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Optogenetic manipulation of neuronal activity through excitatory and inhibitory opsins has become an indispensable experimental strategy in neuroscience research. For many applications bidirectional control of neuronal activity allowing both excitation and inhibition of the same neurons in a single experiment is desired. This requires low spectral overlap between the excitatory and inhibitory opsin, matched photocurrent amplitudes and a fixed expression ratio. Moreover, independent activation of two distinct neuronal populations with different optogenetic actuators is still challenging due to blue-light sensitivity of all opsins. Here we report BiPOLES, an optogenetic tool for potent neuronal excitation and inhibition with light of two different wavelengths. BiPOLES enables sensitive, reliable dual-color neuronal spiking and silencing with single- or two-photon excitation, optical tuning of the membrane voltage, and independent optogenetic control of two neuronal populations using a second, blue-light sensitive opsin. The utility of BiPOLES is demonstrated in worms, flies, mice and ferrets.
Background and Purpose: The cyclic nucleotides cAMP and cGMP are ubiquitous second messengers regulating numerous biological processes. Malfunctional cNMP signalling is linked to diseases and thus is an important target in pharmaceutical research. The existing optogenetic toolbox in Caenorhabditis elegans is restricted to soluble adenylyl cyclases, the membrane-bound Blastocladiella emersonii CyclOp and hyperpolarizing rhodopsins; yet missing are membrane-bound photoactivatable adenylyl cyclases and hyperpolarizers based on K+ currents.
Experimental Approach: For the characterization of photoactivatable nucleotidyl cyclases, we expressed the proteins alone or in combination with cyclic nucleotide-gated channels in muscle cells and cholinergic motor neurons. To investigate the extent of optogenetic cNMP production and the ability of the systems to depolarize or hyperpolarize cells, we performed behavioural analyses, measured cNMP content in vitro, and compared in vivo expression levels.
Key Results: We implemented Catenaria CyclOp as a new tool for cGMP production, allowing fine-control of cGMP levels. We established photoactivatable membrane-bound adenylyl cyclases, based on mutated versions (“A-2x”) of Blastocladiella and Catenaria (“Be,” “Ca”) CyclOp, as N-terminal YFP fusions, enabling more efficient and specific cAMP signalling compared to soluble bPAC, despite lower overall cAMP production. For hyperpolarization of excitable cells by two-component optogenetics, we introduced the cAMP-gated K+-channel SthK from Spirochaeta thermophila and combined it with bPAC, BeCyclOp(A-2x), or YFP-BeCyclOp(A-2x). As an alternative, we implemented the B. emersonii cGMP-gated K+-channel BeCNG1 together with BeCyclOp.
Conclusion and Implications: We established a comprehensive suite of optogenetic tools for cNMP manipulation, applicable in many cell types, including sensory neurons, and for potent hyperpolarization.
The article is about mediating an involvement in the development of the Rosswald Castle Theater between 1750 and 1760. Attention is paid to the theater repertoire and the representation of the artistic atmosphere in the Rosswald Castle. Last but not least, the article outlines the role of the Rosswald sentimental garden, in which the dramas, operas and ballet performances were also located. The article points to the incorporation of creative impulses of Enlightenment into the repertoire of the Rosswald cultural scene. The focus of the investigation is on the activity of Johann Heinrich Friedrich Müller, who implemented the dramatic rules of the Enlightenment in the Rosswald Castle Theater.
Consider two independent random walks. By chance, there will be spells of association between them where the two processes move in the same direction, or in opposite direction. We compute the probabilities of the length of the longest spell of such random association for a given sample size, and discuss measures like mean and mode of the exact distributions. We observe that long spells (relative to small sample sizes) of random association occur frequently, which explains why nonsense correlation between short independent random walks is the rule rather than the exception. The exact figures are compared with approximations. Our finite sample analysis as well as the approximations rely on two older results popularized by Révész (Stat Pap 31:95–101, 1990, Statistical Papers). Moreover, we consider spells of association between correlated random walks. Approximate probabilities are compared with finite sample Monte Carlo results.
