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Dysfunctional islets of Langerhans are a hallmark of type 2 diabetes (T2D). We hypothesize that differences in islet gene expression alternative splicing which can contribute to altered protein function also participate in islet dysfunction. RNA sequencing (RNAseq) data from islets of obese diabetes-resistant and diabetes-susceptible mice were analyzed for alternative splicing and its putative genetic and epigenetic modulators. We focused on the expression levels of chromatin modifiers and SNPs in regulatory sequences. We identified alternative splicing events in islets of diabetes-susceptible mice amongst others in genes linked to insulin secretion, endocytosis or ubiquitin-mediated proteolysis pathways. The expression pattern of 54 histones and chromatin modifiers, which may modulate splicing, were markedly downregulated in islets of diabetic animals. Furthermore, diabetes-susceptible mice carry SNPs in RNA-binding protein motifs and in splice sites potentially responsible for alternative splicing events. They also exhibit a larger exon skipping rate, e.g., in the diabetes gene Abcc8, which might affect protein function. Expression of the neuronal splicing factor Srrm4 which mediates inclusion of microexons in mRNA transcripts was markedly lower in islets of diabetes-prone compared to diabetes-resistant mice, correlating with a preferential skipping of SRRM4 target exons. The repression of Srrm4 expression is presumably mediated via a higher expression of miR-326-3p and miR-3547-3p in islets of diabetic mice. Thus, our study suggests that an altered splicing pattern in islets of diabetes-susceptible mice may contribute to an elevated T2D risk.
Objective: To examine the effect of plyometric jump training on skeletal muscle hypertrophy in healthy individuals. Methods: A systematic literature search was conducted in the databases PubMed, SPORTDiscus, Web of Science, and Cochrane Library up to September 2021. Results: Fifteen studies met the inclusion criteria. The main overall finding (44 effect sizes across 15 clusters median = 2, range = 1-15 effects per cluster) indicated that plyometric jump training had small to moderate effects [standardised mean difference (SMD) = 0.47 (95% CIs = 0.23-0.71); p < 0.001] on skeletal muscle hypertrophy. Subgroup analyses for training experience revealed trivial to large effects in non-athletes [SMD = 0.55 (95% CIs = 0.18-0.93); p = 0.007] and trivial to moderate effects in athletes [SMD = 0.33 (95% CIs = 0.16-0.51); p = 0.001]. Regarding muscle groups, results showed moderate effects for the knee extensors [SMD = 0.72 (95% CIs = 0.66-0.78), p < 0.001] and equivocal effects for the plantar flexors [SMD = 0.65 (95% CIs = -0.25-1.55); p = 0.143]. As to the assessment methods of skeletal muscle hypertrophy, findings indicated trivial to small effects for prediction equations [SMD = 0.29 (95% CIs = 0.16-0.42); p < 0.001] and moderate-to-large effects for ultrasound imaging [SMD = 0.74 (95% CIs = 0.59-0.89); p < 0.001]. Meta-regression analysis indicated that the weekly session frequency moderates the effect of plyometric jump training on skeletal muscle hypertrophy, with a higher weekly session frequency inducing larger hypertrophic gains [beta = 0.3233 (95% CIs = 0.2041-0.4425); p < 0.001]. We found no clear evidence that age, sex, total training period, single session duration, or the number of jumps per week moderate the effect of plyometric jump training on skeletal muscle hypertrophy [beta = -0.0133 to 0.0433 (95% CIs = -0.0387 to 0.1215); p = 0.101-0.751]. Conclusion: Plyometric jump training can induce skeletal muscle hypertrophy, regardless of age and sex. There is evidence for relatively larger effects in non-athletes compared with athletes. Further, the weekly session frequency seems to moderate the effect of plyometric jump training on skeletal muscle hypertrophy, whereby more frequent weekly plyometric jump training sessions elicit larger hypertrophic adaptations.
