Miracle-dz/UniFAR-FTUs huggingface dataset:
Description of the Human Atrial Action Potential Derived From a Single, Congruent Data Source: Novel Computational Models for Integrated Experimental-Numerical Study of Atrial Arrhythmia Mechanisms

Introduction: The development of improved diagnosis, management, and treatment strategies for human atrial fibrillation (AF) is a significant and important challenge in order to improve quality of life for millions and reduce the substantial social-economic costs of the condition. As a complex condition demonstrating high variability and relation to other cardiac conditions, the study of AF requires approaches from multiple disciplines including single-cell experimental electrophysiology and computational modeling. Models of human atrial cells are less well parameterized than those of the human ventricle or other mammal species, largely due to the inherent challenges in patch clamping human atrial cells. Such challenges include, frequently, unphysiologically depolarized resting potentials and thus injection of a compensatory hyperpolarizing current, as well as detecting certain ion currents which may be disrupted by the cell isolation process. The aim of this study was to develop a laboratory specific model of human atrial electrophysiology which reproduces exactly the conditions of isolated-cell experiments, including testing of multiple experimental interventions. Methods: Formulations for the primary ion currents characterized by isolated-cell experiments in the Workman laboratory were fit directly to voltage-clamp data; the fast sodium-current was parameterized based on experiments relating resting membrane potential to maximal action potential upstroke velocity; compensatory hyperpolarizing current was included as a constant applied current. These formulations were integrated with three independent human atrial cell models to provide a family of novel models. Extrapolated intact-cell models were developed through removal of the hyperpolarizing current and introduction of terminal repolarization potassium currents. Results: The isolated-cell models quantitatively reproduced experimentally measured properties of excitation in both control and pharmacological and dynamic-clamp interventions. Comparison of isolated and intact-cell models highlighted the importance of reproducing this cellular environment when comparing experimental and simulation data. Conclusion: We have developed a laboratory specific model of the human atrial cell which directly reproduces the experimental isolated-cell conditions and captures human atrial excitation properties. The model may be particularly useful for directly relating model to experiment, and offers a complementary tool to the available set of human atrial cell models with specific advantages resulting from the congruent input data source.
Current Treatment Strategies in Metastasized Differentiated Thyroid Cancer

On successful completion of this activity one should be able to judge the prognosis of patients harboring metastasized differentiated thyroid cancer (DTC); identify suitable treatment regimens, taking into account the characteristics of the tumor and the patient’s general condition; and know the basics of radioiodine treatment, tyrosine kinase treatment, and redifferentiation treatment for metastasized DTC.
Vesicular trafficking plays a role in centriole disengagement and duplication

Centrosomes are the major microtubule-nucleating and microtubule-organizing centers of cells and play crucial roles in microtubule anchoring, organelle positioning, and ciliogenesis. At the centrosome core lies a tightly associated or “engaged” mother–daughter centriole pair. During mitotic exit, removal of centrosomal proteins pericentrin and Cep215 promotes “disengagement” by the dissolution of intercentriolar linkers, ensuring a single centriole duplication event per cell cycle. Herein, we explore a new mechanism involving vesicular trafficking for the removal of centrosomal Cep215. Using small interfering RNA and CRISPR/Cas9 gene-edited cells, we show that the endocytic protein EHD1 regulates Cep215 transport from centrosomes to the spindle midbody, thus facilitating disengagement and duplication. We demonstrate that EHD1 and Cep215 interact and show that Cep215 displays increased localization to vesicles containing EHD1 during mitosis. Moreover, Cep215-containing vesicles are positive for internalized transferrin, demonstrating their endocytic origin. Thus, we describe a novel relationship between endocytic trafficking and the centrosome cycle, whereby vesicles of endocytic origin are used to remove key regulatory proteins from centrosomes to control centriole duplication.
Antigenic sites in influenza H1 hemagglutinin display species-specific immunodominance

