Miracle-dz/UniFAR-FTUs huggingface dataset:
APR-246/PRIMA-1MET rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations

p53 and p63 share extensive sequence and structure homology. p53 is frequently mutated in cancer, whereas mutations in p63 cause developmental disorders manifested in ectodermal dysplasia, limb defects, and orofacial clefting. We have established primary adult skin keratinocytes from ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome patients with p63 mutations as an in vitro human model to study the disease mechanism in the skin of EEC patients. We show that these patient keratinocytes cultured either in submerged 2D cultures or in 3D skin equivalents have impaired epidermal differentiation and stratification. Treatment of these patient keratinocytes with the mutant p53-targeting compound APR-246/PRIMA-1MET (p53 reactivation and induction of massive apoptosis) that has been successfully tested in a phase I/II clinical trial in cancer patients partially but consistently rescued morphological features and gene expression during epidermal stratification in both 2D and 3D models. This rescue coincides with restoration of p63 target-gene expression. Our data show that EEC patient keratinocytes with p63 mutations can be used for characterization of the abnormal molecular circuitry in patient skin and may open possibilities for the design of novel pharmacological treatment strategies for patients with mutant p63-associated developmental abnormalities.
Hypoxic Cell Death is Reduced by pH Buffering in a Model of Engineered Heart Tissue

Introduction: In this report, we tested the ability of HEPES-buffered culture medium to reduce acidotic cell death in hypoxic monolayer cell cultures and in a diffusion-limited model of engineered heart tissue (EHT). Methods: Neonatal rat cardiomyocytes were either plated (monolayers) or suspended in a hydrogel disc containing HEPES. Results: Monolayers cultured in 0% oxygen exhibited a pH drop to 5.46 ± 0.27 after 4 days with no HEPES, or 7.11 ± 0.09 with 50 mM HEPES. The lowest observed pH in EHTs was estimated as 6.2 with no HEPES and 7.1 with 50 mM HEPES, which were endpoints of noticeably different pH gradients across the EHTs. Addition of HEPES to hypoxic monolayers corresponded with fewer propidium iodide-positive cells and TUNEL-positive cells; addition of HEPES to EHTs resulted in greater calcein staining and less LDH release. Conclusion: Effective pH buffering reduces cell death by attenuating the acidosis that accompanies anaerobic metabolism.
Galaxies at z = 6 - 9 from the WFC3/IR imaging of the HUDF

We present the results of a systematic search for galaxies in the redshift range z = 6 - 9, within the new, deep, near-infrared imaging of the Hubble Ultra Deep Field provided by the Wide Field Camera 3 (WFC3) on HST. We have performed full SED fitting to the optical+infrared photometry of all high-redshift galaxy candidates detected at greater than 5-sigma in at least one of the WFC3/IR broad-band filters. After rejection of contaminants, the result is a sample of 49 galaxies with primary redshift solutions z > 5.9. Our sample, selected without recourse to specific colour cuts, re-selects all but the faintest one of the 16 z-drops selected by Oesch et al. (2009), recovers all 5 of the Y-drops reported by Bouwens et al. (2009), and adds a further 29 galaxy candidates, of which 12 lie beyond z = 6.3, and 4 lie beyond z = 7. We also present confidence intervals on our photometric redshift estimates, and caution that acceptable low-redshift (z 6.3, and for all 8 galaxy candidates at z > 7.5. Nevertheless, the very highest redshift candidates appear to be strongly clustered in the field. We derive new estimates of the ultraviolet galaxy luminosity function at z = 7 and z = 8. Where our results are most robust, at a characteristic luminosity M(1500) ~ -19.5 (AB), we find that the comoving number density of galaxies declines by a factor of ~ 2.5 between z = 6 and z = 7, and by a further factor of ~ 2 by z = 8. These results suggest that it is difficult for the observed population of high-redshift star-forming galaxies to achieve reionisation by z ~ 6 without a significant contribution from galaxies well below the detection limits, plus alterations in the escape fraction of ionising photons and/or continued vigorous star formation at z > 15.
Algorithm Aversion: People Erroneously Avoid Algorithms after Seeing Them Err

