Search

ON MAY 27, 1973, a young journalist named Stephen Walther filed incorporation papers to begin publishing Astronomy magazine. The first issue was August 1973; by 1981, it was the largest-circulation [...]

For patients with advanced non-small-cell lung cancer (NSCLC), dual immune checkpoint blockade (ICB) with CTLA4 inhibitors and PD-1 or PD-L1 inhibitors (hereafter, PD-(L)1 inhibitors) is associated with higher rates of anti-tumour activity and immune-related toxicities, when compared with treatment with PD-(L)1 inhibitors alone. However, there are currently no validated biomarkers to identify which patients will benefit from dual ICB1,2. Here we show that patients with NSCLC who have mutations in the STK11and/or KEAP1tumour suppressor genes derived clinical benefit from dual ICB with the PD-L1 inhibitor durvalumab and the CTLA4 inhibitor tremelimumab, but not from durvalumab alone, when added to chemotherapy in the randomized phase III POSEIDON trial3. Unbiased genetic screens identified loss of both of these tumour suppressor genes as independent drivers of resistance to PD-(L)1 inhibition, and showed that loss of Keap1was the strongest genomic predictor of dual ICB efficacy—a finding that was confirmed in several mouse models of Kras-driven NSCLC. In both mouse models and patients, KEAP1and STK11alterations were associated with an adverse tumour microenvironment, which was characterized by a preponderance of suppressive myeloid cells and the depletion of CD8+cytotoxic T cells, but relative sparing of CD4+effector subsets. Dual ICB potently engaged CD4+effector cells and reprogrammed the tumour myeloid cell compartment towards inducible nitric oxide synthase (iNOS)-expressing tumoricidal phenotypes that—together with CD4+and CD8+T cells—contributed to anti-tumour efficacy. These data support the use of chemo-immunotherapy with dual ICB to mitigate resistance to PD-(L)1 inhibition in patients with NSCLC who have STK11and/or KEAP1alterations.

Copyright of KI - Kälte Luft Klimatechnik is the property of Hüthig GmbH and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Laser beam melting is an additive manufacturing process that enables the production of highly complex components. In this process, metal powder is locally melted using a laser beam and built up layer by layer to form a physical component. Due to the layer-by-layer process manufacturing technique of the additive manufacturing process, the microstructure of a laser-melted 316L austenitic stainless steel differs from that of a conventionally cast material. For brazing technology, the different microstructure morphology is important because it affects the known wetting and diffusion behavior with a brazing filler metal, which affects the ability to produce high-strength brazed joints. Brazeability can be determined by examining the wetting of the brazing filler metal with the material to be joined. Therefore, this study investigates the wetting behavior of nickel-base brazing alloy BNi-5a on conventionally cast and laser-melted 316L austenitic stainless steel. Wetting tests were performed to evaluate the spreading area and wetting angle of BNi-5a on both 316L substrates. The wetting tests were performed in a high-temperature vacuum furnace at 1190 °C for 15 min. The results show that the laser-melted 316L stainless steel exhibits enhanced wettability compared to the conventionally cast material. This is related to a higher surface energy and a more pronounced diffusion mechanism called grain boundary grooving on the surface of the material.

The quantum-mechanical nuclear-shell structure determines the stability and limits of the existence of the heaviest nuclides with large proton numbers Z≳ 100 (refs. 1–3). Shell effects also affect the sizes and shapes of atomic nuclei, as shown by laser spectroscopy studies in lighter nuclides4. However, experimental information on the charge radii and the nuclear moments of the heavy actinide elements, which link the heaviest naturally abundant nuclides with artificially produced superheavy elements, is sparse5. Here we present laser spectroscopy measurements along the fermium (Z= 100) isotopic chain and an extension of data in the nobelium isotopic chain (Z= 102) across a key region. Multiple production schemes and different advanced techniques were applied to determine the isotope shifts in atomic transitions, from which changes in the nuclear mean-square charge radii were extracted. A range of nuclear models based on energy density functionals reproduce well the observed smooth evolution of the nuclear size. Both the remarkable consistency of model prediction and the similarity of predictions for different isotopes suggest a transition to a regime in which shell effects have a diminished effect on the size compared with lighter nuclei.

Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential mediator of the IL-1R and TLR signaling pathways, both of which have been implicated in multiple autoimmune conditions. Hence, blocking the activity of IRAK4 represents an attractive approach for the treatment of autoimmune diseases. The activity of this serine/threonine kinase is dependent on its kinase and scaffolding activities; thus, degradation represents a potentially superior approach to inhibition. Herein, we detail the exploration of structure–activity relationships that ultimately led to the identification of KT-474, a potent, selective, and orally bioavailable heterobifunctional IRAK4 degrader. This represents the first heterobifunctional degrader evaluated in a nononcology indication and dosed to healthy human volunteers. This molecule successfully completed phase I studies in healthy adult volunteers and patients with atopic dermatitis or hidradenitis suppurativa. Phase II clinical trials in both of these indications have been initiated.

