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The control of supramolecular complexes in living systems at the molecular level is an important goal in life-sciences. Spatiotemporal organization of molecular distribution & flow of such complexes are essential physicochemical processes in living cells and important for pharmaceutical processes. Membraneless organelles (MO) found in eukaryotic cells, formed by liquid-liquid phase-separation (LLPS) of intrinsically disordered proteins (IDPs) control and adjust intracellular organization. Artificially designed compartments based on LLPS open up a novel pathway to control chemical flux and partition in vitro and in vivo. We designed a library of chemically precisely defined block copolymer-like proteins based on elastin-like proteins (ELPs) with defined charge distribution and type, as well as polar and hydrophobic block domains. This enables the programmability of physicochemical properties and to control adjustable LLPS in vivo attaining control over intracellular partitioning and flux as role model for in vitro and in vivo applications. Tailor-made ELP-like block copolymer proteins exhibiting IDP-behavior enable LLPS formation in vitro and in vivo allowing the assembly of membrane-based and membraneless superstructures via protein phase-separation in E. coli. Subsequently, we demonstrate the responsiveness of protein phase-separated spaces (PPSSs) to environmental physicochemical triggers and their selective, charge-dependent and switchable interaction with DNA or extrinsic and intrinsic molecules enabling their selective shuttling across semipermeable phase boundaries including (cell)membranes. This paves the road for adjustable artificial PPSS-based storage and reaction spaces and the specific transport across phase boundaries for applications in pharmacy and synthetic biology. • An amphiphilic protein (aELP) library allows for adjustable compartments in vivo. • Extrinsic stimuli modulate protein-phase separated spaces (PPSS) in E. coli. • PPSS formed by charged aELPs direct DNA localization. • Charged aELP forming PPSS can control molecular flux of molecules in vivo. • Responsive PPSS can be used in pharmaceutical applications and synthetic biology. [ABSTRACT FROM AUTHOR]

This paper presents an improved mixed-integer model for the thermal unit commitment problem. By introducing new variables for the temperature of each thermal unit, the off-time-dependent start-up costs are modeled accurately and with a lower integrality gap than state-of-the-art formulations. This new approach significantly improves computational efficiency compared to existing formulations, even if they only model a rough approximation of the start-up costs. Our findings were validated on real-world test cases using CPLEX. [ABSTRACT FROM PUBLISHER]

The world's power systems are facing a structural change including liberalization of markets and integration of renewable energy sources. This paper describes the challenges that lie ahead in this process and points out avenues for overcoming different problems at different scopes, ranging from individual homes to international super-grids. We apply energy system models at those different scopes and find a trade-off between technical and social complexity. Small-scale systems would require technological breakthroughs, especially for storage, but individual agents can and do already start to build and operate such systems. In contrast, large-scale systems could potentially be more efficient from a techno-economic point of view. However, new political frameworks are required that enable long-term cooperation among sovereign entities through mutual trust. Which scope first achieves its breakthrough is not clear yet. [ABSTRACT FROM AUTHOR]

Cytochrome P450 17A1 (CYP17A1) catalyses the formation and metabolism of steroid hormones. They are involved in blood pressure (BP) regulation and in the pathogenesis of left ventricular hypertrophy. Therefore, altered function of CYP17A1 due to genetic variants may influence BP and left ventricular mass. Notably, genome wide association studies supported the role of this enzyme in BP control. Against this background, we investigated associations between single nucleotide polymorphisms (SNPs) in or nearby the CYP17A1 gene with BP and left ventricular mass in patients with arterial hypertension and associated cardiovascular organ damage treated according to guidelines. Patients (n = 1007, mean age 58.0 ± 9.8 years, 83% men) with arterial hypertension and cardiac left ventricular ejection fraction (LVEF) ≥40% were enrolled in the study. Cardiac parameters of left ventricular mass, geometry and function were determined by echocardiography. The cohort comprised patients with coronary heart disease (n = 823; 81.7%) and myocardial infarction (n = 545; 54.1%) with a mean LVEF of 59.9% ± 9.3%. The mean left ventricular mass index (LVMI) was 52.1 ± 21.2 g/m2.7 and 485 (48.2%) patients had left ventricular hypertrophy. There was no significant association of any investigated SNP (rs619824, rs743572, rs1004467, rs11191548, rs17115100) with mean 24 h systolic or diastolic BP. However, carriers of the rs11191548 C allele demonstrated a 7% increase in LVMI (95% CI: 1%-12%, p = 0.017) compared to non-carriers. The CYP17A1 polymorphism rs11191548 demonstrated a significant association with LVMI in patients with arterial hypertension and preserved LVEF. Thus, CYP17A1 may contribute to cardiac hypertrophy in this clinical condition. [ABSTRACT FROM AUTHOR]