Hemagglutination inhibition (HI) titers are a major correlate of protection for influenza-related illness. The influenza virus hemagglutinin possesses antigenic sites that are the targets of HI active antibodies. Here, a panel of mutant viruses each lacking a classically defined antigenic site was created to compare the species-specific immunodominance of the antigenic sites in a clinically relevant hemagglutinin. HI active antibodies of antisera from influenza virus–infected mice targeted sites Sb and Ca2. HI active antibodies of guinea pigs were not directed against any specific antigenic site, although trends were observed toward Sb, Ca2, and Sa. HI titers of antisera from infected ferrets were significantly affected by site Sa. HI active antibodies of adult humans followed yet another immunodominance pattern, in which sites Sb and Sa were immunodominant. When comparing the HI profiles among different species by antigenic cartography, animals and humans grouped separately. This study provides characterizations of the antibody-mediated immune responses against the head domain of a recent H1 hemagglutinin in animals and humans.
MicroRNA High Throughput Loss-of-Function Screening Reveals an Oncogenic Role for miR-21-5p in Hodgkin Lymphoma

Background/Aims: Classical Hodgkin lymphoma (cHL) is among the most frequent lymphoma subtypes. The tumor cells originate from crippled germinal center (GC)-B cells that escaped from apoptosis. MicroRNAs (miRNAs) play important roles in B-cell maturation and aberrant expression of miRNAs contributes to the pathogenesis of cHL. Our aim was to identify oncogenic miRNAs relevant for growth of cHL using a high-throughput screening approach. Methods: A lentiviral pool of 63 miRNA inhibition constructs was used to identify miRNAs essential to cell growth in three cHL cell lines in duplicate. As a negative control we also infected cHL cell lines with a lentiviral barcoded empty vector pool consisting of 222 constructs. The abundance of individual constructs was followed over time by a next generation sequencing approach. The effect on growth was confirmed using individual GFP competition assays and on apoptosis using Annexin-V staining. Our previously published Argonaute 2 (Ago2) immunoprecipitation (IP) data were used to identify target genes relevant for cell growth / apoptosis. Luciferase assays and western blotting were performed to confirm targeting by miRNAs. Results: Four miRNA inhibition constructs, i.e. miR-449a-5p, miR-625-5p, let-7f-2-3p and miR-21-5p, showed a significant decrease in abundance in at least 4 of 6 infections. In contrast, none of the empty vector constructs showed a significant decrease in abundance in 3 or more of the 6 infections. The most abundantly expressed miRNA, i.e. miR-21-5p, showed significantly higher expression levels in cHL compared to GC-B cells. GFP competition assays confirmed the negative effect of miR-21-5p inhibition on HL cell growth. Annexin-V staining of cells infected with miR-21-5p inhibitor indicated a significant increase in apoptosis at day 7 and 9 after viral infection, consistent with the decrease in growth. Four miR-21-5p cell growth- and apoptosis-associated targets were AGO2-IP enriched in cHL cell lines and showed a significant decrease in expression in cHL cell lines in comparison to normal GC-B cells. For the two most abundantly expressed, i.e. BTG2 and PELI1, we confirmed targeting by miR-21-5p using luciferase assays and for PELI1 we also confirmed this at the protein level by western blotting. Conclusion: Using a miRNA loss-of-function high-throughput screen we identified four miRNAs with oncogenic effects in cHL and validated the results for the in cHL abundantly expressed miR-21-5p. MiR-21-5p is upregulated in cHL compared to GC-B cells and protects cHL cells from apoptosis possibly via targeting BTG2 and PELI1.
Genetic risk factors for VIPN in childhood acute lymphoblastic leukemia patients identified using whole-exome sequencing.