The need for echocardiography in pediatric Staphylococcus aureusbacteremia (SAB) remains uncertain. We reviewed 331 pediatric SAB cases. Nine subjects, all with comorbidities, met the echocardiogram criteria for infective endocarditis (IE). IE was associated with congenital heart disease and prolonged bacteremia, suggesting that echocardiography is unnecessary in most children with SAB.Consensus does not exist regarding the use of echocardiography in children with Staphylococcus aureusbacteremia (SAB). Among 331 pediatric SAB cases, 140/331 (42%) underwent an echocardiogram with 9/140 (6%) diagnosed with infective endocarditis (IE). We identified variables associated with echocardiogram-positive IE, guiding the utilization of this test.

ABSTRACTPartial hospital programs (PHPs) represent an important part of the continuum of care for youth with severe and/or refractory OCD, yet little is known about clinical or utilization outcomes in this setting. The current study aimed to characterize symptom improvement and length of stay (LOS) among 185 youth with OCD treated in a PHP setting and to identify demographic, clinical, and treatment characteristics that predict these outcomes. Results demonstrate a 77.3% treatment response rate and a median LOS of 52 days. Holding other predictors constant, less symptom improvement was observed for youth with lower symptom severity at admission, in a racial or ethnic minoritized group, without comorbid anxiety, and receiving more treatment hours per day. Shorter LOS was observed among youth with public (vs. commercial) insurance, receiving more hours of treatment per day, and not taking a serotonin reuptake inhibitor (SRI). Clinical implications and directions for future research are discussed, including a critical need to understand and improve outcomes for minoritized youth.

We study the role of underlying substrates on interfacial heat transfer within supported graphene nanochannels. Due to graphene’s translucency, the underlying substrate, apart from its known hydrodynamic impact on fluid flow, also influences heat transport. We introduce the term “thermal translucency” to describe this phenomenon in the context of interfacial heat transfer. Our findings reveal that the Kapitza resistance, RK, is dependent on the specific underlying substrate. The specific underlying substrate alters the water–graphene interface potential landscape due to graphene’s translucency, leading to a breakdown in the inverse relationship between interfacial water density peaks and RKvalues, typically observed at water–graphene and water–graphite interfaces. Remarkably, higher interfacial water density peaks correlate with more ordered energy patterns, not necessarily tied to more hydrophilic substrates as the literature commonly suggests for lower RKvalues. The insights provided have implications for controlling and tuning thermal transport and heat storage in nanofluidic devices.

The soluble urokinase-type plasminogen activator receptor (suPAR) potentially plays a role in immune-thrombosis, possibly by modulating plasmin activity or contributing to chemotaxis in a complex, poorly understood context. The role of suPAR levels in the short-term prognostic of patients with pulmonary embolism (PE) has not been evaluated.

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.

Most utilities have a state-of-the-art enterprise asset management system to manage and maintain their equipment. However, collecting and analyzing good data can be challenging and if not done properly, hinder [...]

Waterborne resins are important for coatings and adhesives, yet the field of reprocessable covalent adaptable networks (CANs) is dominated by hydrophobic materials. Here, we introduce waterborne CANs that feature dual internal catalysis, dissociative bond exchange, and customizable properties through specific selection of different cross-linkers. The system uses random copolymers based on aspartic acid, which can catalyze formation and exchange of dynamic covalent ester bonds. Cross-linker variation enables vast differences in thermoresponsive properties: diols with a tertiary amine feature the fastest bond exchange and stress relaxation and enable ductile mechanical behavior in ambient conditions. Amine-containing triols instead lead to high nonelastic deformation resistance, linked to, e.g., creep, by slowing stress relaxation until high temperatures. Aliphatic diols exhibit low exchange kinetics while affording glassy mechanical behavior. Our CAN-prepolymer/cross-linker systems offer great potential for aqueous applications due to their good recyclability and excellent tunability, as further demonstrated by their incorporation in waterborne bioinspired nanocomposites.

For the metastable austenitic steel AISI 347 (X6CrNiNb18-10), various electropolishing parameters were evaluated by means of hardness testing, electron backscatter diffraction (EBSD), and atomic force microscopy. Depending on the chosen parameters, different surface characteristics could be achieved simply by only varying voltage, flow rate, and polishing time, although EBSD indexing was always possible. Differences in hardness of up to 20 HV0.5 and in microscopic roughness could be detected on otherwise comparable samples. Finally, the microstructure distribution of a hot rolled bar material with a diameter of 153 mm made from AISI 347 was characterized over the cross section using the previously determined parameter set. Here, insights about recrystallization during forming were concluded and δ-ferrite was differentiated from α’-martensite by kernel average misorientation and morphology.

