Miracle-dz/UniFAR-FTUs huggingface dataset:
The Mammalian Target of Rapamycin Regulates C2C12 Myogenesis via a Kinase-independent Mechanism*

Rapamycin inhibits differentiation of mouse C2C12 myoblasts, a tissue culture model for skeletal muscle differentiation. The mechanism by which a rapamycin-sensitive signaling pathway regulates myogenesis is largely unknown. The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation, but its role in myogenesis has not been examined directly. Here we report the investigation of the function of mTOR and its downstream effectors in muscle differentiation. Rapamycin exerts an inhibitory effect on C2C12 myogenesis at different stages, implying that a rapamycin-sensitive pathway may be required for multiple processes during muscle differentiation. The mTOR protein level increases 10-fold during differentiation, via a post-transcriptional mechanism. As the first direct demonstration of the essential role of mTOR in muscle differentiation, we show that a rapamycin-resistant mTOR, but not S6 kinase 1, can rescue rapamycin-inhibited myogenesis. Remarkably, the myogenic function of mTOR does not require its kinase activity. Two downstream effectors of the rapamycin-sensitive pathway, S6 kinase 1 and eIF4E-binding protein 1, undergo differential regulation during myogenesis, but neither protein is the relevant effector for the myogenic signaling of mTOR. Taken together, our observations suggest a novel mTOR signaling mechanism essential for skeletal muscle differentiation.
Advanced Molecular Detection of Malarone Resistance

ABSTRACT The rapid emergence of drug-resistant malaria parasites during the course of an infection remains a major challenge for providing accurate treatment guidelines. This is particularly important in cases of malaria treatment failure. Using a previously well-characterized case of malaria treatment failure, we show the utility of using next-generation sequencing for early detection of the rise and selection of a previously reported atovaquone-proguanil (malarone) drug resistance-associated mutation.
Gain-of-Function Phenotypes of Many CLAVATA3/ESR Genes, Including Four New Family Members, Correlate with Tandem Variations in the Conserved CLAVATA3/ESR Domain1[W]

Secreted peptide ligands are known to play key roles in the regulation of plant growth, development, and environmental responses. However, phenotypes for surprisingly few such genes have been identified via loss-of-function mutant screens. To begin to understand the processes regulated by the CLAVATA3 (CLV3)/ESR (CLE) ligand gene family, we took a systems approach to gene identification and gain-of-function phenotype screens in transgenic plants. We identified four new CLE family members in the Arabidopsis (Arabidopsis thaliana) genome sequence and determined their relative transcript levels in various organs. Overexpression of CLV3 and the 17 CLE genes we tested resulted in premature mortality and/or developmental timing delays in transgenic Arabidopsis plants. Overexpression of 10 CLE genes and the CLV3 positive control resulted in arrest of growth from the shoot apical meristem (SAM). Overexpression of nearly all the CLE genes and CLV3 resulted in either inhibition or stimulation of root growth. CLE4 expression reversed the SAM proliferation phenotype of a clv3 mutant to one of SAM arrest. Dwarf plants resulted from overexpression of five CLE genes. Overexpression of new family members CLE42 and CLE44 resulted in distinctive shrub-like dwarf plants lacking apical dominance. Our results indicate the capacity for functional redundancy of many of the CLE ligands. Additionally, overexpression phenotypes of various CLE family members suggest roles in organ size regulation, apical dominance, and root growth. Similarities among overexpression phenotypes of many CLE genes correlate with similarities in their CLE domain sequences, suggesting that the CLE domain is responsible for interaction with cognate receptors.
Unlike arginine vasopressin, the selective V1a receptor agonist FE 202158 does not cause procoagulant effects by releasing von Willebrand factor*