AIM To identify genetic markers associated with vincristine-induced peripheral neuropathy (VIPN) in childhood acute lymphoblastic leukemia. PATIENTS & METHODS Whole-exome sequencing data were combined with exome-wide association study to identify predicted-functional germline variants associated with high-grade VIPN. Genotyping was then performed for top-ranked signals (n = 237), followed by validation in independent replication group (n = 405). RESULTS Minor alleles of rs2781377/SYNE2 (p = 0.01) and rs10513762/MRPL47 (p = 0.01) showed increased risk, whereas that of rs3803357/BAHD1 had a protective effect (p = 0.007). Using a genetic model based on weighted genetic risk scores, an additive effect of combining these loci was observed (p = 0.003). The addition of rs1135989/ACTG1 further enhanced model performance (p = 0.0001). CONCLUSION Variants in SYNE2, MRPL47 and BAHD1 genes are putative new risk factors for VIPN in childhood acute lymphoblastic leukemia.
The use of fluorescent staining techniques for microscopic investigation of polymorphonuclear leukocytes and bacteria

The use of fluorescent stains to visually investigate eukaryotic and/or prokaryotic cells is increasing quickly and manuscripts within all areas of research publish results using fluorescent staining techniques. However, in contrast to literature on traditional histological staining techniques, the literature on fluorescent stains and staining techniques does not offer as good an illustration of cellular morphology. The aim of this guideline is to illustrate different fluorescent stains and staining techniques for imaging immune cells, in particular the polymorphonuclear leukocytes (PMNs), in combination with infecting bacteria as seen in chronic bacterial infections. Thereby providing the first guideline for the morphology and identification of fluorescently stained PMNs, bacteria and biofilm.
DEVS modelling and simulation of a multi-paradigm modelling tool

Multi-Paradigm Modelling (MPM) has been proposed to tackle the complexities of the systems we build to-day. MPM proposes to explicitly model all relevant aspects of the system, at the right level(s) of abstraction, using the most appropriate formalism(s), while explicitly modelling the process. This imposes stringent requirements on any tool supporting MPM, such as support for distributed execution, support for multiple users, all while having acceptable performance. In this paper, we wish to aid the development of such complex tools by explicitly modelling the tool using the Parallel DEVS formalism, thereby applying the MPM approach ourselves. This model is applied in two domains: performance evaluation and model debugging. For performance, the DEVS model is used for what-if analysis and automated benchmarks. For debugging, DEVS debuggers are used instead of code debuggers, raising the level of abstraction. In both cases, DEVS yields deterministic execution, aiding in reproducibility.
Effects of exogenously-applied L-ascorbic acid on root expansive growth and viability of the border-like cells

ABSTRACT Functions of exogenous L-ascorbic acid in plant roots are poorly understood. Recent study by Makavitskaya et al. (doi.org/10.1093/jxb/ery056) has demonstrated that exogenous ascorbate can be released from roots in response to salt stress, and can trigger elevation in the cytosolic free Ca2+. Here, we report that exogenous ascorbate significantly modifies root elongation in Arabidopsis thaliana. Using a medium exchange technique, we have shown that 10–100 µM ascorbate induces small but significant increase in root elongation while higher levels cause its dramatic decrease. Root border cells of Pisum sativum have been losing viability twice faster in the presence of ascorbate that under control conditions, as tested by the confocal microscopy and a combined staining with propidium iodide and fluorescein diacetate.
Plasma membrane profiling during enterohemorrhagic E. coli infection reveals that the metalloprotease StcE cleaves CD55 from host epithelial surfaces

Enterohemorrhagic Escherichia coli (EHEC) is one of several E. coli pathotypes that infect the intestinal tract and cause disease. Formation of the characteristic attaching and effacing lesion on the surface of infected cells causes significant remodeling of the host cell surface; however, limited information is available about changes at the protein level. Here we employed plasma membrane profiling, a quantitative cell-surface proteomics technique, to identify host proteins whose cell-surface levels are altered during infection. Using this method, we quantified more than 1100 proteins, 280 of which showed altered cell-surface levels after exposure to EHEC. 22 host proteins were significantly reduced on the surface of infected epithelial cells. These included both known and unknown targets of EHEC infection. The complement decay–accelerating factor cluster of differentiation 55 (CD55) exhibited the greatest reduction in cell-surface levels during infection. We showed by flow cytometry and Western blot analysis that CD55 is cleaved from the cell surface by the EHEC-specific protease StcE and found that StcE-mediated CD55 cleavage results in increased neutrophil adhesion to the apical surface of intestinal epithelial cells. This suggests that StcE alters host epithelial surfaces to depress neutrophil transepithelial migration during infection. This work is the first report of the global manipulation of the epithelial cell surface by a bacterial pathogen and illustrates the power of quantitative cell-surface proteomics in uncovering critical aspects of bacterial infection biology.
Diagnosing idiopathic pulmonary fibrosis in 2018: bridging recommendations made by experts serving different societies

