Miracle-dz/UniFAR-FTUs huggingface dataset:
A Novel Osteogenic Oxysterol Compound for Therapeutic Development to Promote Bone Growth: Activation of Hedgehog Signaling and Osteogenesis Through Smoothened Binding

Osteogenic factors are often used in orthopedics to promote bone growth, improve fracture healing, and induce spine fusion. Osteogenic oxysterols are naturally occurring molecules that were shown to induce osteogenic differentiation in vitro and promote spine fusion in vivo. The purpose of this study was to identify an osteogenic oxysterol more suitable for clinical development than those previously reported, and evaluate its ability to promote osteogenesis in vitro and spine fusion in rats in vivo. Among more than 100 oxysterol analogues synthesized, Oxy133 induced significant expression of osteogenic markers Runx2, osterix (OSX), alkaline phosphatase (ALP), bone sialoprotein (BSP), and osteocalcin (OCN) in C3H10T1/2 mouse embryonic fibroblasts and in M2‐10B4 mouse marrow stromal cells. Oxy133‐induced activation of an 8X‐Gli luciferase reporter, its direct binding to Smoothened, and the inhibition of Oxy133‐induced osteogenic effects by the Hedgehog (Hh) pathway inhibitor, cyclopamine, demonstrated the role of Hh pathway in mediating osteogenic responses to Oxy133. Oxy133 did not stimulate osteogenesis via BMP or Wnt signaling. Oxy133 induced the expression of OSX, BSP, and OCN, and stimulated robust mineralization in primary human mesenchymal stem cells. In vivo, bilateral spine fusion occurred through endochondral ossification and was observed in animals treated with Oxy133 at the fusion site on X‐ray after 4 weeks and confirmed with manual assessment, micro‐CT (µCT), and histology after 8 weeks, with equal efficiency to recombinant human bone morphogenetic protein‐2 (rhBMP‐2). Unlike rhBMP‐2, Oxy133 did not induce adipogenesis in the fusion mass and resulted in denser bone evidenced by greater bone volume/tissue volume (BV/TV) ratio and smaller trabecular separation. Findings here suggest that Oxy133 has significant potential as an osteogenic molecule with greater ease of synthesis and improved time to fusion compared to previously studied oxysterols. Small molecule osteogenic oxysterols may serve as the next generation of bone anabolic agents for therapeutic development. © 2014 American Society for Bone and Mineral Research.
Factors Predicting Erythropoietin Resistance among Maintenance Hemodialysis Patients

Background: Erythropoiesis-stimulating agent (ESA) resistance remains incompletely understood among hemodialysis (HD) patients. Method: A retrospective, multicenter study was designed to analyze data from 1,934 patients followed for up to two years. The outcome measure was the erythropoietin resistance index (ERI), defined as erythropoietin dosage over a week divided by the post-HD weight and hemoglobin value. Results: Multivariate analysis revealed albumin, Kt/V, transferrin saturation, statin use and male gender to be inversely related to ERI, whereas parathyroid hormone and angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) use were associated with higher ESA resistance. ERI was statistically lower in patients with higher levels of albumin (p < 0.001) and with higher transferrin saturation levels (p < 0.05). Discussion: The results allow for a better understanding of predictors of erythropoietin resistance among HD patients including not extensively studied factors such as statin and ACEI/ARB use.
Phonotactics in the perception of Japanese vowel length: evidence for long-distance dependencies

These experiments investigate whether the perceptual boundary between [a] and [a:] is affected by the differing phonotactics of the Sino-Japanese and Foreign strata of the Japanese lexicon. We presented a range of edited natural vowels from [a] to [a:] at the end of carrier nonwords of the form [CoC'__] and asked subjects to judge whether the final vowel was long or short, while C and C' were varied to make 9 carriers ranging from very Sino-Japanese-like to very Foreign-like. The perceptual boundary between [a] and [a:] was affected by both C and C', shifting through about 20 msec—a larger and more robust effect than was obtained in a word-superiority experiment with the same paradigm and subjects. These results cast doubt on explanations of phonotactic effects based on lexical-activation spreading. The influence of C at a distance of three phonemes from the ambiguous segment cannot be explained by simple segment-to-segment transitional probabilities.
Improved vertex control for time-varying and uncertain linear discrete-time systems with control and state constraints

