Miracle-dz/UniFAR-FTUs huggingface dataset:
Distinct Roles of Reactive Nitrogen and Oxygen Species To Control Infection with the Facultative Intracellular Bacterium Francisella tularensis

ABSTRACT Reactive nitrogen species (RNS) and reactive oxygen species (ROS) are important mediators of the bactericidal host response. We investigated the contribution of these two mediators to the control of infection with the facultative intracellular bacterium Francisella tularensis. When intradermally infected with the live vaccine strain F. tularensis LVS, mice deficient in production of RNS (iNOS−/− mice) or in production of ROS by the phagocyte oxidase (p47phox−/− mice) showed compromised resistance to infection. The 50% lethal dose (LD50) for iNOS−/− mice was <20 CFU, and the LD50 for p47phox−/− mice was 4,400 CFU, compared to an LD50 of >500,000 CFU for wild-type mice. The iNOS−/− mice survived for 26.4 ± 1.8 days, and the p47phox−/− mice survived for 10.1 ± 1.3 days. During the course of infection, the serum levels of gamma interferon (IFN-γ) and interleukin-6 were higher in iNOS−/− and p47phox−/− mice than in wild-type mice. Histological examination of livers of iNOS−/− mice revealed severe liver pathology. Splenocytes obtained 5 weeks after primary infection from antibiotic-treated iNOS−/− mice showed an in vitro recall response that was similar in magnitude and greater secretion of IFN-γ compared to cells obtained from wild-type mice. In summary, mice lacking expression of RNS or ROS showed extreme susceptibility to infection with F. tularensis LVS. The roles of RNS and ROS seemed to be distinct since mice deficient in production of ROS showed dissemination of infection and died during the early phase of infection, whereas RNS deficiency led to severe liver pathology and a contracted course of infection.
ROLE OF CALMODULIN IN NEUROTRANSMITTER RELEASE AND SYNAPTIC FUNCTION *

An understanding of the molecular mechanisms underlying calcium-dependent neurotransmitter release ;and other calcium-modulated synaptic functions would greatly enhance our knowledge of synaptic transmission and the action of specific neuropharmacologic agents and possibly provide new insights into human disease processes involving synaptic modulation. Although the role of calcium in synaptic function h a been of great interest, little is known about the molecular mechanisms of calcium in stimulating neurotransmitter release or its other physiological functions in the nerve terminal. It is generally accepted that many of calcium's effects on living tissue are mediated by heat-stable, calcium binding regulator proteins. Calmodulin is a major calcium receptor protein in brain and other tissues that has been well characterized and shown to affect several important enzyme systems. ' Thus, my laboratory has been investigating the possible role of calmodulin in modulating the effects of calcium or neurotransmitter releases and synaptic f u n c t i ~ n . ~ ~ In this report additional evidence is presented to further establish the role of calmodulin in neurotransmitter release and synaptic function. Calmodulin is isolated from synaptosome cytosol and highly enriched synaptic vesicle preparations. Calmodulin and calcium are demonstrated to stimulate the release of acetylcholine and norepinephrine from synaptic vesicles while simultaneously activating synaptic vesicle protein phosphorylation. Depolarization-dependent calcium uptake into synaptosomes is shown to simultaneously stimulate calmodulin modulated vesicle protein phosphorylation and release of acetylcholine and norepinephrine. Calmodulin is also shown to modulate the effects of Ca2+ on protein phosphorylation in preparations of synaptic junctional complexes and postsynaptic densities. In an attempt to investigate the mechanism of calcium and calmodulin in stimulating the release of transmitter from vesicles, a morphological study was undertaken to determine if synaptic vesicles change shape or configuration in the presence of calcium and calmodulin. The results suggest that calcium and calmodulin initiate synaptic vesicle and synaptic membrane interactions that may play a role in mediating the effects of these agents on synaptic function. The results presented in this report provide evidence that calmodulin mediates several synaptic events and are consistent with and expand the initial hypothesis from this laboratory that calmodulin plays a major role in modulating the effects of Caz+ on synaptic function and neurotransmitter
Identification of Rifampin-Resistant Mycobacterium tuberculosis Strains by Hybridization, PCR, and Ligase Detection Reaction on Oligonucleotide Microchips