Two guidance documents for the diagnosis of idiopathic pulmonary fibrosis (IPF) have been recently published by international experts representing major respiratory and radiological societies [1, 2]. Similar documents from other societies are anticipated. This is clearly a positive sign of the increasing attention being paid by the scientific community to a group of fibrotic lung diseases of which IPF is the prototype. Two new documents on the diagnosis of IPF have been published in 2018: their similarities and differences are described and discussed http://ow.ly/856P30lnB2O
3-D interactive visualisation tools for Hi spectral line imaging

Abstract Upcoming HI surveys will deliver such large datasets that automated processing using the full 3-D information to find and characterize HI objects is unavoidable. Full 3-D visualization is an essential tool for enabling qualitative and quantitative inspection and analysis of the 3-D data, which is often complex in nature. Here we present SlicerAstro, an open-source extension of 3DSlicer, a multi-platform open source software package for visualization and medical image processing, which we developed for the inspection and analysis of HI spectral line data. We describe its initial capabilities, including 3-D filtering, 3-D selection and comparative modelling.
Embedding Logical Queries on Knowledge Graphs

Learning low-dimensional embeddings of knowledge graphs is a powerful approach used to predict unobserved or missing edges between entities. However, an open challenge in this area is developing techniques that can go beyond simple edge prediction and handle more complex logical queries, which might involve multiple unobserved edges, entities, and variables. For instance, given an incomplete biological knowledge graph, we might want to predict "em what drugs are likely to target proteins involved with both diseases X and Y? " -- a query that requires reasoning about all possible proteins that might interact with diseases X and Y. Here we introduce a framework to efficiently make predictions about conjunctive logical queries -- a flexible but tractable subset of first-order logic -- on incomplete knowledge graphs. In our approach, we embed graph nodes in a low-dimensional space and represent logical operators as learned geometric operations (e.g., translation, rotation) in this embedding space. By performing logical operations within a low-dimensional embedding space, our approach achieves a time complexity that is linear in the number of query variables, compared to the exponential complexity required by a naive enumeration-based approach. We demonstrate the utility of this framework in two application studies on real-world datasets with millions of relations: predicting logical relationships in a network of drug-gene-disease interactions and in a graph-based representation of social interactions derived from a popular web forum.
Improving TCP Fairness over Latency Controlled 5G mmWave Communication Links

In order to increase the capacity of 5G networks, using mmWave band communication links both for access and backhaul are an important alternative due to the large spectrum portion available at those frequency bands. However, mmWave bands exhibit special propagation characteristics which require the usage of highly directional and beam-steerable antennas in order to cope with the significantly higher path loss. Using such links in urban scenarios may lead to frequent blocking events due to moving pedestrians or cars, which may result in the links dynamically changing their characteristics from Line-of-Sight (LOS) to Non Line-of- Sight (NLOS) or outage (OUT). Due to the immediate significant variation in available capacity when changing the link states, TCP connections may experience rapid spikes in end-to-end latency and severe bufferbloat may build up. Although bufferbloat solutions such as CoDel can be deployed to control the delay, they significantly impact capacity and fairness between different TCP flows sharing the same mmWave link. In this paper, we study this fairness issue when running multiple TCP connections over fluctuating mmWave links and deploying AQM schemes to control the latency. We study the effect of length and severity of the NLOS episode upon fairness and latency. Finally, we develop an algorithm that tunes the AQM parameters in order to increase fairness across flows having different RTTs while at the same time reduce their latency.
Cell shape alteration during adipogenesis is associated with coordinated matrix cues