Pedogenic carbonate is widespread at mid latitudes where warm and dry conditions favor soil carbonate growth from spring to fall. The mechanisms and timing of pedogenic carbonate formation are more ambiguous in the tropical domain, where long periods of soil water saturation and high soil respiration enhance calcite dissolution. This paper provides stable carbon, oxygen and clumped isotope values from Quaternary and Miocene pedogenic carbonates in the tropical domain of Myanmar, in areas characterized by warm (>18°C) winters and annual rainfall up to 1,700 mm. We show that carbonate growth in Myanmar is delayed to the driest and coldest months of the year by sustained monsoonal rainfall from mid spring to late fall. The range of isotopic variability in Quaternary pedogenic carbonates can be solely explained by temporal changes of carbonate growth within the dry season, from winter to early spring. We propose that high soil moisture year-round in the tropical domain narrows carbonate growth to the driest months and makes it particularly sensitive to the seasonal distribution of rainfall. This sensitivity is also enabled by high winter temperatures, allowing carbonate growth to occur outside the warmest months of the year. This high sensitivity is expected to be more prominent in the geological record during times with higher temperatures and greater expansion of the tropical realm. Clumped isotope temperatures, δ13C and δ18O values of tropical pedogenic carbonates are impacted by changes of both rainfall seasonality and surface temperatures; this sensitivity can potentially be used to track past tropical rainfall distribution.
The genus Microhyla Tschudi, 1838 includes 52 species and is one of the most diverse genera of the family Microhylidae, being the most species-rich taxon of the Asian subfamily Microhylinae. The recent, rapid description of numerous new species of Microhyla with complex phylogenetic relationships has made the taxonomy of the group especially challenging. Several recent phylogenetic studies suggested paraphyly of Microhyla with respect to Glyphoglossus Gunther, 1869, and revealed three major phylogenetic lineages of mid-Eocene origin within this assemblage. However, comprehensive works assessing morphological variation among and within these lineages are absent. In the present study we investigate the generic taxonomy of Microhyla-Glyphoglossus assemblage based on a new phylogeny including 57 species, comparative morphological analysis of skeletons from cleared-and-stained specimens for 23 species, and detailed descriptions of generalized osteology based on volume-rendered micro-CT scans for five speciesal-together representing all major lineages within the group. The results confirm three highly divergent and well-supported clades that correspond with external and osteological morphological characteristics, as well as respective geographic distribution. Accordingly, acknowledging ancient divergence between these lineages and their significant morphological differentiation, we propose to consider these three lineages as distinct genera: Microhyla sensu stricto, Glyphoglossus, and a newly described genus, Nanohyla gen. nov.
Breaking down barriers
(2024)
Many researchers hesitate to provide full access to their datasets due to a lack of knowledge about research data management (RDM) tools and perceived fears, such as losing the value of one's own data. Existing tools and approaches often do not take into account these fears and missing knowledge. In this study, we examined how conversational agents (CAs) can provide a natural way of guidance through RDM processes and nudge researchers towards more data sharing. This work offers an online experiment in which researchers interacted with a CA on a self-developed RDM platform and a survey on participants’ data sharing behavior. Our findings indicate that the presence of a guiding and enlightening CA on an RDM platform has a constructive influence on both the intention to share data and the actual behavior of data sharing. Notably, individual factors do not appear to impede or hinder this effect.
Social media constitute an important arena for public debates and steady interchange of issues relevant to society. To boost their reputation, commercial organizations also engage in political, social, or environmental debates on social media. To engage in this type of digital activism, organizations increasingly utilize the social media profiles of executive employees and other brand ambassadors. However, the relationship between brand ambassadors’ digital activism and corporate reputation is only vaguely understood. The results of a qualitative inquiry suggest that digital activism via brand ambassadors can be risky (e.g., creating additional surface for firestorms, financial loss) and rewarding (e.g., emitting authenticity, employing ‘megaphones’ for industry change) at the same time. The paper informs both scholarship and practitioners about strategic trade-offs that need to be considered when employing brand ambassadors for digital activism.
Mastery is a psychological resource that is defined as the extent to which individuals perceive having control over important circumstances of their lives. Although mastery has been associated with various physical and psychological health outcomes, studies assessing its relationship with weight status and dietary behavior are lacking. The aim of this cross-sectional study was to assess the relationship between mastery and weight status, food intake, snacking, and eating disorder (ED) symptoms in the NutriNet-Sante cohort study. Mastery was measured with the Pearlin Mastery Scale (PMS) in 32,588 adults (77.45% female), the mean age was 50.04 (14.53) years. Height and weight were self-reported. Overall diet quality and food group consumption were evaluated with >= 3 self-reported 24-h dietary records (range: 3-27). Snacking was assessed with an ad-hoc question. ED symptoms were assessed with the Sick-Control-One-Fat-Food Questionnaire (SCOFF). Linear and logistic regression analyses were conducted to assess the relationship between mastery and weight status, food intake, snacking, and ED symptoms, controlling for sociodemographic and lifestyle characteristics. Females with a higher level of mastery were less likely to be underweight (OR: 0.88; 95%CI: 0.84, 0.93), overweight [OR: 0.94 (0.91, 0.97)], or obese [class I: OR: 0.86 (0.82, 0.90); class II: OR: 0.76 (0.71, 0.82); class III: OR: 0.77 (0.69, 0.86)]. Males with a higher level of mastery were less likely to be obese [class III: OR: 0.75 (0.57, 0.99)]. Mastery was associated with better diet quality overall, a higher consumption of fruit and vegetables, seafood, wholegrain foods, legumes, non-salted oleaginous fruits, and alcoholic beverages and with a lower consumption of meat and poultry, dairy products, sugary and fatty products, milk-based desserts, and sweetened beverages. Mastery was also associated with lower snacking frequency [OR: 0.89 (0.86, 0.91)] and less ED symptoms [OR: 0.73 (0.71, 0.75)]. As mastery was associated with favorable dietary behavior and weight status, targeting mastery might be a promising approach in promoting healthy behaviors.