Objective:To compare the effects on von Willebrand factor release of the mixed vasopressin type 1a and type 2 receptor agonist arginine vasopressin and the selective vasopressin type 1a receptor agonist FE 202158, [Phe2,Ile3,Hgn4,Orn(iPr)8]vasopressin, at doses required for the treatment of septic shock. Design:Prospective, randomized, controlled laboratory experiment. Setting:University animal research facility. Subjects:Twenty-four chronically instrumented sheep. Interventions:After a 5-day recovery from instrumentation, sheep were randomly assigned to receive a single intravenous bolus of the selective vasopressin type 2 receptor agonist desmopressin (1 nmol·kg−1) or continuous intravenous infusions of arginine vasopressin (3 pmol·kg−1·min−1), the selective vasopressin type 1a receptor agonist FE 202158 (10 pmol·kg−1·min−1), or vehicle (0.9% NaCl) (n = 6 each). Measurements and Main Results:The von Willebrand factor antigen activity relative to hemoglobin concentration (vWF:Ag/Hb ratio) was measured at different time points during the 120-min study period. Maximal vWF:Ag/Hb ratio expressed as percentage of baseline level was significantly increased compared to vehicle-infused animals (3 ± 2%) in the desmopressin (40 ± 6%, p < .001) and arginine vasopressin groups (25 ± 4%, p < .001). The ratio for the FE 202158 group was not statistically different from the sham group (9 ± 2%, p = .208). Notably, maximal vWF:Ag/Hb ratio was lower in the FE 202158 than the arginine vasopressin group (p < .005). Conclusions:Unlike the mixed vasopressin type 1a receptor/vasopressin type 2 receptor agonist arginine vasopressin, the selective vasopressin type 1a receptor agonist FE 202158 does not release von Willebrand factor. Because von Willebrand factor is involved in coagulatory and inflammatory pathways during septic shock, future studies should clarify the role of the vasopressin type 2 receptor–mediated von Willebrand factor increase by arginine vasopressin and the potential benefit of selective vasopressin type 1a receptor–agonists like FE 202158.
Knowledge Diffusion and Trade across Countries and Sectors

Countries and sectors interact through knowledge spillovers and international trade flows. These interactions drive differences in income per capita and innovation not only across countries, but also across sectors within a country. We develop and quantify a model of innovation, knowledge diffusion and trade that can explain these differences. Using data on intersectoral patent citations, R&D expenditures and international trade flows, we calibrate the model and perform several counterfactual exercises. Decreases in trade costs or increases in the speed of diffusion reallocate resources across countries and sectors, generating a distributional effect on aggregate innovation and growth.
Cdx2 Protein Expression in Normal and Malignant Human Tissues: An Immunohistochemical Survey Using Tissue Microarrays

Cdx2 has been identified as a marker of colon cancer in RNA-profiling experiments. We show here that the detection of Cdx2 protein by immunohistochemistry correlates well with RNA transcript levels as detected by oligonucleotide microarrays. Using tissue microarrays containing most normal tissue types and an antibody to the Cdx2 protein, strong diffuse Cdx2 staining was only seen in the nuclei of small and large intestinal epithelium and portions of the pancreatic duct system. In tissue microarrays containing 745 cancers from many anatomic sites, colonic adenocarcinomas showed strong extensive staining in 90% of cases, with adenocarcinomas of the stomach, esophagus, and ovary (endometrioid and mucinous types) showing extensive staining in only 20–30% of cases. Other types of carcinomas showed extensive staining in only ≤1% of cases. Of 30 neuroendocrine tumors examined, carcinoids of the midgut and hindgut had the most cases with extensive staining (73% and 44%, respectively), thus paralleling the distribution of Cdx2 expression in adenocarcinomas. Cdx2 shows a limited range of expression in the spectrum of human tissues and neoplasia and thus may have utility in determining the site of origin of tumors in certain clinical situations.
Advanced glycation end products in human optic nerve head

AIMS To localise advanced glycation end products (AGEs) in human optic nerve head. METHODS Optic nerve samples from 13 elderly individuals (seven diabetics and six non-diabetics) were obtained at necropsy. Pyrraline, an advanced glycation end product, was immunohistochemically localised in the optic nerve heads. RESULTS In the diabetic subjects, moderate to intense immunoreactivity for pyrraline was detected in sclera, pia mater, cribriform plates, connective tissues in the optic nerve, and around vessels in the optic nerve and pia mater. Immunoreactivity for pyrraline was also detected around retinal vessels. In the non-diabetic subjects, slight or no immunoreactivity for pyrraline was found in cribriform plates and around the optic nerve vessels. CONCLUSION Accumulation of AGEs in cribriform plates and around vessels in the optic nerve may contribute to the development of optic neuropathy in diabetic patients.
Alcohol use trajectories among non-treatment-seeking heavy drinkers.

