Miracle-dz/UniFAR-FTUs huggingface dataset:
Surrogate and Intermediate Endpoints in Randomized Trials: What's the Goal?

Establishing trial-level surrogacy of an intermediate endpoint for predicting survival benefit in future trials is extremely challenging because of the extrapolations required, but there are other useful drug development and patient management applications of intermediate endpoints. Clin Cancer Res; 24(10); 2239–40. ©2018 AACR. See related article by Mushti et al., p. 2268
Complement inhibition by FUT‐175 and K76‐COOH in a pig‐to‐human lung xenotransplant model

Abstract: Two complement inhibitors, FUT‐175 (FUT) and K76‐COOH (K76), were studied as single agents in an ex vivo, in situ model of pig lung rejection by human blood. Pulmonary toxicity (primarily increased pulmonary vascular resistance [PVR]) was seen with FUT at a dose which inhibited complement in vitro (0.4 mg/ml); a lower dose (0.1 mg/ml) was therefore used. K76 had little apparent toxicity at a dose which inhibited complement in vitro (6 mg/ml), but activated complement, leading to C3a elaboration. Efficacy was then assessed by 1) deposition of complement pathway components in the lung and 2) lung survival during perfusion with human blood. Neither agent consistently prolonged median lung survival (FUT: 50 min.±8 SEM; K76: 37±6), blocked thromboxane production, or prevented PVR elevation compared to experiments using unmodified human blood (survival 9 min.±2). At the doses used, both agents prevented deposition of terminal complement complex (TCC) in the lung. This finding demonstrates that the various phenomena associated with hyperacute lung rejection (thromboxane release, PVR elevation, capillary leak, and intraalveolar hemorrhage) can all occur despite abrogation of membrane attack complex formation. We can not exclude a contribution by drug toxicity or complement damage (mediated by C3a or other complement pathway components proximal to TCC) to the observed lung injury. We conclude that, although both FUT and K76 inhibit deposition of TCC in the lung, at the dose tested neither drug is useful as a single agent to prolong survival in a pig‐to‐human lung xenograft model.
Individual Vessel Quotas and Unregulated Species: The Norwegian Blue Whiting Fishery

This survey of the Norwegian purse seine fleet licensed to fish blue whiting focuses on the relationship between restricted fisheries, such as spring-spawning herring, North Sea herring, mackerel, and capelin, and unrestricted fisheries, of which blue whiting is the most important. To model the behaviour of the fishermen a restricted profit function is used, where species quotas are treated as fixed factors while blue whiting along with other non-quota species are variable factors. We find no relationship between blue whiting and herring, and mackerel. Blue whiting and capelin are substitutes. So are other non-quota species and spring-spawning herring. Other nonquota species are complements to mackerel and North Sea herring.
Understanding Strategic Information Use During Emotional Expression Judgments in Williams Syndrome

ABSTRACT Detailed analysis of expression judgments in Williams syndrome reveals that successful emotion categorization need not reflect “classic” information processing strategies. These individuals draw upon a distinct set of featural details to identify happy and fearful faces that differ from those used by typically developing comparison groups: children and adults. The diagnostic visual information is also notably less interlinked in Williams syndrome, consistent with reports of diminished processing of configural information during face identity judgments. These results prompt reconsideration of typical models of face expertise by revealing that an age-appropriate profile of expression performance can be achieved via alternative routes.
Circulating miR-146a/b correlates with inflammatory cytokines in COPD and could predict the risk of acute exacerbation COPD

