Search

Rare diseases affect millions of people worldwide, and most have a genetic etiology. The incorporation of next-generation sequencing into clinical settings, particularly exome and genome sequencing, has resulted in an unprecedented improvement in diagnosis and discovery in the past decade. Nevertheless, these tools are unavailable in many countries, increasing health care gaps between high- and low-and-middle-income countries and prolonging the “diagnostic odyssey” for patients. To advance genomic diagnoses in a setting of limited genomic resources, we developed DECIPHERD, an undiagnosed diseases program in Chile. DECIPHERD was implemented in two phases: training and local development. The training phase relied on international collaboration with Baylor College of Medicine, and the local development was structured as a hybrid model, where clinical and bioinformatics analysis were performed in-house and sequencing outsourced abroad, due to lack of high-throughput equipment in Chile. We describe the implementation process and findings of the first 103 patients. They had heterogeneous phenotypes, including congenital anomalies, intellectual disabilities and/or immune system dysfunction. Patients underwent clinical exome or research exome sequencing, as solo cases or with parents using a trio design. We identified pathogenic, likely pathogenic or variants of unknown significance in genes related to the patients´ phenotypes in 47 (45.6%) of them. Half were de novo informative variants, and half of the identified variants have not been previously reported in public databases. DECIPHERD ended the diagnostic odyssey for many participants. This hybrid strategy may be useful for settings of similarly limited genomic resources and lead to discoveries in understudied populations.

The Al18F-labeling approach offers a one-step access to radiofluorinated biomolecules by mimicking the labeling process for radiometals. Although these labeling conditions are considered to be mild compared to classic radiofluorinations, improvements of the chelating units have led to the discovery of (±)-H3RESCA, which allows Al18F-labeling already at ambient temperature. While the suitability of (±)-H3RESCAfor functionalization and radiofluorination of proteins is well established, its use for small molecules or peptides is less explored. Herein, we advanced this acyclic pentadentate ligand by introducing an alkyne moiety for the late-stage functionalization of biomolecules via click chemistry. We show that in addition to Al18F-labeling, the cyclohexanediamine triazole (CHDT) moiety allows stable complexation of 68Ga and 111In. Three novel CHDT-functionalized PSMA inhibitors were synthesized and their Al18F-, 68Ga-, and 111In-labeled analogs were subjected to a detailed in vitroradiopharmacological characterization. Stability studies in vitroin human serum revealed among others a high kinetic inertness of all radiometal complexes. Furthermore, the Al18F-labeled PSMA ligands were characterized for their biodistribution in a LNCaP derived tumor xenograft mouse model by PET imaging. One radioligand, Al[18F]F-CHDT-PSMA-1, bearing a small azidoacetyl linker at the glutamate-urea-lysine motif, provided an in vivoperformance comparable to that of [18F]PSMA-1007but with even higher tumor-to-blood and tumor-to-muscle ratios at 120 min p.i.Overall, our results highlight the suitability of the novel CHDT moiety for functionalization and radiolabeling of small molecules or peptides with Al18F, 68Ga, and 111In and the triazole ring seems to entail favorable pharmacokinetic properties for molecular imaging purposes.

[C3H10N][C12H24BO4]·B(OH)3, orthorhombic, Fdd2 (no. 43), a= 30.3986(6) Å, b= 40.4094(13) Å, c= 7.0603(2) Å, V= 8672.8(4) Å3, Z= 16, Rgt(F) = 0.0324, wRref(F2) = 0.0828, T = 153 K.

During extrusion, the material is subjected to a heterogeneous deformation that results in the formation of gradients of microstructure and thus mechanical properties. In this study, using continuously cast commercially pure aluminum as a reference material, we show how a cast structure with coarse columnar grains affects the formation of these gradients during extrusion at room temperature. Characterization of the initial material as well as the extruded round bars by optical and electron microscopy, X-ray diffraction as well as by means of mechanical testing documents the formation of four characteristic annular sections. For extrusion along the casting direction there is a <100>/<111> double-fiber textured center with lowest hardness, followed by a <111> single-fiber textured ring with a hardness plateau, a double-fiber textured region with grains arranged alternatingly in an iris-like shape, and an (ultra-)fine grained surface layer with highest hardness. For extrusion opposite to the casting direction we find similar characteristics of the center section. With increasing distance from the center follow another double-fiber textured section with increasing hardness, a <111> single-fiber textured ring with nearly homogeneous hardness and a surface layer with a slightly rotated <111> fiber and highest hardness. The key finding is that the macroscopic anisotropy of the cast material, resulting from the grain size, crystal orientation and growth direction of the columnar grains, determines the local material flow during extrusion and thus leads to the formation of these different complex multi-gradient macrostructures that may provide unique properties for complex applications such as light-weight safety-relevant components.

