Miracle-dz/UniFAR-FTUs huggingface dataset:
Experimental library screening demonstrates the successful application of computational protein design to large structural ensembles

The stability, activity, and solubility of a protein sequence are determined by a delicate balance of molecular interactions in a variety of conformational states. Even so, most computational protein design methods model sequences in the context of a single native conformation. Simulations that model the native state as an ensemble have been mostly neglected due to the lack of sufficiently powerful optimization algorithms for multistate design. Here, we have applied our multistate design algorithm to study the potential utility of various forms of input structural data for design. To facilitate a more thorough analysis, we developed new methods for the design and high-throughput stability determination of combinatorial mutation libraries based on protein design calculations. The application of these methods to the core design of a small model system produced many variants with improved thermodynamic stability and showed that multistate design methods can be readily applied to large structural ensembles. We found that exhaustive screening of our designed libraries helped to clarify several sources of simulation error that would have otherwise been difficult to ascertain. Interestingly, the lack of correlation between our simulated and experimentally measured stability values shows clearly that a design procedure need not reproduce experimental data exactly to achieve success. This surprising result suggests potentially fruitful directions for the improvement of computational protein design technology.
Reduction of oxidative stress and modulation of autoantibodies against modified low-density lipoprotein after rosuvastatin therapy.

AIMS To examine the effect of 24 weeks' rosuvastatin treatment on oxidative stress and changes in immune response to oxidized low-density lipoprotein (LDL). METHODS This was an open-label study of patients in Austria receiving 10 or 40 mg rosuvastatin daily alternately during 12 and 24 weeks. Circulating concentrations of antibodies to malondialdehyde-oxidized LDL (MDA-LDL), both IgG and IgM type, to copper-oxidized LDL (Cu-OxLDL-IgG), concentrations of oxidized LDL complexed to IgG (OxLDL-IC) and markers of oxidative stress and systemic inflammation in subjects with plasma LDL cholesterol concentrations between 130 mg dl-1 and 250 mg dl-1 and triglycerides<or=400 mg dl-1 were determined. RESULTS During statin therapy, plasma endogenous peroxides (POX-ACT) concentrations and peroxidase activity were significantly decreased, associated with a modest increase in total antioxidant capacity (TAC). Antibody titres to MDA-LDL-IgM, Cu-OxLDL-IgG and OxLDL-IC decreased, whereas MDA-LDL-IgG concentrations were increased after therapy. These changes were dose- and LDL-independent. POX-ACT concentrations were significantly positively correlated with inflammation markers before and after therapy and inversely with high-density lipoprotein-cholesterol concentrations after therapy. CONCLUSION This study provides in vivo evidence that rosuvastatin significantly reduces oxidative stress and has immunomodulatory properties in a dose- and LDL-independent manner.
Helicobacter pylori infection activates NF-kappa B in gastric epithelial cells.

BACKGROUND & AIMS Helicobacter pylori adheres to gastric epithelial cells and stimulates interleukin (IL)-8 production. This may be instrumental in neutrophil infiltration of the gastric epithelium that characterizes H. pylori gastritis. This study examined the molecular mechanisms leading to H. pylori-induced epithelial cell IL-8 production. METHODS Electrophoretic mobility shift analyses for NF-kappa B were performed on cell and nuclear extracts from H. pylori-infected AGS and Kato III human gastric epithelial cells. RESULTS H. pylori infection activated the transcription factor NF-kappa B and induced nuclear translocation of both NF-kappa B p50/p65 heterodimers and p50 homodimers. Nuclear translocation of NF-kappa B (30 minutes) was followed by increased IL-8 messenger RNA (1 hour) and protein levels (4 hours) consistent with NF-kappa B up-regulation of IL-8 gene transcription. Pretreatment of AGS cells with PDTC, which blocks NF-kappa B activation, inhibited H. pylori-induced increases in IL-8 production by 90%. Immunohistochemical studies using a monoclonal antibody that recognizes the I-kappa B binding region of p65 showed activated NF-kappa B in gastric epithelial cells of patients with H. pylori gastritis. CONCLUSIONS H. pylori infection activates NF-kappa B in gastric epithelial cells in vitro and in vivo. NF-kappa B is a transcriptional regulator of IL-8 production, and its activation after bacterial infection may be an important defense response in gastrointestinal epithelial cells.
Epidemiological, clinical and laboratory aspects of sandfly fever