Abstract The aim of this study was to investigate the predicting value of miR-146a/b for acute exacerbation chronic obstructive pulmonary disease (AECOPD) and COPD, and to explore their associations with inflammatory cytokines in AECOPD and stable COPD patients. One hundred six AECOPD, 122 stable COPD patients, and 110 health volunteers with age and sex matched to total COPD patients (AECOPD and stable COPD) were enrolled. Blood samples were collected from all participants. Relative expression of miR-146a/b was determined by real-time polymerase chain reaction. Tumor necrosis factor-&agr; (TNF-&agr;), interleukin-1&bgr; (IL-1&bgr;), interleukin-6 (IL-6), interleukin-8 (IL-8), leukotriene B4 (LTB-4) expression in serum from AECOPD and stable COPD patients were assessed using commercial ELISA kit. Serum levels of miR-146a and miR-146b were down regulated in AECOPD patients compared with stable COPD patients and HCs. miR-146a and miR-146b are of good values for predicting the risk of AECOPD in HCs with AUC of 0.702 and 0.715. Additionally, miR-146a and miR-146b could distinguish AECOPD from stable COPD patients with AUC of 0.670 and 0.643. In AECOPD patients, levels of miR-146a in AECOPD patients were negatively associated with TNF-&agr;, IL-6, IL-8, and LTE-4 expression. In stable COPD patients, miR-146a expressions were negatively correlated with TNF-&agr;, IL-1&bgr;, IL-6, IL-8, and LTE-4 levels. And, the expressions of miR-146b in AECOPD patients were negatively associated with IL-1&bgr; and LTB-4 expression. While in stable COPD patients, miR-146b expressions were only negatively correlated with TNF-&agr; level. In conclusion, miR-146a and miR-146b were negatively correlated with inflammatory cytokines, and could be promising biomarkers for predicting the risk of AECOPD in stable COPD patients and healthy individuals.
Orientación preferente de láminas delgadas ferroeléctricas de titanato de plomo modificado depositadas sobre distintos substratos

La aparicion de orientaciones preferentes o textura en laminas delgadas policristalinas se puede potenciar de muchas maneras, pero probablemente el factor mas importante a tener en cuenta es la naturaleza del substrato. Si se logra una orientacion preferente de los cristales de la lamina con el eje polar perpendicular al plano de la lamina el comportamiento ferroelectrico del material mejora. Englobado en la busqueda del substrato mas adecuado para obtener laminas delgadas ferroelectricas orientadas, este trabajo estudia por medio de analisis cuantitativo de texturas laminas delgadas de titanato de plomo modificado con calcio depositadas sobre substratos de Si, MgO y SrTiO3 con electrodos de Pt. Se obtiene una orientacion preferente mixta a lo largo de y . A partir de los datos obtenidos se analizan los factores que contribuyen a las diferentes texturas obtenidas. Por un lado se discute el diferente grado de texturacion del Pt sobre los tres substratos, y la formacion de la lamina ferroelectrica sobre ellos, cuya orientacion parece desarrollarse independientemente del Pt en este caso. Y por otro, se estudia el efecto de las tensiones presentes durante el proceso de cristalizacion provocadas por las diferencias entre los coeficientes de expansion de cada uno de los substratos y la lamina, especialmente en el paso de la fase paraelectrica cubica a ferroelectrica tetragonal,
Fully Binary Neural Network Model and Optimized Hardware Architectures for Associative Memories

Brain processes information through a complex hierarchical associative memory organization that is distributed across a complex neural network. The GBNN associative memory model has recently been proposed as a new class of recurrent clustered neural network that presents higher efficiency than the classical models. In this article, we propose computational simplifications and architectural optimizations of the original GBNN. This work leads to significant complexity and area reduction without affecting neither memorizing nor retrieving performance. The obtained results open new perspectives in the design of neuromorphic hardware to support large-scale general-purpose neural algorithms.
Effects of Shambhavi Mahamudra Kriya, a Multicomponent Breath-Based Yogic Practice (Pranayama), on Perceived Stress and General Well-Being

Stress-induced disorders such as anxiety represent the leading causes of adult disability worldwide. Previous studies indicate that yoga and other contemplative practices such as pranayama, or controlled yogic breathing techniques, may be effective in the treatment of mood disorders and stress. In this study, 142 individuals (mean age = 43 years; SD = 13.90) participated in a 3-day retreat program during which they learned Shambhavi Mahamudra kriya, which is a yogic practice that includes both deep breathing and meditation techniques. Participants were instructed to practice the kriya each day for 21 minutes. After 6 weeks of daily practice, participants reported subjectively lower levels of perceived stress (Perceived Stress Scale) and higher levels of general well-being (General Well-Being Scale) compared to baseline. These results support the notion that Shambhavi Mahamudra kriya may represent a natural treatment for stress reduction.
Stress-induced Skeletal Muscle Gadd45a Expression Reprograms Myonuclei and Causes Muscle Atrophy*

