.65 V. The oxygen-reduction activities of catalysts prepared at different temperatures over the range 800-1050{degree sign}C were shown to be equivalent by the Rotating Ring Disk Electrode (RRDE) method. The nitrogen content, however, was observed by XPS to be highly variable with preparation temperature. Thus, in contrast to some reports in the literature, the surface nitrogen content was not strongly correlated to performance. The nature of the active site(s) is currently under investigation.
Unravelling the C 3 /C 4 carbon metabolism in Ralstonia eutropha H16 (2009)

An increased knowledge of the enzymes mediating between C(3) and C(4) intermediates in R. eutropha will facilitate metabolic engineering.
Selective inhibition of isoprenylation of 21-26-kDa proteins by the anticarcinogen d-limonene and its metabolites. (1991)

Limonene has chemotherapeutic activity against chemically induced rat mammary carcinomas, many of which contain activated ras genes. Given the recent discovery of the post-translational modification of p21ras and other cell growth-associated proteins by intermediates in the mevalonic acid pathway, and the common biochemical origins of limonene and these isoprene products, we investigated the effect of limonene on protein isoprenylation. NIH3T3 and human mammary epithelial cells were incubated with lovastatin and [2-14C]mevalonolactone in the absence and presence of limonene. Labeled proteins were then subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis and fluorography. Limonene inhibited isoprenylation of a class of cellular proteins of 21-26 kDa, including p21ras and possibly other small GTP-binding proteins, in a dose-dependent manner in both cell lines. In contrast, limonene did not affect the isoprenylation of several other proteins, including nuclear lamins. Limonene is metabolized extensively in vivo but not in cultured cells. The two major rat serum metabolites of limonene, perillic acid and dihydroperillic acid, were more potent than limonene in the inhibition of isoprenylation. These results demonstrate that limonene selectively inhibits isoprenylation of 21-26-kDa proteins at a point in the mevalonic acid pathway distal to 3-hydroxy-3-methylglutaryl coenzyme A reductase, and they provide a plausible explanation for its chemotherapeutic activity. Inhibition of isoprenylation of proteins such as p21ras and other small GTP-binding proteins would alter their intracellular localization and, hence, disrupt their biological activity.
Emerging Influenza Antiviral Resistance Threats (2010)

Antiviral resistance in influenza may not only develop during treatment but also sometimes transmit widely to replace susceptible strains in the absence of drug pressure. This transmission is exemplified by the global spread of adamantane-resistant A(H3N2) viruses since 2003, oseltamivir-resistant seasonal A(H1N1) viruses since 2007, and adamantane-resistant pandemic A(H1N1) viruses in 2009, events that emphasize the unpredictability of influenza viruses and the increasing challenges of clinical management of influenza, especially given the current paucity of therapeutic choices. Three articles in this issue of The Journal of Infectious Diseases extend these observations, describing the plasticity of seasonal A(H1N1) viruses in developing dual adamantane-oseltamivir resistance [1], the effects on drug susceptibility and viral fitness of various neuraminidase (NA) mutations in pandemic A(H1N1) viruses [2], and the risk of nosocomial spread of oseltamivir-resistant pandemic A(H1N1) virus [3]. Together, these findings illustrate that single reassortment events or mutations can lead to the emergence of transmissible variants of pandemic 2009 or seasonal A(H1N1) viruses unresponsive to most, if not all, of our currently available drugs. This raises multiple questions regarding patient management and preparations for future influenza outbreaks.
Quantitative Morphological Signatures Define Local Signaling Networks Regulating Cell Morphology (2007)

Although classical genetic and biochemical approaches have identified hundreds of proteins that function in the dynamic remodeling of cell shape in response to upstream signals, there is currently little systems-level understanding of the organization and composition of signaling networks that regulate cell morphology. We have developed quantitative morphological profiling methods to systematically investigate the role of individual genes in the regulation of cell morphology in a fast, robust, and cost-efficient manner. We analyzed a compendium of quantitative morphological signatures and described the existence of local signaling networks that act to regulate cell protrusion, adhesion, and tension.
Structure‐function relationships in tendons: a review (2008)