OBJECTIVE Heavy drinking, often defined as more than five drinks per occasion, is a major public health problem worldwide, yet most individuals who drink heavily never receive treatment. Focusing on those who receive treatment, numerous studies have found that alcohol use following treatment is discontinuous, with periods of abstinence alternating with periods of heavy drinking. In contrast, little is known about changes in alcohol use among the majority of individuals who engage in heavy drinking and never receive treatment. The goal of this study was to examine changes in alcohol consumption (proportion of heavy drinking days) in a sample of non-treatment-seeking heavy drinkers (n = 151). METHOD The current study focused on three quantitative models--latent growth curve, latent growth mixture, and latent Markov models--to examine changes in the frequency of heavy drinking days (i.e., ≥ 5/4 drinks per day for men/women) among a sample of heavy drinkers who did not receive any form of treatment or self-help over a 2-year period. RESULTS Participants significantly reduced their frequency of heavy drinking over a 2-year period, and changes in drinking did not show the discontinuity in trajectories often observed in treatment samples. Alcohol use disorder diagnosis predicted higher initial levels of frequent heavy drinking but did not predict changes in the frequency of heavy drinking over time. CONCLUSIONS Most individuals, with or without an alcohol use disorder, reported significant reductions in heavy drinking frequency over time. These results have important implications for a public health approach to the problem of heavy drinking.
Cloud-contaminated image reconstruction with contextual spatio-spectral information

Recently, a novel general method for the contextual reconstruction of cloud-contaminated areas in multitemporal multispectral images has been proposed in the literature. Though promising, this method does not fully exploit all available information, thus leaving room for further methodological enhancements. The aim of this work is to improve the contextual reconstruction process by opportunely capturing spatial and spectral correlations characterizing the considered image. In addition, we propose a novel procedure to generate an error map for providing the end-user with helpful indications about the reconstruction reliability. Thorough experiments conducted on a multitemporal sequence of Landsat-7 ETM+ images are reported and discussed.
An Electrostatic Interaction at the Tetrahelix Bundle Promotes Phosphorylation-dependent Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Channel Opening*

Background: ATP binding promotes CFTR channel opening by an unknown mechanism. Results: Introducing like charges at positions 267 and 1060 in the opposing cytosolic loops that couple the nucleotide binding domains to the pore inhibits channel opening. Conclusion: An electrostatic interaction across the cytosolic loop interface links ATP binding to CFTR opening. Significance: This interaction may be a target for designing CFTR drugs. The CFTR channel is an essential mediator of electrolyte transport across epithelial tissues. CFTR opening is promoted by ATP binding and dimerization of its two nucleotide binding domains (NBDs). Phosphorylation of its R domain (e.g. by PKA) is also required for channel activity. The CFTR structure is unsolved but homology models of the CFTR closed and open states have been produced based on the crystal structures of evolutionarily related ABC transporters. These models predict the formation of a tetrahelix bundle of intracellular loops (ICLs) during channel opening. Here we provide evidence that residues E267 in ICL2 and K1060 in ICL4 electrostatically interact at the interface of this predicted bundle to promote CFTR opening. Mutations or a thiol modifier that introduced like charges at these two positions substantially inhibited ATP-dependent channel opening. ATP-dependent activity was rescued by introducing a second site gain of function (GOF) mutation that was previously shown to promote ATP-dependent and ATP-independent opening (K978C). Conversely, the ATP-independent activity of the K978C GOF mutant was inhibited by charge- reversal mutations at positions 267 or 1060 either in the presence or absence of NBD2. The latter result indicates that this electrostatic interaction also promotes unliganded channel opening in the absence of ATP binding and NBD dimerization. Charge-reversal mutations at either position markedly reduced the PKA sensitivity of channel activation implying strong allosteric coupling between bundle formation and R domain phosphorylation. These findings support important roles of the tetrahelix bundle and the E267-K1060 electrostatic interaction in phosphorylation-dependent CFTR gating.
Extent of thrombus evaluated in patients with recurrent and first deep vein thrombosis.