Tula orthohantavirus (TULV) is a rodent-borne hantavirus with broad geographical distribution in Europe. Its major reservoir is the common vole (Microtus arvalis), but TULV has also been detected in closely related vole species. Given the large distributional range and high amplitude population dynamics of common voles, this host-pathogen complex presents an ideal system to study the complex mechanisms of pathogen transmission in a wild rodent reservoir. We investigated the dynamics of TULV prevalence and the subsequent potential effects on the molecular evolution of TULV in common voles of the Central evolutionary lineage. Rodents were trapped for three years in four regions of Germany and samples were analyzed for the presence of TULV-reactive antibodies and TULV RNA with subsequent sequence determination. The results show that individual (sex) and population-level factors (abundance) of hosts were significant predictors of local TULV dynamics. At the large geographic scale, different phylogenetic TULV clades and an overall isolation-by-distance pattern in virus sequences were detected, while at the small scale (<4 km) this depended on the study area. In combination with an overall delayed density dependence, our results highlight that frequent, localized bottleneck events for the common vole and TULV do occur and can be offset by local recolonization dynamics.
Der Band stellt ein Modell für einen differenzierenden Literaturunterricht vor, der individuelle Förderung für unterschiedliche Bereiche von Heterogenität ermöglicht.
Eine ergiebige Differenzierung nutzt die Aspekte Ziele, Themen und Methoden des Unterrichts sowie Lenkung und Aufgabenformat. Diese Aspekte werden mit Blick auf die einzelnen Phasen des Unterrichts präzisiert. Dabei werden Leistungsunterschiede, sprachliche, kulturelle und soziale sowie individuelle Voraussetzungen der einzelnen Schüler:innen deutlicher adressiert.
Einzelne exemplarische Aufgabensets mit ausführlicher Erläuterung dienen der Veranschaulichung des Modells. Zudem werden Unterrichtseinheiten vorgestellt, die systematisch Möglichkeiten der Differenzierung nutzen.
Simple Summary Gliomas are heterogenous types of cancer, therefore the therapy should be personalized and targeted toward specific pathways. We developed a methodology that corrected strong batch effects from The Cancer Genome Atlas datasets and estimated glioma grade-specific co-enrichment mechanisms using machine learning. Our findings created hypotheses for annotations, e.g., pathways, that should be considered as therapeutic targets. Gliomas develop and grow in the brain and central nervous system. Examining glioma grading processes is valuable for improving therapeutic challenges. One of the most extensive repositories storing transcriptomics data for gliomas is The Cancer Genome Atlas (TCGA). However, such big cohorts should be processed with caution and evaluated thoroughly as they can contain batch and other effects. Furthermore, biological mechanisms of cancer contain interactions among biomarkers. Thus, we applied an interpretable machine learning approach to discover such relationships. This type of transparent learning provides not only good predictability, but also reveals co-predictive mechanisms among features. In this study, we corrected the strong and confounded batch effect in the TCGA glioma data. We further used the corrected datasets to perform comprehensive machine learning analysis applied on single-sample gene set enrichment scores using collections from the Molecular Signature Database. Furthermore, using rule-based classifiers, we displayed networks of co-enrichment related to glioma grades. Moreover, we validated our results using the external glioma cohorts. We believe that utilizing corrected glioma cohorts from TCGA may improve the application and validation of any future studies. Finally, the co-enrichment and survival analysis provided detailed explanations for glioma progression and consequently, it should support the targeted treatment.