Background: In skeletal muscle, diverse stresses induce the transcription factor ATF4, which promotes muscle atrophy by an unknown mechanism. Results: ATF4 causes muscle atrophy by inducing Gadd45a, which reprograms myonuclear gene expression to repress anti-atrophy mechanisms and induce pro-atrophy mechanisms. Conclusion: Gadd45a is a critical stress-induced mediator of muscle atrophy. Significance: The ATF4/Gadd45a pathway is a potential therapeutic target in atrophic muscle. Diverse stresses including starvation and muscle disuse cause skeletal muscle atrophy. However, the molecular mechanisms of muscle atrophy are complex and not well understood. Here, we demonstrate that growth arrest and DNA damage-inducible 45a protein (Gadd45a) is a critical mediator of muscle atrophy. We identified Gadd45a through an unbiased search for potential downstream mediators of the stress-inducible, pro-atrophy transcription factor ATF4. We show that Gadd45a is required for skeletal muscle atrophy induced by three distinct skeletal muscle stresses: fasting, muscle immobilization, and muscle denervation. Conversely, forced expression of Gadd45a in muscle or cultured myotubes induces atrophy in the absence of upstream stress. We show that muscle-specific ATF4 knock-out mice have a reduced capacity to induce Gadd45a mRNA in response to stress, and as a result, they undergo less atrophy in response to fasting or muscle immobilization. Interestingly, Gadd45a is a myonuclear protein that induces myonuclear remodeling and a comprehensive program for muscle atrophy. Gadd45a represses genes involved in anabolic signaling and energy production, and it induces pro-atrophy genes. As a result, Gadd45a reduces multiple barriers to muscle atrophy (including PGC-1α, Akt activity, and protein synthesis) and stimulates pro-atrophy mechanisms (including autophagy and caspase-mediated proteolysis). These results elucidate a critical stress-induced pathway that reprograms muscle gene expression to cause atrophy.
Kinetics of isothermal and non‐isothermal degradation of cellulose: model‐based and model‐free methods

BACKGROUND: The kinetics of the thermal decomposition of cellulosic materials is of interest from the viewpoint of flame retardancy for safety, optimization of incineration processes and reducing energy production from fossil sources and associated pollution. One essential step in these processes is the thermal degradation through mass and energy transport, which determines the rate of evolution of various types of products from cellulosic materials. RESULTS: Kinetic parameters have been determined using various model-based and model-free methods in the thermal degradation of cellulose up to 700 °C in helium atmosphere. The values of the activation energy obtained in isothermal processes and non-isothermal processes have been found to be not far from each other. From the integral method, the random nucleation (F1)-type mechanism has been found most probable for cellulose degradation having an activation energy, Ea, in the range 156.5–166.5 kJ mol−1, lnA = 20–23 min−1, for first-order reaction during its decomposition process at heating rates of 2, 5 and 10 °C min−1. Based on the high correlation coefficient, many types of mechanisms seem equally good for non-isothermal degradation of cellulose. CONCLUSION: The linear correlation coefficient has a limitation for verifying the correctness of a reaction mechanism in the study of degradation kinetics. Therefore, the correctness of a mechanism should be considered on the basis of comparing the kinetic parameters obtained from isothermal as well as non-isothermal methods. Copyright © 2008 Society of Chemical Industry
Endoplasmic Reticulum α-Glycosidases of Candida albicans Are Required for N Glycosylation, Cell Wall Integrity, and Normal Host-Fungus Interaction