Medulloblastoma is a rare brain malignancy. Patients after puberty are rare and bear an intermediate prognosis. Standard treatment consists of maximal resection plus radio-chemotherapy. Treatment toxicity is high and produces disabling long-term side effects. The sonic hedgehog (SHH) subgroup is highly overrepresented in the post-pubertal and adult population and can be targeted by smoothened (SMO) inhibitors. No practice-changing prospective randomized data have been generated in adults. The EORTC 1634-BTG/NOA-23 trial will randomize patients between standard-dose vs. reduced-dosed craniospinal radiotherapy and SHH-subgroup patients between the SMO inhibitor sonidegib (OdomzoTM, Sun Pharmaceuticals Industries, Inc., New York, USA) in addition to standard radio-chemotherapy vs. standard radio-chemotherapy alone to improve outcomes in view of decreased radiotherapy-related toxicity and increased efficacy. We will further investigate tumor tissue, blood, and cerebrospinal fluid as well as magnetic resonance imaging and radiotherapy plans to generate information that helps to further improve treatment outcomes. Given that treatment side effects typically occur late, long-term follow-up will monitor classic side effects of therapy, but also health-related quality of life, cognition, social and professional outcome, and reproduction and fertility. In summary, we will generate unprecedented data that will be translated into treatment changes in post-pubertal patients with medulloblastoma and will help to design future clinical trials.
Background: Tuberous sclerosis complex (TSC), a multisystem genetic disorder, affects many organs and systems, characterized by benign growths. This German multicenter study estimated the disease-specific costs and cost-driving factors associated with various organ manifestations in TSC patients. Methods: A validated, three-month, retrospective questionnaire was administered to assess the sociodemographic and clinical characteristics, organ manifestations, direct, indirect, out-of-pocket, and nursing care-level costs, completed by caregivers of patients with TSC throughout Germany. Results: The caregivers of 184 patients (mean age 9.8 ± 5.3 years, range 0.7–21.8 years) submitted questionnaires. The reported TSC disease manifestations included epilepsy (92%), skin disorders (86%), structural brain disorders (83%), heart and circulatory system disorders (67%), kidney and urinary tract disorders (53%), and psychiatric disorders (51%). Genetic variations in TSC2 were reported in 46% of patients, whereas 14% were reported in TSC1. Mean total direct health care costs were EUR 4949 [95% confidence interval (95% CI) EUR 4088–5863, median EUR 2062] per patient over three months. Medication costs represented the largest direct cost category (54% of total direct costs, mean EUR 2658), with mechanistic target of rapamycin (mTOR) inhibitors representing the largest share (47%, EUR 2309). The cost of anti-seizure drugs (ASDs) accounted for a mean of only EUR 260 (5%). Inpatient costs (21%, EUR 1027) and ancillary therapy costs (8%, EUR 407) were also important direct cost components. The mean nursing care-level costs were EUR 1163 (95% CI EUR 1027–1314, median EUR 1635) over three months. Total indirect costs totaled a mean of EUR 2813 (95% CI EUR 2221–3394, median EUR 215) for mothers and EUR 372 (95% CI EUR 193–586, median EUR 0) for fathers. Multiple regression analyses revealed polytherapy with two or more ASDs and the use of mTOR inhibitors as independent cost-driving factors of total direct costs. Disability and psychiatric disease were independent cost-driving factors for total indirect costs as well as for nursing care-level costs. Conclusions: This study revealed substantial direct (including medication), nursing care-level, and indirect costs associated with TSC over three months, highlighting the spectrum of organ manifestations and their treatment needs in the German healthcare setting.
Traditional ergonomic risk assessment tools such as the Rapid Upper Limb Assessment (RULA) are often not sensitive enough to evaluate well-optimized work routines. An implementation of kinematic data captured by inertial sensors is applied to compare two work routines in dentistry. The surgical dental treatment was performed in two different conditions, which were recorded by means of inertial sensors (Xsens MVN Link). For this purpose, 15 (12 males/3 females) oral and maxillofacial surgeons took part in the study. Data were post processed with costume written MATLAB® routines, including a full implementation of RULA (slightly adjusted to dentistry). For an in-depth comparison, five newly introduced levels of complexity of the RULA analysis were applied, i.e., from lowest complexity to highest: (1) RULA score, (2) relative RULA score distribution, (3) RULA steps score, (4) relative RULA steps score occurrence, and (5) relative angle distribution. With increasing complexity, the number of variables times (the number of resolvable units per variable) increased. In our example, only significant differences between the treatment concepts were observed at levels that are more complex: the relative RULA step score occurrence and the relative angle distribution (level 4 + 5). With the presented approach, an objective and detailed ergonomic analysis is possible. The data-driven approach adds significant additional context to the RULA score evaluation. The presented method captures data, evaluates the full task cycle, and allows different levels of analysis. These points are a clear benefit to a standard, manual assessment of one main body position during a working task.