We present the discovery of a new double-detonation progenitor system consisting of a hot subdwarf B (sdB) binary with a white dwarf companion with a P (orb) = 76.34179(2) minutes orbital period. Spectroscopic observations are consistent with an sdB star during helium core burning residing on the extreme horizontal branch. Chimera light curves are dominated by ellipsoidal deformation of the sdB star and a weak eclipse of the companion white dwarf. Combining spectroscopic and light curve fits, we find a low-mass sdB star, M (sdB) = 0.383 +/- 0.028 M (circle dot) with a massive white dwarf companion, M (WD) = 0.725 +/- 0.026 M (circle dot). From the eclipses we find a blackbody temperature for the white dwarf of 26,800 K resulting in a cooling age of approximate to 25 Myr whereas our MESA model predicts an sdB age of approximate to 170 Myr. We conclude that the sdB formed first through stable mass transfer followed by a common envelope which led to the formation of the white dwarf companion approximate to 25 Myr ago. Using the MESA stellar evolutionary code we find that the sdB star will start mass transfer in approximate to 6 Myr and in approximate to 60 Myr the white dwarf will reach a total mass of 0.92 M (circle dot) with a thick helium layer of 0.17 M (circle dot). This will lead to a detonation that will likely destroy the white dwarf in a peculiar thermonuclear supernova. PTF1 J2238+7430 is only the second confirmed candidate for a double-detonation thermonuclear supernova. Using both systems we estimate that at least approximate to 1% of white dwarf thermonuclear supernovae originate from sdB+WD binaries with thick helium layers, consistent with the small number of observed peculiar thermonuclear explosions.
The aim of this study was to investigate the effects of listening to preferred music during a warm up or exercise, on performance during a 6-min all-out exercise test (6-MT) in young adult males. Twenty-five healthy males volunteered to participate in this study. Following a within subject design, participants performed three test conditions (MDT: music during the test; MDW: music during the warm-up; WM: without music) in random order. Outcomes included mean running speed over the 6-min test (MRS6), total distance covered (TDC), heart rate responses (HRpeak, HRmean), blood lactate (3-min after the test), and the rating of perceived exertion (RPE); additionally, feeling scale scores were recorded. Listening to preferred music during running resulted in significant TDC (Delta up arrow 10%, p=0.006, ES=0.80) and MRS6 (Delta up arrow 14%, p=0.012, ES=1.02) improvement during the 6-MT, improvement was also noted for the warm-up with music condition (TDC:Delta up arrow 8%, p=0.028, ES=0.63; MRS6:Delta up arrow 8%, p=0.032, ES=0.61). A similar reverse "J-shaped" pacing profile was detected during the three conditions. Blood lactate was lower in the MDT condition by 8% (p=0.01, ES=1.10), but not the MDW condition, compared to MW. In addition, no statistically significant differences were found between the test sessions for the HR, RPE, and feeling scale scores. In conclusion, listening to music during exercise testing would be more beneficial for optimal TDC and MRS6 performances compared to MDW and WM.
This study focuses on three key aspects: (a) crude throat swab samples in a viral transport medium (VTM) as templates for RT-LAMP reactions; (b) a biotinylated DNA probe with enhanced specificity for LFA readouts; and (c) a digital semi-quantification of LFA readouts. Throat swab samples from SARS-CoV-2 positive and negative patients were used in their crude (no cleaning or pre-treatment) forms for the RT-LAMP reaction. The samples were heat-inactivated but not treated for any kind of nucleic acid extraction or purification. The RT-LAMP (20 min processing time) product was read out by an LFA approach using two labels: FITC and biotin. FITC was enzymatically incorporated into the RT-LAMP amplicon with the LF-LAMP primer, and biotin was introduced using biotinylated DNA probes, specifically for the amplicon region after RT-LAMP amplification. This assay setup with biotinylated DNA probe-based LFA readouts of the RT-LAMP amplicon was 98.11% sensitive and 96.15% specific. The LFA result was further analysed by a smartphone-based IVD device, wherein the T-line intensity was recorded. The LFA T-line intensity was then correlated with the qRT-PCR Ct value of the positive swab samples. A digital semi-quantification of RT-LAMP-LFA was reported with a correlation coefficient of R2 = 0.702. The overall RT-LAMP-LFA assay time was recorded to be 35 min with a LoD of three RNA copies/µL (Ct-33). With these three advancements, the nucleic acid testing-point of care technique (NAT-POCT) is exemplified as a versatile biosensor platform with great potential and applicability for the detection of pathogens without the need for sample storage, transportation, or pre-processing.
