Miracle-dz/UniFAR-FTUs huggingface dataset:
Negative Selection Assay Based on Stimulation of T Cell Receptor Transgenic Thymocytes with Peptide-MHC Tetramers

Thymocyte negative selection is a requirement for the development of self tolerance. Although it is possible to assay the induction of cell death in thymocytes in vitro using antibody cross-linking, this stimulus is much stronger than the normal range of T cell receptor ligands that could be encountered during normal development. Signaling in thymocytes is finely balanced between positive and negative selection stimuli, where a negative selecting ligand can be only marginally higher affinity than a positive selecting ligand. We have therefore developed an assay for the induction of negative selection that can distinguish such cases, and that is amenable to high-throughput analysis. The assay is based on the induction of activated caspase 3 in thymocytes expressing a defined T cell receptor, after stimulation with MHC-peptide tetramers in vitro for 24 hours or less.
A Structural Approach to Identifying the Sources of Local Currency Price Stability

The inertia of the local-currency prices of traded goods in the face of exchange-rate changes is a well-documented phenomenon in International Economics. This paper develops a structural model to identify the sources of this local-currency price stability and applies it to micro data from the beer market. The empirical procedure exploits manufacturers' and retailers' first-order conditions in conjunction with detailed information on the frequency of price adjustments following exchange-rate changes to quantify the relative importance of local non-traded cost components, markup adjustment by manufacturers and retailers, and nominal price rigidities in the incomplete transmission of such changes to prices. We find that, on average, approximately 60% of the incomplete exchange rate pass-through is due to local non-traded costs; 8% to markup adjustment; 30% to the existence of own-brand price adjustment costs, and 1% to the indirect/strategic effect of such costs, though these results vary considerably across individual brands according to their market shares.
Modulation of a voltage-gated Na+ channel by sevoflurane involves multiple sites and distinct mechanisms

Significance Understanding of the mechanisms of modulation of voltage-gated Na+ (NaV) channels by general anesthetic agents such as sevoflurane is critical to interpret their role in general anesthesia. By using the bacterial NaV channel analogue NaChBac plus a combination of computational and electrophysiological analyses, this work strongly suggests a multisite mechanism of sevoflurane action on NaV channels. Furthermore, computer simulations suggest specific putative anesthetic sites worthy of further investigation. Halogenated inhaled general anesthetic agents modulate voltage-gated ion channels, but the underlying molecular mechanisms are not understood. Many general anesthetic agents regulate voltage-gated Na+ (NaV) channels, including the commonly used drug sevoflurane. Here, we investigated the putative binding sites and molecular mechanisms of sevoflurane action on the bacterial NaV channel NaChBac by using a combination of molecular dynamics simulation, electrophysiology, and kinetic analysis. Structural modeling revealed multiple sevoflurane interaction sites possibly associated with NaChBac modulation. Electrophysiologically, sevoflurane favors activation and inactivation at low concentrations (0.2 mM), and additionally accelerates current decay at high concentrations (2 mM). Explaining these observations, kinetic modeling suggests concurrent destabilization of closed states and low-affinity open channel block. We propose that the multiple effects of sevoflurane on NaChBac result from simultaneous interactions at multiple sites with distinct affinities. This multiple-site, multiple-mode hypothesis offers a framework to study the structural basis of general anesthetic action.
Importance of Continuous Sequential Chemotherapy and Multimodal Treatment for Advanced Testicular Cancer