The access to defined protein-based material systems is a major challenge in bionanotechnology and regenerative medicine. Exact control over sequence composition and modification is an important requirement for the intentional design of structure and function. Herein structural- and matrix proteins provide a great potential, but their large repetitive sequences pose a major challenge in their assembly. Here we introduce an integrative "one-vector-toolbox-platform" (OVTP) approach which is fast, efficient and reliable. The OVTP allows for the assembly, multimerization, intentional arrangement and direct translation of defined molecular DNA-tecton libraries, in combination with the selective functionalization of the yielded protein-tecton libraries. The diversity of the generated tectons ranges from elastine-, resilin, silk- to epitope sequence elements. OVTP comprises the expandability of modular biohybrid-materials via the assembly of defined multi-block domain genes and genetically encoded unnatural amino acids (UAA) for site-selective chemical modification. Thus, allowing for the modular combination of the protein-tecton library components and their functional expansion with chemical libraries via UAA functional groups with bioorthogonal reactivity. OVTP enables access to multitudes of defined protein-based biohybrid-materials for self-assembled superstructures such as nanoreactors and nanobiomaterials, e.g. for approaches in biotechnology and individualized regenerative medicine. [ABSTRACT FROM AUTHOR]

: Treatment of hypertension in hemodialysis (HD) patients is characterised by lack of evidence for both the blood pressure (BP) target goal and the recommended drug class to use. Telmisartan, an Angiotensin receptor blocker (ARB) that is metabolised in the liver and not excreted via HD extracorporeal circuit might be particularly suitable for HD patients. We designed and conducted a randomised, placebo-controlled, double-blind and cross-over trial for treatment of dialysis–associated hypertension with telmisartan 80 mg once daily or placebo on top of standard antihypertensive treatment excluding other Renin-Angiotensin-System (RAS) blockers. In 29 patients after randomization we analysed BP after a treatment period of 8 weeks, while 13 started with telmisartan and 16 with placebo; after 8 weeks 11 continued with telmisartan and 12 with placebo after cross-over, respectively. Patients exhibited a significant reduction of systolic pre-HD BP from 141.9±21.8 before to 131.3±17.3 mmHg after the first treatment period with telmisartan or placebo. However, no average significant influence of telmisartan was observed compared to placebo. The latter may be due to a large inter-individual variability of BP responses reaching from a 40 mmHg decrease under placebo to 40 mmHg increase under telmisartan. Antihypertensive co-medication was changed for clinical reasons in 7 out of 21 patients with no significant difference between telmisartan and placebo groups. Our starting hypothesis, that telmisartan on top of standard therapy lowers systolic office BP in HD patients could not be confirmed. In conclusion, this small trial indicates that testing antihypertensive drug efficacy in HD patients is challenging due to complicated standardization of concomitant medication and other confounding factors, e.g. volume status, salt load and neurohormonal activation, that influence BP control in HD patients. Trial Registration: Clinicaltrialsregister.eu 2005-005021-60 [ABSTRACT FROM AUTHOR]

Abstract: Nuclear fusion can be considered as a base-load power plant technology: High investment costs and limited operational flexibility require continuous operation. Wind and solar, on the other hand, as the putative main pillars of a future renewable energy system, are intermittent power sources. The resulting variations that occur on many different time scales require at first sight a rather flexible back-up system to balance this stochastic behavior. Fusion would appear not to be well suited for this task. The situation changes, however, if a large-scale renewable energy system is envisaged based on a transnational, or even transcontinental power grid. The present paper discusses a possible European power system in the year 2050 and beyond. A high percentage share of renewable energies and a strong power grid spanning the whole of Europe and involving neighboring countries, in particular those in North Africa, are assumed. The linear programming model URBS is used to describe the power system. The model optimizes the overall system costs and simulates power plant operation with an hourly resolution for one whole year. The geographical resolution is at least at the country level. The renewable technologies are modeled first on a more local level and then summed together at the country or regional level. The results indicate that the smoothing effects of the large-scale power grid transform the intermittent renewable supply, which is then more compatible with base-load power plants such as fusion reactors. [Copyright &y& Elsevier]

