Vimentin promotes collective cell migration through collagen networks via increased matrix remodeling and spheroid fluidity.

The intermediate filament (IF) protein vimentin is associated with many diseases with phenotypes of enhanced cellular migration and aggressive invasion through the extracellular matrix (ECM) of tissues, but vimentin's role in in-vivo cell migration is still largely unclear. Vimentin is important for proper cellular adhesion and force generation, which are critical to cell migration; yet the vimentin cytoskeleton also hinders the ability of cells to squeeze through small pores in ECM, resisting migration. To identify the role of vimentin in collective cell migration, we generate spheroids of wide-type and vimentin-null mouse embryonic fibroblasts (mEFs) and embed them in a 3D collagen matrix. We find that loss of vimentin significantly impairs the ability of the spheroid to collectively expand through collagen networks and remodel the collagen network. Traction force analysis reveals that vimentin null spheroids exert less contractile force than their wild-type counterparts. In addition, spheroids made of mEFs with only vimentin unit length filaments (ULFs) exhibit similar behavior as vimentin-null spheroids, suggesting filamentous vimentin is required to promote 3D collective cell migration. We find the vimentin-mediated collective cell expansion is dependent on matrix metalloproteinase (MMP) degradation of the collagen matrix. Further, 3D vertex model simulation of spheroid and embedded ECM indicates that wild-type spheroids behave more fluid-like, enabling more active pulling and reconstructing the surrounding collagen network. Altogether, these results signify that VIF plays a critical role in enhancing migratory persistence in 3D matrix environments through MMP transportation and tissue fluidity.

Enhanced extracellular matrix remodeling due to embedded spheroid fluidization.

Tumor spheroids are in vitro three-dimensional, cellular collectives consisting of cancerous cells. Embedding these spheroids in an in vitro fibrous environment, such as a collagen network, to mimic the extracellular matrix (ECM) provides an essential platform to quantitatively investigate the biophysical mechanisms leading to tumor invasion of the ECM. To understand the mechanical interplay between tumor spheroids and the ECM, we computationally construct and study a three-dimensional vertex model for a tumor spheroid that is mechanically coupled to a cross-linked network of fibers. In such a vertex model, cells are represented as deformable polyhedrons that share faces. Some fraction of the boundary faces of the tumor spheroid contain linker springs connecting the center of the boundary face to the nearest node in the fiber network. As these linker springs actively contract, the fiber network remodels. By toggling between fluid-like and solid-like spheroids via changing the dimensionless cell shape index, we find that the spheroid rheology affects the remodeling of the fiber network. More precisely, fluid-like spheroids displace the fiber network more on average near the vicinity of the spheroid than solid-like spheroids. We also find more densification of the fiber network near the spheroid for the fluid-like spheroids. These spheroid rheology-dependent effects are the result of cellular motility due to active cellular rearrangements that emerge over time in the fluid-like spheroids to generate spheroid shape fluctuations. Our results uncover intricate morphological-mechanical interplay between an embedded spheroid and its surrounding fiber network with both spheroid contractile strength and spheroid shape fluctuations playing important roles in the pre-invasion stages of tumor invasion.

Frequency Propagation: Multimechanism Learning in Nonlinear Physical Networks.

We introduce frequency propagation, a learning algorithm for nonlinear physical networks. In a resistive electrical circuit with variable resistors, an activation current is applied at a set of input nodes at one frequency and an error current is applied at a set of output nodes at another frequency. The voltage response of the circuit to these boundary currents is the superposition of an activation signal and an error signal whose coefficients can be read in different frequencies of the frequency domain. Each conductance is updated proportionally to the product of the two coefficients. The learning rule is local and proved to perform gradient descent on a loss function. We argue that frequency propagation is an instance of a multimechanism learning strategy for physical networks, be it resistive, elastic, or flow networks. Multimechanism learning strategies incorporate at least two physical quantities, potentially governed by independent physical mechanisms, to act as activation and error signals in the training process. Locally available information about these two signals is then used to update the trainable parameters to perform gradient descent. We demonstrate how earlier work implementing learning via chemical signaling in flow networks (Anisetti, Scellier, et al., 2023) also falls under the rubric of multimechanism learning.