AbstractPatients with “difficult-to-treat” advanced testicular cancer can require multiple therapies. We retrospectively assessed our patients with advanced germ cell tumors (GCTs) and characterized the clinical efficacy, outcomes, and factors affecting overall survival (OS). Two hundred fifty-three patients with advanced GCTs were treated at Kyoto Prefectural University of Medicine, Kyoto, Japan, from June 1998 to September 2013. Of 253 patients, 142 patients had salvage chemotherapy.As first-line therapy, bleomycin, etoposide, and cisplatin, and etoposide and cisplatin therapies were performed in 234 cases (92.5%). As second-line therapy, etoposide, ifosfamide, and cisplatin/vinblastine, ifosfamide, and cisplatin, and paclitaxel, ifosfamide, and cisplatin/paclitaxel, ifosfamide, and nedaplatin therapies were carried out in 44 and 59 cases, respectively. Furthermore, 111, 72, 44, and 28 cases had third, fourth, fifth, and sixth-or-later-line chemotherapy, respectively. Five-year OS rate stratified by chemotherapy line was 95.5% in the first line, 89.4% in the second line, 82.1% in the third line, 45.1% in the fourth line, and 58.9% in the fifth or after line. A statistical significant difference was found when comparing fourth-or-after-line versus first to third-line therapy. Additional procedures were performed, including retroperitoneal lymph node dissection (RPLND) (n = 168), extra-RPLN resection (n = 114), and external beam radiotherapy/stereotactic radiotherapy (n = 78). Multivariate analysis showed that factors predicting better outcomes were in serum tumor marker (STM) normalization, RPLND, and extra-RPLN resection.Good outcomes were obtained in patients who completed chemotherapy up to third line. After fourth-line chemotherapy, approximately 50% of “difficult-to-treat” patients could be cured with normalization of STM levels and residual mass resection. Continuous or sequential chemotherapy with multimodality therapy is important for patients with “difficult-to-treat” advanced GCTs. Effective chemotherapy after third line should be developed.
Doxycycline use in patients with lymphangioleiomyomatosis: biomarkers and pulmonary function response *, **

OBJECTIVE: To assess blockade of matrix metalloproteinase (MMP)-2 and MMP-9, as well as the variation in FEV1, in patients with lymphangioleiomyomatosis (LAM) treated with doxycycline (a known MMP inhibitor) for 12 months. METHODS: An open-label, single-arm, interventional clinical trial in which LAM patients received doxycycline (100 mg/day) for 12 months. Patients underwent full pulmonary function testing, a six-minute walk test, and quality of life assessment, as well as blood and urine sampling for quantification of MMP-2, MMP-9, and VEGF-D levels-at baseline, as well as at 6 and 12 months after the initiation of doxycycline. RESULTS: Thirty-one LAM patients received doxycycline for 12 months. Although there was effective blockade of urinary MMP-9 and serum MMP-2 after treatment, there were no significant differences between pre and post-doxycycline serum levels of MMP-9 and VEGF-D. On the basis of their response to doxycycline (as determined by the variation in FEV1), the patients were divided into two groups: the doxycycline-responder (doxy-R) group (n = 13); and the doxycycline-nonresponder (doxy-NR) group (n = 18). The patients with mild spirometric abnormalities responded better to doxycycline. The most common side effects were mild epigastric pain, nausea, and diarrhea. CONCLUSIONS: In patients with LAM, doxycycline treatment results in effective MMP blockade, as well as in improved lung function and quality of life in those with less severe disease. However, these benefits do not seem to be related to the MMP blockade, raising the hypothesis that there is a different mechanism of action.
Modern Determination of Vertical Deflections Using Digital Zenith Cameras

At the beginning of the 21st century, a significant technological change took place in geodetic astronomy. In Zurich and Hannover, digital zenith camera systems were developed based on digital imaging sensors (charge-coupled device) that strongly improved the degree of automation, efficiency, and accuracy of the observation of the direction of the plumb line and its vertical deflection. This paper describes the instrumental design of the new digital zenith camera systems and gives an overview of the data processing with focus on the models used for astrometric data reduction and tilt correction. Results of frequently repeated observations of vertical deflections and comparison measurements show an accuracy of vertical deflection measurements of better than 0.1 arc sec. Application examples for vertical deflection data from zenith camera observations, such as the high-precision local gravity field determination in engineering projects and gravity field validation are summarized.
Plasma vascular endothelial growth factor, angiopoietin-1, and angiopoietin-2 in diabetes: implications for cardiovascular risk and effects of multifactorial intervention.

