STL-based Analysis of TRAIL-induced Apoptosis Challenges the Notion of Type I/Type II Cell Line Classification

Extrinsic apoptosis is a programmed cell death triggered by external ligands, such as the TNF-related apoptosis inducing ligand (TRAIL). Depending on the cell line, the specific molecular mechanisms leading to cell death may significantly differ. Precise characterization of these differences is crucial for understanding and exploiting extrinsic apoptosis. Cells show distinct behaviors on several aspects of apoptosis, including (i) the relative order of caspases activation, (ii) the necessity of mitochondria outer membrane permeabilization (MOMP) for effector caspase activation, and (iii) the survival of cell lines overexpressing Bcl2. These differences are attributed to the activation of one of two pathways, leading to classification of cell lines into two groups: type I and type II. In this work we challenge this type I/type II cell line classification. We encode the three aforementioned distinguishing behaviors in a formal language, called signal temporal logic (STL), and use it to extensively test the validity of a previously-proposed model of TRAIL-induced apoptosis with respect to experimental observations made on different cell lines. After having solved a few inconsistencies using STL-guided parameter search, we show that these three criteria do not define consistent cell line classifications in type I or type II, and suggest mutants that are predicted to exhibit ambivalent behaviors. In particular, this finding sheds light on the role of a feedback loop between caspases, and reconciliates two apparently-conflicting views regarding the importance of either upstream or downstream processes for cell-type determination. More generally, our work suggests that these three distinguishing behaviors should be merely considered as type I/II features rather than cell-type defining criteria. On the methodological side, this work illustrates the biological relevance of STL-diagrams, STL population data, and STL-guided parameter search implemented in the tool Breach. Such tools are well-adapted to the ever-increasing availability of heterogeneous knowledge on complex signal transduction pathways

STSE: Spatio-Temporal Simulation Environment Dedicated to Biology

<p>Abstract</p> <p>Background</p> <p>Recently, the availability of high-resolution microscopy together with the advancements in the development of biomarkers as reporters of biomolecular interactions increased the importance of imaging methods in molecular cell biology. These techniques enable the investigation of cellular characteristics like volume, size and geometry as well as volume and geometry of intracellular compartments, and the amount of existing proteins in a spatially resolved manner. Such detailed investigations opened up many new areas of research in the study of spatial, complex and dynamic cellular systems. One of the crucial challenges for the study of such systems is the design of a well stuctured and optimized workflow to provide a systematic and efficient hypothesis verification. Computer Science can efficiently address this task by providing software that facilitates handling, analysis, and evaluation of biological data to the benefit of experimenters and modelers.</p> <p>Results</p> <p>The Spatio-Temporal Simulation Environment (STSE) is a set of <it>open-source </it>tools provided to conduct spatio-temporal simulations in discrete structures based on microscopy images. The framework contains modules to <it>digitize, represent, analyze</it>, and <it>mathematically model </it>spatial distributions of biochemical species. Graphical user interface (GUI) tools provided with the software enable meshing of the simulation space based on the Voronoi concept. In addition, it supports to automatically acquire spatial information to the mesh from the images based on pixel luminosity (e.g. corresponding to molecular levels from microscopy images). STSE is freely available either as a stand-alone version or included in the linux live distribution Systems Biology Operational Software (SB.OS) and can be downloaded from <url>http://www.stse-software.org/</url>. The Python source code as well as a comprehensive user manual and video tutorials are also offered to the research community. We discuss main concepts of the STSE design and workflow. We demonstrate it's usefulness using the example of a signaling cascade leading to formation of a morphological gradient of Fus3 within the cytoplasm of the mating yeast cell <it>Saccharomyces cerevisiae</it>.</p> <p>Conclusions</p> <p>STSE is an efficient and powerful novel platform, designed for computational handling and evaluation of microscopic images. It allows for an uninterrupted workflow including digitization, representation, analysis, and mathematical modeling. By providing the means to relate the simulation to the image data it allows for systematic, image driven model validation or rejection. STSE can be scripted and extended using the Python language. STSE should be considered rather as an API together with workflow guidelines and a collection of GUI tools than a stand alone application. The priority of the project is to provide an easy and intuitive way of extending and customizing software using the Python language.</p

Association of Longer Leukocyte Telomere Length With Cardiac Size, Function, and Heart Failure.