Research shows that evidence-based algorithms more accurately predict the future than do human forecasters. Yet when forecasters are deciding whether to use a human forecaster or a statistical algorithm, they often choose the human forecaster. This phenomenon, which we call algorithm aversion, is costly, and it is important to understand its causes. We show that people are especially averse to algorithmic forecasters after seeing them perform, even when they see them outperform a human forecaster. This is because people more quickly lose confidence in algorithmic than human forecasters after seeing them make the same mistake. In 5 studies, participants either saw an algorithm make forecasts, a human make forecasts, both, or neither. They then decided whether to tie their incentives to the future predictions of the algorithm or the human. Participants who saw the algorithm perform were less confident in it, and less likely to choose it over an inferior human forecaster. This was true even among those who saw the algorithm outperform the human.
Anticancer and Immunopotentiating Activities of Crude Polysaccharides from Pleurotus nebrodensis on Mouse Sarcoma 180

Pleurotus nebrodensis is an edible and commercially available mushroom in Korea. This study was conducted in order to evaluate the anticancer and immunopotentiating activities of crude polysaccharides, extracted in methanol, neutral saline, and hot water (hereafter referred to as Fr. MeOH, Fr. NaCl, and Fr. HW, respectively) from the fruiting bodies of P. nebrodensis. β-Glucan and protein contents in Fr. MeOH, Fr. NaCl, and Fr. HW extracts of P. nebrodensis ranged from 23.79~36.63 g/100 g and 4.45~6.12 g/100 g, respectively. Crude polysaccharides were not cytotoxic against sarcoma 180, HT-29, NIH3T3, and RAW 264.7 cell lines at a range of 10~2,000 μg/mL. Intraperitoneal injection with crude polysaccharides resulted in a life prolongation effect of 11.76~27.06% in mice previously inoculated with sarcoma 180. Treatment with Fr. NaCl resulted in an increase in the numbers of spleen cells by 1.49 fold at the concentration of 50 μg/mL, compared with control. Fr. HW improved the immuno-potentiating activity of B lymphocytes through an increase in alkaline phosphatase activity by 1.65 fold, compared with control at 200 μg/mL. Maximum production of nitric oxide (14.3 μM) was recorded in the Fr. NaCl fraction at 200 μg/mL. Production of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) was significantly higher, compared to control, and IL-6 production was highest, in contrast to TNF-α, IL-1β, and positive control, concanavalin at the tested concentration of the various fractions. Results of the current study suggest that polysaccharides extracted from P. nebrodensis have a strong anticancer effect and may be useful as an ingredient of biopharmaceutical products for treatment of cancer.
Phagocytosis and Macrophage Activation Associated With Hemorrhagic Microvessels in Human Atherosclerosis

Objective—Previously, we demonstrated that activated inducible NO synthase (iNOS)-expressing foam cells in human carotid plaques often produce autofluorescent (per)oxidized lipids (ceroid). Here, we investigate whether intraplaque microvessels can provide foam cells with lipids and trigger macrophage activation. Methods and Results—Microvessels (von Willebrand factor [vWf] immunoreactivity), activated macrophages (iNOS immunoreactivity), and ceroid were systematically mapped in longitudinal sections of 15 human carotid endarterectomy specimens. An unbiased hierarchical cluster analysis classified vascular regions into 2 categories. One type with normal vWf expression and without inflammatory cells was seen, and another type with cuboidal endothelial cells, perivascular vWf deposits, and iNOS and ceroid-containing foam cells was seen in 4 (27%) of 15 plaques. The perivascular foam cells frequently contained platelets (glycoprotein Ib&agr;) and erythrocytes (hemoglobin, iron), pointing to microhemorrhage/thrombosis and subsequent phagocytosis. Similar lipid-containing cells, expressing both ceroid and iNOS, were generated in atherosclerosis-free settings by incubating murine J774 macrophages with platelets or oxidized erythrocytes and also in vivo in organizing thrombi in normocholesterolemic rabbits. Conclusions—Focal intraplaque microhemorrhages initiate platelet and erythrocyte phagocytosis, leading to iron deposition, macrophage activation, ceroid production, and foam cell formation. Neovascularization, besides supplying plaques with leukocytes and lipoproteins, can thus promote focal plaque expansion when microvessels become thrombotic or rupture prone.
Mechanical properties of aluminium–copper B206 alloys with iron and silicon additions

