Miracle-dz/UniFAR-FTUs huggingface dataset:
Upregulation of GLT‐1 by treatment with ceftriaxone alleviates radicular pain by reducing spinal astrocyte activation and neuronal hyperexcitability

Cervical nerve root injury commonly leads to radicular pain. Normal sensation relies on regulation of extracellular glutamate in the spinal cord by glutamate transporters. The goal of this study was to define the temporal response of spinal glutamate transporters (glial glutamate transporter 1 [GLT‐1], glutamate‐aspartate transporter [GLAST], and excitatory amino acid carrier 1) following nerve root compressions that do or do not produce sensitivity in the rat and to evaluate the role of glutamate uptake in radicular pain by using ceftriaxone to upregulate GLT‐1. Compression was applied to the C7 nerve root. Spinal glutamate transporter expression was evaluated at days 1 and 7. In a separate study, rats underwent a painful root compression and were treated with ceftriaxone or the vehicle saline. Glial glutamate transporter expression, astrocytic activation (glial fibrillary acidic protein [GFAP]), and neuronal excitability were assessed at day 7. Both studies measured behavioral sensitivity for 7 days after injury. Spinal GLT‐1 significantly decreased (P < 0.04) and spinal GLAST significantly increased (P = 0.036) at day 7 after a root injury that also produced sensitivity to both mechanical and thermal stimuli. Within 1 day after ceftriaxone treatment (day 2), mechanical allodynia began to decrease; both mechanical allodynia and thermal hyperalgesia were attenuated (P < 0.006) by day 7. Ceftriaxone also reduced (P < 0.024) spinal GFAP and GLAST expression, and neuronal hyperexcitability in the spinal dorsal horn, restoring the proportion of spinal neurons classified as wide dynamic range to that of normal. These findings suggest that nerve root‐mediated pain is maintained jointly by spinal astrocytic reactivity and neuronal hyperexcitability and that these spinal modifications are associated with reduced glutamate uptake by GLT‐1. © 2013 Wiley Periodicals, Inc.
Toll-Like Receptor 2 Signaling in Response to Brain Injury: An Innate Bridge to Neuroinflammation

Reactive gliosis is a prominent feature of neurodegenerative and neuroinflammatory disease in the CNS, yet the stimuli that drive this response are not known. There is growing appreciation that signaling through Toll-like receptors (TLRs), which is key to generating innate responses to infection, may have pathogen-independent roles. We show that TLR2 was selectively upregulated by microglia in the denervated zones of the hippocampus in response to stereotactic transection of axons in the entorhinal cortex. In mice lacking TLR2, there were transient, selective reductions in lesion-induced expression of cytokines and chemokines. Recruitment of T cells, but not macrophages, was delayed in TLR2-deficient mice, as well as in mice lacking TNFR1 (tumor necrosis factor receptor 1). TLR2 deficiency also affected microglial proliferative expansion, whereas all of these events were unaffected in TLR4-mutant mice. Consistent with the fact that responses in knock-out mice had all returned to wild-type levels by 8 d, there was no evidence for effects on neuronal plasticity at 20 d. These results identify a role for TLR2 signaling in the early glial response to brain injury, acting as an innate bridge to neuroinflammation.
The “Shoulds” and “Should Nots” of Moral Emotions: A Self-Regulatory Perspective on Shame and Guilt

A self-regulatory framework for distinguishing between shame and guilt was tested in three studies. Recently, two forms of moral regulation based on approach versus avoidance motivation have been proposed in the literature. Proscriptive regulation is sensitive to negative outcomes, inhibition based, and focused on what we should not do. Prescriptive regulation is sensitive to positive outcomes, activation based, and focused on what we should do. In the current research, consistent support was found for shame’s proscriptive and guilt’s prescriptive moral underpinnings. Study 1 found a positive association between avoidance orientation and shame proneness and between approach orientation and guilt proneness. In Study 2, priming a proscriptive orientation increased shame and priming a prescriptive orientation increased guilt. In Study 3, transgressions most apt to represent proscriptive and prescriptive violations predicted subsequent judgments of shame and guilt, respectively. This self-regulatory perspective provides a broad interpretive framework for understanding and extending past research findings.
Platelet-activating factor acetylhydrolase and transacetylase activities in human aorta and mammary artery