[SbCl3(C9H11N3S2)2], monoclinic, P21/n(no. 14), a= 13.8069(4) Å, b= 13.5739(6) Å, c= 14.0182(5) Å, β= 94.231(3)°, V= 2,620.04(17) Å3, Z= 4, Rgt(F) = 0.0329, wRref(F2) = 0.0726, T = 153 K.

Der Klimawandel führt zu einem noch nie dagewesenen Gletscherschwund in den Alpen. Daher analysiert dieser Beitrag, wie BesucherInnen von Gletschertourismusstandorten diesen Landschaftswandel wahrnehmen und wie sich diese Standorte positionieren könnten, wenn ihre Hauptattraktionen verschwinden. Konzeptionell verknüpfen wir den wissenschaftlichen Diskurs über den Last Chance Tourism (LCT) mit Positionierung und den touristischen Attraktionssystemen von Leiper. Wir befragten die BesucherInnen von sechs alpinen Gletschertourismusstandorten (n=1330) zu ihrer Besuchsmotivation und ihrer Klimawandelwahrnehmung und verwendeten eine latente Klassenanalyse zur BesucherInnensegmentierung. Eine zweite Befragung an der Pasterze/Franz-Josefs-Höhe (n=201) gibt Einblicke in die Positionierung von Gletschertourismusstandorten und die Rolle des Gletschers als Kern des touristischen Attraktionssystems. Die Ergebnisse zeigen, dass LCT-Motivationen für BesucherInnen aller Standorte wichtig sind, die Gletscher als gefährdete Objekte wahrnehmen. Das Beispiel der Pasterze zeigt, dass für die meisten BesucherInnen der Gletscher als solcher nicht primär ausschlaggebend für die Reiseentscheidung ist, sondern eher einen (kleiner werdenden) Teil des gesamten Landschaftserlebnisses darstellt. Eine LCT-Positionierung wäre daher als Strategie zu eng und zu kurzsichtig, während eine Transformation von Gletscher- zu Landschaftswandel-Destinationen eine tragfähige Positionierung mit langfristiger Perspektive zu sein scheint.

Objectives: To evaluate the mortality after treatment with a paclitaxel (PTX)-coated device and with uncoated devices of iliac, femoropopliteal, and below-the-knee lesions in dialysis patients.Methods: Retrospective mortality analysis of dialysis patients with peripheral artery disease who underwent treatment of iliac, femoropopliteal, and/or infrapopliteal lesions with PTX-coated or uncoated devices.Results: Between 2010 and 2018, 1125 dialysis patients were treated with iliac and/or femoropopliteal and/or infrapopliteal lesions. In all, 359 patients were selected for this retrospective analysis. Of those, 122 patients were treated with uncoated devices without crossover to a PTX-coated device during follow-up and 237 patients were treated with a PTX-coated device. Mean follow-up time was 27.38±24.76 months (range=0–103). For the entire cohort, the overall mortality was 95.1% after uncoated treatment and 75.9% after PTX treatment (p<0.001). After propensity score matching (n=119), overall mortality was 95.0% after uncoated treatment and 78.2% after PTX treatment (p<0.001). For the entire cohort, multivariate logistic regression analysis revealed age (p=0.002) and critical limb ischemia (p<0.001) as independent predictors for mortality. PTX treatment was a protective factor for mortality (p<0.001).Conclusion: Mortality in dialysis patients is in general high and higher after use of uncoated devices compared with PTX-coated devices. Mortality predictors were risk factors and disease severity but not PTX treatment.Clinical Impact After the publication of Katsanos’s metaanalyses, the uncertainty regarding PTX device safety in peripheral interventions in patients mainly without end-stage renal insufficiency was initially considerable. The present study for the first time investigates the potential long-term mortality risk of dialysis patients following PTX device treatment of PAD. In contrast to a recent meta-analysis, this real-world study could show a better survival after PTX treatment in comparison to uncoated devices.