Cocaine diminishes functional network robustness and destabilizes the energy landscape of neuronal activity in the medial prefrontal cortex.

We present analysis of neuronal activity recordings from a subset of neurons in the medial prefrontal cortex of rats before and after the administration of cocaine. Using an underlying modern Hopfield model as a description for the neuronal network, combined with a machine learning approach, we compute the underlying functional connectivity of the neuronal network. We find that the functional connectivity changes after the administration of cocaine with both functional-excitatory and functional-inhibitory neurons being affected. Using conventional network analysis, we find that the diameter of the graph, or the shortest length between the two most distant nodes, increases with cocaine, suggesting that the neuronal network is less robust. We also find that the betweenness centrality scores for several of the functional-excitatory and functional-inhibitory neurons decrease significantly, while other scores remain essentially unchanged, to also suggest that the neuronal network is less robust. Finally, we study the distribution of neuronal activity and relate it to energy to find that cocaine drives the neuronal network towards destabilization in the energy landscape of neuronal activation. While this destabilization is presumably temporary given one administration of cocaine, perhaps this initial destabilization indicates a transition towards a new stable state with repeated cocaine administration. However, such analyses are useful more generally to understand how neuronal networks respond to perturbations.

Impact of autoimmune gastritis on chronic urticaria in paediatric patients - pathophysiological point of views.

We would like to provide an updated comprehensive perspective and identify the components linked to chronic spontaneous urticaria (CSU) without specific triggers in autoimmune atrophic gastritis (AAG). AAG is an organ-specific autoimmune disease that affects the corpus-fundus gastric mucosa. Although we lack a unified explanation of the underlying pathways, when considering all paediatric patients reported in the literature, alterations result in gastric neuroendocrine enterochromaffin-like (ECL) cell proliferation and paracrine release of histamine. Several mechanisms have been proposed for the pathogenesis of CSU, with much evidence pointing towards AAG and ECL cell responses, which may be implicated as potential factors contributing to CSU. The excessive production/release of histamine into the bloodstream could cause or trigger exacerbations of CSU in AAG, independent of Helicobacter pylori; thus, the release of histamine from ECL cells may be the primary modulator. CONCLUSION: Considering the understanding of these interactions, recognising the respective roles of AAG in the pathogenesis of CSU may strongly impact the diagnostic workup and management of unexplained/refractory CSU and may inform future research and interventions in the paediatric population. WHAT IS KNOWN: • Autoimmune atrophic gastritis is a chronic immune-mediated inflammatory disease characterised by the destruction of the oxyntic mucosa in the gastric body and fundus, mucosal atrophy, and metaplastic changes. • Autoimmune atrophic gastritis in paediatric patients is important because of the poor outcome and risk of malignancy and possibly underestimated entities primarily reported in single-case reports. WHAT IS NEW: • Upper gastrointestinal inflammatory disorders, independent of H. pylori, have been implicated as potential inducing factors in the development of chronic spontaneous urticaria. • If a paediatric patient presents with symptoms such as anaemia, reduced vitamin B12 levels, recurrent urticaria with no other detectable aetiology, positive anti-parietal cell antibodies, and elevated gastrin levels, autoimmune atrophic gastritis should be considered a possible cause of chronic urticaria.

Transcription inhibition suppresses nuclear blebbing and rupture independently of nuclear rigidity.

