Convergence of the Euler-Voigt equations to the Euler equations in two dimensions

In this paper, we consider the two-dimensional torus and we study the convergence of solutions of the Euler-Voigt equations to solutions of the Euler equations, under several regularity settings. More precisely, we first prove that for weak solutions of the Euler equations with vorticity in $C([0,T];L^2(\mathbb{T}^2))$ the approximating velocity converges strongly in $C([0,T];H^1(\mathbb{T}^2))$. Moreover, for the unique Yudovich solution of the $2D$ Euler equations we provide a rate of convergence for the velocity in $C([0,T];L^2(\mathbb{T}^2))$. Finally, for classical solutions in higher-order Sobolev spaces we prove the convergence with explicit rates of both the approximating velocity and the approximating vorticity in $C([0,T];L^2(\mathbb{T}^2))$

Early nuclear power plant retirement and policy choices in the New York electricity market

The U.S. nuclear industry has overcome a challenging period during which low wholesale market prices threatened the survival of nuclear power plants (NPPs). From 2017 to 2019, several U.S. states initiated out-of-market support schemes to bolster the financial conditions of NPPs. This paper provides a comparative cost assessment between the preservation of three upstate New York NPPs under the zero-emission credit (ZEC) support scheme or an early retirement. In addition, the paper explores future market development scenarios with a carbon price mechanism. A bespoke cost-minimization dispatch model is developed for the New York electricity market along with four neighboring electricity markets. The comparative cost assessment of a nuclear phaseout and ZEC expenditures is not definitive. Results indicate that phasing out upstate NPPs in 2018 and 2021 incurred a slightly higher cost burden for New York consumers compared to the total ZEC expenditures. In contrast, phasing out upstate NPPs in 2030 incurs a lower cost burden compared to the total ZEC expenditure, mainly due to a high credit price. Furthermore, results show that a low carbon price of USD 51/ton would raise average NYISO prices by USD 24.1/MWh, thereby improving the long-term income conditions of NPPs, and ensuring sufficient accumulation of nuclear decommissioning funds. The study provides policymakers with a sequence of optimal policy options taking into account the pace of renewable development

Dialektik und Kritik: zur systematischen Bedeutung der Kantinterpretation von Theodor W. Adorno

Philosophie im Sinne Adornos bedeutet, die Traditionslinien der Dialektik und der Kritik miteinander engzuführen. Diese Engführung erfolgte bislang vor allem gemäß der Vorgabe Hegels – mit dem Resultat, dass das Profil einer dezidiert negativen Dialektik durch Identitätsdenken überformt und in der Forschung als mangelhafte Kopie der positiv-spekulativen Dialektik gehandelt wurde. Dagegen schlägt diese Arbeit vor, dieses Profil von Kant her zu sichten: Indem die Grundzüge von Adornos Kantinterpretation erhellt werden, soll deren systematische Bedeutung für das adornosche "Antisystem" zur Geltung gelangen. Negative Dialektik, so die These, ist nur als grenzbegriffliche Reflexion auf den Erkenntnisanspruch der traditionellen Dialektik möglich

Biosynthesis of the bacterial antibiotic 3,7-dihydroxytropolone and its potential role for iron-acquisition

