Miracle-dz/UniFAR-FTUs huggingface dataset:
Challenges and controversies in the diagnosis of malignant mesothelioma: Part 2. Malignant mesothelioma subtypes, pleural synovial sarcoma, molecular and prognostic aspects of mesothelioma, BAP1, aquaporin-1 and microRNA

Pleural malignant mesothelioma (MM) includes several unusual and even rare but distinctive histological subtypes, in addition to the usual subdivision into epithelioid, biphasic and sarcomatoid MM. Criteria for discrimination between fibrous pleuritis versus desmoplastic mesothelioma include evidence of neoplastic invasion for diagnosis of desmoplastic MM, but this histological assessment is complicated by the recently-described ‘fake fat phenomenon’ in cases of fibrous pleuritis. The distinction between biphasic and monophasic synovial sarcoma of the pleura versus biphasic and sarcomatoid MM can be problematical and is most cogently based upon molecular detection of the t(X;18) translocation, whereas a clear diagnosis of MM for a pleural tumour histologically resembling synovial sarcoma is favoured by a negative result for this translocation and, probably, microRNA evidence supportive of a diagnosis of MM. Aquaporin-1 (AQP1) is a molecule involved in the growth of MM cells, and yet is a factor reported to correlate with improved survival rates for MM with an epithelioid component, in comparison to AQP1-poor MM, as assessed from AQP1 expression by epithelioid MM cells only (apart from co-expression by stromal endothelial cells in addition to the tumour cells). Recent reports have also focused upon germline mutations in the BRCA1-associated protein 1 (BAP1), not only in cases of familial mesothelioma, but also BAP1 deletion in sporadic MM. Prognostic factors for MM include not only the histological subtypes, but other independent variables that include (among others), AQP1 expression by mesothelioma cells, the clinical status of the patient, the serum neutrophil:lymphocyte ratio and blood thrombocytosis.
Universities, NGOs, and civil society sustainability: preliminary lessons from Ecuador

ABSTRACT The context for NGOs in the Global South – delegitimising discourse, restrictive policies, and decreasing international funding – leads to major concerns about the sustainability of organised civil society. As a result, NGOs are exploring new means to contribute to social development. This article explores developing university–NGO collaborations through the case of Ecuador. It contributes to development research on two fronts. First, it examines the role of the university in the South and their collaborations with NGOs. Second, it situates university–NGO collaborations within concerns about civil society sustainability. The article presents lessons learnt by Ecuadorian NGOs.
Receptor binding, behavioral, and electrophysiological profiles of nonpeptide corticotropin-releasing factor subtype 1 receptor antagonists CRA1000 and CRA1001.

Receptor binding, behavioral, and electrophysiological profiles of 2-[N-(2-methylthio-4-isopropylphenyl)-N-ethylamino]-4-[4-(3-flu orophe nyl)-1,2,3,6-tetrahydropyridin-1-yl)-6-methylpyrimidine (CRA1000) and 2-[N-(2-bromo-4-isopropylphenyl)-N-ethylamino]-4-[4-(3-fluoropheny l)- 1,2,3,6-tetrahydropyridin-1-yl)-6-methylpyrimidine (CRA1001), putative novel and selective antagonists for corticotropin-releasing factor1 (CRF1) receptor were examined. Both CRA1000 and CRA1001 inhibited 125I-ovine CRF binding to membranes of rat frontal cortex with IC50 values of 20.6 and 22.3 nM, respectively. Likewise, CRA1000 and CRA1001 inhibited 125I-ovine CRF binding to membranes of rat pituitary. In contrast, both CRA1000 and CRA1001 were without affinity for the CRF2beta receptor when examined using rat heart. In mice orally administered CRA1000 and CRA1001 reversed the swim stress-induced reduction of the time spent in the light area in the light/dark exploration task. In nonstress conditions, CRA1000 and CRA1001 were without effect on the time spent in the light area in the same task in mice. Orally administered CRA1000 and CRA1001 dose dependently reversed the effects of i.c. v. infusion of CRF on time spent in the open arms in the elevated plus-maze in rats. Lesioning of olfactory bulbs induced hyperemotionality, and this effect was inhibited by either acute or chronic oral administration of CRA1000 and CRA1001 in rats. The firing rate of locus coeruleus neurons was increased by i.c. v. -infused CRF. This excitation of locus coeruleus neurons was significantly blocked by pretreatment with i.v. administration of CRA1000 and CRA1001. CRA1000 and CRA1001 had no effects on the hexobarbital-induced anesthesia in mice, the rotarod test in mice, the spontaneous locomotor activity in mice, and a passive avoidance task in rats. These observations indicate that both CRA1000 and CRA1001 are selective and competitive CRF1 receptor antagonists with potent anxiolytic- and antidepressant-like properties in various experimental animal models, perhaps through inhibition of CRF1 receptors. CRA1000 and CRA1001 may prove effective for treating subjects with depression- and/or anxiety-related disorders without the side effects seen in the related currently prescribed medications.
Cytoskeleton in action: lissencephaly, a neuronal migration disorder

