Miracle-dz/UniFAR-FTUs huggingface dataset:
An evaluation of resampling methods for assessment of survival risk prediction in high‐dimensional settings

Resampling techniques are often used to provide an initial assessment of accuracy for prognostic prediction models developed using high‐dimensional genomic data with binary outcomes. Risk prediction is most important, however, in medical applications and frequently the outcome measure is a right‐censored time‐to‐event variable such as survival. Although several methods have been developed for survival risk prediction with high‐dimensional genomic data, there has been little evaluation of the use of resampling techniques for the assessment of such models. Using real and simulated datasets, we compared several resampling techniques for their ability to estimate the accuracy of risk prediction models. Our study showed that accuracy estimates for popular resampling methods, such as sample splitting and leave‐one‐out cross validation (Loo CV), have a higher mean square error than for other methods. Moreover, the large variability of the split‐sample and Loo CV may make the point estimates of accuracy obtained using these methods unreliable and hence should be interpreted carefully. A k‐fold cross‐validation with k = 5 or 10 was seen to provide a good balance between bias and variability for a wide range of data settings and should be more widely adopted in practice. Published in 2010 by John Wiley & Sons, Ltd.
Characterization of T2* heterogeneity in human brain white matter

Recent in vivo MRI studies at 7.0 T have demonstrated extensive heterogeneity of T2* relaxation in white matter of the human brain. In order to study the origin of this heterogeneity, we performed T2* measurements at 1.5, 3.0, and 7.0 T in normal volunteers. Formalin‐fixed brain tissue specimens were also studied using T2*‐weighted MRI, histologic staining, chemical analysis, and electron microscopy. We found that T2* relaxation rate (R2* = 1/T2*) in white matter in living human brain is linearly dependent on the main magnetic field strength, and the T2* heterogeneity in white matter observed at 7.0 T can also be detected, albeit more weakly, at 1.5 and 3.0 T. The T2* heterogeneity exists also in white matter of the formalin‐fixed brain tissue specimens, with prominent differences between the major fiber bundles such as the cingulum (CG) and the superior corona radiata. The white matter specimen with substantial difference in T2* has no significant difference in the total iron content, as determined by chemical analysis. On the other hand, evidence from histologic staining and electron microscopy demonstrates these tissue specimens have apparent difference in myelin content and microstructure. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.
Autonomous Aerial Water Sampling

Obtaining spatially separated, high‐frequency water samples from rivers and lakes is critical to enhance our understanding and effective management of freshwater resources. In this work, we present an aerial water sampler and assess the system through field experiments. The aerial water sampler has the potential to vastly increase the speed and range at which scientists obtain water samples while reducing cost and effort. The water sampling system includes 1) a mechanism to capture three 20 ml samples per mission, 2) sensors and algorithms for altitude approximation over water, and 3) software components that integrate and analyze sensor data, control the vehicle, drive the sampling mechanism, and manage risk. We validate the system in the lab, characterize key sensors, develop a framework for quantifying risk, and present results of outdoor experiments that characterize the performance of the system under windy conditions. In addition, we compare water samples from local lakes obtained by our system to samples obtained by traditional sampling techniques. We find that even winds of 5.8 m/s have little impact on the water sampling system and that the samples collected are consistent with traditional techniques for most properties. These experiments show that despite the challenges associated with flying precisely over water, it is possible to quickly obtain scientifically useful water samples with an unmanned aerial vehicle.
Open Problems

Compute the Green’s functions for a flat torus. The heat kernel for the torus can be computed by looking into the dual lattice that defines the torus (see §9.5 of [1]). Green’s function can be obtained by integrating the heat kernel in time, after subtracting the constant term. But this is complicated to be expressed in a nice form. For two dimensional tori, Green’s function can be expressed in terms of automorphic forms (see Chapter 2 of Serge Lang’s book [2]). D’Hoker and Phong [3] studied the conformally invariant Green’s function on curves of higher genus, which admits an expression in terms of theta functions (more precisely, in terms of the “prime form”). It is attractive since it depends only on the complex structure and not the metric, and it is used frequently in string theory. In my survey article for IMU [4], I suggested to study zeros and critical points of eigenfunctions, Green’s function and heat kernel. The best testing problem is on flat tori where the problem is already deep and difficult. C. -L. Wang and C. -S. Lin [5] made fundamental progress in the two dimensional case. C. -S. Lin was able to relate it to arithmetic of elliptic
Optimal vibration control of smart composite beams with optimal size and location of piezoelectric sensing and actuation