The study addresses the question, if observed changes in terms of Arctic-midlatitude linkages during winter are driven by Arctic Sea ice decline alone or if the increase of global sea surface temperatures plays an additional role. We compare atmosphere-only model experiments with ECHAM6 to ERA-Interim Reanalysis data. The model sensitivity experiment is implemented as a set of four combinations of sea ice and sea surface temperature boundary conditions. Atmospheric circulation regimes are determined and evaluated in terms of their cyclone and blocking characteristics and changes in frequency during winter. As a prerequisite, ECHAM6 reproduces general features of circulation regimes very well. Tropospheric changes induced by the change of boundary conditions are revealed and further impacts on the large-scale circulation up into the stratosphere are investigated. In early winter, the observed increase of atmospheric blocking in the region between Scandinavia and the Urals are primarily related to the changes in sea surface temperatures. During late winter, we f nd a weakened polar stratospheric vortex in the reanalysis that further impacts the troposphere. In the model sensitivity study a climatologically weakened polar vortex occurs only if sea ice is reduced and sea surface temperatures are increased together. This response is delayed compared to the reanalysis. The tropospheric response during late winter is inconclusive in the model, which is potentially related to the weak and delayed response in the stratosphere. The model experiments do not reproduce the connection between early and late winter as interpreted from the reanalysis. Potentially explaining this mismatch, we identify a discrepancy of ECHAM6 to reproduce the weakening of the stratospheric polar vortex through blocking induced upward propagation of planetary waves.
The capillary-venous pathology cerebral cavernous malformation (CCM) is caused by loss of CCM1/Krev interaction trapped protein 1 (KRIT1), CCM2/MGC4607, or CCM3/PDCD10 in some endothelial cells. Mutations of CCM genes within the brain vasculature can lead to recurrent cerebral hemorrhages. Pharmacological treatment options are urgently needed when lesions are located in deeply-seated and in-operable regions of the central nervous system. Previous pharmacological suppression screens in disease models of CCM led to the discovery that treatment with retinoic acid improved CCM phenotypes. This finding raised a need to investigate the involvement of retinoic acid in CCM and test whether it has a curative effect in preclinical mouse models. Here, we show that components of the retinoic acid synthesis and degradation pathway are transcriptionally misregulated across disease models of CCM. We complemented this analysis by pharmacologically modifying retinoic acid levels in zebrafish and human endothelial cell models of CCM, and in acute and chronic mouse models of CCM. Our pharmacological intervention studies in CCM2-depleted human umbilical vein endothelial cells (HUVECs) and krit1 mutant zebrafish showed positive effects when retinoic acid levels were increased. However, therapeutic approaches to prevent the development of vascular lesions in adult chronic murine models of CCM were drug regiment-sensitive, possibly due to adverse developmental effects of this hormone. A treatment with high doses of retinoic acid even worsened CCM lesions in an adult chronic murine model of CCM. This study provides evidence that retinoic acid signaling is impaired in the CCM pathophysiology and suggests that modification of retinoic acid levels can alleviate CCM phenotypes.
Fetal alcohol-spectrum disorder (FASD) is underdiagnosed and often misdiagnosed as attention-deficit/hyperactivity disorder (ADHD). Here, we develop a screening tool for FASD in youth with ADHD symptoms. To develop the prediction model, medical record data from a German University outpatient unit are assessed including 275 patients aged 0-19 years old with FASD with or without ADHD and 170 patients with ADHD without FASD aged 0-19 years old. We train 6 machine learning models based on 13 selected variables and evaluate their performance. Random forest models yield the best prediction models with a cross-validated AUC of 0.92 (95% confidence interval [0.84, 0.99]). Follow-up analyses indicate that a random forest model with 6 variables - body length and head circumference at birth, IQ, socially intrusive behaviour, poor memory and sleep disturbance - yields equivalent predictive accuracy. We implement the prediction model in a web-based app called FASDetect - a user-friendly, clinically scalable FASD risk calculator that is freely available at https://fasdetect.dhc-lab.hpi.de.
Purpose
Due to the increasing application of genome analysis and interpretation in medical disciplines, professionals require adequate education. Here, we present the implementation of personal genotyping as an educational tool in two genomics courses targeting Digital Health students at the Hasso Plattner Institute (HPI) and medical students at the Technical University of Munich (TUM).
Methods
We compared and evaluated the courses and the students ' perceptions on the course setup using questionnaires.
