The interaction of transcription factors controls the spatial layout of plant aerial stem cell niches.

The plant shoot apical meristem holds a stem cell niche from which all aerial organs originate. Using a computational approach we show that a mixture of monomers and heterodimers of the transcription factors WUSCHEL and HAIRY MERISTEM is sufficient to pattern the stem cell niche, and predict that immobile heterodimers form a regulatory "pocket" surrounding the stem cells. The model achieves to reproduce an array of perturbations, including mutants and tissue size modifications. We also show its ability to reproduce the recently observed dynamical shift of the stem cell niche during the development of an axillary meristem. The work integrates recent experimental results to answer the longstanding question of how the asymmetry of expression between the stem cell marker CLAVATA3 and its activator WUSCHEL is achieved, and recent findings of plasticity in the system.Gatsby Charitable Foundation (GAT3395-PR4

Multi-scale Dynamical Modeling of T Cell Development from an Early Thymic Progenitor State to Lineage Commitment

Intrathymic development of committed progenitor (pro)-T cells from multipotent hematopoietic precursors offers an opportunity to dissect the molecular circuitry establishing cell identity in response to environmental signals. This transition encompasses programmed shutoff of stem/progenitor genes, upregulation of T cell specification genes, proliferation, and ultimately commitment. To explain these features in light of reported cis-acting chromatin effects and experimental kinetic data, we develop a three-level dynamic model of commitment based upon regulation of the commitment-linked gene Bcl11b. The levels are (1) a core gene regulatory network (GRN) architecture from transcription factor (TF) perturbation data, (2) a stochastically controlled chromatin-state gate, and (3) a single-cell proliferation model validated by experimental clonal growth and commitment kinetic assays. Using RNA fluorescence in situ hybridization (FISH) measurements of genes encoding key TFs and measured bulk population dynamics, this single-cell model predicts state-switching kinetics validated by measured clonal proliferation and commitment times. The resulting multi-scale model provides a mechanistic framework for dissecting commitment dynamics

Multi-scale Dynamical Modeling of T Cell Development from an Early Thymic Progenitor State to Lineage Commitment

Intrathymic development of committed progenitor (pro)-T cells from multipotent hematopoietic precursors offers an opportunity to dissect the molecular circuitry establishing cell identity in response to environmental signals. This transition encompasses programmed shutoff of stem/progenitor genes, upregulation of T cell specification genes, proliferation, and ultimately commitment. To explain these features in light of reported cis-acting chromatin effects and experimental kinetic data, we develop a three-level dynamic model of commitment based upon regulation of the commitment-linked gene Bcl11b. The levels are (1) a core gene regulatory network (GRN) architecture from transcription factor (TF) perturbation data, (2) a stochastically controlled chromatin-state gate, and (3) a single-cell proliferation model validated by experimental clonal growth and commitment kinetic assays. Using RNA fluorescence in situ hybridization (FISH) measurements of genes encoding key TFs and measured bulk population dynamics, this single-cell model predicts state-switching kinetics validated by measured clonal proliferation and commitment times. The resulting multi-scale model provides a mechanistic framework for dissecting commitment dynamics

Initial characterisation of commercially available ELISA tests and the immune response of the clinically correlated SARS-CoV-2 biobank "SERO-BL-COVID-19" collected during the pandemic onset in Switzerland

Background To accurately measure seroprevalance in the population, both the expected immune response as well as the assay performances have to be well characterised. Here, we describe the collection and initial characterisation of a blood and saliva biobank obtained after the initial peak of the SARS-CoV-2 pandemic in Switzerland.Methods Two laboratory ELISAs measuring IgA & IgG (Euroimmun), and IgM & IgG (Epitope Diagnostics) were used to characterise the biobank collected from 349 re- and convalescent patients from the canton of Basel-Landschaft.Findings The antibody response in terms of recognized epitopes is diverse, especially in oligosymptomatic patients, while the average strength of the antibody response of the population does correlate with the severity of the disease at each time point.Interpretation The diverse immune response presents a challenge when conducting epidemiological studies as the used assays only detect ∼90% of the oligosymptomatic cases. This problem cannot be rectified by using more sensitive assay setting as they concomitantly reduce specificity.Funding Funding was obtained from the "Amt für Gesundheit" of the canton Basel-Landschaft, Switzerland.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis study was sponsored by Jurg Sommer, head of the Amt fur Gesundheit, and the logistics of the sample collection were provided by the crisis staff and the civil protection service of the canton Basel-Landschaft.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This study is part of the project COVID-19 in Baselland Investigation and Validation of Serological Diagnostic Assays and Epidemiological Study of Sars-CoV-2 specific Antibody Responses (SERO-BL-COVID-19) approved by the ethics board Ethikkommission Nordwest- und Zentralschweiz (EKNZ), Hebelstrasse 53, 4056 Basel representative of Swissethics under the number (2020-00816).All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData are available upon reques