Control performances of smart structures depend on the size and location of the piezoelectric actuators and sensors as well as on the applied control algorithm. This article presents optimal vibration control of a thin-walled composite beam by using the fuzzy optimization strategy based on the particle swarm optimization algorithm. The optimization of the size and location of the conventionally collocated piezoelectric actuators and sensors, and optimization of the controller parameters are performed separately. The optimization criteria for optimal size and location of piezoelectric actuators and sensors are based on eigenvalues of the controllability Grammian matrix. The optimization procedure implies constraint of the original dynamic properties change and limitation of the beam mass increase. The particle swarm optimization-based linear quadratic regulator has been implemented for optimal vibration control in order to maximize the modal closed-loop damping ratios and minimize the control voltages required for actuation while keeping them below breakdown voltage for the used piezoelectric actuator. A pseudo-goal function, derived from the fuzzy set theory, gives an expression for global objective functions eliminating the use of weighting coefficients and penalty functions. The problem is formulated using the finite element method based on the third-order shear deformation theory. Several numerical examples are presented for the cantilever beam.
Education and Biopsychosocial Care for the Patients With Irritable Bowel Syndrome

To the Editor: We read with interest the editorial by Dr. Long-streth concerning patient education for irritable bowel syndrome (IBS) (1), and the article by Colwell et al.(2) on the same subject. We also discovered and reported when IBS education is provided by a specially trained nurse that patients benefitted both in terms of symptom relief and of decreased medical costs (3). However, we would like to clarify one aspect of our office based model. After the initial physician visits involving evaluation, diagnostic procedures and initiation of treatment, it is not necessary for the physician to see the patient on the same day as each "nurse visit. " It is only necessary that the physician be on site at the same time to be potentially available for consultation and to allow for a reimbursement under the "incident to" insurance provisions. This important point was highlighted in an erratum in the subsequent issue of the same nursing journal. For this reason the registered nurse (RN) "nurse visit" is extremely cost effective for providing quality care to patients with chronic GI conditions.
BDNF Val66Met polymorphism interacts with sex to influence bimanual motor control in healthy humans

Brain‐derived neurotrophic factor (BDNF) plays a critical role in brain development. A common single nucleotide polymorphism in the gene encoding BDNF (rs6265, Val66Met) affects BDNF release and has been associated with altered learning and memory performance, and with structural changes in brain morphology and corpus callosum integrity. BDNF Val66Met has more recently been shown to influence motor learning and performance. Some of the BDNF effects seem to be modulated by an individual's sex, but currently the relationship between BDNF and sex in the motor domain remains elusive. Here, we investigate the relationship between BDNF Val66Met genotype and an individual's sex in the motor system. Seventy‐six healthy, previously genotyped, individuals performed a task in which the participant drew lines at different angles of varying difficulty. Subjects controlled the horizontal and vertical movement of the line on a computer screen by rotating two cylinders. We used this bimanual motor control task to measure contributions from both current motor function and the pre‐existing interhemispheric connectivity. We report that BDNF genotype interacts with sex to influence the motor performance of healthy participants in this bimanual motor control task. We further report that the BDNF genotype by sex interaction was present in the more difficult trials only, which is in line with earlier findings that genetic effects may become apparent only when a system is challenged. Our results emphasize the importance of taking sex into account when investigating the role of BDNF genotype in the motor system.
Inclusion body myositis-like phenotype induced by transgenic overexpression of βAPP in skeletal muscle