During neocortical development, the extensive migratory movements of neurons from their place of birth to their final location are essential for the coordinated wiring of synaptic circuits and proper neurological function. Failure or delay in neuronal migration causes severe abnormalities in cortical layering, which consequently results in human lissencephaly (‘smooth brain’), a neuronal migration disorder. The brains of lissencephaly patients have less‐convoluted gyri in the cerebral cortex with impaired cortical lamination of neurons. Since microtubule (MT) and actin‐associated proteins play important functions in regulating the dynamics of MT and actin cytoskeletons during neuronal migration, genetic mutations or deletions of crucial genes involved in cytoskeletal processes lead to lissencephaly in human and neuronal migration defects in mouse. During neuronal migration, MT organization and transport are controlled by platelet‐activating factor acetylhydrolase isoform 1b regulatory subunit 1 (PAFAH1B1, formerly known as LIS1, Lissencephaly‐1), doublecortin (DCX), YWHAE, and tubulin. Actin stress fibers are modulated by PAFAH1B1 (LIS1), DCX, RELN, and VLDLR (very low‐density lipoprotein receptor)/LRP8 (low‐density lipoprotein‐related receptor 8, formerly known as APOER2). There are several important levels of crosstalk between these two cytoskeletal systems to establish accurate cortical patterning in development. The recent understanding of the protein networks that govern neuronal migration by regulating cytoskeletal dynamics, from human and mouse genetics as well as molecular and cellular analyses, provides new insights on neuronal migration disorders and may help us devise novel therapeutic strategies for such brain malformations. WIREs Dev Biol 2013, 2:229–245. doi: 10.1002/wdev.67
Guanine Nucleotide Exchange-Independent Activation of Gs Protein by β2-Adrenoceptor

β2-Adrenoceptor-mediated activation of Gs and adenylyl cyclase or other receptor-mediated G protein activations is believed to occur by receptor-catalyzed replacement of GDP with GTP on the α-subunit of the G protein. Here we showed that a β2-adrenoceptor-Gs system, heterologously expressed in cyc- or human embryonic kidney (HEK)-293 cells, can be activated in the presence of GDP or its phosphorylation-resistant analog, guanosine 5′-O-(2-thiodiphosphate) (GDPβS). The potency and maximal ability of GDP to activate Gs and adenylyl cyclase were identical to those of GTP. GDP-mediated activation of adenylyl cyclase, similar to that mediated by GTP, was concentration-dependent, required high magnesium concentrations, was inhibited by inverse agonists, and was correlated with the efficacy of receptor ligands used to stimulate the receptor. UDP did not block the GDP-mediated activation, although it completely blocked the formation of a small amount of GTP (∼5% GDP) from GDP. Moreover, the activation of Gs in the presence of GDP was insensitive to cholera toxin treatment of the cells, whereas that observed in the presence of GTP was amplified by the treatment, which showed that the activation observed in the presence of GDP was not mediated by GTP. Therefore, we concluded that GDP itself could mediate β-adrenoceptor-induced activation of Gs-adenylyl cyclase system as much as GTP. We discuss the results in the context of the current paradigm of receptor-mediated G protein activation and propose an additional mode of activation for β2-adrenoceptor-Gs adenylyl cyclase system where nucleotide exchange is not necessary and GDP and GTP play identical roles in receptor-induced Gs protein activation.
Flavonoids Isolated from Flowers of Lonicera japonica Thunb. Inhibit Inflammatory Responses in BV2 Microglial Cells by Suppressing TNF‐α and IL‐β Through PI3K/Akt/NF‐kb Signaling Pathways