C23H19NO3Si, monoclinic, P21/n(no. 14), a= 8.5543(3) Å, b= 24.0927(8) Å, c= 9.7971(4) Å, β= 113.265(3)°, V= 1854.96(12) Å3, Z= 4, Rgt(F) = 0.0355, wRref(F2) = 0.0932, T= 153 K.

The presence of biogenic amines (histamine, tyramine, putrescine, and cadaverine) in seafood is a significant concern for food safety. This review describes for the first time a shotgun quantitative proteomics strategy to evaluate and compare foodborne strains of bacteria that produce biogenic amines in seafoods. This approach recognized 35,621 peptide spectrum matches, belonging to 20,792 peptides, and 4621 proteins. It allowed the determination of functional pathways and the classification of the strains into hierarchical clusters. The study identified a protein–protein interaction network involving 1160 nodes/10,318 edges. Proteins were related to energy pathways, spermidine biosynthesis, and putrescine metabolism. Label-free quantitative proteomics allowed the identification of differentially regulated proteins in specific strains such as putrescine aminotransferase, arginine decarboxylase, and l-histidine-binding protein. Additionally, 123 peptides were characterized as virulence factors and 299 peptide biomarkers were selected to identify bacterial species in fish products. This study presents the most extensive proteomic repository and progress in the science of food biogenic bacteria and could be applied in the food industry for the detection of bacterial contamination that produces histamine and other biogenic amines during food processing/storage.

We investigate the structural properties of model amphiphilic conetworks made by heterocomplementary end-linking of tetra-poly(ethylene glycol) tetra-poly(ϵ-caprolactone) PCL star polymers in selective and nonselective solvents using small-angle X-ray scattering, nuclear magnetic resonance (NMR) diffusometry, and double-quantum magic-angle spinning (DQ MAS) NMR techniques. The X-ray scattering experiments reveal the correlation lengths of our networks, including postcuring effects, and the microphase separation (MPS) of the networks swollen by a selective solvent, with cluster sizes independent of concentration. An estimation of hydrodynamic screening length as the length scale governing the diffusion process is achieved by monitoring the diffusion coefficients of polysaccharides and polystyrenes with different molecular weights. Furthermore, chemical-shift-resolved local chain mobilities in the microphase-separated system are observed using DQ MAS NMR, demonstrating immobilization of the linker end group and melt-like dynamics for clustered PCL chains, both of which are in qualitative agreement with bond-fluctuation Monte Carlo simulations of comparable model structures. Our analyses provide valuable insights into the structural properties and behavior of amphiphilic conetworks and the process of MPS under strong topological constraints, highlighting the effects of postcuring in a polymer network with star-shaped building blocks.

Every manufacturing company faces numerous disruptions internally and externally within the supply chain, influenced by its location. The pandemic of 2020 intensified research on efficient disruption management. Most approaches focus on either the supply chain or specific manufacturing systems. To enhance manufacturing robustness, this paper proposes an integrated framework for comprehensive decision support, addressing production scheduling, purchasing, and their interaction in a VUCA (Volatility, Uncertainty, Complexity, Ambiguity) world. This integrated approach helps companies adapt to disruptions, optimizing production and response to demand shifts.

Zusammenfassung: In dieser Arbeit geht es um die Bestimmung der freien Oberfläche eines rotierenden Zweiphasensystems. Es besteht aus einem zylindrischen Rotor mit horizontaler Achse, der teilweise mit einer zähen schweren Flüssigkeit, teilweise mit Luft als passiver Phase gefüllt ist, und einer abschabenden, fest stehenden Platte. In Abhängigkeit vom Füllgrad und von einer Kennzahl, die den relativen Einfluss der Schwerkraft und der Reibungskräfte in der Flüssigkeit anzeigt, werden unterschiedliche Strömungszustände beobachtet. Zur quantitativen Visualisierung der Phasengrenzfläche wird einerseits eine optische Methode auf der Basis ebener Laserlichtschnitte erprobt, andererseits die Röntgen-Computertomographie eingesetzt. Komplementär dazu kann die freie Oberfläche auch durch die numerische Simulation der Zweiphasenströmung berechnet werden. Die mit den verschiedenen Methoden erzeugten Ergebnisse werden miteinander verglichen und bewertet.