Inclusion body myositis (IBM), the most common age-related muscle disease in the elderly population, is an incurable disorder leading to severe disability. Sporadic IBM has an unknown etiology, although affected muscle fibers are characterized by many of the pathobiochemical alterations traditionally associated with neurodegenerative brain disorders such as Alzheimer's disease. Accumulation of the amyloid-β peptide, which is derived from proteolysis of the larger amyloid-β precursor protein (βAPP), seems to be an early pathological event in Alzheimer's disease and also in IBM, where in the latter, it predominantly occurs intracellularly within affected myofibers. To elucidate the possible role of βAPP mismetabolism in the pathogenesis of IBM, transgenic mice were derived in which we selectively targeted βAPP overexpression to skeletal muscle by using the muscle creatine kinase promoter. Here we report that older (>10 months) transgenic mice exhibit intracellular immunoreactivity to βAPP and its proteolytic derivatives in skeletal muscle. In this transgenic model, selective overexpression of βAPP leads to the development of a subset of other histopathological and clinical features characteristic of IBM, including centric nuclei, inflammation, and deficiencies in motor performance. These results are consistent with a pathogenic role for βAPP mismetabolism in human IBM.
Arrival rate approximation by nonnegative cubic splines

We describe an optimization method to approximate the arrival rate of data such as e-mail messages, Web site visits, changes to databases, and changes to Web sites mirrored by other servers. We model these arrival rates as non-homogeneous Poisson process based on observed arrival data. We estimate the arrival function by cubic splines using the maximum likelihood principle. A critical feature of the model is that the splines are constrained to be everywhere nonnegative. We formulate this constraint using a characterization of nonnegative polynomials by positive semidefinite matrices. We also describe versions of our model that allow for periodic arrival rate functions and input data of limited precision. We formulate the estimation problem as a convex program related to semidefinite programming and solve it with a standard nonlinear optimization package called KNITRO. We present numerical results using both an actual record of e-mail arrivals over a period of sixty weeks, and artificially generated data sets. We also present a cross-validation procedure for determining an appropriate number of spline knots to model a set of arrival observations
Treatment of Early Parkinson’s Disease

The management of early Parkinson’s disease (PD) involves the treatment of motor symptoms and, increasingly, non-motor symptoms. Given the fast pace of clinical research in PD, clinicians are faced with the challenge of integrating the latest findings into the ongoing care of individual PD patients. Part 1 of this 2-part article reviews motor symptom efficacy data for the newest PD treatment options, as well as for established therapies. Safety and tolerability data are also reviewed. Part 2 of the article reviews key findings relevant to the assessment of potential neuroprotective therapies and the treatment of non-motor symptoms.
Low MT-CO 1 in Monocytes and Microvesicles Is Associated With Outcome in Patients With Coronary Artery Disease

Background-—Cytochrome oxidase (COX) IV complex regulates energy production in mitochondria. Impaired COX gene expression is related to obesity and type 2 diabetes mellitus, but whether it is directly related to the incidence of cardiovascular events is unknown. We investigated whether COX gene expression in monocytes is predictive for cardiovascular events in coronary artery disease patients. To avoid monocyte isolation from fresh blood, we then aimed to validate our findings in monocyte-derived microvesicles isolated from plasma.
Gender and Willingness-to-pay for Recreational Benefits from Water Quality Improvements

The economics literature has recently turned its attention to the existence of gender differences in various aspects of choice behaviour. This paper focuses upon such differences as may exist in the valuation of environmental resources. Firstly, the paper presents several reasons why women are expected to have a lower willingness-to-pay (WTP) for environmental improvements than do men. Secondly, in order to establish the empirical extent of gender differences the paper presents a model for estimating individual-specific benefits from environmental improvements. CVM referenda data from are collected and used in a double-bounded probit model to estimate female versus male WTP for remedial actions designed to improve three different water-based recreational activities in a previously highly polluted area. For these data, the paper finds that, even after controlling for income differences, women consistently have lower WTP values. The findings in this paper have potentially important consequences for the subsequent calculation of aggregate benefits from contingent valuation models that ignore the role of gender. Since women generally constitute about one half of a population base, turning a blind eye to gender means that aggregate WTP values will overstate the extent of benefits from environmental improvements.
Computing with very weak random sources