Platelet-activating factor (PAF), the potent phospholipid mediator of inflammation, is involved in atherosclerosis. Platelet-activating factor-acetylhydrolase (PAF-AH), the enzyme that inactivates PAF bioactivity, possesses both acetylhydrolase and transacetylase activities. In the present study, we measured acetylhydrolase and transacetylase activities in human atherogenic aorta and nonatherogenic mammary arteries. Immunohistochemistry analysis showed PAF-AH expression in the intima and the media of the aorta and in the media of mammary arteries. Acetylhydrolase and transacetylase activities were (mean ± SE, n = 38): acetylhydrolase of aorta, 2.8 ± 0.5 pmol/min/mg of tissue; transacetylase of aorta, 3.3 ± 0.7 pmol/min/mg of tissue; acetylhydrolase of mammary artery, 1.4 ± 0.3 pmol/min/mg of tissue (P < 0.004 as compared with acetylhydrolase of aorta); transacetylase of mammary artery, 0.8 ± 0.2 pmol/min/mg of tissue (P < 0.03 as compared with acetylhydrolase of mammary artery). Lyso-PAF accumulation and an increase in PAF bioactivity were observed in the aorta of some patients. Reverse-phase HPLC and electrospray ionization mass spectrometry analysis revealed that 1-O-hexadecyl-2 acetyl-sn glycero-3-phosphocholine accounted for 60% of the PAF bioactivity and 1-O-hexadecyl-2-butanoyl-sn-glycerol-3-phosphocholine for 40% of the PAF bioactivity. The nonatherogenic properties of mammary arteries may in part be due to low PAF formation regulated by PAF-AH activity. In atherogenic aortas, an imbalance between PAF-AH and transacetylase activity, as well as lyso-PAF accumulation, may lead to unregulated PAF formation and to progression of atherosclerosis.
Labelling and imaging of single endogenous messenger RNA particles in vivo

ABSTRACT RNA molecules carry out widely diverse functions in numerous different physiological processes in living cells. The RNA life cycle from transcription, through the processing of nascent RNA, to the regulatory function of non-coding RNA and cytoplasmic translation of messenger RNA has been studied extensively using biochemical and molecular biology techniques. In this Commentary, we highlight how single molecule imaging and particle tracking can yield further insight into the dynamics of RNA particles in living cells. In the past few years, a variety of bright and photo-stable labelling techniques have been developed to generate sufficient contrast for imaging of single endogenous RNAs in vivo. New imaging modalities allow determination of not only lateral but also axial positions with high precision within the cellular context, and across a wide range of specimen from yeast and bacteria to cultured cells, and even multicellular organisms or live animals. A whole range of methods to locate and track single particles, and to analyze trajectory data are available to yield detailed information about the kinetics of all parts of the RNA life cycle. Although the concepts presented are applicable to all types of RNA, we showcase here the wealth of information gained from in vivo imaging of single particles by discussing studies investigating dynamics of intranuclear trafficking, nuclear pore transport and cytoplasmic transport of endogenous messenger RNA. Summary: The principal experimental and analytical requirements to visualize and trace single endogenous mRNA particles in living cells are discussed, and the most recent quantitative results are highlighted.
Asset Pricing: A Tale of Two Days

We show that asset prices behave very differently on days when important macroeconomic news is scheduled for announcement. In addition to significantly higher average returns for risky assets on announcement days, return patterns are much easier to reconcile with standard asset pricing theories, both cross-sectionally and over time. On such days, stock market beta is strongly related to average returns. This positive relation holds for individual stocks, for various test portfolios, and even for bonds and currencies, suggesting that beta is after all an important measure of systematic risk. Furthermore, a robust risk–return trade-off exists on announcement days. Expected variance is positively related to future aggregated quarterly announcement day returns, but not to aggregated non-announcement day returns. We explore the implications of our findings in the context of various asset pricing models.
Barcoding aphids (Hemiptera: Aphididae) of the Korean Peninsula: updating the global data set