Purpose of review Sandfly fever viruses are still a significant health problem in many regions of the world, such as Africa, the Mediterranean basin, the Middle East, and Central Asia. This review provides an update on the advances in knowledge about epidemiological, clinical, and laboratory aspects of infections caused by Toscana, Sicilian and Naples viruses. Recent findings Diagnosis of Toscana virus infection has been facilitated by new molecular methods and by immunoenzymatic tests based on the recombinant nucleoprotein. Gene analysis has allowed identification of circulating Toscana variants possibly involved in the protean pathomorphism and extreme variability of the clinical picture. New attention has been addressed to the antigenic properties of the viral proteins (the nucleoprotein N and the surface glycoproteins G1 and G2), in order to understand their immunogenetic role. High genetic divergence within the serocomplexes belonging to each of the Sicilian and the Naples viruses has suggested that infection with one genotype may not completely immunize against infection with all other genotypes in a given serocomplex. These findings could serve as a basis for vaccine development and may account for reports of multiple episodes of sandfly fever in the same host. Recently, the performance of analysis models based on weather data and reported vector surveys has allowed the prediction of the risk of acquiring sandfly infection in the endemic geographic areas. Summary Recent developments include a better knowledge of the epidemiological, clinical, and laboratory aspects of sandfly infection, while the search for effective drugs and vaccines is still in progress.
Prevention of chemotherapy induced nausea and vomiting: a focus on aprepitant

Background: Nausea and vomiting is one of the most feared side effects of chemotherapy; however, in the past 20 years, a better understanding of the pathophysiology of chemotherapy-induced nausea and vomiting (CINV) has led to the introduction of newer antiemetics, which have improved the management of this side effect. Objective: This article reviews the prevention of CINV and the role of aprepitant, the first of the newest class of antiemetics, the neurokinin-1 inhibitors. A brief description of the pathophysiology of CINV and the background on the prevention of CINV using the 5-HT3 antagonists is outlined. The pharmacology, pharmacokinetics, drug interactions and various clinical studies with aprepitant are reviewed. Methods: The literature about aprepitant is reviewed focusing on the role of aprepitant in the management of CINV in relationship to other commonly used antiemetics. The literature was searched regarding aprepitant and its pharmacological characteristics, pharmacokinetics, drug interactions and various clinical studies. Conclusion: Aprepitant has a significant role in the management of CINV, as it allows the majority of patients to complete their chemotherapies without significant morbidity. Its use in a variety of clinical settings in cancer patients needs to be further explored.
Evidence of a molecular barrier limiting susceptibility of humans, cattle and sheep to chronic wasting disease

Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) of deer and elk, and little is known about its transmissibility to other species. An important factor controlling interspecies TSE susceptibility is prion protein (PrP) homology between the source and recipient species/genotypes. Furthermore, the efficiency with which the protease‐resistant PrP (PrP‐res) of one species induces the in vitro conversion of the normal PrP (PrP‐sen) of another species to the protease‐resistant state correlates with the cross‐species transmissibility of TSE agents. Here we show that the CWD‐associated PrP‐res (PrPCWD) of cervids readily induces the conversion of recombinant cervid PrP‐sen molecules to the protease‐resistant state in accordance with the known transmissibility of CWD between cervids. In contrast, PrPCWD‐induced conversions of human and bovine PrP‐sen were much less efficient, and conversion of ovine PrP‐sen was intermediate. These results demonstrate a barrier at the molecular level that should limit the susceptibility of these non‐cervid species to CWD.
An Ontological Approach to Canonical Typology: Laying the foundations for e-Linguistics