This paper addresses the problem of regulating a discrete-time linear uncertain and time-varying system to the origin. It is shown that, based on an interpolation technique, by minimizing an appropriate objective function, how feasibility and a robustly and asymptotically stable closed-loop behavior can be achieved. It is shown that the control is a piecewise afflne and continuous function of the state. Several simulations demonstrate the performance of our results.
Foxn1 maintains thymic epithelial cells to support T-cell development via mcm2 in zebrafish

The thymus is mainly comprised of thymic epithelial cells (TECs), which form the unique thymic epithelial microenvironment essential for intrathymic T-cell development. Foxn1, a member of the forkhead transcription factor family, is required for establishing a functional thymic rudiment. However, the molecular mechanisms underlying the function of Foxn1 are still largely unclear. Here, we show that Foxn1 functions in thymus development through Mcm2 in the zebrafish. We demonstrate that, in foxn1 knockdown embryos, the thymic rudiment is reduced and T-cell development is impaired. Genome-wide expression profiling shows that a number of genes, including some known thymopoiesis genes, are dysregulated during the initiation of the thymus primordium and immigration of T-cell progenitors to the thymus. Functional and epistatic studies show that mcm2 and cdca7 are downstream of Foxn1, and mcm2 is a direct target gene of Foxn1 in TECs. Finally, we find that the thymus defects in foxn1 and mcm2 morphants might be attributed to reduced cell proliferation rather than apoptosis. Our results reveal that the foxn1-mcm2 axis plays a central role in the genetic regulatory network controlling thymus development in zebrafish.
A Combination of CD28 (rs1980422) and IRF5 (rs10488631) Polymorphisms Is Associated with Seropositivity in Rheumatoid Arthritis: A Case Control Study

Introduction The aim of the study was to analyse genetic architecture of RA by utilizing multiparametric statistical methods such as linear discriminant analysis (LDA) and redundancy analysis (RDA). Methods A total of 1393 volunteers, 499 patients with RA and 894 healthy controls were included in the study. The presence of shared epitope (SE) in HLA-DRB1 and 11 SNPs (PTPN22 C/T (rs2476601), STAT4 G/T (rs7574865), CTLA4 A/G (rs3087243), TRAF1/C5 A/G (rs3761847), IRF5 T/C (rs10488631), TNFAIP3 C/T (rs5029937), AFF3 A/T (rs11676922), PADI4 C/T (rs2240340), CD28 T/C (rs1980422), CSK G/A (rs34933034) and FCGR3A A/C (rs396991), rheumatoid factor (RF), anti–citrullinated protein antibodies (ACPA) and clinical status was analysed using the LDA and RDA. Results HLA-DRB1, PTPN22, STAT4, IRF5 and PADI4 significantly discriminated between RA patients and healthy controls in LDA. The correlation between RA diagnosis and the explanatory variables in the model was 0.328 (Trace = 0.107; F = 13.715; P = 0.0002). The risk variants of IRF5 and CD28 genes were found to be common determinants for seropositivity in RDA, while positivity of RF alone was associated with the CTLA4 risk variant in heterozygous form. The correlation between serologic status and genetic determinants on the 1st ordinal axis was 0.468, and 0.145 on the 2nd one (Trace = 0.179; F = 6.135; P = 0.001). The risk alleles in AFF3 gene together with the presence of ACPA were associated with higher clinical severity of RA. Conclusions The association among multiple risk variants related to T cell receptor signalling with seropositivity may play an important role in distinct clinical phenotypes of RA. Our study demonstrates that multiparametric analyses represent a powerful tool for investigation of mutual relationships of potential risk factors in complex diseases such as RA.
A Hydro-elastic Model of Hydrocephalus

We combine elements of poroelasticity and of fluid mechanics to construct a mathematical model of the human brain and ventricular system. The model is used to study hydrocephalus, a pathological condition in which the normal flow of the cerebrospinal fluid is disturbed, causing the brain to become deformed. Our model extends recent work in this area by including flow through the aqueduct, by incorporating boundary conditions which we believe more accurately represent the anatomy of the brain and by including time dependence. This enables us to construct a quantitative model of the onset, development and treatment of this condition. We formulate and solve the governing equations and boundary conditions for this model and give results which are relevant to clinical observations.
Statistical Applications in Genetics and Molecular Biology Lasso Logistic Regression , GSoft and the Cyclic Coordinate Descent Algorithm : Application to Gene Expression Data