DNA barcode (mitochondrial COI) sequences are provided for species identification of aphids from the Korean Peninsula. Most (98%) of the 154 species had distinct COI sequences (average 0.05% intraspecific pairwise divergence) relative to the degree of sequence divergence among species (average value 5.84%). For species in common with other regions, barcodes for Korean samples fell near or within known levels of variation. Based on these results, we conclude that DNA barcodes can provide an effective tool for identifying aphid species in such applications as pest management, monitoring and plant quarantine.
Biosynthesis of an Endogenous Cannabinoid Precursor in Neurons and its Control by Calcium and cAMP

Understanding the mechanisms involved in the biogenesis ofN-arachidonoylethanolamine (anandamide) andNpalmitoylethanolamine is important in view of the possible role of these lipids as endogenous cannabinoid substances. Anandamide (which activates cannabinoid CB1 receptors) andN-palmitoylethanolamine (which activates a CB2-like receptor subtype in mast cells) may both derive from cleavage of precursor phospholipid, N-acylphosphatidylethanolamine (NAPE), catalyzed by Ca2+-activated D-type phosphodiesterase activity. We report here that the de novobiosynthesis of NAPE is enhanced in a Ca2+-dependent manner when rat cortical neurons are stimulated with the Ca2+-ionophore ionomycin or with membrane-depolarizing agents such as veratridine and kainate. This reaction is likely to be mediated by a neuronalN-acyltransferase activity, which catalyzes the transfer of an acyl group from phosphatidylcholine to the ethanolamine moiety of phosphatidylethanolamine. In addition, we show that Ca2+-dependent NAPE biosynthesis is potentiated by agents that increase cAMP levels, including forskolin and vasoactive intestinal peptide. Our results thus indicate that NAPE levels in cortical neurons are controlled by Ca2+ ions and cAMP. Such regulatory effect may participate in maintaining a supply of cannabimimetic N-acylethanolamines during synaptic activity, and prime target neurons for release of these bioactive lipids.
Neuroinflammatory regulation of stress behavior and physiology

Neuropsychiatric diseases represent a major public health burden worldwide; due to gaps in our understanding of the pathogenic mechanisms of disease, approximately 30% of patients are refractory to treatment. Activation of neuroinflammatory signaling cascades has shown promise as a contributing factor for disease development. This hypothesis is driven in part by an intriguing overlap of symptoms in patients with neuropsychiatric and immunological disorders. Patients with depression, bipolar disorder, schizophrenia, and autism commonly present with immune dysfunction, while patients with multiple sclerosis, lupus, and rheumatoid arthritis often experience severe mood disturbances. Diversity in presentation of symptoms, however, has posed a research challenge to our mechanistic understanding of this link. In contrast to the complexity of modeling specific diseases, altered sensitivity to stress is a well-documented vulnerability marker across neuropsychiatric disorders. Of relevance to clinical advancement, aspects of stress behavior and physiology can be modeled and measured in animals, where core components of the stress axis are conserved in humans and rodents. Thus, we performed an examination of the neuroinflammatory regulation of stress behavior and physiology. Using a genetic model of stress sensitivity, we report the discovery that antiinflammatory treatment ameliorates hypothalamic-pituitary-adrenal axis dysregulation, identifying the dorsal raphe (DR) as a locus of heightened responsivity. We then demonstrated sex differences in this brain region in response to the stress neuropeptide, corticotropin-releasing factor, suggesting that differences in its responsivity may underlie sex differences in vulnerability to stress-related disorders. Finally, we used a transgenic approach to show that neuroinflammation localized specifically to the DR results in dysregulated stress behavior and physiology through interactions with the serotonergic neurotransmitter system. Overall, this work demonstrates that hyperor hypo-function of the DR, based on genetic susceptibility, sex, or neuroinflammatory insult, can result in altered stress physiology and behavior. Though the DR has previously been identified as a potential locus of dysregulation, here we establish the specific, mechanistic link between risk factors for stress-related disorders. We present evidence of quantitative changes to this brain region and its functional output, and demonstrate that differences in responsivity of the DR may underlie vulnerability to stress-related disorders. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Neuroscience First Advisor Tracy L. Bale
Mean Platelet Volume, Platelet Distribution Width, and Platelet Count in Varicocele: A Systematic Review and Meta-Analysis