Decoctions of the dried flowers of Lonicera japonica Thunb. (Indongcho) have been utilized in folk remedies against various inflammatory diseases, and it is reported neuroprotective effects. The cytokines release from microglia is closely linked to various chronic neurodegenerative diseases like Alzheimer's disease and Parkinson's disease. It is still unknown whether the neuroprotective effects are associated with the antiinflammatory effects. Here, we determined whether polyphenols extracted from lyophilized Lonicera japonica Thunb. (PELJ) would inhibit inflammatory cytokines and mediators. We stimulated microglia with lipopolysaccharide (LPS) to produce inflammatory cytokines, and then assessed the effects of PELJ on these cytokines. PELJ significantly inhibited LPS‐induced interleukin‐1β and tumor necrosis factor‐α expressions and LPS‐induced nitric oxide (NO) and prostaglandin E2 expressions by down‐regulating inducible enzyme NO synthase and cyclooxygenase‐2 at the protein and mRNA levels. All the suppression of these mediators did not cause any significant cytotoxicity. PELJ also inhibited the nuclear translocation of nuclear factor‐kappa B and phosphorylated Akt. These findings suggest that PELJ may offer substantial therapeutic potential for treating inflammatory and neurodegenerative diseases by inhibiting pro‐inflammatory cytokines through inhibiting phosphoinositol 3‐kinase /Akt/nuclear factor‐kappa B signaling pathway. Copyright © 2016 John Wiley & Sons, Ltd.
Human Resource Management of Japanese Companies in Hungary: How do Japanese and Hungarian Styles Blend?

ABSTRACT A qualitative interview-based research with 32 participating companies, this article investigates the human resource management practices of Japanese subsidiaries in Hungary. The findings indicate that human resource management practices in Hungarian subsidiaries of Japanese companies are characterized as a hybrid of Japanese and Hungarian styles. Greater Japanese influence was found in the characteristics of the human resources department, corporate culture, safety practices, and trainings, whereas greater Hungarian influence was found in pay, benefits, and recruitment methods. The findings contribute uniquely to the understanding of whether and how the country-of-origin effect, localization effect, and dominance effect interplay in configuring human resource management practices in foreign subsidiaries of multinational companies.
Global Economic and Social Governance and the United Nations System

In recent years the world has been experienced a remarkable contrast between strong global adverse economic, social and environmental trends and the weakness of the international system of governance to manage them. These adverse trends include, among others, the global financial and economic crisis, the threats generated by climate change and the growing income inequality that characterizes a large number of countries. In the face of these challenges, the response of the international community has been weak. The major innovation was the creation of the Group of 20 (G-20) at the leaders’ level. However, after a good start, which was reflected in the capacity to avoid another Great Depression, the effectiveness of the G-20 has not been remarkable and this institution poses many questions in terms of legitimacy. In turn, the European system of governance, the most developed in the world, has shown many weaknesses and even a regression during the recent crisis to a dominantly intergovernmental process led by the most powerful countries in the European Union.
Sensitivity analysis of spatial models

Sensitivity analysis is the study of how uncertainty in model predictions is determined by uncertainty in model inputs. A global sensitivity analysis considers the potential effects from the simultaneous variation of model inputs over their finite range of uncertainty. A number of techniques are available to carry out global sensitivity analysis from a set of Monte Carlo simulations; some techniques are more efficient than others, depending on the strategy used to sample the uncertainty of model inputs and on the formulae employed for estimating sensitivity measures. The most common approaches are summarised in this paper by focusing on the limitations of each in the context of a sensitivity analysis of a spatial model. A novel approach for undertaking a spatial sensitivity analysis (based on the method of Sobol' and its related improvements) is proposed and tested. This method makes no assumptions about the model and enables the analysis of spatially distributed, uncertain inputs. The proposed approach is illustrated with a simple test model and a groundwater contaminant model.
Transient receptor potential family members PKD1L3 and PKD2L1 form a candidate sour taste receptor