IMPORTANCE: Longer leukocyte telomere length (LTL) is associated with a lower risk of adverse cardiovascular outcomes. The extent to which variation in LTL is associated with intermediary cardiovascular phenotypes is unclear. OBJECTIVE: To evaluate the associations between LTL and a diverse set of cardiovascular imaging phenotypes. DESIGN, SETTING, AND PARTICIPANTS: This is a population-based cross-sectional study of UK Biobank participants recruited from 2006 to 2010. LTL was measured using a quantitative polymerase chain reaction method. Cardiovascular measurements were derived from cardiovascular magnetic resonance using machine learning. The median (IQR) duration of follow-up was 12.0 (11.3-12.7) years. The associations of LTL with imaging measurements and incident heart failure (HF) were evaluated by multivariable regression models. Genetic associations between LTL and significantly associated traits were investigated by mendelian randomization. Data were analyzed from January to May 2023. EXPOSURE: LTL. MAIN OUTCOMES AND MEASURES: Cardiovascular imaging traits and HF. RESULTS: Of 40 459 included participants, 19 529 (48.3%) were men, and the mean (SD) age was 55.1 (7.6) years. Longer LTL was independently associated with a pattern of positive cardiac remodeling (higher left ventricular mass, larger global ventricular size and volume, and higher ventricular and atrial stroke volumes) and a lower risk of incident HF (LTL fourth quartile vs first quartile: hazard ratio, 0.86; 95% CI, 0.81-0.91; P = 1.8 × 10-6). Mendelian randomization analysis suggested a potential causal association between LTL and left ventricular mass, global ventricular volume, and left ventricular stroke volume. CONCLUSIONS AND RELEVANCE: In this cross-sectional study, longer LTL was associated with a larger heart with better cardiac function in middle age, which could potentially explain the observed lower risk of incident HF

Quantitative predictions on auxin-induced polar distribution of PIN proteins during vein formation in leaves

The dynamic patterning of the plant hormone auxin and its efflux facilitator the PIN protein are the key regulator for the spatial and temporal organization of plant development. In particular auxin induces the polar localization of its own efflux facilitator. Due to this positive feedback auxin flow is directed and patterns of auxin and PIN arise. During the earliest stage of vein initiation in leaves auxin accumulates in a single cell in a rim of epidermal cells from which it flows into the ground meristem tissue of the leaf blade. There the localized auxin supply yields the successive polarization of PIN distribution along a strand of cells. We model the auxin and PIN dynamics within cells with a minimal canalization model. Solving the model analytically we uncover an excitable polarization front that triggers a polar distribution of PIN proteins in cells. As polarization fronts may extend to opposing directions from their initiation site we suggest a possible resolution to the puzzling occurrence of bipolar cells, such we offer an explanation for the development of closed, looped veins. Employing non-linear analysis we identify the role of the contributing microscopic processes during polarization. Furthermore, we deduce quantitative predictions on polarization fronts establishing a route to determine the up to now largely unknown kinetic rates of auxin and PIN dynamics.Comment: 9 pages, 4 figures, supplemental information included, accepted for publication in Eur. Phys. J.

Polygenic basis and biomedical consequences of telomere length variation

Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally occurring variation in leukocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized UK Biobank participants. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 new). Genetically determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular and inflammatory pathologies. Finally, we estimated that, at the age of 40 years, people with an LTL >1 s.d. shorter than the population mean had a 2.5-year-lower life expectancy compared with the group with ≥1 s.d. longer LDL. Overall, we furnish new insights into the genetic regulation of LTL, reveal wide-ranging influences of LTL on physiological traits, diseases and longevity, and provide a powerful resource available to the global research community

Polygenic basis and biomedical consequences of telomere length variation.