Obesity has become one of the leading pathophysiologic disorders in recent years. Adipose tissue is the main tissue related to obesity and is known to play a role in various physiological complications, including type 2 diabetes. To better understand how the fat tissue develops, we used an in vitro live cell imaging system to quantify the adipogenesis by means of nondestructive digital imaging to monitor the accumulation of intracellular lipid droplets (LDs), a hallmark of adipogenesis, from the macro‐ to the micro‐scale. Analyzing the cells’ shape at the single‐cell level allows to quantify the cells’ shape change from a fibroblast to spherical morphology, indicating the start of adipogenesis. To reveal the molecular alterations, we applied a proteomic approach using high‐resolution mass spectrometry of the proliferation, confluent fibroblasts and of adipocytes. During this process, we noted the reorganization of the cells’ extracellular matrix (ECM) network microenvironment from fibrillary collagen types I, III and V to collagens IV and VI, which affected the cells niche. The changes in ECM are translated for cytoskeleton remodeling according to cell fate‐determining mechanisms. We quantified the cytoskeleton rearrangement of long oriented actin fibers or short cortical and disorganized fibers, associated with LDs accumulation in adipocytes. Developing in vitro models and analytical methods enable us to study differentiation into adipocytes that will advance our understanding regarding the niche conditions that affect adipogenesis. Consequently, this will enable the development of new modalities to prevent obesity and its deleterious outcomes and to develop potential treatments to battle pathophysiology‐related diseases.
Unsupervised Learning of View-invariant Action Representations

The recent success in human action recognition with deep learning methods mostly adopt the supervised learning paradigm, which requires significant amount of manually labeled data to achieve good performance. However, label collection is an expensive and time-consuming process. In this work, we propose an unsupervised learning framework, which exploits unlabeled data to learn video representations. Different from previous works in video representation learning, our unsupervised learning task is to predict 3D motion in multiple target views using video representation from a source view. By learning to extrapolate cross-view motions, the representation can capture view-invariant motion dynamics which is discriminative for the action. In addition, we propose a view-adversarial training method to enhance learning of view-invariant features. We demonstrate the effectiveness of the learned representations for action recognition on multiple datasets.
The spatial pattern of methacholine bronchoconstriction recurs when supine, independently of posture during provocation, but does not recur between postures.

The location of lung regions with compromised ventilation (often called ventilation defects) during a bronchoconstriction event may be influenced by posture. We aimed to determine the effect of prone vs. supine posture on the spatial pattern of methacholine-induced bronchoconstriction in six healthy adults (ages 21-41, three females) using specific ventilation imaging. Three postural conditions were chosen to assign the effect of posture to the drug administration and/or imaging phase of the experiment - supine methacholine administration followed by supine imaging, prone methacholine administration followed by supine imaging, and prone methacholine administration followed by prone imaging. The two conditions in which imaging was performed supine had similar spatial patterns of bronchoconstriction despite a change in posture during methacholine administration; the odds ratio for recurrent constriction was mean (SD) = 7.4 (3.9). Conversely, dissimilar spatial patterns of bronchoconstriction emerged when posture during imaging was changed; the odds ratio for recurrent constriction between the prone methacholine/supine imaging condition and the prone methacholine/prone imaging condition was 1.2 (0.9). Logistic regression showed that height above the dependent lung border was a significant negative predictor of constriction in the two supine imaging conditions (p<0.001 for each), but not in the prone imaging condition (p=0.20). These results show that the spatial pattern of methacholine bronchoconstriction is recurrent in the supine posture, regardless of whether methacholine is given prone or supine, but that prone posture during imaging eliminates that recurrent pattern and reduces its dependence on gravitational height.