For any fixed /spl epsiv/>0, we show how to simulate RP algorithms in time n/sup O(log n/) using the output of a /spl delta/-source with min-entropy R(/spl epsiv/). Such a weak random source is asked once for R(/spl epsiv/) bits; it outputs an R-bit string such that any string has probability at most 2/sup -R/(/spl epsiv//). If /spl epsiv/>1-1/(k+1), our BPP simulations take time n/sup O(log(k/ n)) (log/sup (k/) is the logarithm iterated k times). We also give a polynomial-time BPP simulation using Chor-Goldreich sources of min-entropy R/sup /spl Omega/(1/), which is optimal. We present applications to time-space tradeoffs, expander constructions, and the hardness of approximation. Also of interest is our randomness-efficient Leftover Hash Lemma, found independently by Goldreich and Wigderson. <<ETX>>
Use of spacers to facilitate inhaled corticosteroid treatment of asthma.

Budesonide, a topically active corticosteroid, was administered in doses of 400 and 1,600 micrograms/day to 35 asthmatic adults, using a standard inhalation device or a tube or cone spacer. The spacers reduced oropharyngeal candidiasis by an amount equivalent to a 90% reduction in drug dose (p = less than 0.005) and doubled the drug's overall antiasthmatic potency (delta FEV1, p = 0.05) without significantly increasing its overall effect on blood eosinophils (p = 0.14) or the A.M. serum cortisol (p = 0.12). Steroid-induced neutrophilia increased by an amount approximating that produced by an extra half tablet of prednisone per day (p = 0.002). Both the airways and systemic effects of the spacers were greater in patients who had small airways dysfunction present prior to the study. The data suggest an increase in intrapulmonary drug deposition during spacer treatment without a material shift in regional delivery within the lung. Spacers should be particularly useful for patients whose response to inhaled steroid is compromised by by dose-limiting oropharyngeal complications. They can also reduce drug costs. They should be used selectively in children until their effect on regional intrapulmonary drug deposition has been more clearly defined.
Heme Oxygenase-1 : A Multifaceted Triple-Threat Molecule The Role of Heme Oxygenase-1 in Pulmonary Disease

Heme oxygenase (HO)-1, the inducible isoform of heme oxygenase, is a cytoprotective enzyme that plays a central role in the defense against oxidative and inflammatory insults in the lung. HO-1 catalyzes the degradation of heme, a potent oxidant, into biliverdin, iron, and carbon monoxide (CO). These downstream products of heme catabolism have recently been found to mediate the antioxidant, antiapoptotic, antiproliferative, vasodilatory, and anti-inflammatory properties of HO-1. Although absence of HO-1 is rare in humans, a number of HO-1 promoter polymorphisms have been identified that may influence HO-1 expression in vivo and lead to disease states. This review will summarize studies that implicate HO-1 and heme metabolites in the pathophysiology of pulmonary disease and discuss recent advances in the therapeutic applications of HO-1.
Inhibition of Contractile Function in Human Joint Capsule Myofibroblasts by Targeting the TGF-β1 and PDGF Pathways

Background Contractile myofibroblasts (MFs) accumulate in the joint capsules of patients suffering from posttraumatic joint stiffness. MF activation is controlled by a complex local network of growth factors and cytokines, ending in the increased production of extracellular matrix components followed by soft tissue contracture. Despite the tremendous growth of knowledge in this field, inconsistencies remain in practice and prevention. Methods and Findings In this in vitro study, we isolated and cultured alpha-smooth muscle actin (α-SMA) positive human joint capsule MFs from biopsy specimens and investigated the effect of profibrotic and antifibrotic agents on MF function. Both TGF-β1 and PDGF significantly induced proliferation and increased extracellular matrix contraction in an established 3D collagen gel contraction model. Furthermore, both growth factors induced α-SMA and collagen type I gene expression in MFs. TGF-β1 down-regulated TGF-β1 and TGF-β receptor (R) 1 and receptor (R) 2 gene expression, while PDGF selectively down-regulated TGF-β receptor 2 gene expression. These effects were blocked by suramin. Interestingly, the anti-oxidant agent superoxide dismutase (SOD) blocked TGF-β1 induced proliferation and collagen gel contraction without modulating the gene expression of α-SMA, collagen type I, TGF-β1, TGF-β R1 and TGF-β R2. Conclusions Our results provide evidence that targeting the TGF-β1 and PDGF pathways in human joint capsule MFs affects their contractile function. TGF-β1 may modulate MF function in the joint capsule not only via the receptor signalling pathway but also by regulating the production of profibrotic reactive oxygen species (ROS). In particular, anti-oxidant agents could offer promising options in developing strategies for the prevention and treatment of posttraumatic joint stiffness in humans.
Glycan Elongation Beyond the Mucin Associated Tn Antigen Protects Tumor Cells from Immune-Mediated Killing