Background: To investigate patients’ perspectives on polypharmacy and the use of a digital decision support system to assist general practitioners (GPs) in performing medication reviews. Methods: Qualitative interviews with patients or informal caregivers recruited from participants in a cluster-randomized controlled clinical trial (cRCT). The interviews were transcribed verbatim and analyzed using thematic analysis. Results: We conducted 13 interviews and identified the following seven themes: the patients successfully integrated medication use in their everyday lives, used medication plans, had both good and bad personal experiences with their drugs, regarded their healthcare providers as the main source of medication-related information, discussed medication changes with their GPs, had trusting relationships with them, and viewed the use of digital decision support tools for medication reviews positively. No unwanted adverse effects were reported. Conclusions: Despite drug-related problems, patients appeared to cope well with their medications. They also trusted their GPs, despite acknowledging polypharmacy to be a complex field for them. The use of a digital support system was appreciated and linked to the hope that reasons for selecting specific medication regimens would become more comprehensible. Further research with a more diverse sampling might add more patient perspectives.
The nominee approach to equity crowdfunding pools all crowd investors into one (nominee) account where typically the platform acts as the legal owner but the crowd retains beneficial ownership. The platform plays an active digital corporate governance role that simultaneously enfranchises crowd investors with voting and ownership rights but removes the administrative burden on startups of having to deal with several hundred shareholders. Through an inter-platform and intra-platform analysis of a large sample of 1,018 initial equity crowdfunding campaigns, this paper assesses both the short-term and the long-term impact of nominee versus direct ownership. It finds that nominee initial campaigns are on average more successful than direct ownership campaigns in that they are more likely to succeed, raise more funds, attract overfunding and enjoy greater long run success in terms of successful seasoned equity crowdfunded offerings, numbers of such offerings, and probability of survival. These results hold inter-platform between the two main UK equity crowdfunding platforms (Seedrs and Crowdcube) as well as intra-platform, using the post-2015 quasi-natural experiment when the nominee approach became an option for startups raising capital on Crowdcube.
Biomedinformatics: A New Journal for the New Decade to Publish Biomedical Informatics Research
(2021)
With this volume, the peer-reviewed open access journal Biomedinformatics published online on the website https://www.mdpi.com/journal/biomedinformatics, and bearing the current International Standard Serial Number ISSN 2673-7426 enters the scientific community. At the beginning of the 3rd decade of the 21st century, this new journal is dedicated to research reports in the field of biomedical informatics. Biomedinformatics appears at a time when computational methods have reached clinical practice and the transformation to digital medicine is accelerating. Both digitized healthcare and bioinformatics-based research is producing and benefiting from increasingly complex data. This requires the development of tools and methods to extract information from these data and translate it into new knowledge. While biomedical research continues to require clinical and experi- mental data collection, digital healthcare research has clearly evolved from a collection of supporting methods to an equivalent scientific approach, enabling a paradigm shift from almost exclusively hypothesis-driven approaches to increasingly data-driven biomedical research. Indeed, computational science is a rapidly growing multidisciplinary field that uses advanced computational capabilities to understand and solve complex problems by applying new methods of computational intelligence, machine learning, and advanced statistics [1].
The coronavirus SARS-CoV-2 is the cause of the ongoing COVID-19 pandemic. Most SARS-CoV-2 infections are mild or even asymptomatic. However, a small fraction of infected individuals develops severe, life-threatening disease, which is caused by an uncontrolled immune response resulting in hyperinflammation. However, the factors predisposing individuals to severe disease remain poorly understood. Here, we show that levels of CD47, which is known to mediate immune escape in cancer and virus-infected cells, are elevated in SARS-CoV-2-infected Caco-2 cells, Calu-3 cells, and air−liquid interface cultures of primary human bronchial epithelial cells. Moreover, SARS-CoV-2 infection increases SIRPalpha levels, the binding partner of CD47, on primary human monocytes. Systematic literature searches further indicated that known risk factors such as older age and diabetes are associated with increased CD47 levels. High CD47 levels contribute to vascular disease, vasoconstriction, and hypertension, conditions that may predispose SARS-CoV-2-infected individuals to COVID-19-related complications such as pulmonary hypertension, lung fibrosis, myocardial injury, stroke, and acute kidney injury. Hence, age-related and virus-induced CD47 expression is a candidate mechanism potentially contributing to severe COVID-19, as well as a therapeutic target, which may be addressed by antibodies and small molecules. Further research will be needed to investigate the potential involvement of CD47 and SIRPalpha in COVID-19 pathology. Our data should encourage other research groups to consider the potential relevance of the CD47/ SIRPalpha axis in their COVID-19 research.