Chromatin plays an essential role in the nuclear mechanical response and determining nuclear shape, which maintain nuclear compartmentalization and function. However, major genomic functions, such as transcription activity, might also impact cell nuclear shape via blebbing and rupture through their effects on chromatin structure and dynamics. To test this idea, we inhibited transcription with several RNA polymerase II inhibitors in wild-type cells and perturbed cells that presented increased nuclear blebbing. Transcription inhibition suppressed nuclear blebbing for several cell types, nuclear perturbations and transcription inhibitors. Furthermore, transcription inhibition suppressed nuclear bleb formation, bleb stabilization and bleb-based nuclear ruptures. Interestingly, transcription inhibition did not alter the histone H3 lysine 9 (H3K9) modification state, nuclear rigidity, and actin compression and contraction, which typically control nuclear blebbing. Polymer simulations suggested that RNA polymerase II motor activity within chromatin could drive chromatin motions that deform the nuclear periphery. Our data provide evidence that transcription inhibition suppresses nuclear blebbing and rupture, in a manner separate and distinct from chromatin rigidity.

A generalized approach to x-ray data modeling for high-energy-density plasma experiments.

Accurate understanding of x-ray diagnostics is crucial for both interpreting high-energy-density experiments and testing simulations through quantitative comparisons. X-ray diagnostic models are complex. Past treatments of individual x-ray diagnostics on a case-by-case basis have hindered universal diagnostic understanding. Here, we derive a general formula for modeling the absolute response of non-focusing x-ray diagnostics, such as x-ray imagers, one-dimensional space-resolved spectrometers, and x-ray power diagnostics. The present model is useful for both data modeling and data processing. It naturally accounts for the x-ray crystal broadening. The new model verifies that standard approaches for a crystal response can be good approximations, but they can underestimate the total reflectivity and overestimate spectral resolving power by more than a factor of 2 in some cases near reflectivity edge features. We also find that a frequently used, simplified-crystal-response approximation for processing spectral data can introduce an absolute error of more than an order of magnitude and the relative spectral radiance error of a factor of 3. The present model is derived with straightforward geometric arguments. It is more general and is recommended for developing a unified picture and providing consistent treatment over multiple x-ray diagnostics. Such consistency is crucial for reliable multi-objective data analyses.

How cells wrap around virus-like particles using extracellular filamentous protein structures.

Nanoparticles, such as viruses, can enter cells via endocytosis. During endocytosis, the cell surface wraps around the nanoparticle to effectively eat it. Prior focus has been on how nanoparticle size and shape impacts endocytosis. However, inspired by the noted presence of extracellular vimentin affecting viral and bacteria uptake, as well as the structure of coronaviruses, we construct a computational model in which both the cell-like construct and the virus-like construct contain filamentous protein structures protruding from their surfaces. We then study the impact of these additional degrees of freedom on viral wrapping. We find that cells with an optimal density of filamentous extracellular components (ECCs) are more likely to be infected as they uptake the virus faster and use relatively less cell surface area per individual virus. At the optimal density, the cell surface folds around the virus, and folds are faster and more efficient at wrapping the virus than crumple-like wrapping. We also find that cell surface bending rigidity helps generate folds, as bending rigidity enhances force transmission across the surface. However, changing other mechanical parameters, such as the stretching stiffness of filamentous ECCs or virus spikes, can drive crumple-like formation of the cell surface. We conclude with the implications of our study on the evolutionary pressures of virus-like particles, with a particular focus on the cellular microenvironment that may include filamentous ECCs.

Comparison of laparoscopic and open ileocecal resection for Crohn's disease in children.

PURPOSE: Ileocecal resection (ICR) is the most frequently performed surgery in paediatric Crohn's disease (CD) patients. The aim of the study was to compare laparoscopic-assisted and open ICR. METHODS: Retrospective review of consecutive CD patients undergoing ICR between March 2014 and December 2021 was performed. The patients were divided into open (OG) and laparoscopic (LG) groups. Compared parameters included patients' demographics, clinical characteristics, surgery, duration of hospitalisation and follow-up. Complications were classified according to the Clavien-Dindo classification (CDc). Risk factors were identified using multivariable analysis. RESULTS: Sixty-two patients (29 females, 46.7%) were included in the analysis, forty-two patients in OG. The median duration of surgery was 130 in OG versus 148 in LG (p = 0.065) minutes. Postoperative complications were reported in 4 patients (12.1%). There was no significant difference in postoperative complications according to CDc (OG 7.14 vs LG 5%, p = 1). The median length of hospitalisation was 8 in OG and 7 days in LG (p = 0.0005). The median length of follow-up was 21.5 months. CONCLUSION: The laparoscopic-assisted approach had shorter hospital stay and was not associated with increased risk of 30-day postoperative complications. Laparoscopic surgery should be considered the preferred surgical approach for primary ICR.