ABSTRACT Three new molecular approaches were developed to identify drug-resistant strains of Mycobacterium tuberculosisusing biochips with oligonucleotides immobilized in polyacrylamide gel pads. These approaches are significantly faster than traditional bacteriological methods. All three approaches—hybridization, PCR, and ligase detection reaction—were designed to analyze an 81-bp fragment of the gene rpoB encoding the β-subunit of RNA polymerase, where most known mutations of rifampin resistance are located. The call set for hybridization analysis consisted of 42 immobilized oligonucleotides and enabled us to identify 30 mutant variants of the rpoB gene within 24 h. These variants are found in 95% of all mutants whose rifampin resistance is caused by mutations in the 81-bp fragment. Using the second approach, allele-specific on-chip PCR, it was possible to directly identify mutations in clinical samples within 1.5 h. The third approach, on-chip ligase detection reaction, was sensitive enough to reveal rifampin-resistant strains in a model mixture containing 1% of resistant and 99% of susceptible bacteria. This level of sensitivity is comparable to that from the determination of M. tuberculosis drug resistance by using standard bacteriological tests.
Gross Anatomic Organization of the Capybara's (Hydrochaeris hydrochaeris) Brachial Plexus

The innervation of the capybara thoracic limb was characterized. The following nerves were observed constituting the right and left brachial plexus: n. dorsalis scapulae (C4 and C5; C4, C5 and C6) which innervates the m. serratus ventralis cervicis and m. rhomboideus; n. suprascapularis (C4, C5 and C6; C5, C6 and C7) supplying the m. supraspinatus and the m. infraspinatus; cranial and caudal nn. subscapulares (C5 and C6; C5, C6 and C7) innervating the m. subscapularis; n. axillaris (C5 and C6; C6, C7 and C8) which supplies the m. triceps brachii (caput mediale); n. radialis (C6, C7, C8 and T1; C6, C7 and C8) which innervates the m. triceps brachii (caput longum and caput mediale) and the m. extensor carpi radialis, m. extensor digitorum communis, m. extensor digitorum lateralis; n. medianus joined to the n. musculocutaneus (C6, C7, C8 and T1; C6, C7 and C8) supplying the m. biceps brachii, m. flexor carpi radialis and m. coracobrachialis; n. ulnaris (C6, C7, C8 and T1; C6, C7 and C8) leading to the m. flexor carpi radialis, the m. flexor carpi ulnaris and the m. flexor digitorum superficialis; n. thoracodorsalis (C6, C7, C8 and T1; C6, C7 and C8) supplying the m. latissimus dorsi; n. thoracicus lateralis (C8, T1; C7, C8, T1) which innervates m. pectoralis profundus (caudal portion); n. thoracicus longus (C6, C7; C7, C8) which is distributed to the m. serratus ventralis thoracis. A communication between the n. radialis and n. ulnaris was observed at the left brachial plexus.
Static and Dynamic Cognitive Reserve Proxy Measures: Interactions with Alzheimer’s Disease Neuropathology and Cognition

Objective Years of education are the most common proxy for measuring cognitive reserve (CR) when assessing the relationship between Alzheimer’s disease (AD) neuropathology and cognition. However, years of education may be limited as a CR proxy given that it represents a specific timeframe in early life and is static. Studies suggest that measures of intellectual function provide a dynamic estimate of CR that is superior to years of education since it captures the effect of continued learning over time. The present study determined whether dynamic measures of CR were better predictors of episodic memory and executive function in the presence of AD pathology than a static measure of CR. Methods Subjects examined died with a pre-mortem clinical diagnosis of no cognitive impaired, mild cognitive impairment and mild to moderate AD. CERAD and Braak stage were used to stratify the sample by AD pathology severity. Linear regression analyses using CR by CERAD and CR by Braak stage interaction terms were used to determine whether Extended Range Vocabulary Test (ERVT) scores or years of education were significantly associated with episodic memory composite (EMC) and executive function composite (EFC) performance. All models were adjusted for clinical diagnosis, age at death, gender, APOE e4 carrier status and Braak stage. Results For episodic memory, years of education by CERAD interaction were not statistically significant (β=-0.01, SE=0.01, p=0.53). By contrast, ERVT interaction with CERAD diagnosis was statistically significant (β=-0.03, SE=0.01, p=0.004). Among the models using Braak stages, none of the CR by pathology interactions were associated with EMC or EFC. Conclusion Results suggest that a dynamic rather than a static measure is a better indicator of CR and that the relationship between CR and cognition is dependent upon the severity of select AD criteria.
Nuclear Translocation of Mismatch Repair Proteins MSH2 and MSH6 as a Response of Cells to Alkylating Agents*