Animals use their gustatory systems to evaluate the nutritious value, toxicity, sodium content, and acidity of food. Although characterization of molecular identities that receive taste chemicals is essential, molecular receptors underlying sour taste sensation remain unclear. Here, we show that two transient receptor potential (TRP) channel members, PKD1L3 and PKD2L1, are coexpressed in a subset of taste receptor cells in specific taste areas. Cells expressing these molecules are distinct from taste cells having receptors for bitter, sweet, or umami tastants. The PKD2L1 proteins are accumulated at the taste pore region, where taste chemicals are detected. PKD1L3 and PKD2L1 proteins can interact with each other, and coexpression of the PKD1L3 and PKD2L1 is necessary for their functional cell surface expression. Finally, PKD1L3 and PKD2L1 are activated by various acids when coexpressed in heterologous cells but not by other classes of tastants. These results suggest that PKD1L3 and PKD2L1 heteromers may function as sour taste receptors.
Coordinate action of Wt1 and a modifier gene supports embryonic survival in the oviduct

The Wt1 gene, originally identified as a tumor suppressor gene associated with Wilms' tumors, encodes a zinc finger containing transcription factor expressed during gonadal and kidney development. Although Wt1 appears to be required for gonadal and kidney development, no reproductive defects were observed in outbred females heterozygous for a targeted mutation in Wt1. In contrast, no litters were obtained from Wt1 +/− females on a strain 129/Sv inbred genetic background. Ovaries were smaller in Wt1 +/− 129/Sv mice and produced fewer ova, but transplanted Wt1 +/− ovaries from 129/Sv females were able to support successful pregnancies. The inability of Wt1 +/− 129/Sv females to produce successful implantations after ovulation and fertilization appeared to be due to the failure of one‐cell embryos to undergo mitosis, such that they were lost in the oviduct before reaching the uterus. Approximately 50% of Wt1 +/− females generated from a backcross of Wt1 +/− 129/Sv:C57Bl/6 F1 hybrids to 129/Sv were fertile, indicating the presence of a Wt1 modifier gene that affects survival of the preimplantation embryo. Neither levels of WT1 protein nor the ratio of WT1 spice forms were significantly altered in Wt1 +/− reproductive organs, suggesting that this modifier effect acts downstream of WT1. Wt1 is therefore among a small subset of genes required for survival of the pre‐implantation embryo, and appears to function non‐autonomously. Mol. Reprod. Dev. 52:366–375, 1999. © 1999 Wiley‐Liss, Inc.
Direct modulation of GABAA receptor by intracellular ATP in dissociated nucleus tractus solitarii neurones of rat.

1. Effect of intracellular ATP on Cl‐ current (ICl) mediated by the GABA (gamma‐aminobutyric acid) receptor subtype, GABAA, was studied in dissociated nucleus tractus solitarii (NTS) neurones using the whole‐cell mode of patch clamp. A concentration‐jump technique termed ‘Y tube’ was used to rapidly apply agents externally. Dissociated neurones were obtained from 1‐ to 3‐week‐old rats. 2. When the patch‐pipette solution contained 2 mM‐ATP, the amplitude of ICl elicited by 10(‐5) M‐GABA did not show any time‐dependent decrease (apparent run‐down), for more than 60 min after the initial recording. In the presence of ATP, the half‐maximum concentration (KD) and Hill coefficient calculated from the GABA concentration‐response curve were 9.12 microM and 1.47, respectively. 3. In the absence of intracellular ATP, the amplitude of GABA‐induced ICl decreased with time. The relative peak amplitudes after 20 and 60 min from the initial recording were 0.40 +/‐ 0.09 (n = 11) and 0.16 +/‐ 0.05 (n = 8) with respect to the initial response. 4. Removal of Mg2+ from the internal solution induced run‐down of the GABA response even in the presence of 2 mM‐intracellular ATP, suggesting that both intracellular ATP (2 mM or more) and Mg2+ are necessary to prevent run‐down of the GABA response. 5. Activation of dephosphorylation processes by alkaline phosphatase (100‐200 microM) did not affect the GABA response in neurones perfused with internal solution containing 2 mM‐ATP and 3 mM‐Mg2+. Blocking the dephosphorylation process by okadaic acid, a phosphatase inhibitor, did not prevent the run‐down of the GABA response. 6. Calcium influxes passing through both the voltage‐dependent L‐type Ca2+ channel and the glutamate receptor‐operated cation channel did not affect ICl induced by GABA. 7. GABA‐induced ICl was also maintained by adding 2 mM‐ADP or ATP gamma S (adenosine‐5'‐O‐3‐thiotriphosphate) to the internal solution containing Mg2+. Addition of 2 mM‐adenosine, AMP, cyclic AMP, AMP‐PNP (adenylimido‐diphosphate) or ADP beta S (adenosine‐5'‐O‐2‐thiodiphosphate) to the internal solution did not prevent the run‐down of the GABA response even in the presence of 3 mM‐intracellular Mg2+. Based on the chemical specificity of these ATP analogues, it is suggested that there is an ATP‐sensitive binding site (ATP receptor) in the cytoplasmic side of the cell membrane. (ABSTRACT TRUNCATED AT 400 WORDS)
Oxidative stress evaluated using an automated method for hydroperoxide estimation in patients with coronary artery disease

