Miracle-dz/UniFAR-FTUs huggingface dataset:
Using human induced pluripotent stem cell-derived cardiomyocytes to understand the mechanisms driving cardiomyocyte maturation

Cardiovascular diseases are the leading cause of mortality and reduced quality of life globally. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a personalized platform to study inherited heart diseases, drug-induced cardiac toxicity, and cardiac regenerative therapy. However, the immaturity of CMs obtained by current strategies is a major hurdle in utilizing hiPSC-CMs at their fullest potential. Here, the major findings and limitations of current maturation methodologies to enhance the utility of hiPSC-CMs in the battle against a major source of morbidity and mortality are reviewed. The most recent knowledge of the potential signaling pathways involved in the transition of fetal to adult CMs are assimilated. In particular, we take a deeper look on role of nutrient sensing signaling pathways and the potential role of cap-independent translation mediated by the modulation of mTOR pathway in the regulation of cardiac gap junctions and other yet to be identified aspects of CM maturation. Moreover, a relatively unexplored perspective on how our knowledge on the effects of preterm birth on cardiovascular development can be actually utilized to enhance the current understanding of CM maturation is examined. Furthermore, the interaction between the evolving neonatal human heart and brown adipose tissue as the major source of neonatal thermogenesis and its endocrine function on CM development is another discussed topic which is worthy of future investigation. Finally, the current knowledge regarding transcriptional mediators of CM maturation is still limited. The recent studies have produced the groundwork to better understand CM maturation in terms of providing some of the key factors involved in maturation and development of metrics for assessment of maturation which proves essential for future studies on in vitro PSC-CMs maturation.
A review of patient-reported outcomes used for regulatory approval of oncology medicinal products in the European Union between 2017 and 2020

Introduction Cancer and corresponding available treatments are associated with substantial symptoms and functional limitations. In this context, collection of patient-reported outcomes (PRO) in clinical trials gained special interest and is recommended by regulatory authorities. Within clinical trials framework, PRO may provide evidence to support medicines approval, labeling and marketing claims. This study aims to analyze the existing evidence based on PRO as part of new oncology indications receiving positive opinions issued by the European Medicines Agency (EMA) between 2017 and 2020 and to identify PRO related label claims granted. Methodology Oncology medicinal products and indications approved by the European Commission following a positive opinion from the EMA between 2017 and 2020 were identified. European Public Assessment Report (EPAR) and Summary of Product Characteristics (SmPC) were reviewed for each medicinal product to identify use of PRO and PRO label claims. Results A total of 128 oncology indications, corresponding to 76 medicines, were approved; of those, 100 (78.1%) included PRO in the confirmatory clinical trials. Thirty-seven indications were supported by double-blind randomized trials and the remainder 63 by open-label trials. Out of the 104 confirmatory trials analyzed, PRO were defined as a secondary endpoint in 60 studies (57.7%), exploratory in 31 (29.8%) and as both in 13 (12.5%). In total, 54 different PRO measures (PROM) were used, of those 41 (75.9%) were disease-specific measures. Nevertheless, PROM selected relied on the EORTC (41.3%), FACIT (17.1%) and EQ-5D (29.2%) measures. A total of 76 indications (59.4%) had PRO reviewers comments included in the EPAR, however only 22 indications (17.8%) included label claims in the SmPC. The reasons identified in the EMA assessment supporting the exclusion of PRO claims were described for 34 indications (44.7%). Conclusions Despite growing recognition of the value of PRO data for the development of improved cancer therapies, PRO implementation remains challenging. The main reasons identified in our study are related with study design, missing data, study conduct and PROM selection.
QbD-based rivastigmine tartrate-loaded solid lipid nanoparticles for enhanced intranasal delivery to the brain for Alzheimer's therapeutics

