Miracle-dz/UniFAR-FTUs huggingface dataset:
Contractility-dependent actin dynamics in cardiomyocyte sarcomeres

In contrast to the highly dynamic actin cytoskeleton in non-muscle cells, actin filaments in muscle sarcomeres are thought to be relatively stable and undergo dynamics only at their ends. However, many proteins that promote rapid actin dynamics are also expressed in striated muscles. We show that a subset of actin filaments in cardiomyocyte sarcomeres displays rapid turnover. Importantly, we found that turnover of these filaments depends on contractility of the cardiomyocytes. Studies using an actin-polymerization inhibitor suggest that the pool of dynamic actin filaments is composed of filaments that do not contribute to contractility. Furthermore, we provide evidence that ADF/cofilins, together with myosin-induced contractility, are required to disassemble non-productive filaments in developing cardiomyocytes. These data indicate that an excess of actin filaments is produced during sarcomere assembly, and that contractility is applied to recognize non-productive filaments that are subsequently destined for depolymerization. Consequently, contractility-induced actin dynamics plays an important role in sarcomere maturation.
Loss of anchorage in checkpoint-deficient cells increases genomic instability and promotes oncogenic transformation

Mammalian cells generally require both mitogens and anchorage signals in order to proliferate. An important characteristic of many tumour cells is that they have lost this anchorage-dependent cell-cycle checkpoint, allowing them to proliferate without signals provided by their normal microenvironment. In the absence of anchorage signals from the extracellular matrix, many cell types arrest cell-cycle progression in G1 phase as a result of Rb-dependent checkpoints. However, despite inactivation of p53 and Rb proteins, SV40LT-expressing cells retain anchorage dependency, suggesting the presence of an uncharacterised cell-cycle checkpoint, which can be overridden by coexpression of oncogenic Ras. We report here that, although cyclin-CDK complexes persisted in suspension, proliferation was inhibited in LT-expressing cells by the CDK inhibitor p27Kip1 (p27). Interestingly, this did not induce a stable arrest, but aberrant cell-cycle progression associated with stalled DNA replication, rereplication and chromosomal instability, which was sufficient to increase the frequency of oncogenic transformation. These results firstly indicate loss of anchorage in Rb- and p53-deficient cells as a novel mechanism for promotion of genomic instability; secondly suggest that anchorage checkpoints that protect normal cells from inappropriate proliferation act deleteriously in Rb- and p53-deficient cells to promote tumourigenesis; and thirdly indicate caution in the use of CDK inhibitors for cancer treatment.
Evaluación del puntaje SYNTAX por residentes de cardiología clínica

Background The SYNTAX score (SS) is a useful tool for selecting patients with left main or three-vessel coronary artery disease eligible for percutaneous coronary interventions. The score has moderate inter-observer reproducibility among members of the original study. There is not sufficient evidence about the evaluation of the SS by non-interventional cardiologists. Objectives The aim of the study was to evaluate whether residents in cardiology can perform an adequate evaluation of the SS and to detect possible biases in its evaluation. Methods Coronary angiographies with evidence of main left coronary artery disease and/or three-vessel disease were retrospectively selected. A resident in cardiology (RC) calculated the total SS in order to compare it with the score calculated by an interventional cardiologist (IC). Data were analyzed using the kappa coefficient (deciles and tertiles), Lin�s concordance correlation coefficient and the Bland-Altman plot method. Results Ninety three coronary angiographies were analyzed. Mean SS calculated by the IC and the RC were 28.58 (SD 10.0) and 30.44 (SD 10.7), respectively. Mean difference was 1.85 (SD 7.01). The kappa coefficient was 0.57 (0.464-0.678) for deciles and 0.60 for tertiles (0.48-0.72). Lin�s coefficient was 0.75 (0.65 to 0.83). The Bland-Altman analysis detected that the RC had a trend towards underestimating high scores calculated by the IC. Conclusions This study demonstrates a moderate to good inter-observer reproducibility between a RC and an IC. This level of agreement is acceptable to calculate the score, as previously published. A trend to underestimate high SS was detected in the RC.
Persistence of the cell-cycle checkpoint kinase Wee1 in SadA- and SadB-deficient neurons disrupts neuronal polarity

