Miracle-dz/UniFAR-FTUs huggingface dataset:
Dual Activation of Phosphodiesterases 3 and 4 Regulates Basal Spontaneous Beating Rate of Cardiac Pacemaker Cells: Role of Compartmentalization?

Spontaneous firing of sinoatrial (SA) node cells (SANCs) is regulated by cyclic adenosine monophosphate (cAMP)-mediated, protein kinase A (PKA)-dependent (cAMP/PKA) local subsarcolemmal Ca2+ releases (LCRs) from ryanodine receptors (RyR). The LCRs occur during diastolic depolarization (DD) and activate an inward Na+/Ca2+ exchange current that accelerates the DD rate prompting the next action potential (AP). Basal phosphodiesterases (PDEs) activation degrades cAMP, reduces basal cAMP/PKA-dependent phosphorylation, and suppresses normal spontaneous firing of SANCs. The cAMP-degrading PDE1, PDE3, and PDE4 represent major PDE activities in rabbit SANC, and PDE inhibition by 3-isobutyl-1-methylxanthine (IBMX) increases spontaneous firing of SANC by ∼50%. Though inhibition of single PDE1–PDE4 only moderately increases spontaneous SANC firing, dual PDE3 + PDE4 inhibition produces a synergistic effect hastening the spontaneous SANC beating rate by ∼50%. Here, we describe the expression and distribution of different PDE subtypes within rabbit SANCs, several specific targets (L-type Ca2+ channels and phospholamban) regulated by basal concurrent PDE3 + PDE4 activation, and critical importance of RyR Ca2+ releases for PDE-dependent regulation of spontaneous SANC firing. Colocalization of PDE3 and PDE4 beneath sarcolemma or in striated patterns inside SANCs strongly suggests that PDE-dependent regulation of cAMP/PKA signaling might be executed at the local level; this idea, however, requires further verification.
Enhancement of Vascular Smooth Muscle Contractility by Alterations of Membranous Architecture

Plasma membrane (PM) of smooth muscle cells hosts channel molecules regulating the flow of various ions. An intact architecture of PM is essential to orchestrate proper channel functions in order to complete agonist‐mediated contraction, which includes Ca2+ release from the sarcoplasmic reticulum (SR) to initiate contraction, and subsequent Ca2+ refilling into SR through PM to sustain muscle contraction. The Junctional Complex (JC), comprising of junctional SR, and its apposing PM and neighboring caveolae, provides a quasi‐enclosed microdomain housing receptors as well as ion channels and also restricting ion diffusions into the cytosol so the cell achieves optimal performance. The spatial arrangement of the JC is believed to ensure an uninterrupted Ca2+ cycling route. Full understanding of the functional role of the JC is the key to elucidating the contractile mechanisms of vascular smooth muscle and the physiological function of vessel contraction. The JC can be further divided into two sub‐divisions, namely the PM‐SR and caveolar regions. Previously, we demonstrated the role of the PM‐SR region in the initiation of muscle contraction using pharmacological tools on the inferior vena cava (IVC) of rabbit. In the current study, we further dissected the caveolar region using a cholesterol‐disrupting agent to investigate the role of the caveolar region. We conclude that disruption of the caveolar region in rabbit IVC smooth muscle results in augmented muscle contraction in response to adrenergic stimulation and the altered Ca2+ signaling may underlie the augmented contractility. Anat Rec, 302:186–192, 2019. © 2018 Wiley Periodicals, Inc.
Quantification of oleacein and oleuropein aglycone in olive oil using deuterated surrogates by normal-phase ultra high performance liquid chromatography with quadrupole time-of-flight mass spectrometry.