Funder: Health Data Research UK EU/EFPIA Innovative Medicines Initiative Joint Undertaking BigData@Heart (11607).Funder: Health Data Research UKTelomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally occurring variation in leukocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized UK Biobank participants. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 new). Genetically determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular and inflammatory pathologies. Finally, we estimated that, at the age of 40 years, people with an LTL >1 s.d. shorter than the population mean had a 2.5-year-lower life expectancy compared with the group with ≥1 s.d. longer LDL. Overall, we furnish new insights into the genetic regulation of LTL, reveal wide-ranging influences of LTL on physiological traits, diseases and longevity, and provide a powerful resource available to the global research community

COVID-19-ассоциированные изменения желудочно-кишечного тракта: сопоставление данных ультразвуковых и гистологических исследований: пилотное исследование

INTRODUCTION: COVID-19-associated gastrointestinal tract involvement has been reported in 11.4–61.1% of cases. However, there is no data on the incidence of COVID-19-associated pathology in different parts of the gastrointestinal tract, and there’s little understanding about the appearance of COVID-19-associated gastrointestinal lesions on ultrasound diagnostic images.OBJECTIVE: To study of the radiologic pattern of COVID-19-associated changes in the gastrointestinal tract based on the comparison of ultrasound and morphological autopsy data.MATERIALS AND METHODS: The study was approved by the ethical committee of Gomel State Medical University (protocol № 2 of 24.03.2021). For the purposes of this study gastric and intestinal pathological examination was performed in 11 subjects (average age 64.6±10.1 years) who died of COVID-19 infection and 11 subjects who had no clinical or laboratory confirmed signs of COVID-19 infection (average age 67.2±8.8 уears). Using the ImageJ computer program, we determined the surface area of the whole studied object subject, and the affected areas (foci of hyperemia with fine-point hemorrhages), determined the percentage of organ mucosal lesions and also performed an ultrasound examination of the gastric and intestinal wall samples. Statistic: analysis was performed using the Statistica 10.0 software (StatSoft, Inc., USA).RESULTS: The incidence of COVID-19-associated lesions in different parts of the gastrointestinal tract was as follows: stomach, 100.0%; duodenum, 25.0%; jejunum, 55.0%; ileum, 35.0%; cecum, 18%; ascending colon, 15%; transverse colon, 15% descending colon, 41% sigmoid colon, 55%; rectum, 75%. The lesion surface area in different parts of the gastrointestinal tract was as follows (%): stomach, 86,0 (75.0; 90.0); duodenum, 48,0 (39.0; 66.0); jejunum, 55.0 (50.0; 59.0); ileum, 35.0 (30.0; 41.0); cecum, 59.0 (55.0; 69.0); ascending colon, 34,0 (29.0; 41.0); transverse colon 36,0 (30.0; 42.0); descending colon 40.0 (34.0; 47.0); sigmoid colon 65,0 (61.0; 71.0); rectum 69.0 (65.0; 73.0). Ultrasound pattern in COVID-19-associated pathology of the gastrointestinal tract was uniform. Most often, foci of reduced echogenicity with indistinct and uneven margins were detected in the mucosa. Histologically, foci of lymphoid infiltration and formation of lymphoid clusters of B-lymphocytes were found in these areas.CONCLUSION: The most frequent ultrasound pattern in COVID-19-associated gastrointestinal tract involvement is the presence in the mucosa areas of reduced echogenicity with indistinct and uneven margins.ВВЕДЕНИЕ: Ассоциированные с  инфекцией COVID-19 поражения желудочно-кишечного тракта (ЖКТ) отмечаются у 11,4‒61,1% пациентов. При этом отсутствуют данные об инцидентности COVID-19-ассоциированных поражений в разных отделах ЖКТ, а также представления о том, как выглядят такие поражения на ультразвуковых диагностических изображениях.ЦЕЛЬ: Изучение лучевого паттерна COVID-19-ассоциированных изменений желудочно-кишечного тракта на основе сопоставления данных ультразвуковых и морфологических исследований.МАТЕРИАЛЫ И МЕТОДЫ: Исследование одобрено этическим комитетом УО «Гомельский государственный медицинский университет», протокол № 2 от 24.03.2021 г. Для достижения поставленной цели было выполнено секционное исследование желудка и кишечника у 11 субъектов (средний возраст 64,6±10,1 года), умерших от инфекции COVID-19, и 11 субъектов, не имевших клинических и лабораторных признаков инфекции COVID-19 (средний возраст 67,2±8,8 года). С помощью компьютерной программы ImageJ определялись площадь всего исследуемого объекта, площадь пораженных участков (очаги гиперемии с  мелкоточечными кровоизлияниями), определялся процент поражения слизистой оболочки органа и проводилось ультразвуковое исследование образцов стенки желудка и кишечника. Статистика: анализ выполнялся с применением пакета прикладных программ Statistica 10,0 (StatSoft, Inc., США).РЕЗУЛЬТАТЫ: Инцидентность COVID-19-ассоциированных поражений различных отделов желудочно-кишечного тракта была следующей: желудок  — 100,0%; двенадцатиперстная кишка  — 25,0%; тощая кишка  — 55,0%; подвздошная кишка — 35,0%; слепая кишка — 18%; восходящий отдел толстой кишки — 15%; поперечно-ободочная кишка — 15%; нисходящий отдел толстой кишки — 41%; сигмовидная кишка — 55%, прямая кишка — 75%. Площадь поражения различных отделов желудочно-кишечного тракта была следующей: желудок  — 86,0% (75,0; 90,0); двенадцатиперстная кишка — 48,0% (39,0; 66,0); тощая кишка — 55,0% (50,0; 59,0); подвздошная кишка — 35,0% (30,0; 41,0); слепая кишка — 59,0% (55,0;69,0); восходящий отдел толстой кишки — 34,0% (29,0; 41,0); поперечно-ободочная кишка — 36,0% (30,0; 42,0); нисходящий отдел толстой кишки — 40,0% (34,0; 47,0); сигмовидная кишка — 65,0% (61,0; 71,0); прямая кишка — 69,0% (65,0; 73,0). Ультразвуковой паттерн при COVID-19-ассоциированном поражении желудочнокишечного тракта был одинаковым. Чаще всего в толще слизистой оболочки определялись фокусы пониженной эхогенности с нечеткими и неровными контурами. Гистологически в этих участках выявлялись очаги лимфоидной инфильтрации с формированием лимфоидных скоплений В-лимфоцитов.ЗАКЛЮЧЕНИЕ: Наиболее часто встречавшимся вариантом ультразвукового паттерна при COVID-19-ассоциированном поражении желудочно-кишечного тракта является наличие в толще слизистой оболочки участков пониженной эхогенности с нечеткими и неровными контурами