Results
During the course, students changed their attitudes towards genotyping (HPI: 79% [15 of 19], TUM: 47% [25 of 53]). Predominantly, students became more critical of personal genotyping (HPI: 73% [11 of 15], TUM: 72% [18 of 25]) and most students stated that genetic analyses should not be allowed without genetic counseling (HPI: 79% [15 of 19], TUM: 70% [37 of 53]). Students found the personal genotyping component useful (HPI: 89% [17 of 19], TUM: 92% [49 of 53]) and recommended its inclusion in future courses (HPI: 95% [18 of 19], TUM: 98% [52 of 53]).
Conclusion
Students perceived the personal genotyping component as valuable in the described genomics courses. The implementation described here can serve as an example for future courses in Europe.
At the junction of greenhouse and icehouse climate states, the Eocene-Oligocene Transition (EOT) is a key moment in Cenozoic climate history. While it is associated with severe extinctions and biodiversity turnovers on land, the role of terrestrial climate evolution remains poorly resolved, especially the associated changes in seasonality. Some paleobotanical and geochemical continental records in parts of the Northern Hemisphere suggest the EOT is associated with a marked cooling in winter, leading to the development of more pronounced seasons (i.e., an increase in the mean annual range of temperature, MATR). However, the MATR increase has been barely studied by climate models and large uncertainties remain on its origin, geographical extent and impact. In order to better understand and describe temperature seasonality changes between the middle Eocene and the early Oligocene, we use the Earth system model IPSL-CM5A2 and a set of simulations reconstructing the EOT through three major climate forcings: pCO(2) decrease (1120, 840 and 560 ppm), the Antarctic ice-sheet (AIS) formation and the associated sea-level decrease. Our simulations suggest that pCO(2) lowering alone is not sufficient to explain the seasonality evolution described by the data through the EOT but rather that the combined effects of pCO(2) , AIS formation and increased continentality provide the best data-model agreement.pCO(2) decrease induces a zonal pattern with alternating increasing and decreasing seasonality bands particularly strong in the northern high latitudes (up to 8 degrees C MATR increase) due to sea-ice and surface albedo feedback. Conversely, the onset of the AIS is responsible for a more constant surface albedo yearly, which leads to a strong decrease in seasonality in the southern midlatitudes to high latitudes (> 40 degrees S). Finally, continental areas that emerged due to the sea-level lowering cause the largest increase in seasonality and explain most of the global heterogeneity in MATR changes (1MATR) patterns. The Delta MATR patterns we reconstruct are generally consistent with the variability of the EOT biotic crisis intensity across the Northern Hemisphere and provide insights on their underlying mechanisms.
Am Ende der Globalisierung
(2021)
Die Globalisierung ist zur allgegenwärtigen Gewissheit geworden. Doch wie zutreffend ist das Konzept »Globalisierung«, wenn zeitgleich nationale Grenzen gestärkt und transnationale Freihandelszonen ausgeweitet werden, wenn auf unterschiedlichen scales Territorien überwunden und zugleich territoriale Abgrenzungen neu gesetzt werden? Aktuelle Veränderungen als Re-Figuration von Räumen zu verstehen, ermöglicht die Analyse und Diskussion widersprüchlicher, spannungsreicher und konflikthafter räumlicher Prozesse und ihrer alltäglichen Erfahrung. Die interdisziplinären Beiträge des Bandes liefern theoretische und empirische Analysen zu politischen, digitalen und alltäglichen Räumen im Konzept der Re-Figuration.
Deriving mechanism-based pharmacodynamic models by reducing quantitative systems pharmacology models
(2023)
Quantitative systems pharmacology (QSP) models integrate comprehensive qualitative and quantitative knowledge about pharmacologically relevant processes. We previously proposed a first approach to leverage the knowledge in QSP models to derive simpler, mechanism-based pharmacodynamic (PD) models. Their complexity, however, is typically still too large to be used in the population analysis of clinical data. Here, we extend the approach beyond state reduction to also include the simplification of reaction rates, elimination of reactions, and analytic solutions. We additionally ensure that the reduced model maintains a prespecified approximation quality not only for a reference individual but also for a diverse virtual population. We illustrate the extended approach for the warfarin effect on blood coagulation. Using the model-reduction approach, we derive a novel small-scale warfarin/international normalized ratio model and demonstrate its suitability for biomarker identification. Due to the systematic nature of the approach in comparison with empirical model building, the proposed model-reduction algorithm provides an improved rationale to build PD models also from QSP models in other applications.