OBJECTIVE Vascular endothelial growth factor (VEGF) and angiopoietin (Ang)-1 and Ang-2 are mediators of angiogenesis. More recent data suggest that the balance between these growth factors may affect vascular endothelial integrity. Because diabetes is closely associated with endothelial perturbation, we studied plasma levels of these angiogenic growth factors in patients with diabetes; their relationship with glycemia, inflammation, and endothelial damage/dysfunction; and the effect of intensified cardiovascular risk management. RESEARCH DESIGN AND METHODS We measured plasma VEGF, Ang-1, and Ang-2 alongside plasma von Willebrand factor (vWf) and urine albumin-to-creatinine ratio (marking endothelial damage/dysfunction) and interleukin (IL)-6 in 94 patients (38 with overt cardiovascular disease [CVD]) with diabetes and 34 normal control subjects. RESULTS Plasma vWf (P=0.009), IL-6 (P <0.001), VEGF (P=0.001), and Ang-2 (P=0.001), but not Ang-1 (P=0.635), were higher in diabetic patients with and without CVD than in control subjects. On multivariate analysis, HbA1c was an independent predictor of plasma VEGF (P=0.032) and Ang-2 (P=0.015). Of the 94 patients, a subgroup of 33 patients with and 31 patients without CVD participated in a year of intensified cardiovascular risk management. HbA1c and LDL cholesterol reduced significantly with treatment, along with associated reductions in plasma vWf and VEGF in both groups (P <0.001). Ang-2 decreased (P <0.001) only in patients without CVD. There were no significant changes in plasma IL-6 levels in both groups. CONCLUSIONS Plasma Ang-2 (but not Ang-1), like VEGF levels, are selectively elevated in patients with diabetes and are associated with indexes of endothelial damage/dysfunction, regardless of vascular disease. Intensive multifactorial intervention is associated with reductions in plasma VEGF, vWf, and (in patients without CVD) Ang-2 levels, possibly reflecting an improved vascular profile with treatment.
Fluid, solid and fluid–structure interaction simulations on patient-based abdominal aortic aneurysm models

This article describes the use of fluid, solid and fluid–structure interaction simulations on three patient-based abdominal aortic aneurysm geometries. All simulations were carried out using OpenFOAM, which uses the finite volume method to solve both fluid and solid equations. Initially a fluid-only simulation was carried out on a single patient-based geometry and results from this simulation were compared with experimental results. There was good qualitative and quantitative agreement between the experimental and numerical results, suggesting that OpenFOAM is capable of predicting the main features of unsteady flow through a complex patient-based abdominal aortic aneurysm geometry. The intraluminal thrombus and arterial wall were then included, and solid stress and fluid–structure interaction simulations were performed on this, and two other patient-based abdominal aortic aneurysm geometries. It was found that the solid stress simulations resulted in an under-estimation of the maximum stress by up to 5.9% when compared with the fluid–structure interaction simulations. In the fluid–structure interaction simulations, flow induced pressure within the aneurysm was found to be up to 4.8% higher than the value of peak systolic pressure imposed in the solid stress simulations, which is likely to be the cause of the variation in the stress results. In comparing the results from the initial fluid-only simulation with results from the fluid–structure interaction simulation on the same patient, it was found that wall shear stress values varied by up to 35% between the two simulation methods. It was concluded that solid stress simulations are adequate to predict the maximum stress in an aneurysm wall, while fluid–structure interaction simulations should be performed if accurate prediction of the fluid wall shear stress is necessary. Therefore, the decision to perform fluid–structure interaction simulations should be based on the particular variables of interest in a given study.
Using Occupation to Navigate Cultural Spaces: Indian Immigrant Women Settling in New Zealand