Statistical methods generating sparse models are of great value in the gene expression field, where the number of covariates (genes) under study moves about the thousands while the sample sizes seldom reach a hundred of individuals. For phenotype classification, we propose different lasso logistic regression approaches with specific penalizations for each gene. These methods are based on a generalized soft-threshold (GSoft) estimator. We also show that a recent algorithm for convex optimization, namely, the cyclic coordinate descent (CCD) algorithm, provides with a way to solve the optimization problem significantly faster than with other competing methods. Viewing GSoft as an iterative thresholding procedure allows us to get the asymptotic properties of the resulting estimates in a straightforward manner. Results are obtained for simulated and real data. The leukemia and colon datasets are commonly used to evaluate new statistical approaches, so they come in useful to establish comparisons with similar methods. Furthermore, biological meaning is extracted from the leukemia results, and compared with previous studies. In summary, the approaches presented here give rise to sparse, interpretable models that are competitive with similar methods developed in the field.
Rhizophoraceae Mangrove Saplings Use Hypocotyl and Leaf Water Storage Capacity to Cope with Soil Water Salinity Changes

Some of the most striking features of Rhizophoraceae mangrove saplings are their voluminous cylinder-shaped hypocotyls and thickened leaves. The hypocotyls are known to serve as floats during seed dispersal (hydrochory) and store nutrients that allow the seedling to root and settle. In this study we investigate to what degree the hypocotyls and leaves can serve as water reservoirs once seedlings have settled, helping the plant to buffer the rapid water potential changes that are typical for the mangrove environment. We exposed saplings of two Rhizophoraceae species to three levels of salinity (15, 30, and 0–5‰, in that sequence) while non-invasively monitoring changes in hypocotyl and leaf water content by means of mobile NMR sensors. As a proxy for water content, changes in hypocotyl diameter and leaf thickness were monitored by means of dendrometers. Hypocotyl diameter variations were also monitored in the field on a Rhizophora species. The saplings were able to buffer rapid rhizosphere salinity changes using water stored in hypocotyls and leaves, but the largest water storage capacity was found in the leaves. We conclude that in Rhizophora and Bruguiera the hypocotyl offers the bulk of water buffering capacity during the dispersal phase and directly after settlement when only few leaves are present. As saplings develop more leaves, the significance of the leaves as a water storage organ becomes larger than that of the hypocotyl.
Anticancer activities of artemisinin and its bioactive derivatives

Artemisinin, a sesquiterpene lactone derived from the sweet wormwood plant Artemisia annua, and its bioactive derivatives exhibit potent anticancer effects in a variety of human cancer cell model systems. The pleiotropic response in cancer cells includes growth inhibition by cell cycle arrest, apoptosis, inhibition of angiogenesis, disruption of cell migration, and modulation of nuclear receptor responsiveness. These effects of artemisinin and its derivatives result from perturbations of many cellular signalling pathways. This review provides a comprehensive discussion of these cellular responses, and considers the ramifications for the potential development of artemisinin-based compounds in anticancer therapeutic and preventative strategies.
Efficient portfolio valuation incorporating liquidity risk

Abstract According to the theory proposed by Acerbi and Scandolo (2008) [Quant. Finance, 2008, 8, 681–692], an asset is described by the so-called Marginal Supply–Demand Curve (MSDC), which is a collection of bid and ask prices according to its trading volumes, and the value of a portfolio is defined in terms of commonly available market data and idiosyncratic portfolio constraints imposed by an investor holding the portfolio. Depending on the constraints, one and the same portfolio could have different values for different investors. As it turns out, within the Acerbi–Scandolo theory, portfolio valuation can be framed as a convex optimization problem. We provide useful MSDC models and show that portfolio valuation can be solved with remarkable accuracy and efficiency.
The Rodney L. White Center for Financial Research An Exploration of the Effects of Pessimism and Doubt on Asset Returns