TOR1A is the most common inherited form of dystonia with still unclear pathophysiology and reduced penetrance of 30–40%. ∆ETorA rats mimic the TOR1A disease by expression of the human TOR1A mutation without presenting a dystonic phenotype. We aimed to induce dystonia-like symptoms in male ∆ETorA rats by peripheral nerve injury and to identify central mechanism of dystonia development. Dystonia-like movements (DLM) were assessed using the tail suspension test and implementing a pipeline of deep learning applications. Neuron numbers of striatal parvalbumin+, nNOS+, calretinin+, ChAT+ interneurons and Nissl+ cells were estimated by unbiased stereology. Striatal dopaminergic metabolism was analyzed via in vivo microdialysis, qPCR and western blot. Local field potentials (LFP) were recorded from the central motor network. Deep brain stimulation (DBS) of the entopeduncular nucleus (EP) was performed. Nerve-injured ∆ETorA rats developed long-lasting DLM over 12 weeks. No changes in striatal structure were observed. Dystonic-like ∆ETorA rats presented a higher striatal dopaminergic turnover and stimulus-induced elevation of dopamine efflux compared to the control groups. Higher LFP theta power in the EP of dystonic-like ∆ETorA compared to wt rats was recorded. Chronic EP-DBS over 3 weeks led to improvement of DLM. Our data emphasizes the role of environmental factors in TOR1A symptomatogenesis. LFP analyses indicate that the pathologically enhanced theta power is a physiomarker of DLM. This TOR1A model replicates key features of the human TOR1A pathology on multiple biological levels and is therefore suited for further analysis of dystonia pathomechanism.
We establish weighted Lp-Fourier extension estimates for O(N−k)×O(k)-invariant functions defined on the unit sphere SN−1, allowing for exponents p below the Stein–Tomas critical exponent 2(N+1)/N−1. Moreover, in the more general setting of an arbitrary closed subgroup G⊂O(N) and G-invariant functions, we study the implications of weighted Fourier extension estimates with regard to boundedness and nonvanishing properties of the corresponding weighted Helmholtz resolvent operator. Finally, we use these properties to derive new existence results for G-invariant solutions to the nonlinear Helmholtz equation −Δu−u = Q(x)|u|p−2u,u∈W2,p(RN), where Q is a nonnegative bounded and G-invariant weight function.
As a first step towards a realistic phenomenological description of vector and axial-vector mesons in nuclear matter, we calculate the spectral functions of the ρ and the a1 meson in a chiral baryon-meson model as a low-energy effective realization of QCD, taking into account the effects of fluctuations from scalar mesons, nucleons, and vector mesons within the functional renormalization group (FRG) approach. The phase diagram of the effective hadronic theory exhibits a nuclear liquid-gas phase transition as well as a chiral phase transition at a higher baryon-chemical potential. The in-medium ρ and a1 spectral functions are calculated by using the previously introduced analytically-continued FRG (aFRG) method. Our results show strong modifications of the spectral functions—in particular near the critical endpoints of both phase transitions—which may well be of relevance for electromagnetic rates in heavy-ion collisions or neutrino emissivities in neutron-star merger events.