Wee1 is well characterized as a cell-cycle checkpoint kinase that regulates the entry into mitosis in dividing cells. Here we identify a novel function of Wee1 in postmitotic neurons during the establishment of distinct axonal and dendritic compartments, which is an essential step during neuronal development. Wee1 is expressed in unpolarized neurons but is downregulated after neurons have extended an axon. Suppression of Wee1 impairs the formation of minor neurites but does not interfere with axon formation. However, neuronal polarity is disrupted when neurons fail to downregulate Wee1. The kinases SadA and SadB (Sad kinases) phosphorylate Wee1 and are required to initiate its downregulation in polarized neurons. Wee1 expression persists in neurons that are deficient in SadA and SadB and disrupts neuronal polarity. Knockdown of Wee1 rescues the Sada−/−;Sadb−/− mutant phenotype and restores normal polarity in these neurons. Our results demonstrate that the regulation of Wee1 by SadA and SadB kinases is essential for the differentiation of polarized neurons.
Urinary N-Terminal B-Type Natriuretic Peptide Predicts Severe Retinopathy of Prematurity

OBJECTIVE: The goal of this study was to evaluate urinary N-terminal fragment of B-type natriuretic peptide concentrations, normalized to creatinine (UNBCR), to predict morbidities at discharge in preterm infants. METHODS: UNBCR were determined in urine collected on day of life (DOL) 2, 7, 14, and 28 in 136 preterm infants <1500 g birth weight, 22 of whom developed bronchopulmonary dysplasia (BPD), defined as oxygen supplementation at 36 weeks' gestational age) and 11 infants developed severe retinopathy (ROP), defined as stage 3 or stage ≥2 requiring surgery). RESULTS: UNBCR on DOL 7, 14, and 28 was elevated in infants who developed BPD or ROP compared with controls (P ≤ .001). On multiple regression analysis including birth weight and gestational age, ROP but not BPD remained independently associated with UNBCR on DOL 14 and 28. Areas under receiver operating characteristic curves for UNBCR on DOL 14 and 28 to predict ROP were 0.938 (0.027) and 0.954 (0.021), respectively. UNBCR DOL 14 and 28 thresholds exceeded by all infants with severe ROP (100% sensitivity, 100% negative predictive value) had a specificity of 66% and 85%, respectively. CONCLUSIONS: UNBCR might hold promise to reduce unnecessary eye examinations by timely and accurate identification of infants at risk of severe ROP.
Statistically rigorous java performance evaluation

Java performance is far from being trivial to benchmark because it is affected by various factors such as the Java application, its input, the virtual machine, the garbage collector, the heap size, etc. In addition, non-determinism at run-time causes the execution time of a Java program to differ from run to run. There are a number of sources of non-determinism such as Just-In-Time (JIT) compilation and optimization in the virtual machine (VM) driven by timer-based method sampling, thread scheduling, garbage collection, and various. There exist a wide variety of Java performance evaluation methodologies usedby researchers and benchmarkers. These methodologies differ from each other in a number of ways. Some report average performance over a number of runs of the same experiment; others report the best or second best performance observed; yet others report the worst. Some iterate the benchmark multiple times within a single VM invocation; others consider multiple VM invocations and iterate a single benchmark execution; yet others consider multiple VM invocations and iterate the benchmark multiple times. This paper shows that prevalent methodologies can be misleading, and can even lead to incorrect conclusions. The reason is that the data analysis is not statistically rigorous. In this paper, we present a survey of existing Java performance evaluation methodologies and discuss the importance of statistically rigorous data analysis for dealing with non-determinism. We advocate approaches to quantify startup as well as steady-state performance, and, in addition, we provide the JavaStats software to automatically obtain performance numbers in a rigorous manner. Although this paper focuses on Java performance evaluation, many of the issues addressed in this paper also apply to other programming languages and systems that build on a managed runtime system.
How to Evaluate and Interpret Outcome Studies