Indian immigrant women settling in New Zealand encounter new environments and occupational situations. How they navigate these situations either facilitates and enhances the experience of being in a new environment or challenges the process of settling and becoming part of New Zealand society. This study describes the significance of engagement in occupation as central to the settlement process. In-depth interviews and participant observations were used to gather information from 25 Indian immigrant women living in New Zealand towns and cities, regarding their experiences of occupation in a new environment. A grounded theory methodology guided by symbolic interactionism and occupational science was employed. Data were analysed using dimensional analysis, resulting in a substantive grounded theory, Navigating Cultural Spaces. This dynamic process describes how Indian immigrant women interweave aspects of the New Zealand and Indian cultures into everyday occupations as they create a place for themselves and their families in a new country.
Beat it early: putative renoprotective haemodynamic effects of oral hypoglycaemic agents

Diabetic kidney disease represents a considerable burden; around one-third of patients with type 2 diabetes develop chronic kidney disease. In health, the kidneys play an important role in the regulation of glucose homeostasis via glucose utilization, gluconeogenesis and glucose reabsorption. In patients with diabetes, renal glucose homeostasis is significantly altered with an increase in both gluconeogenesis and renal tubular reabsorption of glucose. Environmental factors, both metabolic (hyperglycaemia, obesity and dyslipidaemia) and haemodynamic, together with a genetic susceptibility, lead to the activation of pro-oxidative, pro-inflammatory and pro-fibrotic pathways resulting in kidney damage. Hyperfiltration and its haemodynamic-driven insult to the kidney glomeruli is an important player in proteinuria and progression of kidney disease towards end-stage renal failure. Control of glycaemia and blood pressure are the mainstays to prevent kidney damage and slow its progression. There is emerging evidence that some hypoglycaemic agents may have renoprotective effects which are independent of their glucose-lowering effects. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors may exert a renoprotective effect by a number of mechanisms including restoring the tubuloglomerular feedback mechanism and lowering glomerular hyperfiltration, reducing inflammatory and fibrotic markers induced by hyperglycaemia thus limiting renal damage. Simultaneous use of an SGLT-2 inhibitor and blockade of the renin-angiotensin-aldosterone system may be a strategy to slow progression of diabetic nephropathy more than either drug alone. The use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide 1 receptor agonists may exert a renoprotective effect by reducing inflammation, fibrosis and blood pressure. Given the burden of diabetic kidney disease, any additional renoprotective benefit with hypoglycaemic therapy is to be welcomed. Large randomized controlled trials are currently underway investigating if these new anti-diabetic agents can provide renoprotection in diabetes.
Domain-Sharding for Faster HTTP/2 in Lossy Cellular Networks

HTTP/2 (h2) is a new standard for Web communications that already delivers a large share of Web traffic. Unlike HTTP/1, h2 uses only one underlying TCP connection. In a cellular network with high loss and sudden spikes in latency, which the TCP stack might interpret as loss, using a single TCP connection can negatively impact Web performance. In this paper, we perform an extensive analysis of real world cellular network traffic and design a testbed to emulate loss characteristics in cellular networks. We use the emulated cellular network to measure h2 performance in comparison to HTTP/1.1, for webpages synthesized from HTTP Archive repository data. Our results show that, in lossy conditions, h2 achieves faster page load times (PLTs) for webpages with small objects. For webpages with large objects, h2 degrades the PLT. We devise a new domain-sharding technique that isolates large and small object downloads on separate connections. Using sharding, we show that under lossy cellular conditions, h2 over multiple connections improves the PLT compared to h2 with one connection and HTTP/1.1 with six connections. Finally, we recommend content providers and content delivery networks to apply h2-aware domain-sharding on webpages currently served over h2 for improved mobile Web performance.
Cues to Deception in Social Media Communications