Background/Aims: The aim of this study was to elucidate the usefulness of platelet indices, mean platelet volume (MPV), platelet distribution width (PDW), and platelet count in diagnosis and monitoring of varicocele. Methods: The current study included 525 patients and 379 healthy subjects from five eligible studies. We performed meta-analysis of MPV, PDW, and platelet count and mean differences in these platelet indices between healthy subjects and varicocele patients. Results: The pooled MPVs were 8.168 fL (95% confidence interval [CI] 7.589 to 8.747) and 8.801 fL (95% CI 8.028 to 9.574) in healthy subjects and varicocele patients, respectively. The pooled mean difference in MPV between healthy subjects and varicocele patients was 0.834 fL in case-control studies (95% CI 0.195 to 1.473, P = 0.011). In both healthy subjects and varicocele patients, low platelet count subgroups showed higher MPV than high platelet count subgroups. The mean difference in MPV was higher in low platelet count subgroup. There was no significant difference in PDW between healthy subjects and varicocele patients. Conclusion: Taken together, our data showed that platelet count was significantly lower in varicocele patients than in healthy subjects. Varicocele patients showed significantly higher MPV and lower platelet count than healthy subjects. MPV levels of patients differed according to platelet counts.
SLAT/Def6 Plays a Critical Role in the Development of Th17 Cell-Mediated Experimental Autoimmune Encephalomyelitis1

SWAP-70-like adapter of T cells (SLAT; also known as Def6) is a novel guanine nucleotide exchange factor for Rho GTPases that has been previously shown to play a role in CD4+ T cell activation and Th1/Th2 differentiation. However, the role of SLAT/Def6 in autoimmunity and its associated Th1- and Th17-specific responses has not yet been clearly elucidated. We used a prototypical and pathologically relevant Th1/Th17-mediated autoimmune model, that is, experimental autoimmune encephalomyelitis, to assess the role of SLAT/Def6 in autoantigen-specific T cell response. We found that T cell-expressed SLAT/Def6 was critical for experimental autoimmune encephalomyelitis development and pathogenesis, as evidenced by the resistance of Def6-deficient (Def6−/−) mice to clinical signs of the disease associated with a lack of CNS inflammation and demyelination in myelin oligodendrocyte glycoprotein-immunized Def6−/− mice. Moreover, Def6 deficiency resulted in a severely diminished myelin oligodendrocyte glycoprotein-specific CD4+ T cell proliferation as well as a defect in IFN-γ and IL-17 production in secondary lymphoid organs and the CNS. Lastly, Def6−/− CD4+ T cells were grossly deficient in their ability to differentiate into Th17 cells both in vitro and in vivo in a T cell-intrinsic manner. Therefore, our study establishes T cell-expressed SLAT/Def6 as a pivotal positive regulator of Th17 inflammatory responses and, thus, essential in controlling autoimmune and inflammatory diseases.
Heidegger and the Aesthetics of Rhetoric

This article uses Heidegger’s critique of the aesthetic tradition to reconsider the limits and potential of aesthetic rhetoric. Contextualizing rhetoric’s so-called aesthetic turn within the German aesthetic tradition, we argue that aesthetic rhetoric remains constrained by aesthetics’ traditional opposition to the rational and the true. This theoretical heritage has often prevented contemporary aesthetic rhetorical theory from considering the value of art beyond sense experience and ritualized cultural reproduction. We claim, however, that rhetoric can be artistic and at the same time project a community’s evolving sense of political and social truth. Through an analysis of Simón Bolívar’s Angostura Address, which in 1819 inaugurated a political rebirth of the Venezuelan republic, we demonstrate how the art of rhetoric can exhibit Heidegger’s three senses of “aletheiaic” truth: the bestowing, grounding, and beginning of a political community.
Efficacy and safety of the selective co-stimulation modulator abatacept following 2 years of treatment in patients with rheumatoid arthritis and an inadequate response to anti-tumour necrosis factor therapy