Aim: Comparison of the clinical efficacy (digitally volumetric, aesthetic, patient-centred outcomes) of tunnel technique (TUN) with subepithelial connective tissue graft (CTG) versus coronally advanced flap (CAF) with enamel matrix derivate (EMD) 5 years after gingival recession therapy. Materials and methods: In 18 patients contributing 36 RT1 recessions, study models were collected at baseline and follow-ups. Optical scans assessed recessions computer-assisted [recession depth, recession reduction (RECred), complete root coverage (CRC), percentage of root coverage (RC), pointwise (pTHK) and mean areal (aTHK) marginal soft tissue thickness]. Root coverage aesthetic Score (RES) was used for aesthetic evaluation and visual analogue scales for patient-centred data collection applied. Results: Sixty months after surgery, 50.0% (TUN+CTG) and 0.0% (CAF+EMD) of sites showed CRC (p = 0.0118), 82.2% (TUN+CTG) and 32.0% (CAF+EMD) achieved RC, respectively (p = 0.0023). CTG achieved significantly better RECred (TUN+CTG: 1.75±0.74 mm; CAF+EMD: 0.50 ± 0.39 mm; p = 0.0009) and aTHK (TUN+CTG: 0.95 ± 0.41 mm; CAF+EMD: 0.26 ± 0.28 mm; p = 0.0013). RES showed superior outcomes (p = 0.0533) for TUN+CTG (6.86 ± 2.31) compared to CAF+EMD (4.63 ± 1.99). The study failed to find significant differences related to patient-centred outcomes (TUN+CTG: 8.30 ± 2.21; CAF+EMD: 7.50 ± 1.51; p = 0.1136). Conclusions: Five years after treatment, CTG resulted in better clinical and aesthetic outcomes than CAF+EMD. Increased THK was associated with improved outcomes for RECred and RC.
Global water models (GWMs) simulate the terrestrial water cycle, on the global scale, and are used to assess the impacts of climate change on freshwater systems. GWMs are developed within different modeling frameworks and consider different underlying hydrological processes, leading to varied model structures. Furthermore, the equations used to describe various processes take different forms and are generally accessible only from within the individual model codes. These factors have hindered a holistic and detailed understanding of how different models operate, yet such an understanding is crucial for explaining the results of model evaluation studies, understanding inter-model differences in their simulations, and identifying areas for future model development. This study provides a comprehensive overview of how state-of-the-art GWMs are designed. We analyze water storage compartments, water flows, and human water use sectors included in 16 GWMs that provide simulations for the Inter-Sectoral Impact Model Intercomparison Project phase 2b (ISIMIP2b). We develop a standard writing style for the model equations to further enhance model improvement, intercomparison, and communication. In this study, WaterGAP2 used the highest number of water storage compartments, 11, and CWatM used 10 compartments. Seven models used six compartments, while three models (JULES-W1, Mac-PDM.20, and VIC) used the lowest number, three compartments. WaterGAP2 simulates five human water use sectors, while four models (CLM4.5, CLM5.0, LPJmL, and MPIHM) simulate only water used by humans for the irrigation sector. We conclude that even though hydrologic processes are often based on similar equations, in the end, these equations have been adjusted or have used different values for specific parameters or specific variables. Our results highlight that the predictive uncertainty of GWMs can be reduced through improvements of the existing hydrologic processes, implementation of new processes in the models, and high-quality input data.
The discovery of clustered regularly interspaced short palindromic repeats and their associated proteins (Cas) has revolutionized the field of genome and epigenome editing. A number of new methods have been developed to precisely control the function and activity of Cas proteins, including fusion proteins and small-molecule modulators. Proteolysis-targeting chimeras (PROTACs) represent a new concept using the ubiquitin-proteasome system to degrade a protein of interest, highlighting the significance of chemically induced protein-E3 ligase interaction in drug discovery. Here, we engineered Cas proteins (Cas9, dCas9, Cas12, and Cas13) by inserting a Phe-Cys-Pro-Phe (FCPF) amino acid sequence (known as the π-clamp system) and demonstrate that the modified CasFCPF proteins can be (1) labeled in live cells by perfluoroaromatics carrying the fluorescein or (2) degraded by a perfluoroaromatics-functionalized PROTAC (PROTAC-FCPF). A proteome-wide analysis of PROTAC-FCPF-mediated Cas9FCPF protein degradation revealed a high target specificity, suggesting a wide range of applications of perfluoroaromatics-induced proximity in the regulation of stability, activity, and functionality of any FCPF-tagging protein.