OBJECTIVES The objective of this retrospective study was to document the extent of thrombus in patients with recurrent and first deep vein thrombosis (DVT). PATIENTS AND METHODS A total of 864 patients with DVT of the leg were enrolled in the study. They were divided into two groups: patients with recurrent DVT (n = 233) of the leg, and patients with first DVT of the leg (n = 631). In both groups the extent of the thrombus was evaluated by duplex scanning, contrast venography, or magnetic resonance imaging. Thrombus involving veins distal to the popliteal vein was classified as distal DVT, whereas involvement of the popliteal vein and proximal was classified as proximal DVT. RESULTS We could demonstrate that involvement of proximal segments (CEAP anatomic classification 1-9) occurred significantly more often in patients with recurrent DVT than in patients with the first DVT (P <.001). The incidence of pulmonary embolism (PE) and the clinical symptoms of PE were equally distributed between patients with recurrent DVT and those with first DVT (P >.05). Only one patient died as a consequence of PE in our patient sample. CONCLUSIONS In our experience, patients with recurrent DVT have a higher frequency of proximal DVT. Nevertheless, the incidence of PE is similar in patients with recurrent and those with first DVT.
Speech recognition in noise as a function of highpass-filter cutoff frequency for people with and without low-frequency cochlear dead regions.

Regions in the cochlea with very few functioning inner hair cells and/or neurons are called "dead regions" (DRs). Previously, we measured the recognition of highpass-filtered nonsense syllables as a function of filter cutoff frequency for hearing-impaired people with and without low-frequency (apical) DRs [J. Acoust. Soc. Am. 122, 542-553 (2007)]. DRs were diagnosed using the TEN(HL) test, and psychophysical tuning curves were used to define the edge frequency (fe) more precisely. Stimuli were amplified differently for each ear, using the "Cambridge formula. " The present study was similar, but the speech was presented in speech-shaped noise at a signal-to-noise ratio of 3 dB. For subjects with low-frequency hearing loss but without DRs, scores were high (65-80%) for low cutoff frequencies and worsened with increasing cutoff frequency above about 430 Hz. For subjects with low-frequency DRs, performance was poor (20-40%) for the lowest cutoff frequency, improved with increasing cutoff frequency up to about 0.56fe, and then worsened. As for speech in quiet, these results indicate that people with low-frequency DRs are able to make effective use of frequency components that fall in the range 0.56fe to fe, but that frequency components below 0.56fe have deleterious effects.
Characterization of the cross-reaction between type 19F(19) and 19A(57) pneumococcal capsular polysaccharides: compositional analysis and immunological relation determined with rabbit typing antisera

The immunological relation, physicochemical characteristics, and chemical composition of type 19F(19) and 19A(57) within the cross-reactive group 19 pneumococcal capsular polysaccharides were studied. By using rabbit hyperimmune diagnostic antisera in agglutination, immunodiffusion, quantitative precipitation, and absorption assays, extensive cross-antigenicity and cross-immunogenicity were demonstrable between the disease-associated types 19F(19) and 19A(57). Types 19B(58) and 19C(59), rarely associated with human disease, were extensively cross-reactive with each other but reacted weakly with types 19F(19) and 19A(57). Both types 19F(19) and 19A(57) polysaccharides contained trace amounts of protein and nucleic acid and had comparable molecular sizes as determined by gel filtration. Compositional analysis showed type 19F(19) to contain rhamnose, glucose, N-acetylmannosamine, and a phosphate ester. Type 19A(57) contained these four moieties, and in addition, contained fucose, galactose, and N-acetylglucosamine. Plans for using this information to evaluate current and proposed formulation of multivalent pneumococcal polysaccharide vaccines are discussed.
Panic Attacks in Generalized Anxiety Disorder