Abstract Mechanical properties of B206 aluminium alloys with additions of iron and silicon were studied to investigate the combined effect of these additions on tensile strengths and ductility. Properties are highly influenced by the iron to silicon ratio and the nominal concentration of the single elements. The best properties were obtained with both a ratio close to one and low concentrations of iron and silicon. Present experimental results show that it is possible to multiply by two or three the present limit of 0·1 wt-%Fe in these alloys at natural aging (T4) and still obtain the minimum of 7% elongation required by the automotive industry. At artificial aging (T7), it will be very difficult however to reach the 7% elongation with ∼0·2 wt-%Fe and 0·2 wt-%Si, while this seems impossible with ∼0·3 wt-%Fe and 0·3 wt-%Si. It was found that macrosegregation of Cu in the gage section of the ASTM B108 test bars is responsible for an enrichment of 0·8–0·9 wt-% of this element in the test zone. This has produced microstructures saturated in Cu with little Al2Cu phase remaining after the solution heat treatment. Owing to the low amount of this phase and the round shape of the particles, the remaining Al2Cu phase did not have a significant impact on the ductility. One benefit of working with a Cu saturated microstructure is that one can estimate the true temperature of the solution heat treatment by conducting a post-analysis of Cu content in the dendrites. This should be helpful to reduce the variability in properties and to improve the temperature distribution in heat treating furnaces.
Clinical Utility of an Enzyme-Linked Immunosorbent Assay for Detecting Anti-Melanoma Differentiation-Associated Gene 5 Autoantibodies

Objective Autoantibodies to melanoma differentiation-associated gene 5 (MDA5) are specifically expressed in patients with dermatomyositis (DM) and are associated with a subset of DM patients with rapidly progressive interstitial lung disease (RP-ILD). Here, we examined the clinical utility of a newly developed enzyme-linked immunosorbent assay (ELISA) system for detecting these antibodies. Methods Here we developed an improved ELISA for detecting anti-MDA5 antibodies. We then performed a multicenter clinical study involving 8 medical centers and enrolled 242 adult patients with polymyositis (PM)/DM, 190 with non-PM/DM connective tissue disease (CTD), 154 with idiopathic interstitial pneumonia (IIP), and 123 healthy controls. Anti-MDA5 antibodies in the patients’ serum samples were quantified using our newly developed ELISA, and the results were compared to those obtained using the gold-standard immunoprecipitation (IP) assay. In addition, correlations between the ELISA-quantified anti-MDA5 antibodies and clinical characteristics were evaluated. Results In patients with PM/DM, the anti-MDA5 antibody measurements obtained from the ELISA and IP assay were highly concordant; the ELISA exhibited an analytical sensitivity of 98.2%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 99.5% (compared to the IP assay). Anti-MDA5 antibodies were detected in 22.7% of the DM patients, but not in any of the patients with PM, non-PM/DM CTD, or IIP. Clinically amyopathic DM, RP-ILD, arthritis, and fever were more prevalent in DM patients who were anti-MDA5 antibody-positive than in those who were antibody-negative (P ≤ 0.0002 for all comparisons). In addition, anti-MDA5 antibody-positive patients with RP-ILD exhibited higher antibody levels than those without RP-ILD (P = 0.006). Conclusion Our newly developed ELISA can detect anti-MDA5 antibodies as efficiently as the gold standard IP assay and has the potential to facilitate the routine clinical measurement of anti-MDA5 antibodies in patients who suspected to have DM.
Using Interactive Computer Simulation for Teaching the Proper Use of Personal Protective Equipment