Alzheimer's disease (AD) is a neurodegenerative disease that affects a wide range of populations and is the primary cause of death in various countries. The treatment of AD is still restricted to oral conventional medicines that act only superficially. Fabrication of intranasal solid lipid nanoparticulate system for the uptake of therapeutic agents will act as a convincing approach with limited off-site toxicity and increased pharmacological activity. The objective of this study was to formulate, optimize, and evaluate the efficiency of rivastigmine tartrate (RT)-loaded intranasal solid lipid nanoparticles (SLNs) employing the solvent-evaporation diffusion method. To optimize the formulation parameters, the central composite design (CCD) was used. Lipid concentration (X1) and surfactant concentration (X2) were considered to be independent variables, while particle size (Y1), percentage entrapment efficiency (Y2), and percentage drug release (Y3) were considered as responses. The solid lipid was glyceryl monostearate, while the surfactant was polysorbate 80. The optimized formulation has a particle size of 110.2 nm, % entrapment efficiency of 82.56%, and % drug release of 94.86%. The incompatibility of drug excipients was established by differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR). Nasal histopathology tests on sheep mucosa revealed that the developed SLNs were safe to utilize for intranasal delivery with no toxicity. Ex vivo permeation investigations revealed that the flux and diffusion coefficients for RT solid lipid nanoparticles and RT solution were 3.378 g/cm2 /h and 0.310–3 cm2 /h, respectively. Stability studies demonstrated that the developed SLNs were stable when stored under various storage conditions. The viability and vitality of adopting a lipid particle delivery system for improved bioavailability via the intranasal route were also established in the in vivo pharmacokinetic investigations. According to the histopathological and pharmacokinetic investigations, the developed formulations were safe, non-lethal, efficient, and robust. These results suggest the potentiality provided by rivastigmine tartrate-loaded solid lipid nanoparticles for nasal delivery.
Neural responsiveness to Chinese versus Western food images: An functional magnetic resonance imaging study of Chinese young adults

Cross-cultural studies suggest that people typically prefer to eat familiar foods from their own culture rather than foreign foods from other cultures. On this basis, it is plausible that neural responsiveness elicited by palatable food images from one’s own culture differ from those elicited by food depictions from other cultures. Toward clarifying this issue, we examined neural activation and self-report responses to indigenous (Chinese) versus Western food images among young Chinese adults. Participants (33 women, 33 men) viewed Chinese food, Western food and furniture control images during a functional magnetic resonance imaging (fMRI) scan and then rated the images on “liking,” “wanting,” and “difficult resisting. ” Analyses indicated there were no significant differences in self-report ratings of Chinese versus Western food images. However, Chinese food images elicited stronger activation in regions linked to cravings, taste perception, attention, reward, and visual processing (i.e., cerebellum crus, superior temporal gyrus, supramarginal gyrus, middle temporal gyrus, inferior parietal lobule, posterior insula, middle occipital gyrus; inferior occipital gyrus). Conversely, Western food images elicited stronger activation in areas involved in visual object recognition and visual processing (inferior temporal gyrus, middle occipital gyrus, calcarine). These findings underscored culture as a potentially important influence on neural responses to visual food cues and raised concerns about the ecological validity of using “standard” Western food images in neuroimaging studies of non-Western samples. Results also provide foundations for designing culturally informed research and intervention approaches in non-Westerns contexts guided by the use of external food cues that are most salient to the cultural group under study.
Pain acceptance and illness intrusiveness in low-back pain: A longitudinal study