The purpose of the current review is to highlight the structure-function relationship of tendons and related structures to provide an overview for readers whose interest in tendons needs to be underpinned by anatomy. Because of the availability of several recent reviews on tendon development and entheses, the focus of the current work is primarily directed towards what can best be described as the 'tendon proper' or the 'mid-substance' of tendons. The review covers all levels of tendon structure from the molecular to the gross and deals both with the extracellular matrix and with tendon cells. The latter are often called 'tenocytes' and are increasingly recognized as a defined cell population that is functionally and phenotypically distinct from other fibroblast-like cells. This is illustrated by their response to different types of mechanical stress. However, it is not only tendon cells, but tendons as a whole that exhibit distinct structure-function relationships geared to the changing mechanical stresses to which they are subject. This aspect of tendon biology is considered in some detail. Attention is briefly directed to the blood and nerve supply of tendons, for this is an important issue that relates to the intrinsic healing capacity of tendons. Structures closely related to tendons (joint capsules, tendon sheaths, pulleys, retinacula, fat pads and bursae) are also covered and the concept of a 'supertendon' is introduced to describe a collection of tendons in which the function of the whole complex exceeds that of its individual members. Finally, attention is drawn to the important relationship between tendons and fascia, highlighted by Wood Jones in his concept of an 'ectoskeleton' over half a century ago - work that is often forgotten today.
Inflammatory signals in dendritic cell activation and the induction of adaptive immunity (2008)

Pathogen invasion induces a rapid inflammatory response initiated through the recognition of pathogen-derived molecules by pattern recognition receptors (PRRs) expressed on both immune and non-immune cells. The initial wave of pro-inflammatory cytokines and chemokines limits pathogen spread and recruits and activates immune cells to eradicate the invaders. Dendritic cells (DCs) are responsible for initiating a subsequent phase of immunity, dominated by the action of pathogen-specific T and B cells. As for the early pro-inflammatory response, DC activation is triggered by PRR signals. These signals convert resting DCs into potent antigen-presenting cells capable of promoting the expansion and effector differentiation of naive pathogen-specific T cells. However, it has been argued that signals from PRRs are not a prerequisite for DC activation and that pro-inflammatory cytokines have the same effect. Although this may appear like an efficient way to expand the number of DCs that initiate adaptive immunity, evidence is accumulating that DCs activated indirectly by inflammatory cytokines are unable to induce functional T-cell responses. Here, we review the differences between PRR-triggered and cytokine-induced DC activation and speculate on a potential role for DCs activated by inflammatory signals in tolerance induction rather than immunity.
TGF-β1 Release from Biodegradable Polymer Microparticles: Its Effects on Marrow Stromal Osteoblast Function (2001)

Controlled release of TGF-beta1 from PLGA/PEG microparticles is representative of emerging tissue engineering technologies that may modulate cellular responses to encourage bone regeneration at a skeletal defect site.
TLR2 Signaling in Chondrocytes Drives Calcium Pyrophosphate Dihydrate and Monosodium Urate Crystal-Induced Nitric Oxide Generation (2005)