Objective: To evaluate the safety and efficacy of abatacept during 2 years of the ATTAIN (Abatacept Trial in Treatment of Anti-TNF INadequate responders) trial in patients with rheumatoid arthritis. Methods: Patients completing the 6-month, double-blind period were eligible to enter the long-term extension; patients received abatacept ∼10 mg/kg, plus disease-modifying antirheumatic drugs. Safety and efficacy (American College of Rheumatology (ACR) criteria responses, DAS28 (C-reactive protein), HAQ-DI, SF-36, Medical Outcomes Study Sleep Problems Index, fatigue VAS) were assessed through 2 years. Results: 317 patients (218 from the abatacept and 99 from the placebo group) entered and 222 (70%) completed 18 months of long-term extension treatment. The incidence and type of adverse events were consistent between the double-blind and cumulative (double-blind plus long-term extension) periods. Rates of serious adverse events were 25.6 and 23.4 per 100 patient-years in the double-blind versus cumulative period. At 6 months and 2 years, using non-responder analyses, ACR responses in abatacept-treated patients were: ACR 20, 59.4% and 56.2%; ACR 50, 23.5% and 33.2%; ACR 70, 11.5% and 16.1%; HAQ-DI responses were 54.4% and 47.9%. At 6 months and 2 years, using post-hoc as-observed analyses, the percentage of patients (95% confidence interval) achieving DAS28 (C-reactive protein) low disease activity score (⩽3.2) and DAS28 (C-reactive protein)-defined remission (<2.6) increased from 18.3% (13.0, 23.5) to 32.0% (24.6, 39.4) and 11.1% (6.8, 15.3) to 20.3% (13.9, 26.6). Clinically meaningful improvements in SF-36, pain, fatigue and sleep problems were also maintained throughout the 2 years of abatacept treatment. Conclusion: No unique safety observations were reported during open-label exposure. Improvements in the signs and symptoms of rheumatoid arthritis, physical function and health-related quality of life observed after 6 months, were maintained throughout the 2 years in this population with difficult-to-treat disease. Trial registration number: NCT00124982.
Target optimization studies for surface muon production

The current paper discusses possible designs for a stand alone muon target for MuSR studies of condensed matter science. Considering the ISIS 7 mm graphite target as a reference, Geant4 simulations have been performed in order to optimize the target parameters with respect to muon and pion yield. Previous studies suggested that the muon production can be optimized by using a thin graphite slab target with an incident proton energy significantly lower than initially considered. Surface muon production obtained by firing an 800 MeV proton beam energy onto the target is simulated and potential improvements to the target material, geometry and angle orientation with respect to the incoming proton beam as well as an estimated performance of the muon target are presented in this paper. Implications for the ISIS muon facility are also discussed. A comparison of the pion production cross section between experimental data and three theoretical models for the latest four Geant4 versions is also included in this paper.
Mutations in 5-methylcytosine oxidase TET2 and RhoA cooperatively disrupt T cell homeostasis

Angioimmunoblastic T cell lymphoma (AITL) represents a distinct, aggressive form of peripheral T cell lymphoma with a dismal prognosis. Recent exome sequencing in patients with AITL has revealed the frequent coexistence of somatic mutations in the Rho GTPase RhoA (RhoAG17V) and loss-of-function mutations in the 5-methylcytosine oxidase TET2. Here, we have demonstrated that TET2 loss and RhoAG17V expression in mature murine T cells cooperatively cause abnormal CD4+ T cell proliferation and differentiation by perturbing FoxO1 gene expression, phosphorylation, and subcellular localization, an abnormality that is also detected in human primary AITL tumor samples. Reexpression of FoxO1 attenuated aberrant immune responses induced in mouse models adoptively transferred with T cells and bearing genetic lesions in both TET2 and RhoA. Our findings suggest a mutational cooperativity between epigenetic factors and GTPases in adult CD4+ T cells that may account for immunoinflammatory responses associated with AITL patients.