Abstract Background: Reactive oxygen species (ROS) play a major role in the pathogenesis of different chronic and degenerative diseases, including atherosclerosis. However, the lack of feasible and reliable methods limits the spread of oxidative stress estimation for routine application in clinical chemistry laboratories. We have recently evaluated the analytical characteristics of an automated test for the measurement of hydroperoxides (HPs) and its performance in determining oxidative stress levels in a general population. In this study we applied this method for the evaluation of oxidative stress in a cohort of patients with coronary artery disease (CAD). Methods: A total of 69 patients with angiographically verified CAD and 34 age- and sex-matched control subjects were enrolled in the study. Results: HPs were higher in patients with CAD (p<0.01), significantly increasing with disease severity (p<0.01). HPs were also higher in subjects with diabetes, dyslipidemia or C-reactive protein >1.5mg/L. A significant positive correlation was observed between glucose and HP levels. In a multivariate model, diabetes (odds ratio OR=3.5, 95% CI 1.2–10, p<0.05) and CAD (OR=5.7, CI 1.1–28.5, p<0.05) were independent determinants for the 75th HP percentile. Conclusions: The results obtained with this method largely reproduce those found using other oxidative stress biomarkers, but the method is faster, easy to perform and does not require skilled operators or complex instrumentation, and thus is a reliable procedure that might represent a feasible tool for oxidative stress estimation in the cardiovascular setting. Clin Chem Lab Med 2007;45:367–71.
Pulse Oximetry: A Survey of Knowledge among Staff of an Emergency Department

Introduction Pulse oximetry measures arterial oxygen saturation and was introduced into the clinical field since the 1980s. It provides a simple, portable, non-invasive and inexpensive way for monitoring blood oxygen saturation. Previous studies demonstrated that most hospital staff had limited knowledge on the correct use of pulse oximetry and what might affect the readings. This study aimed at evaluating the extent of knowledge in pulse oximetry among the clinical staff of an emergency department. Method A 25-item multiple-choice type questionnaire was given to the medical and nursing staff of the Accident and Emergency Department (AED) of the Alice Ho Miu Ling Nethersole Hospital. In addition to demographic information, respondents were required to answer questions relating to the basic principles of pulse oximetry, recognition of physiological factors limiting its accuracy and management regarding hypothetical scenarios. The scores were expressed and analysed on a scale of 0–100. Results A total of 44 questionnaires were completed by 27 nurses and 17 doctors with their test scores ranging from 20 to 72 (median=46). Doctors (median=56) did better than nurses (median=44) in general (P=0.036) but this advantage, however, did not apply to questions on hypothetical scenarios where nurses performed better on the contrary. Correlation analysis proved that there was no linear relationship between respondents' test scores and their years of clinical experience (r=0.051, Spearman). This absence of linear relationship also applied to individual doctors (r=0.244, Spearman) and nurses groups (r=0.162, Spearman). Conclusion There was insufficient knowledge on the use of pulse oximetry among staff of the AED. The level of understanding did not correlate with their clinical experience. Training programs targeting both the fresh and the experienced staff are recommended.