Mammalian mismatch repair has been implicated in mismatch correction, the prevention of mutagenesis and cancer, and the induction of genotoxicity and apoptosis. Here, we show that treatment of cells specifically with agents inducing O6-methylguanine in DNA, such asN-methyl-N′-nitro-N-nitrosoguanidine and N-methyl-N-nitrosourea, elevates the level of MSH2 and MSH6 and increases GT mismatch binding activity in the nucleus. This inducible response occurs immediately after alkylation, is long-lasting and dose-dependent, and results from translocation of the preformed MutSα complex (composed of MSH2 and MSH6) from the cytoplasm into the nucleus. It is not caused by an increase in MSH2 gene activity. Cells expressing the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), thus having the ability to repair O6-methylguanine, showed no translocation of MutSα, whereas inhibition of MGMT by O6-benzylguanine provoked the translocation. The results demonstrate that O6-methylguanine lesions are involved in triggering nuclear accumulation of MSH2 and MSH6. The finding that treatment of cells with O6-methylguanine-generating mutagens results in an increase of MutSα and GT binding activity in the nucleus indicates a novel type of genotoxic stress response.
Autoantibodies Other than Antineutrophil Cytoplasmic Antibodies Are Not Positive in Patients with Psoriasis Vulgaris

There is a great deal of evidences that a link may exist between psoriasis and autoimmunity. In this study, thirty‐six patients with psoriasis vulgaris and twenty healthy controls were screened for antinuclear antibody (ANA), anti‐ds‐DNA antibodies, anti‐SSA (anti‐Ro), anti‐SSB (anti‐La), anti‐Scl‐70, anti‐Jo‐1, rheumatoid factor (RF), C3 and C4 levels, IgG and IgM anti‐cardiolipin antibodies (aCL) and anti‐neutrophil cytoplasmic antibodies (pANCA and cANCA) in order to determine the role of autoimmunity in the pathogenesis. In addition, the MPO‐ANCA test was performed on pANCA‐positive patients. In ANA screening, one patient showed 1/80 granular positivity. No positive results were obtained from either the study or control groups for anti‐dsDNA, anti‐SSA, anti‐SSB, anti‐Scl‐70, or anti‐Jo‐1 determinations. For RF, 5.8% of the patients had positive values. Both C3 and C4 levels were found to be significantly elevated in psoriasis patients compared to healthy controls (p<0.001). IgG‐aCL and IgM‐aCL positivity was not significantly different between the two group. pANCA was positive in 33.3% of the patients and a significant difference was observed between study and control groups (p<0.05). MPO‐ANCA was negative in all the pANCA‐positive patients. In conclusion, only serum C3 and C4 levels and pANCA determinations showed significant differences when compared to healthy controls. Our findings may be evidence of associations between autoimmunity and psoriasis vulgaris. However, more detailed studies in this field need to be done to determine the relationship between them.
Escaping Damocles' Sword: Endogenous Climate Shocks in a Growing Economy

Climate economics has been criticized for ignoring uncertainty, catastrophic changes, and tipping points (Stern 2016). The present paper addresses these issues. We consider multiple climate shocks which are recurring, random, uninsurable, and potentially large. The associated damages and the hazard rate are endogenously driven by the stock of greenhouse gases. We provide closed-form solutions for the optimal climate policy and the growth rate of the economy. The optimal path is characterized by a constant growth rate of consumption and of the capital stock until a shock arrives, triggering a downward jump in both variables. The mitigation policy consists of a simple and intuitive rule which requires spending a constant fraction of output on emissions abatement. In a quantitative assessment we show that under favorable conditions the abatement expenditure represents 0.5% of output, equivalent to $37 per ton carbon. Under less favorable conditions with respect to abatement technology and damages, coupled with a relative risk aversion which exceeds unity, the abatement propensity increases to 2.9%, equivalent to $212 per ton carbon, and it jumps to a striking 10% in the pessimistic scenario involving severe shocks and a possible crossing of a tipping point.
Computational modelling of anti-angiogenic therapies based on multiparametric molecular imaging data