Microcrystals of calcium pyrophosphate dihydrate (CPPD) and monosodium urate (MSU) deposited in synovium and articular cartilage initiate joint inflammation and cartilage degradation in large part by binding and directly activating resident cells. TLRs trigger innate host defense responses to infectious pathogens, and the expression of certain TLRs by synovial fibroblasts has revealed the potential for innate immune responses to be triggered by mesenchymally derived resident cells in the joint. In this study we tested the hypothesis that chondrocytes also express TLRs and that one or more TLRs centrally mediate chondrocyte responsiveness to CPPD and MSU crystals in vitro. We detected TLR2 expression in normal articular chondrocytes and up-regulation of TLR2 in osteoarthritic cartilage chondrocytes in situ. We demonstrated that transient transfection of TLR2 signaling-negative regulator Toll-interacting protein or treatment with TLR2-blocking Ab suppressed CPPD and MSU crystal-induced chondrocyte release of NO, an inflammatory mediator that promotes cartilage degeneration. Conversely, gain-of-function of TLR2 in normal chondrocytes via transfection was associated with increased CPPD and MSU crystal-induced NO release. Canonical TLR signaling by parallel pathways involving MyD88, IL-1R-associated kinase 1, TNF receptor-associated factor 6, and IkappaB kinase and Rac1, PI3K, and Akt critically mediated NO release in chondrocytes stimulated by both CPPD and MSU crystals. We conclude that CPPD and MSU crystals critically use TLR2-mediated signaling in chondrocytes to trigger NO generation. Our results indicate the potential for innate immunity at the level of the articular chondrocyte to directly contribute to inflammatory and degenerative tissue reactions associated with both gout and pseudogout.
Bispecific humanized anti-IL-2 receptor alpha beta antibodies inhibitory for both IL-2- and IL-15-mediated proliferation (1997)

Humanized anti-Tac (HAT) and Mik beta1 (HuMik beta 1) Abs directed at IL-2R alpha and IL-2R beta, respectively, inhibit IL-2 binding and biological activity and together act synergistically in vitro. The Abs have been used successfully in primate models of allograft rejection, graft-vs-host disease, and autoimmunity. We produced bifunctional humanized anti-IL-2R alpha beta Abs (BF-IgG) to combine the specificity of the two Abs into one entity by fusing HAT-producing NSO cells and HuMik beta 1-producing Sp2/0 cells. BF-IgG was purified using protein G-Sepharose affinity chromatography, followed by IL-2R alpha and IL-2R beta affinity chromatography and hydrophobic interaction chromatography. BF-IgG exhibited both anti-IL-2R alpha and anti-IL-2R beta specificities in binding assays. While the Ab binds the IL-2R with intermediate affinity (Kd = 2.82 nM), it does not inhibit IL-15 binding to its high affinity IL-15R. In Kit225/K6 (IL-2R alpha beta gamma+) cells, BF-IgG was 10-fold more potent than a HAT/HuMik beta 1 equimolar mixture in blocking IL-2-induced proliferation and, unexpectedly, was at least 65-fold more active than the mixture in blocking IL-15-induced proliferation. This dual inhibitory activity may be due to cross-linking of the IL-2R alpha and IL-2R beta, thus blocking IL-2 binding and possibly impeding the association of IL-2R beta with IL-15R. BF-IgG has potent immunosuppressant activities against both IL-2- and IL-15-mediated responses, and this antagonist could be more efficacious than HAT and/or HuMik beta 1 for the treatment of autoimmunity and the prevention of allograft rejection.
Reliable Systems on Unreliable Fabrics (2008)

The continued scaling of silicon fabrication technology has led to significant reliability concerns, which are quickly becoming a dominant design challenge. Design integrity is threatened by complexity challenges in the form of immense designs defying complete verification, and physical challenges such as silicon aging and soft errors, which impair correct system operation. The Gigascale Systems Research Center Resilient-System Design Team is addressing these key challenges through synergistic research thrusts, ranging from near-term reliability stress reduction techniques to methods for improving the quality of today's silicon, to longer-term technologies that can detect, recover, and repair faulty systems. These efforts are supported and complemented by an active fault-modeling research effort and a strong focus on functional-verification methodologies. The team's goal is to provide highly effective, low-cost solutions to ensure both correctness and reliability in future designs and technology nodes, thereby extending the lifetime of silicon fabrication technologies beyond what can be currently foreseen as profitable.
RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia (2013)