An analytical method for the analysis of relevant secoiridoid-based components in olive oil, oleacein and oleuropein aglycone, is described using for the first time deuterated surrogates. 0.2 g of sample was necessary to perform the analysis using liquid-liquid extraction and ultrasound-assisted extraction with a mixture of methanol/water (4:1, v/v). To avoid the formation of by-products, normal-phase ultra high performance liquid chromatography was chosen for the chromatographic separation. The selected mobile phase was a gradient mixture of tetrahydrofurane and hexane, and an ACE Excel 3 CN-ES column as stationary phase. The detection and quantification was performed with a SYNAPT G2-Si mass spectrometer. The calibration curves for oleacein and oleuropein aglycone were linear and quadratic, respectively. The validation was done at three levels of concentration. Relative errors from 0.1 to 10.5% and relative standard deviations lower than 9% were obtained. The method was applied to study different samples of olive oil.
Biological transport networks

Cord-forming fungi form extensive networks that continuously adapt to maintain an efficient transport system, and we can photograph their growth, digitize the network structure, and measure the movement of radio-tracers. Mycelial networks are more accessible than the transport networks of other multicellular organisms, but there are many open questions concerning the coordination of growth and transport within fungal networks. As osmotically driven water uptake is often distal from the growing margin, and aqueous fluids are effectively incompressible, we propose that growth induces mass flows across the mycelium, towards the growing regions. We imaged the temporal evolution of networks formed by Phanerochaete velutina, and at each stage calculated the unique set of currents that account for the observed changes in cord volume, while minimizing the work required to overcome viscous drag. Predicted speeds were in reasonable agreement with experimental data, and cords that were predicted to carry large currents were significantly more likely to increase in size than cords with small currents. We have also developed an efficient method for calculating the exact quantity of resource in each part of an arbitrary network, where the resource is lost or delivered out of the network at a given rate, while being subject to advection and diffusion. This method enabled us to model the spatial distribution of resource that emerges as a fungal network grows over time, and we found good empirical agreement between our model and experimental data gathered using radio-labelled tracers. Our results suggest that in well insulated fungal networks, growth-induced mass flow is sufficient to account for long distance transport. We conclude that active transport mechanisms may only be required at the very end of the transport pathway, near the growing tips. We also developed a simple model of glucose delivery through vascular networks, which indicates that increasing the number of blood vessels in a region can actually decrease the total rate of glucose delivery.
Wise Interventions: Psychological Remedies for Social and Personal Problems

Long-standing social problems such as poor achievement, personal and intergroup conflict, bad health, and unhappiness can seem like permanent features of the social landscape. We describe an approach to such problems rooted in basic theory and research in social psychology. This approach emphasizes subjective meaning-making—working hypotheses people draw about themselves, other people, and social situations; how deleterious meanings can arise from social and cultural contexts; how interventions to change meanings can help people flourish; and how initial change can become embedded to alter the course of people’s lives. We further describe how this approach relates to and complements other prominent approaches to social reform, which emphasize not subjective meaning-making but objective change in situations or in the habits and skills of individuals. In so doing, we provide a comprehensive theoretical review and organization of a psychologically informed approach to social problems, one that encompasses a wide-range of interventions and applies to diverse problem areas.
Microbial transglutaminase for biotechnological and biomedical engineering

Abstract Research on bacterial transglutaminase dates back to 1989, when the enzyme has been isolated from Streptomyces mobaraensis. Initially discovered during an extensive screening campaign to reduce costs in food manufacturing, it quickly appeared as a robust and versatile tool for biotechnological and pharmaceutical applications due to its excellent activity and simple handling. While pioneering attempts to make use of its extraordinary cross-linking ability resulted in heterogeneous polymers, currently it is applied to site-specifically ligate diverse biomolecules yielding precisely modified hybrid constructs comprising two or more components. This review covers the extensive and rapidly growing field of microbial transglutaminase-mediated bioconjugation with the focus on pharmaceutical research. In addition, engineering of the enzyme by directed evolution and rational design is highlighted. Moreover, cumbersome drawbacks of this technique mainly caused by the enzyme’s substrate indiscrimination are discussed as well as the ways to bypass these limitations.
Postoperative complications are associated with worse survival after laparoscopic surgery for non-metastatic colorectal cancer – interim analysis of 3-year overall survival

