Miracle-dz/UniFAR-FTUs huggingface dataset:
Flexible Dependence Modeling of Operational Risk Losses and Its Impact on Total Capital Requirements

Operational risk data, when available, are usually scarce, heavy-tailed and possibly dependent. In this work, we introduce a model that captures such real-world characteristics and explicitly deals with heterogeneous pairwise and tail dependence of losses. By considering flexible families of copulas, we can easily move beyond modeling bivariate dependence among losses and estimate the total risk capital for the seven- and eight-dimensional distributions of event types and business lines. Using real-world data, we then evaluate the impact of realistic dependence modeling on estimating the total regulatory capital, which turns out to be up to 38% smaller than what the standard Basel approach would prescribe.
Phase I trial of XR9576 in healthy volunteers demonstrates modulation of P-glycoprotein in CD56+ lymphocytes after oral and intravenous administration.

XR9576 is a novel inhibitor of P-glycoprotein (P-gp) that has been shown to reverse P-gp-dependent multidrug-resistance in tumor cell lines and tumor-bearing animals. Here we report the first i.v. and p.o. administration to healthy volunteers of XR9576 in dose-escalating studies with the aim of investigating its effects on safety, its pharmacokinetics, and a surrogate marker of efficacy. XR9576 was administered as a single dose-upward titration of 0.1, 0.2, 0.5, 1.0, and 2 mg/kg XR9576 i.v. or 50, 100, 200, 500, and 750 mg/volunteer p.o. The surrogate marker for in vivo efficacy examined the accumulation of the P-gp substrate Rhodamine-123 (Rh-123) in P-gp-expressing CD56+ lymphocytes by flow cytometry. Addition of Rh-123 to blood samples from subjects given XR9576 or a placebo demonstrated drug-dependent modulation of P-gp activity. Even at the lowest doses, significant effects were observed on Rh-123 accumulation in CD56+ cells. Maximal effects were seen during the i.v. infusion or 4-6 h after oral administration. As the dose was increased, a concomitant rise in the level and duration of P-gp blockade was observed. A dose of 2.0 mg/kg i.v. and > or = 200 mg/volunteer p.o. gave approximately 100% inhibition of P-gp for in excess of 24 h. All doses of XR9576 were well tolerated. Inhibition increased with XR9576 plasma concentration, and maximal activity was achieved at 150-200 ng/ml XR9576. In conclusion, XR9576 has demonstrated sustained inhibition of P-gp after i.v. and oral administration and, supported by the elimination half-life of about 24 h, XR9576 is being taken into Phase II as a once-daily agent.
Selective Inhibition of Inducible NO Synthase Activity In Vivo Reverses Inflammatory Abnormalities in Surfactant Protein D-Deficient Mice1

Surfactant protein D (SP-D)-deficient (SP-D−/−) mice exhibit early development of emphysema. Previously we have shown that SP-D deficiency results in increased production and activity of inducible NO synthase (iNOS). In this study, we examined whether treatment with the iNOS inhibitor 1400W could inhibit the inflammatory phenotype. Mice were treated with 1400W systemically for 7 wk from 3 wk of age. Treatment reduced total lung NO synthase activity to 14.7 ± 6.1% of saline-treated 10-wk-old SP-D−/− littermates. Long-term administration of 1400W reduced lung inflammation and cellular infiltration; and significantly attenuated the increased levels of matrix metalloproteinases 2 and 9, chemokines (KC, TARC), and cytokines (IFN-γ) seen in bronchoalveolar lavage (BAL) of SP-D−/− mice. Abrogation of these levels was associated with decreasing BAL chemotactic activity for RAW cells. Two weeks of treatment with 1400W reduced total lung NO synthase (NOS) activity to 12.7 ± 6.3% of saline-treated SP-D−/− mice. Short-term iNOS inhibition resulted in attenuation of pulmonary inflammation within SP-D−/− mice as shown by decreases in total BAL cell count (63 ± 6% of SP-D−/− control), macrophage size (>25 μm) within the BAL (62 ± 10% of SP-D−/− control), and a percentage of BAL macrophages producing oxidants (76 ± 9% of SP-D−/− control). These studies showed that s.c. delivery of 1400W can be achieved in vivo and can attenuate the inflammatory processes within SP-D deficiency. Our results represent the first report linking defects in the innate immune system in the lung with alterations in NO homeostasis.
Acute Renal Failure After Administration of Intravenous Immunoglobulin: Review of the Literature and Case Report