Surface morpholgy of dental implants after subgingival decontamination in the concept of periimplantitis therapy. A Profilometric comparison of the effects of diamant burs, sandblasting and ultrasonic activated particles in-vitro

Ziel der vorliegenden In-Vitro-Untersuchung war es, verschiedene Methoden der mechanischen Dekontamination von Titanoberflächen im Rahmen einer chirurgischen Periimplantitis-Behandlung quantitativ miteinander zu vergleichen. Es wurde untersucht, welche der angewandten konventionellen und experimentellen Methoden die in der Literatur für eine Osseointegration geforderte optimale subgingivale Oberflächenmorphologie (Rauigkeit) hinterlassen. Eine Überprüfung der intra- und interindividuellen Reliabilität der Bearbeitungsmethoden und Messvorschriften zeigte, dass die Methoden teilweise untersuchersensitiv zu sein scheinen. Hinsichtlich des Materialabtrags (sofern erwünscht) und der Oberflächenrauigkeit empfiehlt es sich, die zugänglichen Stellen mit einem roten Diamant zu instrumentieren und dort, wo man mit rotierenden Instrumenten keinen Zugang findet, mit ultraschallaktivierten Partikeln (Vector mit Stahlspitze und grober Spüllösung) oder – noch effektiver – mit dem Al2O3-Sandstrahlen nachzuarbeiten. Alternativ zum Diamanten könnte man auch gleich mit mittlerer Körnung sandstrahlen, wobei das Risiko eines Emphysems und die Kontaminierung des gesamten Wundgebietes mit Strahlpartikeln, Abriebpartikeln und verschleppten Keimen berücksichtigt werden muss. Diese Nachteile könnten mit dem Vector® allerdings entfallen. Es muss bei der Bewertung der Rauigkeitsparameter zwischen sub- und supragingivaler Implantatoberfläche unterschieden werden. Bei der subgingivalen Implantatoberfläche ist die Schaffung einer mäßig rauen, osteophilen Implantatoberfläche und entsprechend eine Bindegewebs- oder Knochenapposition wünschenswert. Bei der supragingivalen Implantatoberfläche hingegen muss die Anlagerung von Plaque oder Zahnstein und somit die Rekolonisation von parodontopathogenen Keimen vermieden werden. Hier sind raue Strukturen eher unerwünscht und die untersuchten Verfahren, mit Ausnahme des Salzkristalls beziehungsweise Vector® in bestimmten Arbeitsspitzen-Spüllösungs-Kombinationen, nicht zu empfehlen. Klinische Schlussfolgerungen können mit den vorliegenden Daten derzeit nicht gezogen werden.The aim of this in-vitro-study was to compare different methods of mechanical decontamination of titanium-surfaces in the concept of surgical treatment of periimplantitis. We investigated which of the commonly used conventional and experimentally new methods leave a surface morphology that is described in dental literature as an optimal subgingival surface for osseointegration. The intra- and interindividual reliability of the treatment methods and the measurement instructions showed that the methods seem to be investigator sensitive. Regarding the removal of the material (if desired) and the surface roughness it is commonly recommended to work on surface parts that are freely accessible with a red diamond bur. Where one cannot access the surface with rotating instruments, the surface should be worked on with ultrasonic activated particles (Vector) or with Al2O3-sandblasting. As an alternative to the diamond bur the titanium surfaces could immediately be sandblasted with a medium graining, whereas the risk of setting an emphysema and the contamination of the whole operational area with sandblasting particles, abrasion particles and displaced bacteria should be seen. These disadvantages might not apply with the Vector system. When surface rougness paramaters are evaluated there must be differed between sub- and supragingival implant surface. When subgingival implant surfaces are treated then a creation of a medium rough, osteophil implant surface for a connective tissue or bone apposition would be desirable. Supragingival implant surfaces should avoid the attachment of plaque or dental calculus and consequently the recolonisation of parodontopathogen germs. On these surfaces rough structures are not wanted and this study shows that the methods that were evaluated, except the sandblasting with saline crystal or Vector® using certain combinations of application-tips and rinsing solutions respectively, cannot be recommended. Clinical conclusions cannot be drawn with the evaluated data of this study