The subjective distribution of growth rates of aggregate consumption is characterized by pessimism if it is first-order stochastically dominated by the objective distribution. Uniform pessimism is a leftward translation of the objective distribution of the logarithm of the growth rate. The subjective distribution is characterized by doubt if it is mean-preserving spread of the objective distribution. Pessimism and doubt both reduce the riskfree rate and thus can help resolve the riskfree rate puzzle. Uniform pessimism and doubt both increase the average equity premium and thus can help resolve the equity premium puzzle. I thank Bill Dupor, David Gross, Urban Jermann, Qiang Kang, Raj Mehra, Thomas Sargent, Amir Yaron, Lu Zhang, the Penn Macro Lunch Group, and an anonymous referee for helpful comments.
Pre‐Kidney Transplant Lower Extremity Impairment and Post‐Kidney Transplant Mortality

Prediction models for post‐kidney transplantation mortality have had limited success (C‐statistics ≤0.70). Adding objective measures of potentially modifiable factors may improve prediction and, consequently, kidney transplant (KT) survival through intervention. The Short Physical Performance Battery (SPPB) is an easily administered objective test of lower extremity function consisting of three parts (balance, walking speed, chair stands), each with scores of 0–4, for a composite score of 0–12, with higher scores indicating better function. SPPB performance and frailty (Fried frailty phenotype) were assessed at admission for KT in a prospective cohort of 719 KT recipients at Johns Hopkins Hospital (8/2009 to 6/2016) and University of Michigan (2/2013 to 12/2016). The independent associations between SPPB impairment (SPPB composite score ≤10) and composite score with post‐KT mortality were tested using adjusted competing risks models treating graft failure as a competing risk. The 5‐year posttransplantation mortality for impaired recipients was 20.6% compared to 4.5% for unimpaired recipients (p < 0.001). Impaired recipients had a 2.30‐fold (adjusted hazard ratio [aHR] 2.30, 95% confidence interval [CI] 1.12–4.74, p = 0.02) increased risk of postkidney transplantation mortality compared to unimpaired recipients. Each one‐point decrease in SPPB score was independently associated with a 1.19‐fold (95% CI 1.09–1.30, p < 0.001) higher risk of post‐KT mortality. SPPB‐derived lower extremity function is a potentially highly useful and modifiable objective measure for pre‐KT risk prediction.
Bronchial anthracofibrosis and tuberculosis: CT features before and after treatment.

Long R, Wong E, Barrie J(AQ1) ronchial narrowing or obliteration with black pigmentation of overlying mucosa has been termed “anthracofibrosis” [1]. Its occurrence in nonsmoking Koreans, especially women, who have had no occupational exposure to coal dust but who were possibly exposed to wood smoke has been associated with tuberculosis (TB) [1, 2]. Anthracofibrosis is said to occur in other Asian populations and blacks, but no documentation of this is available to our knowledge, nor are reports of this syndrome in Asian or black immigrants to North America. The response of anthracofibrosis-related TB to antituberculosis drugs is unknown. In Alberta, a province of Canada that accepts more than 15,000 new immigrants annually, we diagnosed two cases of anthracofibrosis-related pulmonary TB in adult female immigrants from East India. These cases constituted 7.7% (2/26) of all culture-positive pulmonary TB cases diagnosed in adult (≥14 years), female, foreign-born persons in the province in calendar year 2002. We report the pretreatment and posttreatment contrast-enhanced CT scan and bronchoscopic findings of this syndrome.
Experience with a Computer Word-Entry Method in Processing Chinese Characters by Fluent Typists

A 2003 study by Green and Bavelier showed that action video-game playing modified the visual selective attention of habitual players so the present hypothesis was whether processing of Chinese characters became more phonologically or orthographically oriented depending on whether participants were experienced typing with the phonological (zhuyin) or the orthographic (changjie) word-entry method. In Exp. 1, 38 changjie and 40 zhuyin users typed a short text on a computer using the word-entry method they had experienced. Every keystroke was recorded, and typing errors were categorized. In Exp. 2, 25 changjie and 25 zhuyin users had to circle all characters which contained a predesignated radical when they read a short passage. In Exp. 3, 25 changjie and 20 zhuyin users heard pairs of syllables and had to decide whether the two syllables in a pair shared the same onset consonant in one block of trials or the same rhyme in another block of trials. Analysis showed participants with extensive experience using phonological typing displayed more phonologically related typing errors, better sensitivity to the onset and rhyme of a syllable, but poorer sensitivity to the radical of a character. Participants with extensive experience using orthographic typing displayed opposite results. Although the general cognitive system might be similar in the two groups of participants, the specific configuration of the system can vary to meet the demand of a particular design of the artifactual environment.
Animation pipeline: realistic speech based on observed 3D face dynamics