Background In chronic pain syndromes, acceptance of pain may be a better approach than pain control. So far, little data have been available on how pain and its acceptance affect illness intrusiveness among patients with low-back pain (LBP). Objective The present longitudinal study evaluates the impact of pain acceptance on illness intrusiveness in patients with LBP. Methods Study participants were asked to complete the following questionnaires during their visit (T1) at one of four diverse rheumatologic outpatient clinics, and then 2–3 months later (T2) via phone or online: Chronic Pain Acceptance Questionnaire (CPAQ), Illness Intrusiveness Rating Scale (IIRS), Roland-Morris Disability Questionnaire (RMDQ), Patient Health Questionnaire Depression subscale (PHQ9), and socioeconomic data. Results One hundred and twenty-seven individuals completed the questionnaires at baseline (31 having acute, 15 subacute and 81 chronic low back pain) and 97 at follow-up. Illness intrusiveness was negatively correlated with chronic pain acceptance both at T1 (r = −0.39) and T2 (r = –0.44). Illness intrusiveness scores have not changed significantly from T1 (M = 28.59 SD = 13.08) to T2 (M = 28.24, SD = 15.76). In a multiple regression model—including pain intensity, functional status, pain acceptance, depression severity, age, sex and educational level—the independent predictors of follow-up illness intrusiveness scores were lower pain acceptance and higher depression scores. Conclusions In our study, patients with acute, subacute and chronic low back pain reported similar levels of illness intrusiveness. In addition, illness intrusiveness scores have not changed significantly during the 2-month follow-up period and pain acceptance proved to be a significant independent predictor of illness intrusiveness among patients with chronic low-back pain.
Cinnamomum cassia (L.) J.Presl Alleviates Allergic Responses in Asthmatic Mice via Suppression of MAPKs and MMP-9

The prevalence of asthma is gradually increasing, and endangers human health. Many therapeutic agents have been developed to address this concern. Cinnamomum cassia (L.) J.Presl is a traditional herbal remedy in China, Japan, and Korea and used mainly to control common cold, cough, pneumonitis and fever in Donguibogam, a medical encyclopedia of Korea. Therefore, we investigated whether C. cassia (L.) J.Presl extract (CCE) confers protective effects on asthma model induced by ovalbumin (OVA). The animals were received intraperitoneal administration of OVA on day 1 and 14, and then subjected to OVA inhalation from day 21–23. They were orally treated CCE (30 and 100 mg/kg) from day 18–23. CCE administration decreased allergic responses, including airway hyperresponsiveness, eosinophilia, inflammatory cytokine production, and immunoglobulin E in OVA-exposed mice, along with the decline in inflammatory cell count and mucus secretion in respiratory tract. Additionally, CCE suppressed MAPK phosphorylation and MMP-9 expression in OVA-exposed mice. Overall, CCE treatment attenuated allergic responses induced by OVA exposure, which may be connected to the suppression of MAPK phosphorylation.
Multifactorial methods integrating haplotype and epistasis effects for genomic estimation and prediction of quantitative traits

The rapid growth in genomic selection data provides unprecedented opportunities to discover and utilize complex genetic effects for improving phenotypes but methodology is lacking. Epistasis effects are interaction effects and haplotype effects may contain local high-order epistasis effects. Multifactorial methods with SNP, haplotype and epistasis effects up to the third-order are developed to investigate the contributions of global low-order and local high-order epistasis effects to the phenotypic variance and the accuracy of gnomic prediction of quantitative traits. These methods include genomic best linear unbiased prediction (GBLUP) with associated reliability for individuals with and without phenotypic observations including a computationally efficient GBLUP method for large validation populations, and genomic restricted maximum estimation (GREML) of the variance and associated heritability using a combination of EM-REML and AI-REML iterative algorithms. These methods were developed for two models, Model-I with 10 effect types, and Model-II with 13 effect types including intra- and inter-chromosome pairwise epistasis effects that replace the pairwise epistasis effects of Model-I. GREML heritability estimate and GBLUP effect estimate for each effect of an effect type are derived except for third-order epistasis effects. The multifactorial models evaluate each effect type based on the phenotypic values adjusted for the remaining effect types and can use more effect types than separate models of SNP, haplotype and epistasis effects; and provide a methodology capability to evaluate the contributions of complex genetic effects to the phenotypic variance and prediction accuracy, and to discover and utilize complex genetic effects for improving the phenotypes of quantitative traits.
Open to a fault: On the passive compromise of TLS keys via transient errors