Telomere length has emerged as a biological correlate for ageing, which in turn is a risk factor for the manifestation of cardiovascular diseases. This study investigated the relation between leucocyte telomere length (LTL) and its genetic background to cardiac structure and function in patients with arterial hypertension. We analysed a cohort of 1,106 treated hypertensive patients (83.3% males; mean age, 57.9 ± 9.8 years) with an ejection fraction (EF) over 40% and documented cardiovascular disease or target organ damage. LTL and genotypes of single nucleotide polymorphisms (SNPs), previously implicated in LTL, were determined by real-time PCR. The mean left ventricular mass index (LVMI) and EF were 51.8 ± 21.0 g/H and 61.1 ± 9.6%, respectively. In multivariate adjusted analysis, a 1.5-fold LTL was positively related with a 2.2% increase of LVMI (CI = 0.1% to 4.2%, p = 0.044) and an absolute increase in EF of 0.6% (CI = 0.1% to 1.1%, p = 0.028). One SNP near TERC (rs16847897) showed a significant absolute difference in EF dependent on allele status (rs16847897, G allele 2.7%; CI = 0.7% to 4.6%; p = 0.008, p = 0.048, after adjustment for multiple testing). This applied also for two SNPs in BICD1 (rs2630578, C allele −1.8%; CI = −2.8% to −0.7%; p = 0.002, p = 0.018; rs1151026, G allele −1.9%, CI = −3.0% to −0.8%; p < 0.001, p = 0.002) with the extension that a frequent haplotype in BICD1 showed an absolute −1.8% (CI = −3.0% to −0.7%; p = 0.002, p = 0.008) lower EF compared with those lacking this haplotype. Our results point to a role of genetic variants recently implicated in LTL for left ventricular function in hypertensive patients. [ABSTRACT FROM AUTHOR]

Since the beginning of the industrial revolution, atmospheric carbon dioxide (CO 2) concentrations have risen steadily and have induced a decrease of the averaged surface ocean pH by 0.1 units, corresponding to an increase in ocean acidity of about 30 %. In addition to ocean warming, ocean acidification poses a tremendous challenge to some marine organisms, especially calcifiers. The need for long-term oceanic observations of pH and temperature is a key element to assess the vulnerability of marine communities and ecosystems to these pressures. Nearshore productive environments, where a large majority of shellfish farming activities are conducted, are known to present pH levels as well as amplitudes of daily and seasonal variations that are much larger than those observed in the open ocean. Yet, to date, there are very few coastal observation sites where these parameters are measured simultaneously and at high frequency. To bridge this gap, an observation network was initiated in 2021 in the framework of the CocoriCO 2 project. Six sites were selected along the French Atlantic and Mediterranean coastlines based on their importance in terms of shellfish production and the presence of high- and low-frequency monitoring activities. At each site, autonomous pH sensors were deployed, both inside and outside shellfish production areas, next to high-frequency CTD (conductivity–temperature–depth) probes operated through two operating monitoring networks. pH sensors were set to an acquisition rate of 15 min, and discrete seawater samples were collected biweekly in order to control the quality of pH data (laboratory spectrophotometric measurements) as well as to measure total alkalinity and dissolved inorganic carbon concentrations for full characterization of the carbonate system. While this network has been up and running for more than 2 years, the acquired dataset has already revealed important differences in terms of pH variations between monitored sites related to the influence of diverse processes (freshwater inputs, tides, temperature, biological processes). Data are available at 10.17882/96982 (Petton et al., 2023a). [ABSTRACT FROM AUTHOR]

Since the beginning of the industrial revolution, atmospheric carbon dioxide (CO2) concentrations have risen steadily and have induced a decrease of the averaged surface ocean pH by 0.1 units, corresponding to an increase in ocean acidity of about 30 %. In addition to ocean warming, ocean acidification poses a tremendous challenge to some marine organisms, especially calcifiers. The need for long-term oceanic observations of pH and temperature is a key element to assess the vulnerability of marine communities and ecosystems to these pressures. Nearshore productive environments, where a large majority of shellfish farming activities are conducted, are known to present pH levels as well as amplitudes of daily and seasonal variations that are much larger than those observed in the open ocean. Yet, to date, there are very few coastal observation sites where these parameters are measured simultaneously and at high frequency. To bridge this gap, an observation network was initiated in 2021 in the framework of the CocoriCO2 project. Six sites were selected along the French Atlantic and Mediterranean coastlines based on their importance in terms of shellfish production and the presence of high- and low-frequency monitoring activities. At each site, autonomous pH sensors were deployed both inside and outside shellfish production areas, next to high-frequency CTD (conductivity- temperature-depth) probes operated through two operating monitoring networks. pH sensors were set to an acquisition rate of 15 min and discrete seawater samples were collected biweekly in order to control the quality of pH data (laboratory spectrophotometric measurements) as well as to measure total alkalinity and dissolved inorganic carbon concentrations for full characterization of the carbonate system. While this network has been up and running for more than two years, the acquired dataset has already revealed important differences in terms of pH variations between monitored sites related to the influence of diverse processes (freshwater inputs, tides, temperature, biological processes). [ABSTRACT FROM AUTHOR]