The finding that a GGGGCC (G4C2) hexanucleotide repeat expansion in the chromosome 9 ORF 72 (C9ORF72) gene is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) links ALS/FTD to a large group of unstable microsatellite diseases. Previously, we showed that microsatellite expansion mutations can be bidirectionally transcribed and that these mutations express unexpected proteins by a unique mechanism, repeat-associated non-ATG (RAN) translation. In this study, we show that C9ORF72 antisense transcripts are elevated in the brains of C9ORF72 expansion-positive [C9(+)] patients, and antisense GGCCCC (G2C4) repeat-expansion RNAs accumulate in nuclear foci in brain. Additionally, sense and antisense foci accumulate in blood and are potential biomarkers of the disease. Furthermore, we show that RAN translation occurs from both sense and antisense expansion transcripts, resulting in the expression of six RAN proteins (antisense: Pro-Arg, Pro-Ala, Gly-Pro; and sense: Gly-Ala, Gly-Arg, Gly-Pro). These proteins accumulate in cytoplasmic aggregates in affected brain regions, including the frontal and motor cortex, hippocampus, and spinal cord neurons, with some brain regions showing dramatic RAN protein accumulation and clustering. The finding that unique antisense G2C4 RNA foci and three unique antisense RAN proteins accumulate in patient tissues indicates that bidirectional transcription of expanded alleles is a fundamental pathologic feature of C9ORF72 ALS/FTD. Additionally, these findings suggest the need to test therapeutic strategies that target both sense and antisense RNAs and RAN proteins in C9ORF72 ALS/FTD, and to more broadly consider the role of antisense expression and RAN translation across microsatellite expansion diseases.
A structural rationale for stalling of a replicative DNA polymerase at the most common oxidative thymine lesion, thymine glycol (2007)

Thymine glycol (Tg) is a common product of oxidation and ionizing radiation, including that used for cancer treatment. Although Tg is a poor mutagenic lesion, it has been shown to present a strong block to both repair and replicative DNA polymerases. The 2.65-A crystal structure of a binary complex of the replicative RB69 DNA polymerase with DNA shows that the templating Tg is intrahelical and forms a regular Watson-Crick base pair with the incorporated A. The C5 methyl group protrudes axially from the ring of the damaged pyrimidine and hinders stacking of the adjacent 5' template guanine. The position of the displaced 5' template guanine is such that the next incoming nucleotide cannot be incorporated into the growing primer strand, and it explains why primer extension past the lesion is prohibited even though DNA polymerases can readily incorporate an A across from the Tg lesion.
Light-emitting iridium complexes with tridentate ligands (2008)

Once the Cinderella amongst the Platinum Group Metals at the Photochemistry Ball, iridium has become of intense interest since the beginning of the decade. Complexes of iridium(III) can be prepared that are highly luminescent, with emission wavelengths tuneable over the whole of the visible region. Whilst most studies have focused on tris-bidentate complexes, a rich and varied chemistry is also possible using tridentate ligands. In this review, we discuss the synthesis and excited-state properties of such complexes, exploring in particular how the number of cyclometallating carbon atoms in the coordination sphere of the metal ion influences the luminescence. Moving from [IrN6]3+ to [IrN3X3] coordination via [IrN5X]2+ and cis/trans-[IrN4X2]+ complexes, where N is a heterocyclic nitrogen and X is an anionic ligand or cyclometallated carbon, a whole range of luminescence efficiencies are encountered, ranging from the barely detectable to room temperature quantum yields approaching unity. We consider the extent to which these profound differences, arising as a result of subtle changes in molecular structure, can be rationalised in terms of the nature of the frontier orbitals.
The renaissance of gallager's low-density parity-check codes (2003)

LDPC codes were invented in 1960 by R. Gallager. They were largely ignored until the discovery of turbo codes in 1993. Since then, LDPC codes have experienced a renaissance and are now one of the most intensely studied areas in coding. In this article we review the basic structure of LDPC codes and the iterative algorithms that are used to decode them. We also briefly consider the state of the art of LDPC design.
Adeno-associated virus (AAV) vectors: will they work? (1994)

Adeno-associated Virus (AAV) Vectors: Will They Work? Editorial Adeno-associated virus (AAV) has been a dark horse among the vector systems that are commonly considered for human gene therapy. Discovered in the middle 1960's, AAV has re- ceived relatively little attention from virologists. This was due