The following new taxa are described from the Philippines: Mioscarta nubisa Crispolon & Soulier-Perkins sp. nov., M. translucida Crispolon & Yap sp. nov. and Trigonoschema Crispolon & Soulier-Perkins gen. nov. with three new species: T. manoborum Crispolon & Soulier-Perkins sp. nov. (as type species), T. negrosensis Crispolon & Yap sp. nov and T. rubercella Crispolon &Guilbert sp. nov. Trigonoschema pallida (Lallemand, 1927) comb. nov. is transferred from Mioscarta Breddin, 1901. Descriptions of male genitalia are illustrated and keys to species of Philippine Mioscarta and Trigonoschema gen. nov. are provided. Although phylogenetic results confirm the monophyly of all genera and Trigonoschema being a distinct genus from Mioscarta, relationships between genera remain uncertain. A checklist of the genera and species of Cercopidae found in the Philippines is included.
In order to form an organ, cells need to take up specialized functions and tasks. Cellular specialization is guided by an interplay of chemical signals and physical forces, where one influences the other. One aspect in cellular identity is its shape, which e.g. defines how susceptible the cell may be to intercellular signaling or in which section of the cell cycle it is and therefore can tell us about its current state. Shape changes are introduced by motor proteins that are controlled and activated in a locally confined manner. For my thesis, I was interested to understand better how cellular shape and geometry impacts downstream cell and organ development. What happens if a cell cant transition to a specific shape? How does it affect tissue structure? How does it affect further development?
One regulator of motor proteins like non-muscle myosin is Shroom3, which recently has been been shown to be expressed and involved in the development of the zebrafish lateral line organ (1 ). Development of the lateral line occurs through a migrating cluster of initially about 150 cells, the posterior lateral line primordium (pLLP), which migrates from the anterior (head) to the posterior (tail) while depositing cell clusters in a regular pattern. Literature on development of the lateral line suggests that in order for a cell cluster to be deposited from the pLLP, rosette formation is a key requirement. Therefore our expectation from the shroom3 mutant was that the number of clusters deposited was significantly reduced. To our surprise, when we first inspected the end of migration lateral line phenotype we found many individuals with a significant increase in cell clusters deposited.
This made us re-think the role of Shroom3 during rosette assembly and the processes its involved in.
To study the effects of Shroom3 on lateral line development, a mutant line was generated and crossed with various transgenic lines which express fluorescently labeled proteins that locate to organelles such as the plasmamembrane or the nucleus. Following, the mutant with its fluorescent labels was microscopically imaged under different conditions to quantify and analyze various cell-morphometric features. Even though the zebrafish is a popular model organism and its perfectly suited for developmental biology and advanced microscopy, there were no methods that would allow for a standardized and more automated pipeline of data acquisition and processing.
Therefore, in order to accurately quantify the morphogenic processes Shroom3 is involved in, I developed a new toolset that significantly improved and facilitated my research. The toolset consists of (1) a new sample mounting method that is based on a 3D agarose gel that increases the number of embryos that can be mounted and imaged at once and speeds up the imaging process significantly (2) for subseqent image analysis I developed four programs that automate the process and therefore make the results much more reproducible and the analysis much more efficient. The first program is used for end of migration analyses, to deduce the pattern, count and size of Lateral Line cell clusters. The second is used not for end of migration, but for migration analyses (on timelapse recordings). Besides this it also prepares the images for more advanced downstream migration analyses and allows to analyse fluorescence signal on a second channel. The third program is used to analyse the pLLP only at high spatial resolution and to deduce the cell count, 3D cell morphometrics (like the volume) and cell orientation. The fourth program finally is used downstream of the second and third program and is capable of detecting and comparing them with the look of wildtype rosettes.
Here I show that in absence of Shroom3 rosette formation in the migrating pLLP is destabilized leading to facilitated cell cluster deposition and I show how this might be related to traction forces due to a possible interdependence of pLLP acceleration and speed of migration. Furthermore I show that apical constriction and rosette formation is not blocked in Shroom3 deficient embryos, but that larger rosettes are fragmented into many smaller ones. Finally, I give an outlook on how the absense of Shroom3 and hence the absense of morphological changes may deregulate gene transcription by elevating the levels Atoh1a, a transcription factor necessary for hair cell development.
My results and methodology demonstrate the importance of morphology in guiding developmental processes and how rather small morphological changes on the cellular level can impact further development significantly. My work also shows how powerful modern genetics, imaging and image analysis are and how diverse they are in terms of range of questions they are capable of answering. The methods and tools I developed prepare the ground for at least three quarters of the analyses I carried out and together with the documentation and data I provide, they are highly reproducible. In that regard I am especially happy that one of my developments, an improved sample preparation method, is already used by many different labs all over the world helping them to make their results more reproducible.