Within in last 7 years the literature has published several reports of acute renal failure after the administration of intravenous immunoglobulin. Review of these cases finds that all occurrences in the United States except one involved a sucrose‐containing immunoglobulin preparation, leading to the suspicion that sucrose may be the cause of the renal failure. Further investigation found that approximately 50 years ago, when sucrose was used as an osmotic diuretic, investigators reported acute renal failure in humans after intravenous infusions of 50 g or more. A patient at our institution developed acute renal failure similar to that described in published case reports after being administered a sucrose‐containing immunoglobulin.
ROCK inhibition enhances neurite outgrowth in neural stem cells by upregulating YAP expression in vitro

Spontaneous axonal regeneration of neurons does not occur after spinal cord injury because of inhibition by myelin and other inhibitory factors. Studies have demonstrated that blocking the Rho/Rho-kinase (ROCK) pathway can promote neurite outgrowth in spinal cord injury models. In the present study, we investigated neurite outgrowth and neuronal differentiation in neural stem cells from the mouse subventricular zone after inhibition of ROCK in vitro. Inhibition of ROCK with Y-27632 increased neurite length, enhanced neuronal differentiation, and upregulated the expression of two major signaling pathway effectors, phospho-Akt and phospho-mitogen-activated protein kinase, and the Hippo pathway effector YAP. These results suggest that inhibition of ROCK mediates neurite outgrowth in neural stem cells by activating the Hippo signaling pathway.
Milankovitch‐paced Termination II in a Nevada speleothem?

The Devils Hole (DH) calcite record from the Great Basin, Nevada, provided the first radiometrically dated time series of late‐Pleistocene climate fluctuations,. In doing so, DH suggested that the penultimate deglaciation, Termination II (T‐II), occurred at 142 ± 3 ka, which is ∼10 kyr before the associated rise in summer insolation, helping to launch the “causality problem” for Milankovitch. The interpretation of the DH record has been subject to considerable discussion ever since. We present the first attempt to reproduce the DH record of an early T‐II in the Great Basin based on a stalagmite from Lehman Caves, Nevada, which is ∼400 km northeast of Devils Hole. Our speleothem records at least the latter part of T‐II over its period of growth from ∼133–129 ka, which appears to disagree with the early timing of T‐II in DH. DH also exhibits important differences from many other paleoclimate records over the past two deglaciations, though these are reduced somewhat after ice‐volume correcting DH δ18O. We suggest that the climatic signal in the DH record remains to be fully explained.
Hepcidin in iron metabolism

Purpose of reviewHepcidin is a recently discovered hepatic peptide that regulates intestinal iron absorption as well as maternal-fetal iron transport across the placenta. It probably also affects the release of iron from hepatic stores and from macrophages involved in the recycling of iron from hemoglobin. Connecting iron metabolism to innate immunity, hepcidin is a key mediator of hypoferremia of inflammation. Recent findingsThe essential role of hepcidin in iron metabolism is being elucidated through mouse and human genetics, biochemistry, and cell biology. SummaryStudies of hepcidin are leading to fundamental understanding of iron homeostasis and pointing to potential treatments for hemochromatosis and anemia of inflammation (anemia of chronic disease).
Renormalization-Group Method for Reduction of Evolution Equations; Invariant Manifolds and Envelopes