Introduction Postoperative morbidity after colorectal resections for cancer remains a significant problem. Data on the influence of complications on survival after laparoscopic colorectal resection are still limited. Aim To analyze the impact of postoperative complications on long-term survival after radical laparoscopic resection for colorectal cancer. Material and methods Two hundred and sixty-five consecutive non-metastatic colorectal cancer patients undergoing laparoscopic colorectal resection for cancer were included in the analysis. The entire study group was divided into two subgroups based on the occurrence of postoperative complications. Group 1 included patients without postoperative morbidity and group 2 included patients with complications. The primary outcome was overall survival. Results Median follow-up was 45 (IQR: 34–55) months. Group 1 consisted of 187 (70.5%) patients and group 2 comprised 78 (29.5%) patients. Studied groups were comparable in terms of sex, age, body mass index, ASA class, cancer staging, localization of the tumor and operative time. Patients in group 1 had significantly better overall 3-year survival compared to those with complications (84.9% vs. 69.8%, p = 0.022). Kaplan-Meier curves showed significantly improved survival rates in patients without complications compared with complicated cases. The Cox proportional multivariate model showed that postoperative complications (HR = 2.83; 95% CI: 1.35–5.92; p = 0.0058) and AJCC III (HR = 3.17; 95% CI: 1.52–6.6; p = 0.0021) were independent predictors of worse survival after laparoscopic colorectal cancer surgery. Conclusions Our analysis of interim results after 3 years confirms that complications after laparoscopic colorectal cancer surgery have an impact on survival. For this reason, these patients should be carefully monitored after surgery aiming at early detection of recurrence.
Super-resolution radar imaging via convex optimization

A radar system emits probing signals and records the reflections. Estimating the relative angles, delays, and Doppler shifts from the received signals allows to determine the locations and velocities of objects. However, due to practical constraints, the probing signals have finite bandwidth B, the received signals are observed over a finite time interval of length T only, and a radar typically has only one or a few transmit and receive antennas. These constraints fundamentally limit the resolution up to which objects can be distinguished. Specifically, a radar can not distinguish objects with delay and Doppler shifts much closer than 1/B and 1/T, respectively, and a radar system with N_T transmit and N_R receive antennas cannot distinguish objects with angels closer than 1/(N_T N_R). As a consequence, the delay, Doppler, and angular resolution of standard radars is proportional to 1/B and 1/T, and 1/(N_T N_R). In this chapter, we show that the continuous angle-delay-Doppler triplets and the corresponding attenuation factors can be resolved at much finer resolution, using ideas from compressive sensing. Specifically, provided the angle-delay-Doppler triplets are separated either by factors proportional to 1/(N_T N_R-1) in angle, 1/B in delay, or 1/T in Doppler direction, they can be recovered a significantly smaller scale or higher resolution.
The biosimilars journey: current status and ongoing challenges

Biosimilar products are already approved and marketed in several countries. The Food and Drug Administration has approved ten different biosimilars, and the European Medicines Agency has approved 40. Even though this scenario has provided important experience with biosimilar products, there are still challenges and unanswered questions. Up to now, a good amount of knowledge has been gathered in order to support the importance of the totality of evidence and the construction of a biosimilarity exercise for regulatory approval. In addition, the extrapolation of indications has been proved viable when a careful analysis is performed. The models for clinical trials and the use of the most sensible populations have been extensively discussed, and there is apparent homogeneity in manufacturer choices for study designs. However, some challenges remain. The lack of regulatory harmony, especially concerning naming, the marketed intended copies, the interchangeability, and the biosimilars in orphan diseases are some of those and are the focus of discussion in this review.
Space Radiation Alters Genotype–Phenotype Correlations in Fear Learning and Memory Tests