Abstract: Immune-mediated heparin-induced thrombocytopenia (HIT) is the clinically most important adverse drug reaction (ADR) in response to heparin therapy characterized by a prothrombotic state despite a decrease in platelet count. We conducted a genome-wide association study in 96 suspected HIT cases and 96 controls to explore the genetic predisposition for HIT within a case-control pharmacovigilance study followed by replication in additional 86 cases and 86 controls from the same study. One single nucleotide polymorphism (SNP, rs1433265, P = 6.5 × 10−5, odds ratio (OR) 2.79) from 16 identified SNPs was successfully replicated (P = 1.5 × 10−4, OR 2.77; combined data set P = 2.7 × 10−8, OR 2.77) and remained the most strongly associated SNP after imputing locus genotypes. Fine mapping revealed a significantly associated risk-conferring haplotype (P = 4.9 × 10−6, OR 2.41). In order to find rare variants contributing to the association signals, we applied a targeted resequencing approach in a subgroup of 73 HIT patients and 23 controls for the regions with the 16 most strongly HIT-associated SNPs. C-alpha testing was applied to test for the impact of rare variants and we detected two candidate genes, the discoidin domain receptor tyrosine kinase 1 (DDR1, P = 3.6 × 10−2) and the multiple C2 and transmembrane domain containing 2 (MCTP2, P = 4.5 × 10−2). For the genes interactor of little elongation complex ELL subunit 1 (ICE1) and a disintegrin-like and metalloproteinase with thrombospondin type 1 motif, 16 (ADAMTS16) nearby rs1433265, we identified several missense variants. Although replication in an independent population is warranted, these findings provide a basis for future studies aiming to identify and characterize genetic susceptibility factors for HIT.Key messages: We identified and validated a HIT-associated locus on chromosome 5.Targeted NGS analysis for rare variants identifies DDR1 and MCTP2 as novel candidates.In addition, missense variants for ADAMTS16 and ICE1 were identified in the locus. [ABSTRACT FROM AUTHOR]

Inflammasomes are multiprotein complexes that control the innate immune response by activating caspase-1, thus promoting the secretion of cytokines in response to invading pathogens and endogenous triggers. Assembly of inflammasomes is induced by activation of a receptor protein. Many inflammasome receptors require the adapter protein ASC [apoptosis-associated speck-like protein containing a caspase-recruitment domain (CARD)], which consists of two domains, the N-terminal pyrin domain (PYD) and the C-terminal CARD. Upon activation, ASC forms large oligomeric filaments, which facilitate procaspase-1 recruitment. Here, we characterize the structure and filament formation of mouse ASC in vitro at atomic resolution. Information from cryo-electron microscopy and solid-state NMR spectroscopy is combined in a single structure calculation to obtain the atomic-resolution structure of the ASC filament. Perturbations of NMR resonances upon filament formation monitor the specific binding interfaces of ASC-PYD association. Importantly, NMR experiments show the rigidity of the PYD forming the core of the filament as well as the high mobility of the CARD relative to this core. The findings are validated by structure-based mutagenesis experiments in cultured macrophages. The 3D structure of the mouse ASC-PYD filament is highly similar to the recently determined human ASC-PYD filament, suggesting evolutionary conservation of ASC-dependent inflammasome mechanisms. [ABSTRACT FROM AUTHOR]