Model-based approaches accounting for physical activity to personalize insulin treatment in type 1 diabetes

Each year, around 150,000 children and adolescents are newly diagnosed with type 1 diabetes (T1D). It is one of the most widespread autoimmune diseases worldwide, in which the body is no longer able to produce insulin due to the destruction of insulin-producing pancreatic $\beta$-cells. Insulin is the hormone responsible for lowering blood glucose (BG) levels, and people with T1D therefore require insulin treatment to adequately manage their BG. This presents a daily challenge, as BG is affected by a multitude of factors such as meals and physical activity (PA). The management of PA is particularly challenging. PA-driven changes in glucose metabolism lead to an increase in hypoglycemia risk, as an increase in glucose utilization by the exercising muscles may cause BG levels to decline. Furthermore, hypoglycemia can still occur several hours after the activity due to a rise in insulin sensitivity. To prevent hypoglycemia and maintain stable BG levels during and after PA, insulin dose reductions and additional carbohydrate intake may be required. However, the effects of PA on BG levels depend strongly on PA intensity and duration. In addition, they change dynamically over time, which makes suitable treatment adjustment to PA difficult. In this thesis, we study the effects of PA on BG dynamics and propose a control strategy for insulin delivery to improve glycemic control in the presence of PA. We first identify the open challenges in PA management and evaluate existing treatment recommendations in an in-silico study. We use a published model of glucose-insulin regulation that includes moderate-intensity PA to test these guidelines and assess BG outcomes for a range of different PA scenarios. While the risk for acute hypoglycemia is significantly reduced, we observe that the risk for late-onset hypoglycemia remains elevated, indicating that further treatment adjustments are needed in the hours following the PA session. Next, we present a new model of the glucoregulatory system that incorporates the acute and prolonged effects of moderate- to high-intensity PA on glucose metabolism. We propose a stepwise approach for model calibration to describe a T1D population and further demonstrate the model's ability to capture individual-subject data from an observational study conducted under free-living conditions. The resulting model covers the relevant PA processes affecting BG levels during activity and recovery. It allows to simulate realistic full-day scenarios and could facilitate the in-silico development of treatment strategies for PA of various intensities and durations. Finally, we address the particular need for strategies that reduce late-onset hypoglycemia and develop an approach for insulin dosing adjustments following PA. First, we propose to estimate insulin sensitivity from continuous glucose measurements using an unscented Kalman filter to quantify PA-related changes in insulin requirements. Importantly, this approach does not rely on any PA inputs, and we show that the prolonged rise in insulin sensitivity after PA can be tracked successfully. Subsequently, we introduce a bolus calculator that uses these estimates to scale meal and basal boluses. We further extend this to continuous dosing adjustments based on model predictive control, to offer approaches both for people who cover their insulin needs with multiple daily injections and who use an insulin pump for continuous insulin delivery. Our results indicate that the presented control strategy leads to improved BG outcomes and that it reduces the risk for PA-related late-onset hypoglycemia

Simulation-Based Evaluation of Treatment Adjustment to Exercise in Type 1 Diabetes