Abstract Panic attacks have been reported by patients with generalized anxiety disorder (GAD) in response to catastrophic worry. This has not been characterized in the literature. We examined the prevalence of GAD panic attacks in an anxiety disorders clinic sample. Charts of 254 patients with DSM-IV GAD were retrospectively evaluated. The presence and type of panic attacks were examined as well as correlates including comorbidity, baseline symptom severity, demographic variables, and family history. Twenty-one percent had GAD panic attacks, 21.7% had situationally predisposed attacks, 15.6% had situationally bound attacks, and 39.4% had unexpected panic attacks. The individuals who had GAD panic attacks had higher scores on the Anxiety Sensitivity Index compared with those who also had other types of panic attacks. One in five patients with GAD reported GAD panic attacks; however, these individuals did not differ significantly on the correlates that were evaluated. These findings require replication and further evaluation.
Is Romantic Desire Predictable? Machine Learning Applied to Initial Romantic Attraction

Matchmaking companies and theoretical perspectives on close relationships suggest that initial attraction is, to some extent, a product of two people’s self-reported traits and preferences. We used machine learning to test how well such measures predict people’s overall tendencies to romantically desire other people (actor variance) and to be desired by other people (partner variance), as well as people’s desire for specific partners above and beyond actor and partner variance (relationship variance). In two speed-dating studies, romantically unattached individuals completed more than 100 self-report measures about traits and preferences that past researchers have identified as being relevant to mate selection. Each participant met each opposite-sex participant attending a speed-dating event for a 4-min speed date. Random forests models predicted 4% to 18% of actor variance and 7% to 27% of partner variance; crucially, however, they were unable to predict relationship variance using any combination of traits and preferences reported before the dates. These results suggest that compatibility elements of human mating are challenging to predict before two people meet.
Understanding the Biases of Generalised Recombination: Part I

This is the first part of a two-part paper where we propose, model theoretically and study a general notion of recombination for fixed-length strings, where homologous recombination, inversion, gene duplication, gene deletion, diploidy and more are just special cases. The analysis of the model reveals that the notion of schema emerges naturally from the model's equations. In Part I, after describing and characterising the notion of generalised recombination, we derive both microscopic and coarse-grained evolution equations for strings and schemata and illustrate their features with simple examples. Also, we explain the hierarchical nature of the schema evolution equations and show how the theory presented here generalises past work in evolutionary computation. In Part II, the study provides a variety of fixed points for evolution in the case where recombination is used alone, which generalise Geiringer's theorem. In addition, we numerically integrate the infinite-population schema equations for some interesting problems, where selection and recombination are used together to illustrate how these operators interact. Finally, to assess by how much genetic drift can make a system deviate from the infinite-population-model predictions we discuss the results of real GA runs for the same model problems with generalised recombination, selection and finite populations of different sizes.
The psychosocial impact of human papillomavirus testing in primary cervical screening— a study within a randomized trial

The purpose of the study was to assess the psychosocial impact of human papillomavirus (HPV) testing as an adjunct to cytology in routine primary cervical screening. A controlled study of the psychosocial impact of HPV testing within a randomized trial of HPV testing to assess its efficacy in cervical screening was carried out. The trial provides a randomized setting of revealed HPV results versus concealed results permitting valid comparisons for assessing true psychosocial impact. The setting comprised a large number of general practices in primary care. Women aged 20–64 years who underwent routine cervical screening participated in the study. The intervention was a revealed high-risk HPV test result in addition to cervical cytology. The main outcome was measured using General Health Questionnaire (GHQ-28), Spielberger State–Trait Anxiety Inventory, and Sexual Rating Scale (SRS). Among women with either mildly abnormal or normal cytology, receiving an HPV(+ ve) result did not impact significantly on GHQ caseness and mean scores or on Spielberger State and Trait scores when compared with women in whom the HPV(+ ve) test result was concealed. Among women with normal cytology, receiving an HPV(+ ve) result was associated with a reduction in the Sexual Rating Scale compared with similar women whose HPV(+ ve) result was concealed. HPV testing does not add significant psychologic distress when combined with cytology in routine primary cervical screening.