Simulation of Organ Patterning on the Floral Meristem Using a Polar Auxin Transport Model

An intriguing phenomenon in plant development is the timing and positioning of lateral organ initiation, which is a fundamental aspect of plant architecture. Although important progress has been made in elucidating the role of auxin transport in the vegetative shoot to explain the phyllotaxis of leaf formation in a spiral fashion, a model study of the role of auxin transport in whorled organ patterning in the expanding floral meristem is not available yet. We present an initial simulation approach to study the mechanisms that are expected to play an important role. Starting point is a confocal imaging study of Arabidopsis floral meristems at consecutive time points during flower development. These images reveal auxin accumulation patterns at the positions of the organs, which strongly suggests that the role of auxin in the floral meristem is similar to the role it plays in the shoot apical meristem. This is the basis for a simulation study of auxin transport through a growing floral meristem, which may answer the question whether auxin transport can in itself be responsible for the typical whorled floral pattern. We combined a cellular growth model for the meristem with a polar auxin transport model. The model predicts that sepals are initiated by auxin maxima arising early during meristem outgrowth. These form a pre-pattern relative to which a series of smaller auxin maxima are positioned, which partially overlap with the anlagen of petals, stamens, and carpels. We adjusted the model parameters corresponding to properties of floral mutants and found that the model predictions agree with the observed mutant patterns. The predicted timing of the primordia outgrowth and the timing and positioning of the sepal primordia show remarkable similarities with a developing flower in nature