Natural products serve as promising drug leads due to their manifold and potent bioactivities. Tropone natural products with their unusual seven-membered aromatic ring exhibit antibacterial, antiviral and anticancer activities and therefore mark a promising group of compounds for further investigation. In the past, their biosynthesis in bacteria has been linked to phenylacetic acid degradation, where a shunt product was identified as putative universal precursor for tropone natural products such as 3,7-dihydroxytropolone (3,7-DHT). Since then, considerable efforts have been made to elucidate the downstream processing of this precursor, and although the involvement of a few individual enzymes has been demonstrated, a complete biosynthetic pathway for such a tropone natural product had so far not been elucidated. In this work, the biosynthetic pathway for 3,7-DHT of the Gram-positive Actinobacterium Streptomyces cyaneofuscatus Soc7 could be reconstituted in vitro for the first time. Furthermore, in a collaborative effort, some insights into the biosynthesis of 3,7-DHT in Gram-negative Pseudomonas sp. Ps652 could also be obtained, which surprisingly proceeds via a different enzymatic route. Additionally, a siderophore-interacting protein (SIP), that likely facilitates iron-acquisition using tropone natural products and/or grants self-resistance against these compounds could be identified and characterized. Structural and biochemical properties of all enzymes were investigated using a combination of methods including high-performance liquid chromatography (HPLC), mass spectrometry (MS), nuclear magnetic resonance (NMR) spectroscopy and protein X-ray crystallography, leading to the main findings that are summarized below: - Enzymes encoded by genes from the trl gene cluster of Gram-positive Streptomyces cyaneofuscatus Soc 7 including the putative enoyl-CoA hydratase TrlA, thioesterase TrlF, NADH- and FAD-dependent two-component flavoprotein monooxygenase (FPMO) TrlCD and NADPH- and FAD-dependent FPMO TrlE were heterologously produced in Escherichia coli BL21 pL1SL2 and subsequently purified via affinity chromatography. A protein crystal structure of TrlE could be obtained, which allowed further structural characterization. (Part I) - HPLC and MS-measurements as well as NMR spectroscopy allowed the identification of reaction intermediates and products from in vitro assays with these enzymes. This enabled the full reconstitution of the 3,7-DHT biosynthetic pathway. Accordingly, TrlF cleaves the CoA-ester bond of the tropone natural product precursor from PAA catabolism. TrlE performs an ipso-substitution of a carboxylic acid group with a hydroxyl group (decarboxylation coupled to hydroxylation) and further catalyzes a ring-oxidation to yield tropolone. TrlCD then performs two subsequent ring-hydroxylations of tropolone to afford 7-hydroxytropolone (7-HT) and finally 3,7-DHT. Only TrlA showed no enzymatic activity in vitro under the tested conditions and was therefore substituted by a previously characterized enoyl-CoA hydratase (PaaZ-E256Q variant) from PAA catabolism. (Part I) - In a collaboration with the group of Prof. Dr. Truman from the John Innes Center in Norwich, UK, the biosynthesis of tropone natural products in Gram-negative Pseudomonas sp. Ps652 was investigated. The results revealed that Pseudomonas sp. Ps652 is able to produce 3,7-DHT and that enzymes encoded in the tpo gene cluster play crucial roles in the biosynthesis. My contribution to this study, assisted by a master student, included the heterologous expression of the FPMO TpoE and the thiosterase TpoD from Pseudomonas sp. Ps652 in Escherichia coli BL21 and the subsequent purification via affinity chromatography. Furthermore, I conducted HPLC- and MS-measurements of the in vitro assays, which revealed that these enzymes work together to convert the tropone precursor from PAA catabolism to a likely on-pathway intermediate for 3,7-DHT biosynthesis. (Part II) - During the investigation of the genomic environment of the trl gene cluster in Actinobacteria, a co-located gene encoding a predicted SIP could be identified in multiple bacteria. The SIP from the Gram-positive Actinobacterium Amycolatopsis regifaucium was heterologously produced in Escherichia coli BL21 pL2SL2 and subsequently purified via affinity chromatography. Thermal shift measurements as well as photometric assays revealed that this enzyme is able to reduce (di)hydroxytropolone- Fe3+ complexes and thereby provide Fe2+ for the cell. Moreover, a protein crystal structure of this SIP could be obtained and allowed further structural investigation. The combined findings from the enzymatic assays and the protein structure suggests that the current categorization of SIPs should be revisited, as the investigated enzyme showed unusual properties regarding cofactor specificity and structural composition, which do not fit the in the current categorization system similar to other recently reported SIPs. (Part III) In summary this thesis provides insights into the biosynthesis of tropone natural products, especially 3,7-DHT, for both Gram-negative and Gram-positive bacteria. In particular, the biosynthesis in Gram-positive bacteria could be elucidated by reconstituting the complete pathway in vitro starting from phenylacetyl-CoA. Furthermore, the identification and characterization of a SIP associated with tropone natural product biosynthesis will facilitate future studies on the ecological role of 3,7-DHT and related compounds in iron-acquisition and possibly self-resistance

Understanding configurational entropy and polymorphism: a computational study of lithium alanate and molecular crystals