With the rise of the Web as an important medium for displaying and curating typological data, the next generation of linguists will have access to thousands of data sets on many of the world’s remaining languages. It is not out of the question that many or most of the grammars ever published and possibly many sets of field notes will be digitised and stored in a Web accessible format (cf. Google Book Search). As more and more resources are digitised, there is an ever-increasing need for interoperability of data and transparency regarding the intended meaning of annotation elements. Standardisation of terminology is certainly one approach; however, there are more basic challenges, including a clear articulation of a conceptual framework for specific areas of linguistics including, among many others, canonical typology. Put another way, there is currently no broadly accepted logic or computer language that would allow arbitrary descriptive data to be automatically published, searched, and visualised, i.e., no possibility of an e-linguistics. In this paper, we explore laying the foundations for such an enterprise by drawing on recent and emerging Web technologies, as well as from applied formal ontology. In particular, we will address work within the GOLD Community of Practice whose aim is the creation of a General Ontology for Linguistic Description. We will argue that the resulting conceptual framework can be employed to solve some basic issues concerning an implementation of canonical typology. An OWL-DL implementation of GOLD is presented with relevant examples for canonical typology.
Willingness to Pay for Clean Air: Evidence from Air Purifier Markets in China

We develop a framework to estimate willingness to pay for clean air from defensive investments on differentiated products. Applying this framework to scanner data on air purifier sales in China, we find that a household is willing to pay $1.34 annually to remove 1 μg/m3 of air pollution (PM10) and $32.7 annually to eliminate the pollution induced by the Huai River heating policy. Substantial heterogeneity is explained by income and exposure to information on air pollution. Using these estimates, we evaluate various environmental policies and quantify the value of recent air quality improvements since China declared a war on pollution in 2014.
Rapid method for thermal dose‐based safety supervision during MR scans

To maximize diagnostic accuracy and minimize costs, magnetic resonance imaging (MRI) scanners expose patients to electromagnetic exposure levels well above the established maximum, but in a well‐controlled environment. In this paper, we discuss a novel safety assessment model that offers maximum flexibility while ensuring no local tissue damage due to radiofrequency induced heating occurs. This model is based on the cumulative equivalent minutes at 43 °C (CEM43) thermal dose concept, which naturally considers exposure duration, tissue sensitivity and the transient nature of heating, and permits rapid assessment of exposure safety of a given MRI scan using information about the transient specific absorption rate (SAR). It builds upon theoretical considerations (e.g., relating peak temperatures in the presence and absence of local thermoregulation) as well as data extracted from simulations involving anatomical models (e.g., to determine the characteristic time of temperature changes). The model is capable of predicting CEM43 for patients with either uncompromised thermoregulation or absent thermoregulation. The model predictions approximate detailed simulations well and results illustrate the importance of adequately considering changes in perfusion. The model presented herein offers an MRI safety assessment approach that overcomes problems associated with traditional SAR‐based limits. Its limitations and the associated uncertainties are discussed together with remaining open questions. Bioelectromagnetics. 36:398–407, 2015. © 2015 Wiley Periodicals, Inc.
Surface shape and reflectance analysis using polarisation