Membrane bound mucins are up-regulated and aberrantly glycosylated during malignant transformation in many cancer cells. This results in a negatively charged glycoprotein coat which may protect cancer cells from immune surveillance. However, only limited data have so far demonstrated the critical steps in glycan elongation that make aberrantly glycosylated mucins affect the interaction between cancer cells and cytotoxic effector cells of the immune system. Tn (GalNAc-Ser/Thr), STn (NeuAcα2-6GalNAc-Ser/Thr), T (Galβ1–3GalNAc-Ser/Thr), and ST (NeuAcα2-6Galβ1–3GalNAc-Ser/Thr) antigens are recognized as cancer associated truncated glycans, and are expressed in many adenocarcinomas, e.g. breast- and pancreatic cancer cells. To investigate the role of the cancer associated glycan truncations in immune-mediated killing we created glyco-engineered breast- and pancreatic cancer cells expressing only the shortest possible mucin-like glycans (Tn and STn). Glyco-engineering was performed by zinc finger nuclease (ZFN) knockout (KO) of the Core 1 enzyme chaperone COSMC, thereby preventing glycan elongation beyond the initial GalNAc residue in O-linked glycans. We find that COSMC KO in the breast and pancreatic cancer cell lines T47D and Capan-1 increases sensitivity to both NK cell mediated antibody-dependent cellular-cytotoxicity (ADCC) and cytotoxic T lymphocyte (CTL)-mediated killing. In addition, we investigated the association between total cell surface expression of MUC1/MUC16 and NK or CTL mediated killing, and observed an inverse correlation between MUC16/MUC1 expression and the sensitivity to ADCC and CTL-mediated killing. Together, these data suggest that up-regulation of membrane bound mucins protects cells from immune mediated killing, and that particular glycosylation steps, as demonstrated for glycan elongation beyond Tn and STn, can be important for fine tuning of the immune escape mechanisms in cancer cells.
Targeted Lipidomic and Transcriptomic Analysis Identifies Dysregulated Renal Ceramide Metabolism in a Mouse Model of Diabetic Kidney Disease

Both type 1 and type 2 diabetes are associated with altered lipid metabolism, which might in part contribute to debilitating complications such as diabetic kidney disease (DKD). Ceramides are bioactive sphingolipids that have been implicated in a variety of diseases as they can regulate cellular responses to stress and invoke a myriad of downstream signaling responses. To investigate a potential role of altered ceramide metabolism in DKD, we utilized a highly sensitive and specific mass spectrometry (MS) method to quantitatively measure species in plasma and kidney cortex from the C57BLKS db/db mouse model of DKD and littermate controls. Long-chain ceramides (C14:0, C16:0, C18:0, C20:0) and a glucosylceramide (Glu-Cer C18:0) were increased in diabetic mouse plasma, while long-chain (C14:0, C16:0, C18:0) and very-long-chain (C24:0, C24:1) ceramides and a glucosylceramide (Glu-Cer C16:0) were decreased in diabetic mouse kidney tissue. Kidney and plasma ceramide levels correlated to functional and histopathological features of DKD. Transcriptomic analysis of mouse kidney tissue revealed expression changes indicative of decreased ceramide synthesis (Degs2, Smpd2) and increased conversion to sphingosine (Acer2) and downstream sphingosine-1-phosphate signaling. Correlation analysis identified a negative relationship between plasma and kidney tissue levels of ceramide C16:0 and ceramide C24:1. Overall, the findings suggest a previously unrecognized role for ceramide metabolism in DKD.