The use of personal protective equipment is one of the basic infection control precautions in health care. The effectiveness of personal protective equipment is highly dependent on adequate staff training. In this project, a computer simulation program, as a supplement to conventional training approaches, was developed to facilitate the learning of the proper use of personal protective equipment. The simulation program was a Web-based interactive software with user-friendly graphical interface for users to practice the use of personal protective equipment usage via drag-and-drop metaphors and respond to questions online. The effectiveness of the computer simulation software was investigated by a controlled study. Fifty healthcare workers were randomly assigned into two groups: one received conventional personal protective equipment training only (control group), whereas the other also received the same conventional training but followed by using the developed simulation program for self-learning (experimental group). Their performance was assessed by personal protective equipment donning and doffing evaluation before and after the training. The results showed that the computer simulation program is able to improve the healthcare workers’ understanding and competence in using personal protective equipment.
A clinical survival score predicts the likelihood to benefit from preoperative thallium scanning and coronary revascularization before major vascular surgery.

AIMS Guidelines advocate selective non-invasive testing before major non-cardiac surgery, yet data defining who may benefit from such tests is lacking. We aimed to find the predictors that define patients who are most likely to benefit from preoperative cardiac testing and coronary revascularization (CR). METHODS AND RESULTS In 624 consecutive major vascular surgery patients, the preoperative thallium scanning (PTS) results and subsequent CRs were correlated with long-term (3-15 years) survival. Of all patients, 510 (80.6%) had PTS, 154 (24.7%) had moderate-severe ischaemia on PTS, and 96 (15.4%) underwent CR. Seven predictors: age >or=65, diabetes, cerebrovascular disease, ischaemic heart disease, congestive heart failure, ST-depression on preoperative ECG, and renal insufficiency, independently determined long-term survival. A long-term survival score (LTSS) comprised of these predictors, divided all patients into low, intermediate, and high-risk groups (0-1, 2-3, >or=4 predictors, respectively) with a 5-year survival of 83 +/- 2%, 60 +/- 3%, and 34 +/- 6%, respectively. Compared with low-risk patients, intermediate and high-risk patients had worse survival [HR (CI) = 2.6 (2.0-3.4) and 5.9 (4.1-8.9), respectively, P < 0.001]. Yet, only the intermediate-risk group had better long-term survival following preoperative CR [HR = 0.48 (0.31-0.75), P = 0.001]. The low-risk groups' favourable survival and high-risk groups' poor survival were not significantly affected by CR. CONCLUSION Intermediate-risk patients (LTSS 2-3) are most likely to have a long-term survival benefit from PTS and CR.
Enhanced Motor Cortex Excitability During Ipsilateral Voluntary Hand Activation in Healthy Subjects and Stroke Patients

Background and Purpose— It is still a matter of debate whether the ipsilateral voluntary hand activation has a facilitatory or inhibitory effect on the nondominant or affected hemisphere. To give an answer to this question is of great importance for the rehabilitation of stroke patients, because they often use the unaffected hand for compensation. Methods— Ten healthy volunteers and 11 stroke patients were investigated using transcranial magnetic stimulation (TMS). TMS was applied to the dominant/unaffected hemisphere during performance of different tasks (simple index finger abduction, pinch grip, and power grip) at various force levels (5%, 10%, 50%, and 100% maximal voluntary contraction) with the ipsilateral hand. Peak-to-peak amplitudes of motor-evoked potentials were used as measure for motor cortex excitability. Results— Both simple and complex tasks led to a facilitation of the contralateral corticospinal system at all levels of applied force. Not only the facilitatory effect in general but also the slope of the relationship between force level and MEP amplitude were significantly lower in stroke patients indicating that both the general activation level of the impaired motor system and the bandwidth of possible activation levels are diminished. Conclusion— Voluntary activation of the hand does not exert an inhibitory effect on the excitability of the ipsilateral hemisphere in healthy volunteers or in stroke patients.
Reduction of Miscarriages through Universal Screening and Treatment of Thyroid Autoimmune Diseases