How cells wrap around virus-like particles using extracellular filamentous protein structures.

Nanoparticles, such as viruses, can enter cells via endocytosis. During endocytosis, the cell surface wraps around the nanoparticle to effectively eat it. Prior focus has been on how nanoparticle size and shape impacts endocytosis. However, inspired by the noted presence of extracellular vimentin affecting viral and bacteria uptake, as well as the structure of coronaviruses, we construct a computational model in which both the cell-like construct and the virus-like construct contain filamentous protein structures protruding from their surfaces. We then study the impact of these additional degrees of freedom on viral wrapping. We find that cells with an optimal density of filamentous extracellular components (ECCs) are more likely to be infected as they uptake the virus faster and use relatively less cell surface area per individual virus. At the optimal density, the cell surface folds around the virus, and folds are faster and more efficient at wrapping the virus than crumple-like wrapping. We also find that cell surface bending rigidity helps generate folds, as bending rigidity enhances force transmission across the surface. However, changing other mechanical parameters, such as the stretching stiffness of filamentous ECCs or virus spikes, can drive crumple-like formation of the cell surface. We conclude with the implications of our study on the evolutionary pressures of virus-like particles, with a particular focus on the cellular microenvironment that may include filamentous ECCs.

Pyrocumulonimbus affect average stratospheric aerosol composition.

Pyrocumulonimbus (pyroCb) are wildfire-generated convective clouds that can inject smoke directly into the stratosphere. PyroCb have been tracked for years, yet their apparent rarity and episodic nature lead to highly uncertain climate impacts. In situ measurements of pyroCb smoke reveal its distinctive and exceptionally stable aerosol properties and define the long-term influence of pyroCb activity on the stratospheric aerosol budget. Analysis of 13 years of airborne observations shows that pyroCb are responsible for 10 to 25% of the black carbon and organic aerosols in the "present-day" lower stratosphere, with similar impacts in both the North and South Hemispheres. These results suggest that, should pyroCb increase in frequency and/or magnitude in future climates, they could generate dominant trends in stratospheric aerosol.

Rigidity transitions in zero-temperature polygons.

We study geometrical clues of a rigidity transition due to the emergence of a system-spanning state of self-stress in underconstrained systems of individual polygons and spring networks constructed from such polygons. When a polygon with harmonic bond edges and an area spring constraint is subject to an expansive strain, we observe that convexity of the polygon is a necessary condition for such a self-stress. We prove that the cyclic configuration of the polygon is a sufficient condition for the self-stress. This correspondence of geometry and rigidity is akin to the straightening of a one dimensional chain of springs to rigidify it. We predict the onset of the rigidity transition and estimate the transition strain using purely geometrical methods. These findings help determine the rigidity of an area-preserving polygon just by knowing its geometry. Since two-dimensional spring networks can be considered as a network of polygons, we look for similar geometric features in underconstrained spring networks under isotropic expansive strain. We observe that all polygons attain convexity at the rigidity transition such that the fraction of convex, but not cyclic, polygons predicts the onset of the rigidity transition. Acyclic polygons in the network correlate with larger tensions, forming effective force chains.

Thermal Fluctuations of Singular Bar-Joint Mechanisms.