Computational tumour models have emerged as powerful tools for the optimization of cancer therapies; ideally, these models should incorporate patient-specific imaging data indicative of therapeutic response. The purpose of this study was to develop a tumour modelling framework in order to simulate the therapeutic effects of anti-angiogenic agents based upon clinical molecular imaging data. The model was applied to positron emission tomography (PET) data of cellular proliferation and hypoxia from a phase I clinical trial of bevacizumab, an antibody that neutralizes the vascular endothelial growth factor (VEGF). When using pre-therapy PET data in combination with literature-based dose response parameters, simulated follow-up hypoxia data yielded good qualitative agreement with imaged hypoxia levels. Improving the quantitative agreement with follow-up hypoxia and proliferation PET data required tuning of the maximum vascular growth fraction (VGFmax) and the tumour cell cycle time to patient-specific values. VGFmax was found to be the most sensitive model parameter (CV = 22%). Assuming availability of patient-specific, intratumoural VEGF levels, we show how bevacizumab dose levels can potentially be ‘tailored’ to improve levels of tumour hypoxia while maintaining proliferative response, both of which are critically important in the context of combination therapy. Our results suggest that, upon further validation, the application of image-driven computational models may afford opportunities to optimize dosing regimens and combination therapies in a patient-specific manner.
A Literature Review on Institutional Environment and Technological Innovation

This article is a literature review on institutional environment and technology innovation. The author discusses the origin and classification of the institutional environment, has a through understanding of the institutional environment, and examines studies about institutional environment and technology innovation from different perspectives to reach some constructive suggestions to better promote technology innovation.
Estimating the scale of profit shifting and tax revenue losses related to foreign direct investment

Governments’ revenues are lower when multinational enterprises avoid paying corporate income tax by shifting their profits to tax havens. In this paper, we ask which countries’ tax revenues are affected most by this tax avoidance and how much. To estimate the scale of profit shifting, we begin by observing that the higher the share of foreign direct investment from tax havens, the lower the reported rate of return on this investment. Similarly to the United Nations Conference on Trade and Development’s World Investment Report 2015, we argue that the reported rate of return is lower due to profit shifting. Unlike the report, however, we provide illustrative country-level estimates of profit shifting for as many countries as possible, including low-income ones, which enables us to study the distributional effects of international corporate tax avoidance. We compare estimated corporate tax revenue losses, relative to their GDP and tax revenues, of country groups classified by income per capita and we find that there are almost no statistically significant differences across these groups. Furthermore, we compare our results with four other recent studies that use different methodologies to estimate tax revenue losses due to profit shifting. In the first such comparison made, we find that most studies identify some differences across income groups, but the nature of these differences varies across the studies.
Glucose disposal in obese non-diabetic and diabetic type II patients. A study by indirect calorimetry and euglycemic insulin clamp.

Insulin resistance is a characteristic finding in obesity and in non insulin dependent (Type II) diabetes mellitus. However, the interaction between diabetes and obesity has been poorly characterized and the metabolic disturbances contributing to the defect in insulin-mediated glucose uptake have not been defined. To examine these questions euglycemic and hyperinsulinemic clamp studies (40 mU/m2/min) were performed in 10 control non-obese subjects, 10 non diabetic obese subjects, 8 normal weight Type II diabetics, and 12 obese Type II diabetics. During the insulin clamp study total body glucose uptake in the obese non diabetics (157 +/- 18 mg/m2.min, p less than 0.01), the normal weight diabetics (159 +/- 21, p less than 0.01) and the obese diabetics (125 +/- 11, p less than 0.001) was significantly reduced compared to the non-obese non diabetic control group (249 +/- 22 mg/m2.min). The impairment in total body glucose uptake was the result mainly of a defect in non-oxidative glucose disposal. Indeed non-oxidative glucose disposal was blunted by 50% in the obese groups (p less than 0.01), somewhat less significantly in the non-obese diabetic group (p less than 0.05) but more when obesity and diabetes mellitus were combined (p less than 0.001). Total glucose oxidation was significantly diminished (p less than 0.01) in both diabetic groups but not in the obese non diabetic group when compared to lean control. A significant inverse correlation between the fasting free fatty acids levels and total glucose uptake (r = -0.453, p less than 0.001) and total glucose oxidation (r = -0.446, p less than 0.001) during the clamp was observed. (ABSTRACT TRUNCATED AT 250 WORDS)
The Effect of the Botulinum Toxin-A on Craniofacial Development: An Experimental Study