When unpolarised light is reflected from a smooth dielectric surface, it becomes partially polarised. This is due to the orientation of dipoles induced in the reflecting medium and applies to both specular and diffuse reflection. This thesis aims to exploit the polarising properties of surface reflection for computer vision applications. Most importantly, the thesis proposes novel shape and reflectance function estimation techniques. The methods presented rely on polarisation data acquired using a standard digital camera and a linear polariser. Fresnel theory lies at the heart of the thesis and is used to process the polarisation data in order to estimate the surface normals of target objects. Chapter 2 surveys the related literature in the fields of polarisation vision, shape-fromshading, stereo techniques, and reflectance function analysis. Chapter 3 commences by presenting the underlying physics of polarisation by reflection, starting with the Fresnel equations. The outcome of this theory is a means to ambiguously estimate surface normals from polarisation data, given a rough estimate of the material refractive index. The first novel technique is then presented, which is a simple single-view approach to shape reconstruction. In this case, efficiency is given priority over accuracy. Chapter 3 ends with a description of a device for measuring refractive indices. Chapter 4 is concerned with image-based reflectance function estimation. Firstly, the special case of retro-reflection is assumed. An algorithm is described that constructs a histogram of surface zenith angles and pixel intensities. Probability density functions are then robustly fitted to this histogram to obtain a one-dimensional “slice” of the material BRDF. A second algorithm is then presented, which is designed for more general illumination conditions. This uses a three-dimensional histogram that includes the surface azimuth angles, in addition to the zenith angles and pixel intensities. Simulated annealing optimisation is then used to fit surfaces to the histogram, thus estimating a two-dimensional slice of the BRDF. Chapter 4 also contains a method for photometric stereo, which is used by the above two-dimensional BRDF technique to fully constrain the previously ambiguous surface normal estimates.
Cashew nut allergy is associated with a high risk of anaphylaxis

Cashew allergy is an evolving clinical problem. A retrospective chart review of 213 children with peanut or tree nut allergy was undertaken over a 42 month period. Anaphylaxis to cashew nut was more common than to peanut (74.1% v 30.5%). Children with cashew allergy are at risk of anaphylaxis.
Dyskerin is required for tumor cell growth through mechanisms that are independent of its role in telomerase and only partially related to its function in precursor rRNA processing

Dyskerin is an essential nucleolar protein required for the biogenesis of ribonucleoproteins that incorporate H/ACA RNAs. Through binding to specific H/ACA RNAs, dyskerin exerts most of its influence in the cell. To that end, dyskerin is a core component of the telomerase complex and is required for normal telomere maintenance. Dyskerin is also required for post‐transcriptional processing of precursor rRNA. Germline dyskerin mutations increase cancer susceptibility. Conversely, wild‐type dyskerin is usually over‐expressed and not mutated in sporadic cancers. However, the contributions of dyskerin to sporadic tumorigenesis are unknown. Described herein, we demonstrate that acute loss of dyskerin function by RNA interference significantly reduced steady‐state levels of H/ACA RNAs, disrupted the morphology and inhibited anchorage‐independent growth of telomerase‐positive and telomerase‐negative human cell lines. Unexpectedly, dyskerin depletion only transiently delayed rRNA maturation but with no appreciable effect on the levels of total 18S or 28S rRNA. Instead, while rRNA processing defects typically trigger p53‐dependent G1 arrest, dyskerin‐depleted cells accumulated in G2/M by a p53‐independent mechanism, and this was associated with an accumulation of aberrant mitotic figures that were characterized by multi‐polar spindles. Telomerase activity and the rate of rRNA processing are typically increased during neoplasia. However, our cumulative findings indicate that dyskerin contributes to tumor cell growth through mechanisms which do not require the presence of cellular telomerase activity, and which may be only partially dependent upon the protein's role in rRNA processing. These data also reinforce the notion that loss and gain of dyskerin function may play important roles in tumorigenesis. Mol. Carcinog. © 2010 Wiley‐Liss, Inc.
Supraglottic and Pharyngeal Sensory Abnormalities in Stroke Patients with Dysphagia