Scholars and practitioners are urgently highlighting the need to apply a relational approach to effectively address societal crises. At the same time, little is known about the associated challenges, and there is little advice regarding how to operationalize this approach in sustainability science. Against this background, this article explores how we can break out of our current paradigms and approaches, and instead apply relational thinking, being, and acting in the way we conduct research. To achieve this, we systematically list all major research phases, and assess possible pathways for integrating a relational paradigm for each step. We show that moving toward a relational paradigm requires us to methodically question and redefine existing theories of change, concepts, and approaches, for instance by combining abductive reasoning, first-person inquiries, and decentering the human through critical complexity theory. Challenging mainstream thought, and daring to ask different questions in each step is crucial to ultimately shift scientific norms and systems. Hence, we offer a catalog of questions that may help to systematically integrate relational being, thinking, and acting into the process, as a tool for transforming current paradigms in research, and associated education and practice. Finally, we highlight the importance of further research to develop and refine our outcomes.

In modern electrochemical coating technology, it is common practice to create uniform layers. However, this study focuses on the deposition of non-uniform layers achieved through a deliberate arrangement of micro structured electrodes on the anode side. The "dog bone effect” was employed as the primary approach [1]. When electroplating on an otherwise uniform surface, this effect selectively processes an area influenced by the geometric edge effect (figure 1 left). The coating within this area is intended to be (i) unevenly distributed and (ii) non-reproducible. Process data was obtained through electrochemical simulations and subsequently applied to a specially designed micro-galvanic setup. This enabled the production of suitable micro structured anodes, validation of coating parameters, and the deposition of visually imperceptible structured areas with inhomogeneous properties using "adhesive gold" on appropriate substrates such as silver and nickel. The layers and their local topography were characterized and analyzed using confocal laser microscopy, X-Ray fluorescence analysis (XRF), as well as a self-designed and constructed laser interference device. As a result, this specific galvanic process technology successfully produced metallic layers that (i) cannot be visually confirmed by the naked eye, (ii) exhibit varied microstructural anode geometries, (iii) display unique differences in layer thickness, (iv) possess non-reproducible and chaotic topographies, and (v) can be detected and identified using conventional analysis techniques or a simple interference setup.

Organ models that resemble the original anatomy are needed in the education and training of human and veterinary doctors. The organs should be as close as possible to the original in shape, colour and feel. Furthermore, these organ models must be able to be handled in such a way that they can be examined by palpation and imaging (ultrasound, X-ray, CT and endoscopy). The diagnostic procedures should detect pathologies such as cysts, tumours, ruptures, haemorrhages or air collections. Following the diagnostic measures, it must be possible to initiate a therapy. Possible therapeutic measures are surgery with a scalpel, electrosurgery or puncture. The present work deals with the production of training models by means of a casting process. With this method, the models can be produced quickly and at low cost. Different compositions of hydrogels and other biomaterials are investigated. These gels are examined for the following properties, among others: thermostability, electrical conductivity and dimensional stability under pressure. Other parameters such as pot life, cross-linking time and durability in relation to mould formation will also be considered.

During the COVID-19 pandemic, governments worldwide implemented nonpharmaceutical lockdown policies to mitigate the impact of the virus. The effectiveness of these policies depended on public support, and they came with serious consequences for the population. Given that people’s perceptions can influence their support for lockdown policies, we aimed to elicit perceptions of policy stringency among people in Denmark, France, Germany, Italy, the Netherlands, Portugal, and the United Kingdom in early 2021 as part of the European Covid Survey. We examined the extent to which objective measures of policy stringency and other factors were associated with these perceptions, focusing on disadvantaged populations. We found that objective measures of stringency did not accurately capture the impact of lockdown policies on people. Moreover, we found that socioeconomically disadvantaged people perceived policies as stricter than did less disadvantaged people and that trust in information sources greatly influenced such perceptions. Our findings underscore the importance of understanding factors influencing policy perception to help policy makers develop more effective and equitable infection containment strategies.