ABSTRACT The cell surface of Candida albicans is enriched in highly glycosylated mannoproteins that are involved in the interaction with the host tissues. N glycosylation is a posttranslational modification that is initiated in the endoplasmic reticulum (ER), where the Glc3Man9GlcNAc2 N-glycan is processed by α-glucosidases I and II and α1,2-mannosidase to generate Man8GlcNAc2. This N-oligosaccharide is then elaborated in the Golgi to form N-glycans with highly branched outer chains rich in mannose. In Saccharomyces cerevisiae, CWH41, ROT2, and MNS1 encode for α-glucosidase I, α-glucosidase II catalytic subunit, and α1,2-mannosidase, respectively. We disrupted the C. albicans CWH41, ROT2, and MNS1 homologs to determine the importance of N-oligosaccharide processing on the N-glycan outer-chain elongation and the host-fungus interaction. Yeast cells of Cacwh41Δ, Carot2Δ, and Camns1Δ null mutants tended to aggregate, displayed reduced growth rates, had a lower content of cell wall phosphomannan and other changes in cell wall composition, underglycosylated β-N-acetylhexosaminidase, and had a constitutively activated PKC-Mkc1 cell wall integrity pathway. They were also attenuated in virulence in a murine model of systemic infection and stimulated an altered pro- and anti-inflammatory cytokine profile from human monocytes. Therefore, N-oligosaccharide processing by ER glycosidases is required for cell wall integrity and for host-fungus interactions.
Finding sacral: Developmental evolution of the axial skeleton of odontocetes (Cetacea)

Axial morphology was dramatically transformed during the transition from terrestrial to aquatic environments by archaeocete cetaceans, and again during the subsequent odontocete radiation. Here, we reconstruct the sequence of developmental events that underlie these phenotypic transitions. Archaeocete innovations include the loss of primaxial/abaxial interaction at the sacral/pelvic articulation and the modular dissociation of the fluke from the remainder of the tail. Odontocetes subsequently integrated lumbar, sacral, and anterior caudal vertebrae into a single torso module, and underwent multiple series‐specific changes in vertebral count. The conservation of regional proportions despite regional fluctuations in count strongly argues that rates of somitogenesis can vary along the column and that segmentation was dissociated from regionalization during odontocete evolution. Conserved regional proportions also allow the prediction of the location and count of sacral homologs within the torso module. These predictions are tested with the analysis of comparative pudendal nerve root location and geometric morphometrics. We conclude that the proportion of the column represented by the sacral series has been conserved, and that its vertebrae have changed in count and relative centrum length in parallel with other torso vertebrae. Although the sacral series of odontocetes is de‐differentiated, it is not de‐regionalized.
Clustered F8 missense mutations cause hemophilia A by combined alteration of splicing and protein biosynthesis and activity

Dissection of pleiotropic effects of missense mutations, rarely investigated in inherited diseases, is fundamental to understanding genotype-phenotype relationships. Missense mutations might impair mRNA processing in addition to protein properties. As a model for hemophilia A, we investigated the highly prevalent F8 c.6046c>t/p.R2016W (exon 19) mutation. In expression studies exploiting lentiviral vectors, we demonstrated that the amino acid change impairs both Factor VIII (FVIII) secretion (antigen 11.0±0.4% of wild-type) and activity (6.0±2.9%). Investigations in patients’ ectopic F8 mRNA and with minigenes showed that the corresponding nucleotide change also decreases correct splicing to 70±5%, which is predicted to lower further FVIII activity (4.2±2%), consistently with patients’ levels (<1–5%). Masking the mutated exon 19 region by antisense U7snRNA supported the presence of a splicing regulatory element, potentially affected by several missense mutations causing hemophilia A. Among these, the c.6037g>a (p.G2013R) reduced exon inclusion to 41±3% and the c.6053a>g (p.E2018G) to 28±2%, similarly to a variant affecting the 5′ splice site (c.6113a>g, p.N2038S, 26±2%), which displayed normal protein features upon recombinant expression. The p.G2013R reduced both antigen (7.0±0.9%) and activity (8.4±0.8%), while the p.E2018G produced a dysfunctional molecule (antigen: 69.0±18.1%; activity: 19.4±2.3%). In conclusion, differentially altered mRNA and protein patterns produce a gradient of residual activity, and clarify genotype-phenotype relationships. Data detail pathogenic mechanisms that, only in combination, account for moderate/severe disease forms, which in turn determine the mutation profile. Taken together we provide a clear example of interplay between mRNA and protein mechanisms of disease that operate in shaping many other inherited disorders.
Structured diaphragm with a centre boss and four peninsulas for high sensitivity and high linearity pressure sensors