The pharmacoeconomic literature is a vast and powerful source of information for pharmacists and others who must make decisions about services and products. Published studies can provide data quickly and inexpensively, but they may not necessarily meet criteria for quality and may not be generalizable to a specific situation. Guidelines are available that are intended to standardize study methods, minimize potential bias, and increase the comparability and credibility of data. Before relying on a published study, decision‐makers should ensure that it meets criteria related to objective, perspective, pharmacoeconomic method, design, interventions, costs, outcomes, discounting, results, sensitivity analysis, extrapolation from conclusions, and sponsorship. A sound study can be used to support decisions in such diverse areas as individual patient treatment, formulary management, drug‐use guideline development, disease management initiatives, and pharmaceutical service evaluation. A decision‐maker may be able to use the results by applying them at face value, employing a sensitivity analysis, performing a meta‐analysis, incorporating the data into a pharmacoeconomic model, or reproducing the study on a smaller scale. The selection of an application strategy should be based on the potential impact of the decision on the quality and cost of care, with more rigorous and complex strategies reserved for more extreme impacts. Published pharmacoeconomic data can help pharmacists make better and more informed decisions about pharmaceutical services and products.
CANDID: preventing sql injection attacks using dynamic candidate evaluations

SQL injection attacks are one of the topmost threats for applications written for the Web. These attacks are launched through specially crafted user input on web applications that use low level string operations to construct SQL queries. In this work, we exhibit a novel and powerful scheme for automatically transforming web applications to render them safe against all SQL injection attacks. A characteristic diagnostic feature of SQL injection attacks is that they change the intended structure of queries issued. Our technique for detecting SQL injection is to dynamically mine the programmer-intended query structure on any input, and detect attacks by comparing it against the structure of the actual query issued. We propose a simple and novel mechanism, called C<scp>ANDID</scp>, for mining programmer intended queries by dynamically evaluating runs over benign candidate inputs. This mechanism is theoretically well founded and is based on inferring intended queries by considering the symbolic query computed on a program run. Our approach has been implemented in a tool called C<scp>ANDID</scp>, that retrofits Web applications written in Java to defend them against SQL injection attacks. We report extensive experimental results that show that our approach performs remarkably well in practice.
Higher education students registered with disability services and practice educators: issues and concerns for professional placements†

Introduction: The number of students with disabilities accessing Higher Education Institutions (HEIs), including professional courses, has increased substantially within the Republic of Ireland over the past 10 years [AHEAD (Association of Higher Education, Access, and Disability) 2012. “Survey on the Participation Rates of Students with Disabilities in Higher Education for the Academic Year 2011/2012. ” http://www.ahead. ie/userfiles/file/PR_2012. pdf]. In one HEI in the Republic of Ireland, it was noticed that there was a large increase in students with disabilities, from 67 in 2006 to 259 in 2013 on professional courses. The aim of this study was to identify the issues and concerns of practice educators (PEs) in both supporting students with disabilities and exploring the concerns for students with disabilities on professional courses. Methods: A survey design was employed to meet the aims of this study and ethical permission was granted from the Faculty of Health Science Ethics Committee. Results: Respondents included 68 PEs and 63 students with disabilities. PEs were found to be concerned with students reaching the required standard of proficiency on placement, and how to support students in this. Students on the other hand identified stigma and disclosure of a disability as a concern. Conclusion: This study highlighted a difference in perceptive between PEs and students with disabilities in relation to disclosure and support needs for their disabilities.
Physically based hydraulic erosion simulation on graphics processing unit