It is well known in the cryptographic literature that the most common digital signature schemes used in practice can fail catastrophically in the presence of faults during computation. We use passive and active network measurements to analyze organically-occuring faults in billions of digital signatures generated by tens of millions of hosts. We ﬁnd that a persistent rate of apparent hardware faults in unprotected implementations has resulted in compromised certiﬁcate RSA private keys for years. The faulty signatures we observed allowed us to compute private RSA keys associated with a top-10 Alexa site, several browser-trusted wildcard certiﬁcates for organiza-tions that used a popular VPN product, and a small sporadic population of other web sites and network devices. These measurements illustrate the fragility of RSA PKCS#1v1.5 signature padding and provide insight on the risks faced by unprotected implementations on hardware at Internet scale.
Potential impactThe contribution of shipping to air pollution in the Mediterranean region – a multimodel evaluation: Comparison of photooxidants NO2 and O3

Shipping has a significant sharecontribution to the emissions of air pollutants such as NOx and particulate matter (PM), and the global maritime transport volumes are projected to increase further in the future. The Mediterranean Sea contains the major route for short sea shipping within Europe and contains the main shipping route between Europe and East Asia. Thus, it is a highly frequented shipping area, and high levels of air pollutants with significant contributionpotential impacts 15 from shipping emissions are observed at monitoring stations in many cities along the Mediterranean coast. The present study is part of the EU H2020 project SCIPPER (Shipping contribution to Inland Pollution Push for the Enforcement of Regulations). Five different regional chemistry transport models (CAMx, CHIMERE, CMAQ, EMEP, LOTOS-EUROS) were used to simulate the transport, chemical transformation and fate of atmospheric pollutants in the Mediterranean Sea for 2015. Shipping emissions were calculated with STEAM version 3.3. 0, and land-based emissions were 20 taken from the CAMS-REG v2.2. 1 dataset for a domain covering the Mediterranean Sea on a resolution of 12x12 km2 (or 0.1° x 0.1°). All models used their standard setup for further input. Ship contribution Potential impact of ships was calculated with the zero-out method. One run using the tagging method was performed with LOTOS-EUROS. The model outputs results were compared against each other and to measured background data at monitoring stations. The model results showed differing outputsare differing regarding the time series and pattern of model outputs but are similar 25 results with regard toconcerning the overall underestimation of NO2 and overestimation of O3. The contributionpotential impact from ships to the total NO2 concentration was especially high at the main shipping routes and coastal regions (25% to 85%). The contributionpotential impact from ships to the total O3 concentration was lowest in regions with the highest NO2 contribution impact (down to -20%). A comparison of the zero-out and tagging methods has shown that the annual mean ship contribution to the total NO2 concentration is smaller (up to 75%) and has a lower range when the tagging method is used. 30 CAMx and CHIMERE simulated the highest ship contributionpotential impacts of ships to the NO2 and O3 air concentrations. Additionally, the strongest correlation was found between CAMx and CHIMERE, which can be traced back to the usage of
Effect of Dipping Time in Brine on the Quality of Smoked Silver Carp ( Hypophthalmichthys molitrix ) Stored at 23 – 26 0 C and 4 0 C.

This experiment was conducted to evaluate the effect of dipping time in brine on the shelf-life of hot-smoked Silver carp ( Hypophthalmichthys molitrix ) stored at ambient (23-26ºC) and refrigeration (4ºC) temperature. The fish in two treatments named A and B were salt-dipped for 15 and 30 minutes respectively in a saturated brine solution (≈25% NaCl). The fish were then smoked at 75ºC in an improved traditional smoking kiln followed by cooling. After sealing in polythene bags the smoked products were stored separately at ambient and refrigeration temperature. Four major analysis viz. sensory assessment, initial and final proximate analysis, chemical analysis and microbial analysis were carried out on the samples. According to sensory assessment the 30 minutes brine dipped smoked fish kept at ambient temperature showed a higher shelf-life of four days. On 5 th day, appearance of fungus on the product of treatment B confirmed its acceptability up to 4 days. Similarly the samples of two treatments A and B stored at refrigeration temperature showed a longer shelf-life of up to 41 and 48 days respectively. The rate of lipid deterioration and protein breakdown were found very gradual and not significant. In all cases ash content increased slightly. No appreciable changes in proximate composition in two treatments during storage condition were observed. Values of TVB-N in the samples kept at ambient temperature showed more rapid increase to 34.6 mg/100g on 4 th day of observation in contrast to 35.9 mg/100g on 49 th day in fish kept at refrigeration temperature. However, smoked silver carp in treatment B maintained its excellent quality up to 14 days of storage, and considered as acceptable for 41days and was just to satisfactory level for 48 days under refrigerated condition.
Environmental News Emotion and Air Pollution in China