Abstract The renormalization group (RG) method as a powerful tool for reduction of evolution equations is formulated in terms of the notion of invariant manifolds. We start with derivation of an exact RG equation which is analogous to the Wilsonian RG equations in statistical physics and quantum field theory. It is clarified that the perturbative RG method constructs invariant manifolds successively as the initial value of evolution equations, thereby the meaning to set t0=t is naturally understood where t0 is the arbitrary initial time. We show that the integral constants in the unperturbative solution constitutes natural coordinates of the invariant manifold when the linear operator A in the evolution equation is semi-simple, i.e., diagonalizable; when A is not semi-simple and has a Jordan cell, a slight modification is necessary because the dimension of the invariant manifold is increased by the perturbation. The RG equation determines the slow motion of the would-be integral constants in the unperturbative solution on the invariant manifold. We present the mechanical procedure to construct the perturbative solutions hence the initial values with which the RG equation gives meaningful results. The underlying structure of the reduction by the RG method as formulated in the present work turns out to completely fit to the universal one elucidated by Kuramoto some years ago. We indicate that the reduction procedure of evolution equations has a good correspondence with the renormalization procedure in quantum field theory; the counter part of the universal structure of reduction elucidated by Kuramoto may be Polchinski's theorem for renormalizable field theories. We apply the method to interface dynamics such as kink–anti-kink and soliton–soliton interactions in the latter of which a linear operator having a Jordan-cell structure appears.
Social epidemiology of excess weight and central adiposity in older Indians: analysis of Study on global AGEing and adult health (SAGE)

Objectives We aimed to estimate the prevalence of overweight and obesity, represented by extra body weight and abdominal circumference, among older Indians; and to characterise the social pattern of obesity and measure the magnitude of hypertension attributable to it. Setting A nationally representative sample of older Indians was selected from 6 Indian states, including Rajasthan, Uttar Pradesh, West Bengal, Assam, Maharashtra and Karnataka, as a part of the multicountry Study on global AGEing and adult health (SAGE). Participants Indians aged 50 years or more (n=7273) were included in the first wave of the SAGE (2010), which we used in our study. Primary and secondary outcome measures The primary outcome measures included excess weight (EW), defined by body mass index (BMI) >25 kg/m2, and central adiposity (CA), defined by waist circumference >90 cm for men and >80 cm for women. The secondary outcome included hypertension, defined by systolic blood pressure >139 or diastolic blood pressure >79 mm Hg, or by those receiving antihypertensive medications. Results 14% of older Indians possessed EW, whereas 35% possessed CA; 50.9% of the wealthier third and 27.7% of the poorer two-thirds have CA; the proportions being 69.1% and 46.2%, respectively, in older women. Mostly wealth (adjusted OR for CA: 4.36 (3.23 to 5.95) and EW: 4.39 (3.49 to 5.53)), but also urban residence, privileged caste, higher education, white-collared occupation and female gender, were important determinants. One of 17 older Indians overall and 1 of 18 in the poorer 70% suffered from CA-driven hypertension, independent of BMI. Conclusions The problem of CA and its allied diseases is already substantial and expected to rise across all socioeconomic strata of older Indians, though currently, CA affects the privileged more than the underprivileged, in later life. Population-based promotion of appropriate lifestyles, with special emphasis on women, is required to counteract prosperity-driven obesity before it becomes too entrenched and expensive to uproot.
Phenoxodiol Increases Cisplatin Sensitivity in Ovarian Clear Cancer Cells Through XIAP Down-regulation and Autophagy Inhibition.

BACKGROUND/AIM To investigate whether XIAP down-regulation and autophagy inhibition sensitize ovarian clear cell cancer cells to cisplatin. MATERIALS AND METHODS The ovarian clear cancer cell line KK was used for in vitro analysis. Hydroxychloroquine (HCQ) and phenoxodiol (PXD) or embelin were used as autophagy and XIAP inhibitors, respectively. Non-specific and XIAP-specific siRNAs were transfected using Lipofectamine. Cytotoxicity was assessed by MTT assays. Protein expression was confirmed by western blotting. RESULTS In KK, down-regulation of XIAP using specific siRNAs together with HCQ treatment enhanced the anti-tumor effect of cisplatin. Although embelin sensitized KK to cisplatin through XIAP down-regulation, it induced autophagy. However, PXD increased cisplatin sensitivity through XIAP down-regulation and autophagy inhibition. Expression of Atg7, Atg12, and Beclin 1 was decreased after PXD treatment. CONCLUSION PXD increased cisplatin sensitivity through XIAP down-regulation and autophagy inhibition and could be a new candidate for ovarian clear cell carcinoma treatment.
MetaTutor: A MetaCognitive Tool for Enhancing Self-Regulated Learning