Background/Aims: Universal screening for thyroid diseases during pregnancy is controversial. Targeted screening does not identify all women with thyroid dysfunction. Furthermore, antithyroid peroxidase antibodies (TPOAb) are suspected to be associated with an increased risk of fetal loss, premature delivery and hypothyroidism. The aim of our study was to assess the rationale behind universal screening and propose thyroxine treatment in particular cases. Methods: Between January 2008 and May 2009, 537 consecutive iodine-supplemented women with a singleton pregnancy [441 TPOAb– controls and 96 TPOAb+ women (47 nontreated and 49 treated)] were evaluated using thyroid and obstetric parameters. According to our algorithm for thyroid screening in pregnancy, if thyroid-stimulating hormone (TSH) exceeded 1 mU/l in TPOAb+ women, 50 µg of levothyroxine (L-T4) was prescribed. Results: The miscarriage rate was significantly higher in the nontreated TPOAb+ group compared with the treated group (16 vs. 0%; p = 0.02). Compared to the control group, TSH in TPOAb+ patients was higher at the first prenatal visit prior to L-T4 treatment (p < 0.01), while free thyroxine was higher than in the control group after the 20th week (p < 0.05). Conclusions: Our study supports the potential benefit of universal screening and L-T4 treatment for autoimmune thyroid disease during pregnancy. Efforts are still needed to further decrease miscarriage rates.
CONTRAfold: RNA secondary structure prediction without physics-based models

MOTIVATION For several decades, free energy minimization methods have been the dominant strategy for single sequence RNA secondary structure prediction. More recently, stochastic context-free grammars (SCFGs) have emerged as an alternative probabilistic methodology for modeling RNA structure. Unlike physics-based methods, which rely on thousands of experimentally-measured thermodynamic parameters, SCFGs use fully-automated statistical learning algorithms to derive model parameters. Despite this advantage, however, probabilistic methods have not replaced free energy minimization methods as the tool of choice for secondary structure prediction, as the accuracies of the best current SCFGs have yet to match those of the best physics-based models. RESULTS In this paper, we present CONTRAfold, a novel secondary structure prediction method based on conditional log-linear models (CLLMs), a flexible class of probabilistic models which generalize upon SCFGs by using discriminative training and feature-rich scoring. In a series of cross-validation experiments, we show that grammar-based secondary structure prediction methods formulated as CLLMs consistently outperform their SCFG analogs. Furthermore, CONTRAfold, a CLLM incorporating most of the features found in typical thermodynamic models, achieves the highest single sequence prediction accuracies to date, outperforming currently available probabilistic and physics-based techniques. Our result thus closes the gap between probabilistic and thermodynamic models, demonstrating that statistical learning procedures provide an effective alternative to empirical measurement of thermodynamic parameters for RNA secondary structure prediction. AVAILABILITY Source code for CONTRAfold is available at http://contra.stanford. edu/contrafold/.
Contrast invariance of orientation tuning in cat primary visual cortex neurons depends on stimulus size

The process of orientation tuning is an important and well‐characterized feature of neurons in primary visual cortex. The combination of ascending and descending circuits involved is not only relevant to understanding visual processing but the function of neocortex in general. The classic feed‐forward model of orientation tuning predicts a broadening effect due to increasing contrast; yet, experimental results consistently report contrast invariance. We show here that contrast invariance actually depends on stimulus size such that large stimuli extending beyond the neuron's receptive field engage circuits that promote invariance, whereas optimally sized, smaller stimuli result in contrast variance that is more in line with the classical orientation tuning model. These results illustrate the importance of optimizing stimulus parameters to best reflect the sensory pathways under study and provide new clues about different circuits that may be involved in variant and invariant response properties.
Path integration in mammals

It is often assumed that navigation implies the use, by animals, of landmarks indicating the location of the goal. However, many animals (including humans) are able to return to the starting point of a journey, or to other goal sites, by relying on self‐motion cues only. This process is known as path integration, and it allows an agent to calculate a route without making use of landmarks. We review the current literature on path integration and its interaction with external, location‐based cues. Special importance is given to the correlation between observable behavior and the activity pattern of particular neural cell populations that implement the internal representation of space. In mammals, the latter may well be the first high‐level cognitive representation to be understood at the neural level. © 2004 Wiley‐Liss, Inc.