A bar-joint mechanism is a deformable assembly of freely rotating joints connected by stiff bars. Here we develop a formalism to study the equilibration of common bar-joint mechanisms with a thermal bath. When the constraints in a mechanism cease to be linearly independent, singularities can appear in its shape space, which is the part of its configuration space after discarding rigid motions. We show that the free-energy landscape of a mechanism at low temperatures is dominated by the neighborhoods of points that correspond to these singularities. We consider two example mechanisms with shape-space singularities and find that they are more likely to be found in configurations near the singularities than others. These findings are expected to help improve the design of nanomechanisms for various applications.

Extracellular Vimentin as a Target Against SARS-CoV-2 Host Cell Invasion.

Infection of human cells by pathogens, including SARS-CoV-2, typically proceeds by cell surface binding to a crucial receptor. The primary receptor for SARS-CoV-2 is the angiotensin-converting enzyme 2 (ACE2), yet new studies reveal the importance of additional extracellular co-receptors that mediate binding and host cell invasion by SARS-CoV-2. Vimentin is an intermediate filament protein that is increasingly recognized as being present on the extracellular surface of a subset of cell types, where it can bind to and facilitate pathogens' cellular uptake. Biophysical and cell infection studies are done to determine whether vimentin might bind SARS-CoV-2 and facilitate its uptake. Dynamic light scattering shows that vimentin binds to pseudovirus coated with the SARS-CoV-2 spike protein, and antibodies against vimentin block in vitro SARS-CoV-2 pseudovirus infection of ACE2-expressing cells. The results are consistent with a model in which extracellular vimentin acts as a co-receptor for SARS-CoV-2 spike protein with a binding affinity less than that of the spike protein with ACE2. Extracellular vimentin may thus serve as a critical component of the SARS-CoV-2 spike protein-ACE2 complex in mediating SARS-CoV-2 cell entry, and vimentin-targeting agents may yield new therapeutic strategies for preventing and slowing SARS-CoV-2 infection.

[Expectations of patients and relatives for modern hospital care in geriatric psychiatry]. / Erwartungen von Patienten und Angehörigen an eine moderne alterspsychiatrische Krankenhausversorgung.

OBJECTIVE: In order to improve health care in geriatric psychiatry, users must be granted a larger role in shaping their treatment. To this aim we identify factors that are essential to psychiatric care from users' perspectives. METHODS: Focus groups and interviews (n = 12) were conducted to identify the health care factors that were most essential to its users. In addition, patients (n = 72) and relatives (n = 62) evaluated the current health care in a questionnaire. RESULTS: The most essential factors were longer consultations with doctors and treatment providers, comprehensive and comprehensible information, individualized procedures and therapies, having clearly defined scopes for each professional group, environmental factors and the integration of relatives into the therapy process. CONCLUSION: The reported factors could help improve health services in geriatric psychiatry by pointing towards potential changes and room for optimization in health care on both structural and process levels.

[Health, performance and use of medication in professional Swiss meat rabbit production]. / Gesundheit, Leistung und Medikamenten­einsatz in der professionellen Schweizer Fleischkaninchenproduktion.

INTRODUCTION: Husbandry conditions for rabbits in Switzerland are at a high animal welfare level in international comparison. Wire mesh flooring is prohibited and group housing is mandatory up to the age of eight weeks. Despite these animal-friendly husbandry standards, animal losses seem to be a significant problem, although reliable data on professional Swiss meat rabbit production is lacking to date. A herd survey was carried out in 52 rabbit farms to address this situation. At the same time, each new litter and each fattening group was documented with a standardized form focusing on animal death and the use of medication by the farmer over a one year period. In the case of increased mortality or new health problems, dead rabbits were sent to the National Reference Center for Poultry and Rabbit Diseases (Zurich) for pathological examination including bacteriological and parasitological diagnostics. Data from 32 farms were evaluated. The average mortality of young animals (birth to weaning) was 14.9% (1.0-30.0%) and of fattening rabbits (weaning to slaughter) 17.3% (4.3-31.8%). Intestinal diseases, mainly dysentery, intestinal coccidiosis and mucoid enteropathies, were the primary cause of death (68.2%). Eimeria spp., Escherichia coli and Clostridium perfringens were identified as the most frequent pathogens. Respiratory diseases were found in 18.7% of the examined rabbits, with Pasteurella multocida identified as the most common pathogen. 60.0% of the farms used antibiotics during the study period and a third (34.7%) of all the fattening animals were medicated with at least one antibiotic. The present results confirm that despite high animal welfare standards infectious diseases and mortality rates represent a considerable problem in professional Swiss meat rabbit production. Risk factors of increased morbidity and mortality should be identified to improve rabbit health, to reduce the high mortality rate and the extensive use of antibiotics in professional Swiss meat rabbit production. Practicable management improvements with specific prevention strategies should be developed.