Learning about complex and challenging science topics with advanced learning technologies requires students to regulate their learning. The deployment of key cognitive and metacognitive regulatory processes is key to enhancing learning in open-ended learning environments such as hypermedia. In this paper, we propose a metaphor—Computers as MetaCognitive tools—to characterize the complex nature of the learning context, self- regulatory processes, task conditions, and features of advanced learning technologies. We briefly outline the theoretical and conceptual assumptions of self-regulated learning (SRL) underlying MetaTutor, a hypermedia environment designed to train and foster students’ SRL processes in biology. Lastly, we provide preliminary learning outcome and SRL process data on the deployment of SRL processes during learning with MetaTutor.
Method Schemas

A method schema is a simple programming formalism for object-oriented databases with features such as classes, methods, inheritance, name overloading, and late binding. An important problem is to check whether a given method schema can lead to an inconsistency in some interpretation. This consistency question is shown to be undecidable in general. Decidability is obtained for monadic and/or recursion-free method schemas. In particular, consistency of monadic method schemas is shown to be decidable in O(nc 3) time, where n is the size of the method deenitions and c is the size of the class hierarchy; also, it is logspace-complete in PTIME, even for monadic, recursion-free schemas. Method signature covariance is shown to simplify the computational complexity of key decidable cases. For example: one coded method in the context of base methods with covariant signatures can be tested for consistency in O(n+c) time for the monadic case (without covariance this problem is in O(nc 2) time) and in PTIME for the xed arity polyadic case (without covariance this problem is NP-complete). Incremental consistency checking of method schemas is a formalization of the database schema evolution problem, for which a sound, but necessarily incomplete, heuristic is proposed.
Delayed breeding in Little Penguins - evidence of climate change?

In the past few years there has been a resurgence of interest in the possibility of detecting climate change using natural systems (see, for example, Crick and Sparks 1999; Sparks and Menzel 2002; Hughes 2003; Parmesan and Yohe 2003; Root et al. 2003). The study of recurring natural (or biological) events, often in relation to climate, is known as phenology. These studies typically record events such as the arrival of migratory birds, first egg-laying or the commencement of flowering (e.g. Crick and Sparks 1999; Keatley et al. 2002; Root et al. 2003). Early studies of meteorology were strongly linked with phenology, with the timings of events in nature being used, for example, by the British Royal Meteorological Society (RMS), as measures of variations in climate (Sparks et al. 2002; Sparks and Smithers 2002). The RMS used a phenological network to study the timing of the seasons from 1875 to 1947, when the last coordinator retired (Sparks and Smithers 2002). During the same period many other countries in the northern hemisphere also had phenological schemes. In the subsequent 40 years phenology became less popular with meteorological agencies in many countries, often being regarded as not ‘real science’ (Keatley et al. 2002; Sparks and Menzel, 2002). This image of phenology has largely been altered by growing concerns over global warming and its potential impact on natural ecosystems. Sparks and Smithers (2002), summarise why phenology is now seen by many governments as important: (a) ‘The growing consensus that greenhouse-gas emissions are causing global climate change. ’ (b)‘The realisation that phenological events can be very sensitive to climate fluctuations. ’ (c) ‘Phenological events are cheap and easy to record. ’ (d)‘Phenology can motivate and enthuse a large body of committed recorders. ’ (e) ‘Phenological events are excellent vehicles through which to demonstrate a changing climate to the general public. ’ Most of the phenological studies published so far are limited to results for the northern hemisphere. Within Australia there has not been a coordinated approach to phenological records and the extent and availability of such records is largely unknown (Keatley et al. 2002; Hughes 2003). Long-term datasets, of greater than 20 years, with relatively consistent collection and recording methods, are rare. One such dataset is that collected on breeding in the Little Penguin on Phillip Island, in Victoria, to which this paper is dedicated. Aust. Met. Mag. 53 (2004) 13-19
THE RELATIONSHIP BETWEEN CORPORATE SOCIAL AND FINANCIAL PERFORMANCE : DO ENDOGENEITY , NON-LINEARITY AND ADJUSTMENT ISSUES MATTER ?