This thesis investigates complex energy landscapes and phase transitions of two different classes of materials; alanates and molecular crystals. With the use of the Minima Hopping structure search method, the effects of a structurally tolerant phase are studied in the case of lithium alanate and the molecular crystal consisting of N-(4'Methylbenzylidene)-4-methylalanine. A structurally tolerant phase allows for many variations of its basic structural motif that change the energy only marginally. Firstly, a new implementation of Minima Hopping method is discussed. The Minima Hopping method combines short molecular dynamics trajectories with local geometry optimizations to efficiently explore the potential energy surface and locate the global minimum. With the new implementation in the Python language, different existing and new features have been brought together into one software package. Furthermore, the code is interfaced to the atomic simulation environment which offers a broad variety of energy and force evaluation routines. The method's effectiveness is demonstrated through its application to broad range of materials, highlighting its capability to overcome the challenges posed by the vast and high-dimensional search spaces typical of potential energy surfaces. Combined with a machine learned potential, the Minima Hopping method is applied to lithium alanate, a promising candidate for hydrogen storage applications, to explore the configurational density of states. Lithium alanate exhibits an ionic phase which, unlike its polymeric counterpart, demonstrates high structural tolerance. The configurational density of states derived from Minima Hopping runs reveals that the ionic phase is stabilized through configurational entropy. A detailed analysis shows that despite the polymeric form being lower in energy, the ionic form remains prevalent due to its higher configurational entropy, explaining the absence of the polymeric phase in experiments. Finally, the polymorphism in molecular crystals is studied, with a particular focus on N-(4'-Methylbenzylidene)-4-methylalanine. The configurational density of states, derived from Minima Hopping runs, indicates that Form II is the most structurally tolerant despite being higher in energy compared to Form III, the form lowest in energy. The phenomenon of disappearing polymorphism, where a stable polymorph transforms into another, rendering the original form challenging to reproduce, is explored for the case of Form I of N-(4'-Methylbenzylidene)-4-methylalanine. Such transformations had significant implications in pharmaceutical applications, where the stability of the polymorphic form directly impacts drug efficacy. The Boltzmann probabilities of different polymorphic forms are calculated to understand their thermodynamic stability, revealing that structural tolerance plays a critical role in the persistence of certain phases

Gremlin1 controls digit numbers and identities by spatial regulation of two early limb bud mesenchymal progenitor populations

The developing vertebrate limb bud is an excellent model to study the mechanisms that provide the vertebrate embryo with robustness during pattern formation and organogenesis. We have previously shown that the core of this signaling system consists of SHH/GREM1/AER-FGF feedback signaling. The BMP antagonist GREM1 is a key node for the control of patterning, proliferation, and survival of limb mesenchymal progenitors (LMPs). Inactivation of Grem1 in mice limb bud results in skeletal defects, including a severe reduction in digit numbers. Whole limb RNA-sequencing (RNA-seq) for several distinct mutations in Grem1-enhancers that reduce Grem1 expression revealed that genotypes with a visible digit phenotype, have many differentially expressed genes in key developmental pathways while mutants with no apparent phenotype are able to compensate the Grem1 deficiency. Amongst the mutants with a phenotype, specific deletion of multiple enhancers has shown to alter the spatial expression of Grem1 in such a way that it causes the loss of one digit, resulting in stable tetradactyly. With the use of specific recombinant Cre alleles and lineage tracing, we determined that the missing digit is d2. In order to understand the digit loss on a molecular and cellular level, single cell RNA-seq analysis of wildtype and two distinct tetradactyl mutants (E1C5Δ/Δ, E1C8Δ/Δ) was performed at E10.75 (37 – 39 somites), which revealed molecular signatures of two LMP populations. In the mutants, both populations exhibit altered cell numbers and levels of expression, compared to the wildtype. RNA-Fluorescence in situ hybridization (RNA-FISH) analysis of key signature markers for these progenitor populations confirmed a reduction of the most distal population (dLMP) at the expense of an expansion of the peripheral one (pLMP). This result points to a problem in specification of the cells that will give rise to the handplate, including the digits. The reduction in dLMPs detected at E10.75 persists during progression of limb bud outgrowth and onset of handplate development (E10.75-E11.25, 37-43 somites) showing that mutants fail to catch up to wildtypes and eventually end up with one digit less. To gain insight into how these populations behave in the context of digit loss/gain, mutants that are models for human malformations were analyzed, namely Tbx3Δ/Δ, ShhΔ/Δ and Gli3Δ/Δ. Genetic inactivation of Shh disrupts Grem1 expression and results in digit agenesis such that only a rudimentary condensation forms. In contrast to wildtype forelimb buds, the pLMP signature genes are expressed uniformly in the peripheral mesenchyme of ShhΔ/Δ forelimb buds at E10.75, whereas expression of dLMP marker genes is not detected. By E10.75, Grem1 expression is expanded anteriorly in Gli3Δ/Δ forelimb buds. Concurrent with this anterior expansion, the anterior bias in pLMPs is lost, while markers of dLMPs are also anteriorly expanded. This analysis of Gli3Δ/Δ limb buds shows that this early peripheral distal-anterior expansion of dLMP signature foreshadows anterior digit duplications, while loss of the anterior bias in pLMP signatures correlates with the loss of anterior digit identities and asymmetry. Furthermore, single cell analysis and RNA-FISH were done on mutant forelimb buds without Grem1 expression (Grem NULL) in comparison to wildtype. dLMPs were severely reduced with some of their makers depleted while pLMPs were increased and had a symmetric expression, corroborating the conclusions of previous analysis. Tetradactyl mice exhibit a paraxonic skeletal phenotype, resembling that of pigs at corresponding developmental stages. We further investigated gene expression patterns by analyzing mRNA levels of key progenitor population markers. This analysis revealed similarities in the expression of pLMPs but also identified an expanded dLMP domain. Taken together, our findings provide new insights into the molecular mechanisms of digit specification and show how the balance of two distinct progenitor populations can shift the limb axis asymmetry and influence digit numbers and identities