INTRODUCTION: Les conditions d'élevage des lapins en Suisse sont d'un niveau élevé en comparaison internationale. Il est interdit de les garder sur un sol en treillis métallique et leur détention en groupe est obligatoire jusqu'à l'âge de huit semaines. Malgré ces normes d'élevage respectueuses des animaux, les pertes d'animaux semblent être un problème important, les données fiables sur la production professionnelle suisse de lapins de boucherie faisant largement défaut à ce jour. Afin de remédier à cette situation, une enquête d'exploitation a été réalisée dans 52 élevages cunicoles. En parallèle, chaque nouvelle portée et chaque groupe d'engraissement était documenté par le chef d'élevage avec un formulaire standardisé au cours d'une année, l'accent étant principalement mis sur les pertes d'animaux et l'utilisation de médicaments. En cas d'augmentation de la mortalité ou de nouveaux problèmes de santé, les lapins morts étaient envoyés au Centre national de référence pour les maladies de la volaille et des lapins (Zurich) pour une autopsie comprenant des examens bactériologiques et parasitologiques. Les données de 32 entreprises ont pu être évaluées. La mortalité moyenne des jeunes animaux (de la naissance au sevrage) était de 14,9% (1,0­30,0%), celle des lapins à l'engrais (du sevrage à l'abattage) était de 17,3% (4,3­ 31,8%). Les maladies intestinales ont été retrouvées en premier lieu (68,2%), principalement la dysenterie, suivie par la coccidiose intestinale et les entéropathies mucoïdes. Eimeria spp., Escherichia coli et Clostridium perfringens ont été identifiés comme les agents pathogènes les plus fréquents par ordre décroissant. Des maladies respiratoires ont été trouvées chez 18,7% des lapins examinés, le pathogène le plus courant étant Pasteurella multocida. 60,0% des élevages examinés ont utilisé des antibiotiques au cours de la période d'étude, environ un tiers (34,7%) de tous les processus d'engraissement examinés ont été traités avec au moins un antibiotique. Les résultats confirment que les maladies infectieuses et les pertes de lapins en Suisse représentent un problème considérable dans l'élevage professionnel malgré un élevage respectueux des animaux. Afin d'améliorer la santé des lapins dans les entreprises de production professionnelles suisses et de réduire ainsi les taux de mortalité élevés et l'utilisation intensive d'antibiotiques, les facteurs de risque d'augmentation de la morbidité et de la mortalité doivent être déterminés dans une étape supplémentaire afin de développer des améliorations de gestion réalisables dans le cadre de stratégies de prévention spécifiques.

Age-Related Progression of Microvascular Dysfunction in Cystic Fibrosis: New Detection Ways and Clinical Outcomes.