A major quantitative trait locus (QTL) on rat chromosome (RNO)6 was linked to albuminuria in Munich Wistar Frömter rats (MWF). We tested whether transfer of MWF RNO6 into the background of albuminuria-resistant spontaneously hypertensive rats (SHR) induces albuminuria in consomic SHR-6MWF animals. Male MWF, SHR, and SHR-6MWF were sham operated and treated between 6 and 24 wk of age with normal water (Sham) or with water containing 20 mg/l NG-nitro-L-arginine methyl ester (L-NAME) or unilaterally nephrectomized (Nx). Compared with SHR albuminuria was not increased in SHR-6MWF in both Sham and Nx groups. All animals survived the observation period in Sham and Nx groups, while premature mortality occurred from 12-14 wk on in L-NAME-treated SHR and SHR-6MWF compared with MWF L-NAME animals, in which survival was not affected (P < 0.005, respectively). Subsequent further analysis of L-NAME-treated animals at 12 wk of age showed significantly increased arterial blood pressures in both SHR and SHR-6MWF compared with control (P < 0.05), with higher levels in SHR compared with consomics (P < 0.05). However, L-NAME-treated consomic animals demonstrated increased albuminuria compared with SHR (12.7 ± 3.5 vs. 0.8 ± 0.2 mg/24 h; P < 0.05) and an induction of tubulointerstitial structural injury and expression of neutrophil gelatinase- associated lipocalin mRNA (P < 0.05 vs. other strains). Our study demonstrates that isolation of the RNO6 albuminuria QTL from the MWF background and transfer into SHR fails to induce an albuminuria phenotype during normal conditions or after nephron reduction. Moreover, our data indicate that genes on RNO6 contribute to the development of L-NAME-induced renal damage in the SHR strain. [ABSTRACT FROM AUTHOR]

Background: Large-scale mutagenesis screens in the zebrafish employing the mutagen ENU have isolated several hundred mutant loci that represent putative developmental control genes. In order to realize the potential of such screens, systematic genetic mapping of the mutations is necessary. Here we report on a large-scale effort to map the mutations generated in mutagenesis screening at the Max Planck Institute for Developmental Biology by genome scanning with microsatellite markers. Results: We have selected a set of microsatellite markers and developed methods and scoring criteria suitable for efficient, high-throughput genome scanning. We have used these methods to successfully obtain a rough map position for 319 mutant loci from the Tübingen I mutagenesis screen and subsequent screening of the mutant collection. For 277 of these the corresponding gene is not yet identified. Mapping was successful for 80 % of the tested loci. By comparing 21 mutation and gene positions of cloned mutations we have validated the correctness of our linkage group assignments and estimated the standard error of our map positions to be approximately 6 cM. Conclusion: By obtaining rough map positions for over 300 zebrafish loci with developmental phenotypes, we have generated a dataset that will be useful not only for cloning of the affected genes, but also to suggest allelism of mutations with similar phenotypes that will be identified in future screens. Furthermore this work validates the usefulness of our methodology for rapid, systematic and inexpensive microsatellite mapping of zebrafish mutations. [ABSTRACT FROM AUTHOR]

Recent experimental work indicates that the hyperglycemia-induced increase in mesangial matrix production, which is a hallmark in the development of diabetic nephropathy, is mediated by increased expression of GLUT1. Mesangial cells stably transfected with human GLUT1 mimic the effect of hyperglycemia on the production of the extracellular matrix proteins, particularly fibronectin, when cultured under normoglycemic conditions. Our investigation of the molecular mechanism of this effect has revealed that the enhanced fibronectin production was not mediated by the prosclerotic cytokine transforming growth factor (TGF)-beta1. We found markedly increased nuclear content in Jun proteins, leading to enhanced DNA-binding activity of activating protein 1 (AP-1). AP-1 inhibition reduced fibronectin production in a dosage-dependent manner. Moreover, inhibition of classic protein kinase C (PKC) isoforms prevented both the activation of AP-1 and the enhanced fibronectin production. In contrast to mesangial cells exposed to high glucose, no activation of the hexosamine biosynthetic, p38, or extracellular signal-related kinase 1 and 2 mitogen-activated protein kinase pathways nor any increase in TGF-beta1 synthesis could be detected, which could be explained by the absence of oxidative stress in cells transfected with the human GLUT1 gene. Our data indicate that increased glucose uptake and metabolism induce PKC-dependent AP-1 activation that is sufficient for enhanced fibronectin production, but not for increased TGF-beta1 expression. [ABSTRACT FROM AUTHOR]