With the increasing reliance on social media as a dominant communication medium for current news and personal communications, communicators are capable of executing deception with relative ease. While past-related research has investigated written deception in traditional forms of computer mediated communication (e.g. email), we are interested determining if those same indicators hold in social media-like communication and if new, social-media specific linguistic cues to deception exist. Our contribution is two-fold: 1) we present results on human subjects experimentation to confirm existing and new linguistic cues to deception; 2) we present results on classifying deception from training machine learning classifiers using our best features to achieve an average 90% accuracy in cross fold validation.
Management Practice, Organization Climate, and Performance

This study reports a single time-series quasi-experiment in a Canadian firm to evaluate the effect over a five-year period of implementing a structured, seven-step strategy to obtain improved organization performance through employee-centered management. A significant change in the condition of the human organization resulting from the intervention was measured over the five-year period and shown to be correlated with a 66% increase in profitability. The results of the study indicate that in the Canadian/U.S. context, employee-centered management is at least compatible with high performance and competitive advantage. There is also evidence that in some instances organization performance can be significantly enhanced through the participation and contribution of employees in problem-solving and decision-making processes.
The rise and fall of candidate Perot: Unmediated versus mediated politics—Part I

The article uses Ross Perot's campaign for president in 1992 as a case study in how two key political institutions, the conventional political press and the party system, mediate the effects of political communication. From an analysis of events in both the spring of 1992 and the general election, the Texan was highly effective when he could appeal to voters in an essentially unmediated fashion. His candidacy failed, however, because it could not deal effectively with the political institutions by which the United States customarily selects its presidents. For example, Perot's appearances on morning interview programs persuaded roughly 20 percent of those seeing them to support his candidacy. Because the audiences for these shows were relatively small, however, Perot's initial rise in the polls and his subsequent decline were driven mainly by coverage in the conventional press. Part I of the article deals with the earliest, relatively unmediated phase of Perot's campaign and the take‐off phase of the medi.
The New Sustainability Advantage: Seven Business Case Benefits of a Triple Bottom Line

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ARE FAMILY FRIENDLY WORKPLACE PRACTICES A VALUABLE FIRM RESOURCE

We study the determinants and consequences of family-friendly workplace practices (FFWP) using a sample of over 450 manufacturing firms in Germany, France, U.K., and U.S. We find a positive correlation between firm productivity and FFWP. This association disappears, however, once we control for a measure of the quality of management practices. We further find that firms with a higher proportion of female managers and more skilled workers, as well as well-managed firms, tend to implement more FFWP. Conversely, a firm's environment does not have a significant impact on the FFWP it provides.
Disturbance gradients on inshore and offshore coral reefs caused by a severe tropical cyclone

Tropical storms (cyclones, hurricanes, or typhoons) are the most severe form of mechanical disturbance of coral reefs. In 2005, severe tropical cyclone Ingrid crossed the far northern Great Barrier Reef, a region that had not been affected by a major disturbance for several decades, and where benthic data had been collected before the cyclone crossed. This storm provided a unique opportunity to improve understanding of the extent and type of damage inflicted on inshore and offshore coral reefs along a gradient of wind speeds. Modeled maximum wind speeds ranged from 46 m s−1 (equivalent to category 4) near the path to 22 m s−1 (category 1) ~70 km to either side of the path. Surveys of 82 sites on 32 reefs along the wind gradient showed that the types and intensity of disturbance were well explained by local maximum wind speed, and by spatial and biotic factors. While offshore reefs had the deepest depth of damage, inshore reefs had the greatest rates of coral breakage and dislodgement. On a severely affected inshore reef, hard coral cover decreased about 800%, taxonomic richness decreased 250%, the density of coral recruits decreased by 30%, while massive coral cover remained unaltered. Maximum winds <28 m s−1 for <12 h inflicted only minor damage on any reef, but winds >33 m s−1 and >40 m s−1 caused catastrophic damage on inshore and offshore reefs, respectively. Observations from this cyclone were used to predict potential changes in storm‐related coral loss under altered cyclone‐intensity scenarios.