Dysphagia and aspiration are two devastating sequelae of stroke, accounting for nearly 40,000 deaths from aspiration pneumonia each year in the United States. While motor deficits in the larynx and pharynx are thought responsible for dysphagia and aspiration in stroke patients, no prior study has evaluated whether these patients also have sensory deficits. The aim of this study was to evaluate the sensory capacity of the laryngopharynx (LP) in supratentorial or brain stem stroke patients who presented with dysphagia. Fifteen stroke patients (mean age, 66.7 ± 13.8 [SD] years) were prospectively evaluated by means of our previously described method whereby air pulse stimuli were delivered via a flexible fiberoptic telescope to the mucosa innervated by the superior laryngeal nerve. There were 15 age-matched controls. No LP sensory deficits were found in any of the age-matched controls. In all stroke patients studied, either unilateral (n = 9) or bilateral (n=6) sensory deficits were identified. Deficits were defined as either a moderate impairment in sensory discrimination thresholds (3.5 to 6.0 mm Hg) or a severe sensory impairment (>6.0 mm Hg). These sensory discrimination thresholds were significantly greater than in age-matched controls (7.05 ± 0.17 mm Hg for the supratentorial group and 6.05 ± 1.22 mm Hg for the infratentorial group versus 2.61 ± 0.69 mm Hg for the controls). Among patients with unilateral deficits, sensory thresholds were moderately to severely elevated in all 9 cases on the affected side compared with the unaffected side (p < .01, Fisher's exact test). Moreover, the sensory thresholds of the unaffected side were not significantly different from those of age-matched controls (2.51 ± 0.25 mm Hg versus 2.61 ± 0.69 mm Hg, respectively). All 6 patients with bilateral deficits had severe impairments. The results of an outcome assessment in 13 of 15 patients revealed that 2 out of 5 patients with moderate LP sensory impairment and 5 out of 8 with severe impairment developed aspiration. Our results show for the first time that stroke patients with dysphagia have significant sensory deficits in the LP and that these impairments are likely to contribute to the development of aspiration.
In vivo uptake and subcellular distribution of tritium-labeled estrogens in human endometrium, myometrium, and vagina.

Uptake, retention, and subcellular distribution of 17β-estradiol (E2), estrone (E1), and estriol (E3) in endometrial, myometrial, and vaginal tissue in 18 normal postmenopausal women under physiological conditions were studied by giving [3H]E2, [3H]Ei, or [3H]E3 in subphysiological doses by continuous infusion lasting 12 h before hysterectomy. Endometrial, myometrial, and vaginal tissues from each woman were separated into five cellular fractions: two cytosol fractions (free estrogen fraction and specifically bound fraction) and three nuclear fractions. The results show an accumulation of [3H]E2 in the target tissue after [3H]E2 and [3H]Ei infusions; we found an approximately 30 times higher [3H]E2 concentration after [3H]E2 infusion in endometrium (disintegrations per min/ g) than in plasma (disintegrations per min/ml), 20 times higher in myometrium, and 10 times higher in vaginal tissue. The corresponding [3H]Ei tissue to plasma ratios were 7, 4, and 6, respectively, for endometrium, myometrium, and vag.
Digital technology use in ELT classrooms and self-directed learning

The digital era is a new challenge for teachers. While children get acquainted with digital technology before the age of six, teachers, who have encountered the digital world at a later time in their lives, struggle with it. Selfdirected learning, which is crucial for lifelong learning, can be enhanced by the use of technology within and beyond classroom settings. The aim of this study was to examine the difference between the perceptions of students in lowand high-income groups about their use of technology in a general sense and their teachers’ use of technology in ELT classrooms. It also tested the correlation between the perceptions of their self-directed learning behaviours and their own/their teachers’ technology use. The population of the study consisted of 75 students from highand 70 students from low-income groups. Causal comparative and correlational research methods were adopted in the study. The surveys to measure the students’ perceptions about technology use were developed by the researchers. A scale, established by Demirtas and Sert (2010), was used to identify the level of self-directed learning views of the students. The data were collected at the beginning of the first term of the 2015-2016 school year. The results indicated that there was no significant difference between perceptions of the lowand high-income students regarding their own technology use. Likewise, perceptions of the lowand high-income students did not differ regarding their teachers’ technology use. There was no correlation between the perceptions of the low-/high-income mixed group regarding their use of technology and their teachers’ use of technology. Lastly, self-directed learning perceptions of the low-/high-income mixed group did not correlate with their perceptions on any aspects of technology use. The educational implications of these results were discussed and suggestions were put forward in order to produce more effective learning environments.