The reaction of Co(NCS)2with N-methylaniline leads to the formation of [Co(NCS)2(N-methylaniline)2]n(1), in which the cobalt(II) cations are octahedrally coordinated and linked into linear chains by pairs of thiocyanate anions. In contrast to [Co(NCS)2(aniline)2]n(2) reported recently, in which the Co(NCS)2chains are linked by strong interchain N–H···S hydrogen bonding, such interactions are absent in 1. Computational studies reveal that the cobalt(II) ions in compound 1show an easy-axis anisotropy that is lower than in 2, but with the direction of the easy axis being similar in both compounds. The high magnetic anisotropy is also confirmed by magnetic and FD-FT THz-EPR spectroscopy, which yield a consistent gzvalue. These investigations prove that the intrachain interactions in 1are slightly higher than in 2. Magnetic measurements reveal that the critical temperature for magnetic ordering in 1is significantly lower than in 2, which indicates that the elimination of the hydrogen bonds leads to a weakening of the interchain interactions. This is finally proven by FD-FT THz-EPR experiments, which show that the interchain interaction energy in the N-methylaniline compound 1is nine-fold smaller than in the aniline compound 2.

Na2Ga7crystallizes with the orthorhombic space group Pnma(no. 62; a= 14.8580(6) Å, b= 8.6766(6) Å, and c= 11.6105(5) Å; Z= 8) and constitutes a filled variant of the Li2B12Si2structure type. The crystal structure consists of a network of icosahedral Ga12units with 12 exohedral bonds and four-bonded Ga atoms in which the Na atoms occupy the channels and cavities. The atomic arrangement is consistent with the Zintl [(4b)Ga]−and Wade [(12b)Ga12]2–electron counting approach. The compound forms peritectically from Na7Ga13and the melt at 501 °C and does not show a homogeneity range. The band structure calculations predict semiconducting behavior consistent with the electron balance [Na+]4[(Ga12)2–][Ga–]2. Magnetic susceptibility measurements show that Na2Ga7is diamagnetic.

Selon la Haute Autorité de santé (HAS), l’éducation thérapeutique du patient (ETP) est au cœur de la prise en charge de l’obésité, pour l’organisation et l’implantation des parcours de soins. L’ETP permet une approche centrée sur la personne et pas seulement sur l’excès de poids. Les parcours de soins multi-composantes et pluri-professionnels sont nécessaires pour mieux appréhender la situation parfois complexe des personnes en situation d’obésité et pour personnaliser et graduer le parcours de soins. La relation soignant–soigné est la pierre angulaire de l’ETP, dont le but est de développer (1) les compétences d’auto-soins (self-managementet automesure) pour permettre à la personne de changer progressivement son mode de vie ; (2) les compétences psychosociales ou d’adaptation qui sont cognitives, émotionnelles et sociales ; elles permettent au patient de faire face à la maladie et de vivre au mieux en s’adaptant à la situation et à son environnement. Nous proposons d’intégrer à la démarche éducative différentes approches pour améliorer l’engagement des patients : empowerment, résilience, partenariat patients–professionnels de santé, médecine narrative. Le résultat attendu est une amélioration de la relation soignant–soigné, bénéfique aux deux parties.

The electronic exchange─correlation (XC) kernel constitutes a fundamental input for the estimation of a gamut of properties such as the dielectric characteristics, the thermal and electrical conductivity, or the response to an external perturbation. In this work, we present a formally exact methodology for the computation of the system specific static XC kernel exclusively within the framework of density functional theory (DFT) and without employing functional derivatives─no external input apart from the usual XC-functional is required. We compare our new results with exact quantum Monte Carlo (QMC) data for the archetypical uniform electron gas model under both ambient and warm dense matter conditions. This gives us unprecedented insights into the performance of different XC functionals, and it has important implications for the development of new functionals that are designed for the application at extreme temperatures. In addition, we obtain new DFT results for the XC kernel of warm dense hydrogen as it occurs in fusion applications and astrophysical objects. The observed excellent agreement to the QMC reference data demonstrates that presented framework is capable to capture nontrivial effects such as XC-induced isotropy breaking in the density response of hydrogen at large wave numbers.