In this study, we developed a novel experimental model to evaluate muscular action on bone formation and remodeling by the help of Botulinum toxin-A (BTX). Forty-nine 15-day-old male Wistar rats were put into 4 groups randomly. Group 1 was the control group. BTX 0.4 IU (0.05 mL) was injected into the right masseter muscle in group 2 and into right temporalis muscle in group 3. The same volume of sterile saline was given into the both above-mentioned muscles in group 4. At the end of the fourth month, all animals were killed. Histology and weight of the masseter and temporalis muscles were studied. Thirty different osteometric measurements were also taken from skulls.Significant atrophy in BTX injected muscles was observed in groups 2 and 3. In group 4 (saline injection), only few osteometric measurements were significantly reduced, indicating the effect of the injection itself. Both groups 2 and 3 have apparent decrease in nasal bone, premaxilla, maxilla, and zygomatic dimensions on the injected side. When masseter group was compared with control and saline groups, no significant difference was found in skull base dimensions and mandibular length. In contrast, temporal group has also shown significant decrease in skull base dimensions.Our conclusions are as follows: (1) With this model, it is possible to study muscular action on bone formation and modeling without any surgical intervention, that is, by avoiding surgical artifacts, such as scar and contracture; (2) denervation of the skeletal muscles with BTX during the growing phase does effect bone development in a negative way; (3) pediatric use of the BTX deserves reevaluation under the light of these findings.
Orphan nuclear receptor NR4A2 induces synoviocyte proliferation, invasion, and matrix metalloproteinase 13 transcription.

OBJECTIVE To address the role of the nuclear receptor 4A (NR4A) family of orphan nuclear receptors in synoviocyte transformation, hyperplasia, and regulation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in models of inflammatory arthritis. METHODS NR4A messenger RNA levels in synovial tissue and primary synoviocytes were measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR). NR4A2 was stably overexpressed in normal synoviocytes, and cell proliferation, survival, anchorage-independent growth, migration, and invasion were monitored in vitro. MMP and TIMP expression levels were analyzed by quantitative RT-PCR, and MMP-13 promoter activity was measured using reporter assays. Stable depletion of endogenous NR4A levels was achieved by lentiviral transduction of NR4A short hairpin RNA (shRNA), and the effects on proliferation, migration, and MMP-13 expression were analyzed. RESULTS NR4A2 was expressed at elevated levels in normal, OA, and RA synovial tissue and in primary RA synoviocytes. Tumor necrosis factor α (TNFα) rapidly and selectively induced expression of NR4A2 in synoviocytes. Ectopic expression of NR4A2 in normal synoviocytes significantly increased proliferation and survival, promoted anchorage-independent growth, and induced migration and invasion. MMP-13 gene expression was synergistically induced by NR4A2 and TNFα, while expression of TIMP-2 was antagonized. NR4A2 directly transactivated the proximal MMP-13 promoter, and a point mutation in the DNA binding domain of NR4A2 abolished transcriptional activation. Depletion of endogenous NR4A receptors with shRNA reduced synoviocyte proliferation, migration, and MMP-13 expression. CONCLUSION The orphan nuclear receptor NR4A2 is a downstream mediator of TNFα signaling in synovial tissue. NR4A2 transcriptional activity contributes to the hyperplastic and invasive phenotype of synoviocytes that leads to cartilage destruction, suggesting that this receptor may show promise as a therapeutic target in inflammatory arthritis.