Visual simulation of natural erosion on terrains has always been a fascinating research topic in the field of computer graphics. While there are many algorithms already developed to improve the visual quality of terrain, the recent simulation methods revolve around physically-based hydraulic erosion because it can generate realistic natural-looking terrains. However, many of such algorithms were tested only on low resolution terrains. When simulated on a higher resolution terrain, most of the current algorithms become computationally expensive. This is why in many applications today, terrains are generated off-line and loaded during the application runtime. This method restricts the number of terrains which can be stored if there is a limitation on storage capacity. Recently, graphics hardware has evolved into an indispensable tool in improving the speed of computation. This has motivated us to develop an erosion algorithm to map to graphics hardware for faster terrain generation. In this paper, we propose a fast and efficient hydraulic erosion procedural technique that utilizes the GPUs powerful computation capability in order to generate high resolution erosion on terrains. Our method is based on the Newtonian physics approach that is implemented on a two-dimensional data structure which stores height fields, water amount, and dissolved sediment and water velocities. We also present a comprehensive comparison between the CPU and GPU implementations together with the visual results and the statistics on simulation time taken.
Stargazin-related protein γ7 is associated with signalling endosomes in superior cervical ganglion neurons and modulates neurite outgrowth

The role(s) of the newly discovered stargazin-like γ-subunit proteins remains unclear; although they are now widely accepted to be transmembrane AMPA receptor regulatory proteins (TARPs), rather than Ca2+ channel subunits, it is possible that they have more general roles in trafficking within neurons. We previously found that γ7 subunit is associated with vesicles when it is expressed in neurons and other cells. Here, we show that γ7 is present mainly in retrogradely transported organelles in sympathetic neurons, where it colocalises with TrkA–YFP, and with the early endosome marker EEA1, suggesting that γ7 localises to signalling endosomes. It was not found to colocalise with markers of the endoplasmic reticulum, mitochondria, lysosomes or late endosomes. Furthermore, knockdown of endogenous γ7 by short hairpin RNA transfection into sympathetic neurons reduced neurite outgrowth. The same was true in the PC12 neuronal cell line, where neurite outgrowth was restored by overexpression of human γ7. These findings open the possibility that γ7 has an essential trafficking role in relation to neurite outgrowth as a component of endosomes involved in neurite extension and growth cone remodelling.
Small molecules, big roles – the chemical manipulation of stem cell fate and somatic cell reprogramming

Summary Despite the great potential of stem cells for basic research and clinical applications, obstacles – such as their scarce availability and difficulty in controlling their fate – need to be addressed to fully realize their potential. Recent achievements of cellular reprogramming have enabled the generation of induced pluripotent stem cells (iPSCs) or other lineage-committed cells from more accessible and abundant somatic cell types by defined genetic factors. However, serious concerns remain about the efficiency and safety of current genetic approaches to cell reprogramming and traditional culture systems that are used for stem cell maintenance. As a complementary approach, small molecules that target specific signaling pathways, epigenetic processes and other cellular processes offer powerful tools for manipulating cell fate to a desired outcome. A growing number of small molecules have been identified to maintain the self-renewal potential of stem cells, to induce lineage differentiation and to facilitate reprogramming by increasing the efficiency of reprogramming or by replacing genetic reprogramming factors. Furthermore, mechanistic investigations of the effects of these chemicals also provide new biological insights. Here, we examine recent achievements in the maintenance of stem cells, including pluripotent and lineage-specific stem cells, and in the control of cell fate conversions, including iPSC reprogramming, conversion of primed to naïve pluripotency, and transdifferentiation, with an emphasis on manipulation with small molecules.
Contrasting roles of condensin I and condensin II in mitotic chromosome formation

In vertebrates, two condensin complexes exist, condensin I and condensin II, which have differing but unresolved roles in organizing mitotic chromosomes. To dissect accurately the role of each complex in mitosis, we have made and studied the first vertebrate conditional knockouts of the genes encoding condensin I subunit CAP-H and condensin II subunit CAP-D3 in chicken DT40 cells. Live-cell imaging reveals highly distinct segregation defects. CAP-D3 (condensin II) knockout results in masses of chromatin-containing anaphase bridges. CAP-H (condensin I)-knockout anaphases have a more subtle defect, with chromatids showing fine chromatin fibres that are associated with failure of cytokinesis and cell death. Super-resolution microscopy reveals that condensin-I-depleted mitotic chromosomes are wider and shorter, with a diffuse chromosome scaffold, whereas condensin-II-depleted chromosomes retain a more defined scaffold, with chromosomes more stretched and seemingly lacking in axial rigidity. We conclude that condensin II is required primarily to provide rigidity by establishing an initial chromosome axis around which condensin I can arrange loops of chromatin.
A framework for socially communicative faces for game and interactive learning applications