There are concerns about altered vascular functions that could play an important role in the pathogenesis and influence the severity of chronic disease, however, increased cardiovascular risk in paediatric cystic fibrosis (CF) has not been yet fully understood. Aim was to analyse vascular disease risk and investigate changes over times in CF and controls. We prospectively enrolled 22 CF subjects (a median age of 16.07 years), and 22 healthy demographically matched controls (a median age of 17.28 years) and determined endothelial function. We utilised a combined diagnostic approach by measuring the plethysmographic Reactive Hyperemia Index (RHI) as the post-to preocclusive endothelium-dependent changes of vascular tone, and biomarkers that are known to be related to endothelial dysfunction (ED): asymmetric dimethyl arginine (ADMA), high-sensitive CRP (hsCRP), VCAM-1 and E-selectin. RHI values were significantly lower in CF young adults (p<0.005). HsCRP (p<0.005), E-selectin (p<0.001) and VCAM-1 (p<0.001) were significantly increased in CF patients since childhood. The findings have provided a detailed account of the ongoing process of microvascular dysfunction with gradual progression with the age of CF patients, making them further at risk of advanced vascular disease. Elevations of biomarkers in CF children with not yet demonstrated RHI changes but with significantly reduced RHI in adulthood and lipid profile changes indicate the possible occurrence of ED with CF-related specific risk factors over time and will enable us to provide the best possible support.

Leveraging Radiobiology for Arrhythmia Management: A New Treatment Paradigm?

Radiation therapy is a well-established approach for safely and non-invasively treating solid tumours and benign diseases with high precision and accuracy. Cardiac radiation therapy has recently emerged as a non-invasive treatment option for the management of refractory ventricular tachycardia. Here we summarise existing clinical and preclinical literature surrounding cardiac radiobiology and discuss how these studies may inform basic and translational research, as well as clinical treatment paradigms in the management of arrhythmias.

The assessment of plasma fatty acid profiles in newly diagnosed treatment-naive paediatric Crohn's disease.

Fatty acid (FA) profiles as potentially relevant components of Crohn's disease (CD) have been insufficiently analysed. We sought to explore the plasma profiles of n-3 and n-6 polyunsa-turated fatty acids (PUFAs) in newly diagnosed untreated active CD. We included 26 consecutive CD pediatric patients (<19 years) and 14 healthy controls (HCs). Disease characteristics, including inflammatory markers, dietary histories, and the Pediatric Crohn's Disease Activity Index (PCDAI), were obtained. The profiles of plasma FAs in plasma lipid classes were analysed by gas chromatography with FID detection of methyl esters. The erythrocyte sedimentation rate, C-reactive protein level and fecal calprotectin level (all p<0.001) were significantly higher in CD patients than in HCs. Most changes were observed in plasma phospholipids (PLs), such as a higher content of n-3 and changes in n-6 long-chain PUFAs in the CD group. The CD group had a lower ratio of n-6/n-3 PUFAs in PLs (p<0.001) and triacylglycerols (TAGs) (p<0.01). Correlations of the FA content in plasma PLs with disease activity scores of CD were also observed, which were positive for the sum of monounsaturated fatty acids (MUFAs) as well as oleic acid (18:1n-9) (both p<0.05). The metabolism of PUFAs is significantly altered even in treatment-naive newly diagnosed active pediatric CD, and the content of major FAs in PLs correlates with disease activity and inflammatory markers, thus probably contributing to the still unclear early disease pathogenesis.

Photoredox-enabled 1,2-dialkylation of α-substituted acrylates via Ireland-Claisen rearrangement.

Herein, we report the 1,2-dialkylation of simple feedstock acrylates for the synthesis of valuable tertiary carboxylic acids by merging Giese-type radical addition with an Ireland-Claisen rearrangement. Key to success is the utilization of the reductive radical-polar crossover concept under photocatalytic reaction conditions to force the [3,3]-sigmatropic rearrangement after alkyl radical addition to allyl acrylates. Using readily available alkyl boronic acids as radical progenitors, this redox-neutral, transition-metal-free protocol allows the mild formation of two C(sp3)-C(sp3) bonds, thus providing rapid access to complex tertiary carboxylic acids in a single step. Moreover, this strategy enables the efficient synthesis of highly attractive α,α-dialkylated γ-amino butyric acids (GABAs) when α-silyl amines are used as radical precursors - a structural motif that was still inaccessible in related transformations. Depending on the nature of the radical precursors and their inherent oxidation potentials, either a photoredox-induced radical chain or a solely photoredox mechanism is proposed to be operative.