Volume rendering for surgical planning in virtual reality

The number of high-complexity surgeries has been steadily increasing over the last decades. One reason for this is the demographic trend of an aging population observed in many countries, which results in an increasing number of patients requiring complex interventions. Another important factor is the development and continued improvement of advanced surgical techniques and devices, such as minimally invasive surgeries, which enable surgeons to treat more challenging cases successfully. While these techniques can improve the surgical outcome, they are also considerably more difficult and require careful planning and training. Surgical planning of complex cases is typically done using volumetric medical images, such as computed tomography (CT) scans or magnetic resonance imaging (MRI) data sets. These modalities capture the imaging subject in three dimensions, allowing a more detailed analysis of the patient's anatomy compared to the planar projection created by an X-ray device. Despite the three-dimensiona

Exploring the landscape of mTOR substrates: identification of two novel targets

TOR (Target of Rapamycin), is a highly conserved serine/threonine protein kinase that plays a central role in regulating cell growth and metabolism. It is activated by nutrients, growth factors, and cellular energy. TOR forms two structurally and functionally distinct complexes, TORC1 and TORC2. TOR signaling activates cell growth, defined as an increase in biomass, by stimulating anabolic metabolism while inhibiting catabolic processes. With emphasis on mammalian TOR (mTOR), we comprehensively reviewed the literature and identified all reported direct substrates. In the context of recent structural information, we discuss how mTORC1 and mTORC2, despite having a common catalytic subunit, phosphorylate distinct substrates. Based on this analysis we conclude that mTORC1 and mTORC2 phosphorylate a common, minimal motif but rely mostly on distinct binding sequences for substrate recognition. mTORC1, for instance, recognizes some of its substrates via a five amino acid target sequence called TOR signaling (TOS) motif. mTORC1 binding to a TOS peptide facilitates phosphorylation of the target site differently located than the binding site. Furthermore, by exploiting the aforementioned information, we identified two previously uncharacterized mTOR substrates: LST2 and RTN4. Here we show that LST2, also known as ZFYVE28, contains a TOS motif and is phosphorylated by mTORC1 at serine 670 (S670). Phosphorylation on LST2 S670 by mTORC1 primes monoubiquitination on lysine 87 (K87). Monoubiquitinated and phosphorylated LST2 is stable and display a broad reticular distribution. When mTORC1 is inactive, unphosphorylated LST2 localizes to the endosome and is degraded by the proteasome. Cells deficient in LST2 have higher levels of the epidermal growth factor receptor (EGFR). We therefore propose a mechanism in which mTORC1, via LST2, negatively feeds back on its upstream receptor EGFR in order to maintain signaling homeostasis. In the second part of this thesis, we searched previously reported phosphorproteomics datasets for the identification of novel mTOR substrates. We found that the ER residential protein reticulon 4 (RTN4) is phosphorylated by mTOR on S15, S107 and S181. Although still preliminary, our data suggest that mTOR-dependent phosphorylation of RTN4 regulates calcium and lipid homeostasis through its interaction with specific partners. RTN4 appears to also regulate the ER-mitochondria associated membranes (MAM) structure. In addition, both RTN4 mRNA and protein levels are increased in a mTOR-driven hepatocellular cancer (HCC) mouse model. Our data suggest that mTOR could regulate ER and mitochondria metabolism through phosphorylation of RTN4. Collectively, this thesis offers a complete list of all reported mTOR substrates and provides insights into the discovery and characterization of two new mTOR substrates, LST2 and RTN4