Noise and Robustness in Phyllotaxis

A striking feature of vascular plants is the regular arrangement of lateral organs on the stem, known as phyllotaxis. The most common phyllotactic patterns can be described using spirals, numbers from the Fibonacci sequence and the golden angle. This rich mathematical structure, along with the experimental reproduction of phyllotactic spirals in physical systems, has led to a view of phyllotaxis focusing on regularity. However all organisms are affected by natural stochastic variability, raising questions about the effect of this variability on phyllotaxis and the achievement of such regular patterns. Here we address these questions theoretically using a dynamical system of interacting sources of inhibitory field. Previous work has shown that phyllotaxis can emerge deterministically from the self-organization of such sources and that inhibition is primarily mediated by the depletion of the plant hormone auxin through polarized transport. We incorporated stochasticity in the model and found three main classes of defects in spiral phyllotaxis – the reversal of the handedness of spirals, the concomitant initiation of organs and the occurrence of distichous angles – and we investigated whether a secondary inhibitory field filters out defects. Our results are consistent with available experimental data and yield a prediction of the main source of stochasticity during organogenesis. Our model can be related to cellular parameters and thus provides a framework for the analysis of phyllotactic mutants at both cellular and tissular levels. We propose that secondary fields associated with organogenesis, such as other biochemical signals or mechanical forces, are important for the robustness of phyllotaxis. More generally, our work sheds light on how a target pattern can be achieved within a noisy background

HALT (Hernia Active Living Trial): protocol for a feasibility study of a randomised controlled trial of a physical activity intervention to improve quality of life in people with bowel stoma with a bulge/parastomal hernia

Background Parastomal hernia (PSH) can be repaired surgically, but results to date have been disappointing, with reported recurrence rates of 30 to 76%. Other types of intervention are therefore needed to improve the quality of life of people with PSH. One potential intervention is physical activity. We hypothesise that the intervention will increase core activation and control across the abdominal wall at a site of potential weakness and thus reduce the risk of PSH progression. Increases in physical activity will improve body image and quality of life (QoL). Methods Subjects and sample There were approximately 20 adults with a bowel stoma and PSH. People with previous PSH repair will be excluded as well as people who already do core training. Study design This is a feasibility study of a randomised controlled trial with 2 months follow-up, in 2 sites using mixed methods. Stage 1 involves intervention development and in stage 2, intervention and trial parameters will be assessed. Intervention A theoretically informed physical activity intervention was done, targeting people with PSH. Main outcome of feasibility study The main outcome is the decision by an independent Study Steering Committee whether to proceed to a full randomised controlled trial of the intervention. Other outcomes We will evaluate 4 intervention parameters—fidelity, adherence, acceptability and safety and 3 trial parameters (eligible patients’ consent rate, acceptability of study design and data availability rates for following endpoints): I. Diagnosis and classification of PSH II. Muscle activation III. Body composition (BMI, waist circumference) IV. Patient reported outcomes: QoL, body image and physical functioning V. Physical activity; VI. Psychological determinants of physical activity Other data Included are other data such as interviews with all participants about the intervention and trial procedures. Data analysis and statistical power As this is a feasibility study, the quantitative data will be analysed using descriptive statistics. Audio-recorded qualitative data from interviews will be transcribed verbatim and analysed thematically. Discussion The feasibility and acceptability of key intervention and trial parameters will be used to decide whether to proceed to a full trial of the intervention, which aims to improve body image, quality of life and PSH progression. Trial registration ISRCTN1520759