We propose an efficient system for realistic speech animation. The system supports all steps of the animation pipeline, from the capture or design of 3D head models up to the synthesis and editing of the performance. This pipeline is fully 3D, which yields high flexibility in the use of the animated character. Real detailed 3D face dynamics, observed at video frame rate for thousands of points on the face of speaking actors, underpin the realism of the facial deformations. These are given a compact and intuitive representation via Independent Component Analysis (ICA). Performances amount to trajectories through this ‘Viseme Space’. When asked to animate a face the system replicates the ‘Visemes’ that it has learned, and adds the necessary coarticulation effects. Realism has been improved through comparisons with motion captured groundtruth. Faces for which no 3D dynamics could be observed can be animated nonetheless. Their visemes are adapted automatically to their physiognomy by localising the face in a ‘Face Space’.
Negative resist image by dry etching as a novel top surface imaging process for ion-beam lithography

Focused Ion beam (FIB) lithography has significant advantages over the electron beam counterpart in terms of resist sensitivity, backscattering and proximity effects. However, combining the FIB lithography with Top Surface Imaging (TSI) will extend its advantages by allowing anisotropic processing of thicker resist layers. This paper reports the development of novel single layer lithography process by combining focused Ga+ ion beam (Ga+ FIB) lithography, silylation and oxygen dry etching. The Negative Resist Image by Dry Etching (NERIME) is a TSI scheme for DNQ/novolak based resists and can result in either positive or negative resist images depending on the extent of the ion beam exposure dose. Results show that Ga+ ion beam dose in the range of 1μC/cm2 to 50μC/cm2 at 30keV can successfully prevent silylation of the resist, thus resulting in the formation of positive image after the dry etching. A negative image can be formed by using a second Ga+ ion beam exposure with a dose higher than 900 μC/cm2 at 30keV to pattern lines into the original exposed resist area. It was observed that resist regions exposed to such high doses can effectively withstand oxygen dry development, thus giving formation of negative resist image. In this study, nanometer resist patterns with high aspect ratio up to 15 were successfully resolved due to the ion beam exposure and anisotropic dry development. This novel TSI scheme for ion beam lithography could be utilized for the fabrication of critical CMOS process steps, such as deep isolation trench formation and lithography over substantial topography.
The autoimmune response to chromatin antigens in systemic lupus erythematosus: autoantibodies against histone H1 are a highly specific marker for SLE associated with increased disease activity

This study investigates specificity, sensitivity and concomitant presence of antibodies against histone H1 (H1), nucleosomes (NUC), chromatin (CHR) and dsDNA in patients with systemic lupus erythematosus (SLE), analyses their association with SLE disease activity and characterizes the immunodominant epitope reactivity of anti-H1 antibodies and its relation to SLE disease activity. In a cross-sectional study 394 sera of patients with various rheumatic diseases and healthy subjects were analysed by ELISA for antibodies against H1, NUC, CHR and dsDNA. In addition, a longitudinal analysis was performed that included 121 sequential serum samples derived from 16 SLE patients to assess the relation of these antibodies as well as antibodies to histone H2B to SLE disease activity. To assess epitope reactivity of anti-H1 antibodies overlapping synthetic peptides covering the entire H1 sequence were used. Anti-H1 antibodies yielded a sensitivity of approximately 45% and a specificity of over 98% for SLE, which was comparable to that found for anti-dsDNA antibodies. Anti-CHR and anti-NUC antibodies were of similar sensitivity but slightly (anti-CHR) or considerably (anti-NUC) less specific for SLE (95 and 85%, respectively). The sequential analysis revealed a strong correlation of anti-H1 antibodies with SLE disease activity that was better than the correlation of anti-dsDNA and anti-NUC antibodies, while only weak correlation was found for anti-CHR and anti-H2B antibodies. The immunodominant epitope for anti-H1 was localised between amino acids 204 and 218 (pp204–218) and immune reactivity to this epitope also correlated with disease activity. Anti-H1 is a highly specific marker for SLE with a diagnostic value comparable to anti-dsDNA. A positive testing for anti-H1 indicates increased disease activity, as does the appearance of antibodies to its immunodominant epitope pp204–218.