Recent experimental work indicates that the hyperglycemia-induced increase in mesangial matrix production, which is a hallmark in the development of diabetic nephropathy, is mediated by increased expression of GLUTI. Mesangial cells stably transfected with human GLUT1 mimic the effect of hyperglycemia on the production of the extracellular matrix proteins, particularly fibronectin, when cultured under normoglycemic conditions. Our investigation of the molecular mechanism of this effect has revealed that the enhanced fibronectin production was not mediated by the prosclerotic cytokine transforming growth factor (TGF)-β1. We found markedly increased nuclear content in Jun proteins, leading to enhanced DNA-binding activity of activating protein 1 (AP-1). AP-1 inhibition reduced fibronectin production in a dosage-dependent manner. Moreover, inhibition of classic protein kinase C (PKC) isoforms prevented both the activation of AP-1 and the enhanced fibronectin production. In contrast to mesangial cells exposed to high glucose, no activation of the hexosamine biosynthetic, p38, or extracellular signal-related kinase 1 and 2 mitogen-activated protein kinase pathways nor any increase in TGF-β1 synthesis could be detected, which could be explained by the absence of oxidative stress in cells transfected with the human GLUT1 gene. Our data indicate that increased glucose uptake and metabolism induce PKC-dependent AP-1 activation that is sufficient for enhanced fibronectin production, but not for increased TGF-β1 expression. [ABSTRACT FROM AUTHOR]

• Archetypes to summarize countries globally regarding their energy system. • Framework to define, model and validate these archetypes. • Archetype classification 44% better than simple geographic grouping. • Photovoltaics and flexibility are identified and quantified as global challenges by the archetype modeling. • Country modeling validates archetype approach with few outliers. Energy system models help to find the optimal technology mixes for decarbonization strategies in countries worldwide. To reduce the modeling effort and analyze as many countries as possible, this paper proposes a novel approach of energy system archetypes which can be directly evaluated. These archetypes classify similar countries worldwide independently from their geographic location. Advantages of this idea are the setup of a transferable global database allowing for data reconstruction between countries, market size estimations, and the ability to compare peer countries facing similar challenges. To enable such modeling, a framework is developed in which the archetypes are defined, standardized modeling rules are developed, and the results are evaluated for validation. In a benchmark against simple geographic classifications, the presented clustering approach, which results in 15 archetypes, improves the variance between all countries and their corresponding archetypes by 44% compared to the variance between the countries and their geographic sub-regions. The model results of these archetypes state the need of balancing technologies for the daily cycle of photovoltaic generation and the general importance of flexibility in future decarbonized energy systems. Overall, the results confirm that archetypes are an adequate approach to derive the set of solutions for the decarbonization of worldwide countries. [ABSTRACT FROM AUTHOR]

Pathways leading to a carbon neutral future for the German energy system have to deal with the expected phase-out of coal-fired power generation, in addition to the shutdown of nuclear power plants and the rapid ramp-up of photovoltaics and wind power generation. An analysis of the expected impact on electricity market, security of supply, and system stability must consider the European context because of the strong coupling—both from an economic and a system operation point of view—through the cross-border power exchange of Germany with its neighbors. This analysis, complemented by options to improve the existing development plans, is the purpose of this paper. We propose a multilevel energy system modeling, including electricity market, network congestion management, and system stability, to identify challenges for the years 2023 and 2035. Out of the results, we would like to highlight the positive role of innovative combined heat and power (CHP) solutions securing power and heat supply, the importance of a network congestion management utilizing flexibility from sector coupling, and the essential network extension plans. Network congestion and reduced security margins will become the new normal. We conclude that future energy systems require expanded flexibilities in combination with forward planning of operation. [ABSTRACT FROM AUTHOR]

The decarbonization of energy systems has led to a fundamental change in their topology since generation is shifted to locations with favorable renewable conditions. In planning, this change is reflected by applying optimization models to regions within a country to optimize the distribution of generation units and to evaluate the resulting impact on the grid topology. This paper proposes a globally applicable framework to find a suitable regionalization for energy system models with a data-driven approach. Based on a global, spatially resolved database of demand, generation, and renewable profiles, hierarchical clustering with fine-tuning is performed. This regionalization approach is applied by modeling the resulting regions in an optimization model including a synthesized grid. In an exemplary case study, South Africa's energy system is examined. The results show that the data-driven regionalization is beneficial compared to the common approach of using political regions. Furthermore, the results of a modeled 80% decarbonization until 2045 demonstrate that the integration of renewable energy sources fundamentally changes the role of regions within South Africa's energy system. Thereby, the electricity exchange between regions is also impacted, leading to a different grid topology. Using clustered regions improves the understanding and analysis of regional transformations in the decarbonization process. [ABSTRACT FROM AUTHOR]