This study investigates the short-term and long-term relationship between corporate social performance (CSP) and corporate financial performance (CFP) throughout UK companies listed on the FTSE4GOOD index, where a self-constructed unique measure based on inclusion to and deletion from the FTSE4GOOD acts as a proxy measure of longevity for each company‟s CSP; evaluates the relationship between prior and subsequent CFP and prior and subsequent CSP; and investigates the relationships among the CSP, CFP, corporate risk, liquidity, research and development, capital structure, current and future growth, and company size. Our major findings are that in general no linear relationship exists between concurrent CSP and concurrent CFP. We instead detect the presence of parabolic and cubic links between CSP-CFP. The results also suggest that firms adjust periodically their level of commitment to the society. Finally, the recently developed system-GMM estimation technique reveals the relevance of the endogeneity problem while conducting regression analyses.
Protein-Protein and Protein-RNA Contacts both Contribute to the 15.5K-Mediated Assembly of the U4/U6 snRNP and the Box C/D snoRNPs

ABSTRACT The k-turn-binding protein 15.5K is unique in that it is essential for the hierarchical assembly of three RNP complexes distinct in both composition and function, namely, the U4/U6 snRNP, the box C/D snoRNP, and the RNP complex assembled on the U3 box B/C motif. 15.5K interacts with the cognate RNAs via an induced fit mechanism, which results in the folding of the surrounding RNA to create a binding site(s) for the RNP-specific proteins. However, it is possible that 15.5K also mediates RNP formation via protein-protein interactions with the complex-specific proteins. To investigate this possibility, we created a series of 15.5K mutations in which the surface properties of the protein had been changed. We assessed their ability to support the formation of the three distinct RNP complexes and found that the formation of each RNP requires a distinct set of regions on the surface of 15.5K. This implies that protein-protein contacts are essential for RNP formation in each complex. Further supporting this idea, direct protein-protein interaction could be observed between hU3-55K and 15.5K. In conclusion, our data suggest that the formation of each RNP involves the direct recognition of specific elements in both 15.5K protein and the specific RNA.
Adaptive-Robust Control of a Class of EL Systems With Parametric Variations Using Artificially Delayed Input and Position Feedback

In this paper, the tracking control problem of an Euler–Lagrange system is addressed with regard to parametric uncertainties, and an adaptive-robust control (ARC) strategy, christened time-delayed ARC (TARC), is presented. TARC approximates the unknown dynamics through the time-delayed estimation, and the ARC provides robustness against the approximation error. The novel adaptation law of TARC, in contrast to the conventional ARC methodologies, requires neither complete model of the system nor any knowledge of predefined uncertainty bounds to compute the switching gain, and circumvents the overestimation and underestimation problems of the switching gain. Moreover, TARC only utilizes position feedback and approximates the velocity and acceleration terms from the past position data. The adopted state-derivatives estimation method in TARC avoids any explicit requirement of external low-pass filters for the removal of measurement noise. A new stability notion in the continuous-time domain is proposed considering the time delay, adaptive law, and state-derivatives estimation, which in turn provides a selection criterion for gains and sampling interval of the controller. Experimental results of the proposed methodology using a multiple degrees-of-freedom robot are presented, and improved tracking accuracy of the proposed control law is demonstrated compared with the conventional adaptive sliding mode control.
Renal hypercalciuria: a physiological TRiP along the calciotropics

Calcium is very important for many physiological functions that take place in the body. The interaction between intestines, kidneys, and bone is essential to maintain a normal calcium balance. The process of active calcium in the intestines and kidneys is very important to determine the amount of calcium resent in the body, which is regulated by calciotropic hormones like vitamin D and parathyroid hormone. In the kidney, calcium is reabsorbed from the pro-urine to the blood in a passive (paracellular, 85%) as well as an active (transcellular, 15%) manner. Furthermore, a small amount of calcium is excreted via the urine. The calcium channel TRPV5 is a key player in the process of active calcium reabsorption in the kidney. A mouse hypercalciuric mouse model was investigated intensively and the research described in this thesis shows new insights into the mechanisms that are involved in calcium homeostasis. This knowledge facilitates the development of new treatments for people with a disturbed calcium balance.