Using the structured diaphragm with a centre boss and four peninsulas (CBP structure), a high sensitivity and high linearity pressure sensor for low pressure ranges was demonstrated. The finite element analysis indicated that the CBP structure could achieve a far better performance than other typical structures for low pressure applications. In accordance with the simulation, the fabricated pressure sensor showed a sensitivity of 21.0 mV/V full-scale output and a nonlinearity error of 0.15% full-scale span in the pressure range of 0–5 kPa. The sensors with the CBP structure are potentially a better choice for measuring low pressures.
Comparing Health Care Financial Burden With an Alternative Measure of Unaffordability

Health insurance plans with high deductibles increase exposure to health care costs, raising concerns about how the growth in these plans may be impacting both the financial burden of health care expenditures on families and their access to health care. We find that foregoing medical care is common among low-income, privately insured families, occurring at a greater rate than those with higher incomes or Medicare coverage. To better understand the relationship between out-of-pocket (OOP) spending and access, we used the 2011-2014 Medical Expenditure Panel Survey (MEPS) data and a logistic model to analyze the likelihood of avoiding or delaying needed medical care based on health insurance design and other individual and family characteristics. We find that avoiding or delaying medical care is strongly correlated with coverage under a high-deductible health plan, and with depression, poor perceived health, or poverty. However, it is relatively independent of the percent of income spent on OOP costs, making the percent of income spent on OOP costs by itself a poor measure of health care unaffordability. Individuals who spend a small percentage of their income on health care costs may still be extremely burdened by their health plan when financial concerns prevent access to health care. This work emphasizes the importance of insurance design as a predictor of access and the need to expand the definition of financial barriers to care beyond expenditures, particularly for the low-income, privately insured population.
Analysis on Color Application in Modern Architecture

Both in the East and West, the modern architectural color application is largely different with traditional architectural color application. The formation of this difference is closely related to ideological changes, scientific and technological development. Through research, we can understand this period of history better and thus interpret the stories about the changing course of modern architectural color.
Risky Sexual Behavior and Alcohol Use among Young Adults: Results from a National Survey

Purpose. To examine the relationship between alcohol use and sexual activity in a sample of young adults. Design. Data were collected as part of a 1990 survey of a multistage area household probability sample. Setting. In-home interviews were conducted by experienced interviewers. Subjects. In total, 1006 persons from 18 to 30 years of age living in the contiguous United States were contacted. Measures. Detailed information was collected on alcohol use and sexual behavior. To minimize the reluctance of respondents to answer queries on sexual behavior, those questions were contained in a self-administered questionnaire. Results. At the population level, having had multiple sexual partners in the past year was more likely among men who consumed five or more drinks per sitting. Condom use was less likely among respondents who had consumed five or more drinks on at least one occasion in the past year. In multivariate analyses, the amount of alcohol consumed at the new partner event was not associated with condom use with a new partner. When the effects of other demographic and psychosocial factors were removed, the number of drinks consumed during the heaviest drinking event was a significant predictor of engaging in sex for women but not for men. Conclusion. In young adults, alcohol use with sex does not necessarily lead directly to lapses in judgment about safe sexual practices. Alcohol is but one of a number of factors that play an important role in determining the riskiness of a particular sexual encounter.
Defining response profiles after alemtuzumab

Alemtuzumab is a humanized monoclonal antibody that causes a rapid but long-lasting depletion of the CD52-bearing lymphoid lineage. Selective pulsed depletion is followed by a complex pattern of immune cell reconstitution that reflects the reshaping and potential reprogramming of immune networks, including the development of tolerance.1 Recent studies showed that pulsed-immune reconstitution therapy with alemtuzumab can produce durable efficacy after 2 courses of treatment (year 1 and 2). 2–5