In this paper, we describe a modular multi-dimensional parameter space for real-time face game-based animation. Faces are our most expressive communication tools. Therefore a synthetic facial creation and animation system should have its own tailored authoring environment rather than using general purpose tools from image, 2D and 3D animation. This environment would take advantage of a knowledge space of faces types, expressions, and behavior, encoding known facial knowledge and meaning into a comprehensive, intuitive facial language and set of user tools. Since faces and face expression work on so many cognitive levels, we propose a multi-dimension parameter space called FaceSpace as the basic face model, and a comprehensive authoring environment based on this model. We describe the underlying mechanisms of our environment, and also demonstrate its early game applications and content process.
In tight junctions, claudins regulate the interactions between occludin, tricellulin and marvelD3, which, inversely, modulate claudin oligomerization

Summary Tight junctions seal the paracellular cleft of epithelia and endothelia, form vital barriers between tissue compartments and consist of tight-junction-associated marvel proteins (TAMPs) and claudins. The function of TAMPs and the interaction with claudins are not understood. We therefore investigated the binding between the TAMPs occludin, tricellulin, and marvelD3 and their interaction with claudins in living tight-junction-free human embryonic kidney-293 cells. In contrast to claudins and occludin, tricellulin and marvelD3 showed no enrichment at cell–cell contacts indicating lack of homophilic trans-interaction between two opposing cell membranes. However, occludin, marvelD3 and tricellulin exhibited homophilic cis-interactions, along one plasma membrane, as measured by fluorescence resonance energy transfer. MarvelD3 also cis-interacted with occludin and tricellulin heterophilically. Classic claudins, such as claudin-1 to -5 may show cis-oligomerization with TAMPs, whereas the non-classic claudin-11 did not. Claudin-1 and -5 improved enrichment of occludin and tricellulin at cell–cell contacts. The low mobile claudin-1 reduced the membrane mobility of the highly mobile occludin and tricellulin, as studied by fluorescence recovery after photobleaching. Co-transfection of claudin-1 with TAMPs led to changes of the tight junction strand network of this claudin to a more physiological morphology, depicted by freeze-fracture electron microscopy. The results demonstrate multilateral interactions between the tight junction proteins, in which claudins determine the function of TAMPs and vice versa, and provide deeper insights into the tight junction assembly.
Spd2 assists Spd1 in the modulation of ribonucleotide reductase architecture but does not regulate deoxynucleotide pools

ABSTRACT In yeasts, small intrinsically disordered proteins (IDPs) modulate ribonucleotide reductase (RNR) activity to ensure an optimal supply of dNTPs for DNA synthesis. The Schizosaccharomyces pombe Spd1 protein can directly inhibit the large RNR subunit (R1), import the small subunit (R2) into the nucleus and induce an architectural change in the R1–R2 holocomplex. Here, we report the characterization of Spd2, a protein with sequence similarity to Spd1. We show that Spd2 is a CRL4Cdt2-controlled IDP that functions together with Spd1 in the DNA damage response and in modulation of RNR architecture. However, Spd2 does not regulate dNTP pools and R2 nuclear import. Furthermore, deletion of spd2 only weakly suppresses the Rad3ATR checkpoint dependency of CRL4Cdt2 mutants. However, when we raised intracellular dNTP pools by inactivation of RNR feedback inhibition, deletion of spd2 could suppress the checkpoint dependency of CRL4Cdt2 mutant cells to the same extent as deletion of spd1. Collectively, these observations suggest that Spd1 on its own regulates dNTP pools, whereas in combination with Spd2 it modulates RNR architecture and sensitizes cells to DNA damage.