Behavioral and cognitive traits have a genetic component even though contributions from individual genes and genomic loci are in many cases modest. Changes in the environment can alter genotype–phenotype relationships. Space travel, which includes exposure to ionizing radiation, constitutes environmental challenges and is expected to induce not only dramatic behavioral and cognitive changes but also has the potential to induce physical DNA damage. In this study, we utilized a genetically heterogeneous mouse model, dense genotype data, and shifting environmental challenges, including ionizing radiation exposure, to explore and quantify the size and stability of the genetic component of fear learning and memory-related measures. Exposure to ionizing radiation and other external stressors altered the genotype–phenotype correlations, although different behavioral and cognitive measures were affected to different extents. Utilizing an integrative genomic approach, we identified pathways and functional ontology categories associated with these behavioral and cognitive measures.
Real-Time Recognition of Signboards with Mobile Device using Deep Learning for Information Identification Support System

In this paper, a framework that uses deep learning on a server to recognize signboards in streets with mobile devices is proposed. The proposed framework enables a user to determine the type of shops in his/her location. Our experimental results revealed that the proposed framework recognized signboards with an 86% accuracy within 1 second.
A Locally Distributed Mobile Computing Framework for DNN based Android Applications

In recent years, with the development of deep neural network (DNN), more and more applications (e.g., image classification, target recognition and audio processing) are supported by it. However, the disadvantage of its own large model makes it difficult to apply on resource-constrained devices such as mobile devices. In order to solve this problem, the existing research and technology mainly focus on the DNN model compression and the segmentation migration of the model. The former is generally at the expense of reducing accuracy, and the segmentation of the model has no unified migration tool for the DNN model of different applications. In this work, we propose a universal neural network layer segmentation tool, which enables the trained DNN model to be migrated, and migrates the segmentation layer to the nodes in the current network in accordance with the dynamic optimal allocation algorithm proposed in this paper. The experimental results show that the tool can adapt to various neural networks with different structures and perform optimal allocation of layers through algorithm. When the number of working nodes increases from 1 to 5, this method can speed up DNN 2-2.5 times, and shows a good acceleration effect.
Haploid Germ Cells Generated in Organotypic Culture of Testicular Tissue From Prepubertal Boys

While in mice various studies have described the completion of spermatogenesis in vitro using either organotypic culture of prepubertal testicular tissue or 3D culture of isolated cells, in humans it has not been possible to achieve germ cell differentiation from immature testicular tissue (ITT). In our study, we evaluated the ability of human ITT to differentiate via a long-term organotypic culture of frozen–thawed 1 mm3 testicular fragments from five prepubertal boys in two different culture media. Tissue and supernatants were analyzed at regular intervals up to day 139. Sertoli cell (SC) viability and maturation was evaluated using immunohistochemistry (IHC) for SOX9, GDNF, anti-Mullerian hormone (AMH) and androgen receptor (AR), and AMH concentration in supernatants. Spermatogonia (SG) and proliferating cells were identified by MAGE-A4 (for SG) and Ki67 (for proliferating cells) via immunohistochemistry (IHC). Apoptotic cells were studied by active caspase 3. To evaluate Leydig cell (LC) functionality testosterone was measured in the supernatants and steroidogenic acute regulatory protein (STAR) IHC was performed. Germ cell differentiation was evaluated on Hematoxylin-Eosin histological sections, via IHC for synaptonemal complex 3 (SYCP3) for spermatocytes, Protein boule-like (BOLL) for spermatocytes and round spermatids, angiotensin-converting enzyme (ACE), protamine 2 and transition protein 1 (for elongated spermatids) and via chromogenic in situ hybridization (CISH). We reported the generation of meiotic and postmeiotic cells after 16 days of culture, as shown by the histological analyses, the presence of differentiation markers and the increase of haploid germ cells. We showed SC viability and maturation by a decrease of AMH secretion in the supernatants (p ≤ 0.001) while the number of SOX9 positive cells did not show any variation. A decrease of spermatogonia (p ≤ 0.001) was observed. The number of apoptotic cells did not vary. LC functionality was shown by the increase in STAR expression (p ≤ 0.007) and a peak in testosterone secretion, followed by a reduction (p ≤ 0.001) with stabilization. According to our knowledge, this is the first report of generation of haploid cells in human ITT. Differentiating germ cells have to be further evaluated for their ability to complete differentiation, their fecundability and epigenetic characteristics.
Pharmacokinetic Characteristics and Limited Sampling Strategies for Therapeutic Drug Monitoring of Colistin in Patients With Multidrug-Resistant Gram-Negative Bacterial Infections