In 2013, the Chinese central government launched a war on air pollution. As a new and major source of information, the Internet plays an important role in diffusing environmental news emotion and shaping people's perceptions and emotions regarding the pollution. How could the government make use of the environmental news emotion as an informal regulation of pollution? The paper investigates the causal relationship between web news emotion (defined by the emotional tone of web news) and air pollution (SO2, NO2, PM2.5 and PM10) by exploiting the central government's war on air pollution. We combine daily monitoring data of air pollution at different levels (cities and counties, respectively the second and third administrative levels in China) with the GDELT database that allows us to have information on Chinese web news media (e.g. emotional tone of web news on air pollution). We find that a decrease of the emotional tone in web news (i.e. more negative emotions in the articles) can help to reduce air pollution at both city and county level. We attribute this effect to the context of China’s war on air pollution in which the government makes use of the environmental news emotion as an informal regulation of pollution. our
14.1 A 2.9TOPS/W deep convolutional neural network SoC in FD-SOI 28nm for intelligent embedded systems

A booming number of computer vision, speech recognition, and signal processing applications, are increasingly benefiting from the use of deep convolutional neural networks (DCNN) stemming from the seminal work of Y. LeCun et al. [1] and others that led to winning the 2012 ImageNet Large Scale Visual Recognition Challenge with AlexNet [2], a DCNN significantly outperforming classical approaches for the first time. In order to deploy these technologies in mobile and wearable devices, hardware acceleration plays a critical role for real-time operation with very limited power consumption and with embedded memory overcoming the limitations of fully programmable solutions.
Application of sustainability design to an existing viaduct in a hilly area

The World Commission on Environment and Development of the United Nations defined “sustainable development” for the first time in 1987, indicating the necessity for considering development that fulfils the needs of both present and future generations. However, the current situation of the sharp growth in the population and resources/energy consumption that adversely affects the global climate has been adding significance to the concept of sustainable development. From this background, the authors proposed a sustainability design system. This design method includes systems to clearly set the performance requirements to be considered with respect to social, economic, and environmental aspects, calculate the attained performance, and verify if the performance requirements are met. This paper describes the application feasibility of the sustainability design through the above procedures using an existing prestressed concrete viaduct. Additionally, comprehensive evaluation is carried out regarding the relationship between the elements of sustainability in comparison with the general method to clarify the effectiveness of sustainability design. It is concluded that sustainability design system has great potential of its applicability to concrete structures and promoting technical innovation based on setting of high‐performance requirements.
Learning Random Feature Dynamics for Uncertainty Quantification

An inherent challenge of learning-based control tasks is posed by uncertainty due to finite training datasets. Even though there are principled tools to obtain confidence bounds for pointwise evaluation of learned dynamics models, it remains a challenging task to quantify the induced uncertainty in downstream quantities of interest due to the intrinsic recursive structure of dynamic systems. In this paper, we view the unknown one-step dynamics as a smooth function in a reproducing kernel Hilbert space and leverage random features for an approximate but highly structured parameterization of pointwise confidence bounds. As a result, we obtain downstream confidence bounds through an optimal control formulation under an uncertainty-aware random feature dynamics model. Our model is effectively a shallow neural network, which enables us to view the corresponding dynamic system as a deep neural network. Exploiting this perspective, we show that a Pontryagin’s minimum principle solution is equivalent to using the Frank-Wolfe algorithm on the induced neural network. Various numerical experiments on dynamics learning showcase the capacity of our methodology.