The nematode Caenorhabditis eleganshas been widely used as a model organism for assessing chemical toxicity. So far, however, a respective baseline narcosis reference has been lacking to predict narcosis-level toxicity and to identify excess-toxic compounds and associated mechanisms of action. Employing 22 organic narcotics that cover 7.2 units of their log Kow(octanol/water partition coefficient) from −1.20 to 6.03, a baseline narcosis model has been derived for a glass-vial 96-h growth inhibition test with C. elegans, both without and with correction for compound loss through volatilization and sorption. The resultant effective concentrations yielding 50% growth inhibition, EC50, vary by 6.4 log units from 5.04 · 10–1to 1.90 · 10–7mol/L (exposure-corrected). Application of the new model is illustrated through sensing the toxicity enhancement (Te) of four Michael-acceptor carbonyls driven by their reactive mode of action. Moreover, narcosis-level predicted vs experimental EC50of two α,β-unsaturated alcohols demonstrate the biotransformation capability of C. elegansregarding ADH (alcohol dehydrogenase). The discussion includes narcosis-level and excess-toxicity doses (critical body burdens) as well as chemical activities A50(at the EC50) as compared to fish, daphnids, ciliates, bacteria, zebrafish embryo, and cell lines. Overall, the presently introduced model for predicting C. elegansbaseline narcosis enables generating respective pre-test expectations, enriches experimental results by mechanistic information, and may complement 3Rs (reduce, refine, replace) test batteries through its ADH metabolic capacity.

We investigated single deprotonated phthalocyanine molecules (HPc) on (3×3)Bi/Ag(111)R30° by means of scanning tunneling microscopy (STM). Atomic-resolution topographic data reveal that the HPc adsorbs flat on top of a Bi atom. At sufficient bias voltage, STM-induced rotation and tautomerization of the HPc molecule are observed. Current- and bias voltage-dependent studies show that both processes are triggered via the molecule’s N–H stretching mode by a single electron. A constant ratio between the tautomerization and the rotation rate is observed, corroborating that both processes originate from the same stimulus. Furthermore, molecular nanoprobe (MONA) experiments provide insight into the ballistic charge transport properties of the (3×3)Bi/Ag(111)R30° substrate. A distance-dependent study shows that the excitation rate decays with ∼d–1, indicating that ballistic transport mainly proceeds via the substrate’s surface state. Direction-dependent MONA measurements reveal that the HPc molecule exhibits two different faces with distinct excitation probabilities.

The gravitational pressure in many astrophysical objects exceeds one gigabar (one billion atmospheres)1–3, creating extreme conditions where the distance between nuclei approaches the size of the K shell. This close proximity modifies these tightly bound states and, above a certain pressure, drives them into a delocalized state4. Both processes substantially affect the equation of state and radiation transport and, therefore, the structure and evolution of these objects. Still, our understanding of this transition is far from satisfactory and experimental data are sparse. Here we report on experiments that create and diagnose matter at pressures exceeding three gigabars at the National Ignition Facility5where 184 laser beams imploded a beryllium shell. Bright X-ray flashes enable precision radiography and X-ray Thomson scattering that reveal both the macroscopic conditions and the microscopic states. The data show clear signs of quantum-degenerate electrons in states reaching 30 times compression, and a temperature of around two million kelvins. At the most extreme conditions, we observe strongly reduced elastic scattering, which mainly originates from K-shell electrons. We attribute this reduction to the onset of delocalization of the remaining K-shell electron. With this interpretation, the ion charge inferred from the scattering data agrees well with ab initio simulations, but it is significantly higher than widely used analytical models predict6.

Ultrasonic scanning of large spiral bevel gears and the subsequent fracture analyses of early-stage tooth flank fractures imply a mode II crack initiation under surface-parallel, orthogonal shear stresses. An iteration of the Dang Van criterion is presented that focuses exclusively on surface-parallel material planes, yielding a standardizable approach for the study of tooth flank fracture in spiral bevel gears. It is shown that Dang Van’s shear stress amplitude and maximum hydrostatic stress along a surface-perpendicular path can adequately be described by the Hertzian orthogonal shear stress amplitude and Lang’s compressive residual stress. The fatigue properties along the same path are estimated from Thomas’ hardness model and augmented by ISO-inspired lifetime, size and conversion factors. The article closes with a comparison between the commonly used Witzig-Boiadjiev, Hertter-Wirth, DNV subsurface fatigue and the herein proposed, rationalized Dang Van criterion.