Regular exercise is beneficial and recommended for people with type 1 diabetes, but increased glucose demand and changes in insulin sensitivity require treatment adjustments to prevent exercise-induced hypoglycemia. Several different adjustment strategies based on insulin bolus reductions and additional carbohydrate intake have been proposed, but large inter- and intraindividual variability and studies using different exercise duration, intensity, and timing impede a direct comparison of their effects. In this study, we use a mathematical model of the glucoregulatory system and implement published guidelines and strategies in-silico to provide a direct comparison on a single ‘typical’ person on a standard day with three meals. We augment this day by a broad range of exercise scenarios combining different intensity and duration of the exercise session, and different timing with respect to adjacent meals. We compare the resulting blood glucose trajectories and use summary measures to evaluate the time-in-range and risk scores for hypo- and hyperglycemic events for each simulation scenario, and to determine factors that impede prevention of hypoglycemia events. Our simulations suggest that the considered strategies and guidelines successfully minimize the risk for acute hypoglycemia. At the same time, all adjustments substantially increase the risk of late-onset hypoglycemia compared to no adjustment in many cases. We also find that timing between exercise and meals and additional carbohydrate intake during exercise can lead to non-intuitive behavior due to superposition of meal- and exercise-related glucose dynamics. Increased insulin sensitivity appears as a major driver of non-acute hypoglycemic events. Overall, our results indicate that further treatment adjustment might be required both immediately following exercise and up to several hours later, but that the intricate interplay between different dynamics makes it difficult to provide generic recommendations. However, our simulation scenarios extend substantially beyond the original scope of each model component and proper model validation is warranted before applying our in-silico results in a clinical setting.ISSN:1664-239

Model predictive control to account for prolonged changes in insulin requirements following exercise in type 1 diabetes

Automated insulin delivery systems are becoming increasingly available in the treatment of type 1 diabetes. They can improve glycemic outcomes while reducing patient burden, but good glycemic control during and after exercise remains challenging. Exercise causes substantial and prolonged changes in insulin sensitivity that consequently affect insulin requirements, and can lead to late-onset hypoglycemia if not accounted for. Here, we present a model predictive control algorithm that adjusts insulin delivery during the recovery period to improve glycemic outcomes after aerobic exercise. The algorithm continuously estimates insulin sensitivity from glucose measurements via an unscented Kalman filter. It integrates the estimate by continuously updating the target insulin input as well as the process model to account for changing insulin demands. The proposed approach is generic and transferable to other control formulations. We evaluate our new control strategy in-silico using a validated diabetes patient model with aerobic exercise. We consider a virtual patient population in full-day simulations including a wide variety of exercise scenarios covering moderate to high intensities and different timing and duration of the exercise. We demonstrate improved glycemic outcomes over night following a day with exercise for all scenarios and show robustness of our approach to common disturbances. & COPY; 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).ISSN:0959-1524ISSN:1873-277

Estimating insulin sensitivity after exercise using an Unscented Kalman Filter

Insulin sensitivity is an important physiological parameter for determining insulin requirements for patients with type 1 diabetes. In addition to being highly variable between patients, insulin sensitivity increases substantially during exercise and stays elevated for several hours during subsequent recovery. We propose an unscented Kalman filter for estimating insulin sensitivity from continuous glucose monitoring data that does not require the underlying model to capture exercise and relies on average values for patient-specific parameters. Using in silico full-day simulations including exercise and meals, we study how adjusting insulin doses for elevated insulin sensitivity could decrease the risk of hypoglycemia after exercise and improve time-in-range and related metrics.ISSN:2405-896

The interaction of transcription factors controls the spatial layout of plant aerial stem cell niches

The plant shoot apical meristem holds a stem cell niche from which all aerial organs originate. Using a computational approach we show that a mixture of monomers and heterodimers of the transcription factors WUSCHEL and HAIRY MERISTEM is sufficient to pattern the stem cell niche, and predict that immobile heterodimers form a regulatory “pocket” surrounding the stem cells. The model achieves to reproduce an array of perturbations, including mutants and tissue size modifications. We also show its ability to reproduce the recently observed dynamical shift of the stem cell niche during the development of an axillary meristem. The work integrates recent experimental results to answer the longstanding question of how the asymmetry of expression between the stem cell marker CLAVATA3 and its activator WUSCHEL is achieved, and recent findings of plasticity in the system