Bayesian spatial-temporal modelling to assess the impact of climate variability and control interventions on the burden of malaria in Kenya

Malaria, one of the oldest and most persistent infectious diseases, continues to pose a significant public health challenge, particularly in sub-Saharan Africa (SSA), where it disproportionately affects children under 5 years of age. The risk of malaria in Kenya is heterogeneous; with western Kenya experiencing a high burden. Contributing factors include a favourable climate for mosquitoes, weak health systems, and socioeconomic challenges. This research aimed to evaluate the influence of climatic, environmental, and non-climatic factors, alongside control interventions, on malaria incidence and mortality in Kenya. Using data from Kisumu's Health and Demographic Surveillance System (HDSS) (2008–2022) and Kenya Malaria Indicator Surveys (2015 and 2020), the study employed advanced statistical and geostatistical models. It analysed trends in malaria incidence, parasitemia prevalence, and mortality, considering factors such as temperature, rainfall, bed net use, socioeconomic status, and proximity to health facilities. Additionally, the study applied empirical dynamic modelling to establish causal links and forecast malaria transmission. The findings enhance our understanding of malaria epidemiology and highlight the significant and varied effects of climatic factors on malaria transmission. Results underscore the protective role of bed nets, the influence of socioeconomic disparities, and the spatial and temporal heterogeneity of malaria risk. The work provides critical tools for mapping and targeting malaria control efforts, with implications for the National Malaria Control Program (NMCP). Additionally, the forecasting model offers actionable insights for localized, short- and long-term malaria prediction, supporting more effective resource allocation and intervention strategies

Endovascular Treatment for Stroke Due to Occlusion of Medium or Distal Vessels

BACKGROUND Endovascular treatment (EVT) of stroke with large-vessel occlusion is known to be safe and effective. The effect of EVT for occlusion of medium or distal vessels is unclear. METHODS We randomly assigned participants with an isolated occlusion of medium or distal vessels (occlusion of the nondominant or codominant M2 segment of the middle cerebral artery [MCA]; the M3 or M4 segment of the MCA; the A1, A2, or A3 segment of the anterior cerebral artery; or the P1, P2, or P3 segment of the posterior cerebral artery) to receive EVT plus best medical treatment or best medical treatment alone within 24 hours after the participant was last seen to be well. The primary outcome was the level of disability at 90 days, as assessed with the modified Rankin scale score. RESULTS A total of 543 participants (women, 44%; median age, 77 years) were included in the analysis: 271 were assigned to receive EVT plus best medical treatment and 272 to receive best medical treatment alone. The median score on the National Institutes of Health Stroke Scale (range, 0 to 42, with higher scores indicating more severe symptoms) at admission was 6 (interquartile range, 5 to 9). Intravenous thrombolysis was given to 65.4% of the participants. The predominant occlusion locations were the M2 segment (in 44.0% of the participants), M3 segment (in 26.9%), P2 segment (in 13.4%), and P1 segment (in 5.5%). In the comparison between EVT plus best medical treatment and best medical treatment alone, no significant difference in the distribution of modified Rankin scale scores was observed at 90 days (common odds ratio for improvement in the score, 0.90; 95% confidence interval, 0.67 to 1.22; P=0.50). All-cause mortality was similar in the two groups (15.5% with EVT plus best medical treatment and 14.0% with best medical treatment alone), as was the incidence of symptomatic intracranial hemorrhage (5.9% and 2.6%, respectively). CONCLUSIONS In persons with stroke with occlusion of medium or distal vessels, EVT did not result in a lower level of disability or a lower incidence of death than best medical treatment alone. (Funded by the Swiss National Science Foundation and others; DISTAL ClinicalTrials.gov number, NCT05029414.