Background: Colistin is increasingly used as the last therapeutic option for the treatment of multidrug-resistant, Gram-negative bacterial infections. To ensure safe and efficacious use of colistin, therapeutic drug monitoring (TDM) is needed due to its narrow therapeutic window. This study aimed to evaluate the pharmacokinetic (PK) characteristics of colistin and to guide TDM in colistin-treated patients in Korea. Methods: In a prospective study, we analyzed PK characteristics in 15 patients who intravenously received colistin methanesulfonate twice per day. Colistin methanesulfonate doses were adjusted based on renal function of the subjects. The appropriate blood sampling points for TDM were evaluated by analyzing the correlations between the PK parameters and the plasma concentrations at each time point. Results: The mean values for the minimum, maximum, and average concentrations (Cmin, Cmax, and Caverage) of colistin at steady state were 2.29, 5.5, and 3.38 mg/L, respectively. The dose-normalized Cmin, Cmax, Caverage, and area under the plasma concentration–time curve from 0 to the last measurable concentration (AUClast) showed negative correlations with the creatinine clearance. The combination of the 0- and 2-hour post-dose plasma concentrations was evaluated as the appropriate sampling point for TDM. Two patients reported nephrotoxic adverse events during colistin administration. Conclusions: Our study clarifies the PK characteristics of successful colistin treatment using TDM. Further evaluations in a larger patient population are needed to confirm the clinical usefulness of colistin TDM.
Modelling tropical forest responses to drought and El Niño with a stomatal optimization model based on xylem hydraulics

The current generation of dynamic global vegetation models (DGVMs) lacks a mechanistic representation of vegetation responses to soil drought, impairing their ability to accurately predict Earth system responses to future climate scenarios and climatic anomalies, such as El Niño events. We propose a simple numerical approach to model plant responses to drought coupling stomatal optimality theory and plant hydraulics that can be used in dynamic global vegetation models (DGVMs). The model is validated against stand-scale forest transpiration (E) observations from a long-term soil drought experiment and used to predict the response of three Amazonian forest sites to climatic anomalies during the twentieth century. We show that our stomatal optimization model produces realistic stomatal responses to environmental conditions and can accurately simulate how tropical forest E responds to seasonal, and even long-term soil drought. Our model predicts a stronger cumulative effect of climatic anomalies in Amazon forest sites exposed to soil drought during El Niño years than can be captured by alternative empirical drought representation schemes. The contrasting responses between our model and empirical drought factors highlight the utility of hydraulically-based stomatal optimization models to represent vegetation responses to drought and climatic anomalies in DGVMs. This article is part of a discussion meeting issue ‘The impact of the 2015/2016 El Niño on the terrestrial tropical carbon cycle: patterns, mechanisms and implications’.
A modular approach to integrate verification tools in model based development

The problem of integrating an existing formal verification tool in a given software specification tool arises repeatedly both in industry and academia. At present this task is executed in an ad-hoc manner and is time consuming. Moreover, interpreting the results of the verification to locate and fix the bug (by the human user) is implicitly complicated, hence, time consuming. In this work we draft a solution for reducing the complexity of these tasks and aim at reducing the time required to complete them. We sketch a framework formalizing the concepts required to execute these tasks in a modular fashion and implement a solution based on domain specific languages (DSLs) and parameterizable model transformations. We expect that the modularity of our framework will raise its potential to be reused. We plan on evaluating this work on a set of modeling environments and a set of verification tools.