As climate change and resource scarcity intensify, the need for energy efficiency, emissions reduction, and resource conservation grows. Forming technology offers significant potential for light weighting, cost and resource efficiency. However, current component design often neglects forming-related damage, such as voids, focusing primarily on mechanical properties and safety factors. Integrating knowledge of these voids into the design process can improve efficiency and increase light weighting potential. Advanced scanning electron methods, such as electron contrast channeling imaging, evaluated forming-induced damage and correlated it with fatigue properties. Crack initiation occurred mainly near manganese sulfide inclusions or near-surface voids, influencing crack propagation. Analyzing void distribution using advanced secondary electron methods enabled the development of a 3D volume model.

In this article, the development of MoBeMeG, a modular device for bending-corrosion-fatigue investigations and variable specimen geometry in corrosive media with galvanic isolation between the test chamber and the test system, is presented. The main application is the investigation of hybrid laminates with high potential for galvanic corrosion, e.g., aluminum ∪ carbon fiber–reinforced plastics, focusing on the description of failure mechanisms and failure evolution at the interface under the influence of bending-corrosion-fatigue loading. The anvil distances are adjustable for the application of varying specimen geometries while retaining the full functionality of the test chamber and securing a full flexible testing possibility without the necessity of new constructions. The test engineering development results in considerable time savings as well as unparalleled efficiency enhancement in terms of bending-corrosion-fatigue performance assessments.

Gene therapies represent promising new therapeutic options for a variety of indications. However, despite several approved drugs, its potential remains untapped. For polymeric gene delivery, endosomal escape represents a bottleneck. SO1861, a naturally occurring triterpene saponin with endosomal escape properties isolated from Saponaria officinalisL., has been described as additive agent to enhance transfection efficiency (sapofection). However, the challenge to synchronize the saponin and gene delivery system in vivoimposes limitations. Herein, we address this issue by conjugating SO1861 to a peptide-based gene vector using a pH-sensitive hydrazone linker programmed to release SO1861 at the acidic pH of the endosome. Nanoplexes formulated with SO1861-equipped peptides were investigated for transfection efficiency and tolerability in vitroand in vivo. In all investigated cell lines, SO1861-conjugated nanoplexes have shown superior transfection efficiency and cell viability over supplementation of transfection medium with free SO1861. Targeted SO1861-equipped nanoplexes incorporating a targeting peptide were tested in vitroand in vivoin an aggressively growing neuroblastoma allograft model in mice. Using a suicide gene vector encoding the cytotoxic protein saporin, a slowed tumor growth and improved survival rate were observed for targeted SO1861-equipped nanoplexes compared to vehicle control.

Antibacterial formulations based on zinc oxide nanoparticles (ZnO NPs) are widely used for antibiotic replacement in veterinary medicine and animal nutrition. However, the undesired environmental impact of ZnO NPs triggers a search for alternative, environmentally safer solutions. Here, we show that Zn2+in its ionic form is a more eco-friendly antibacterial, and its biocidal action rivals that of ZnO NPs (<100 nm size), with a minimal biocidal concentration being 41(82) μg mL–1vs 5 μg mL–1of ZnO NPs, as determined for 103(106) CFU mL–1E. coli. We demonstrate that the biocidal activity of Zn2+ions is primarily associated with their uptake by E. coliand spontaneous in vivo transformation into insoluble ZnO nanocomposites at an internal bacterial pH of 7.7. Formed in vivo nanocomposite then damages E. colimembrane and intracellular components from the inside, by forming insoluble biocomposites, whose formation can also trigger ZnO characteristic reactions damaging the cells (e.g., by generation of high-potential reactive oxygen species). Our study defines a special route in which Zn2+metal ions induce the death of bacterial cells, which might be common to other metal ions capable of forming semiconductor oxides and insoluble hydroxides at a slightly alkaline intracellular pH of some bacteria.

Despite a distinct developmental origin, extraembryonic cells in mice contribute to gut endoderm and converge to transcriptionally resemble their embryonic counterparts. Notably, all extraembryonic progenitors share a non-canonical epigenome, raising several pertinent questions, including whether this landscape is reset to match the embryonic regulation and if extraembryonic cells persist into later development. Here we developed a two-colour lineage-tracing strategy to track and isolate extraembryonic cells over time. We find that extraembryonic gut cells display substantial memory of their developmental origin including retention of the original DNA methylation landscape and resulting transcriptional signatures. Furthermore, we show that extraembryonic gut cells undergo programmed cell death and neighbouring embryonic cells clear their remnants via non-professional phagocytosis. By midgestation, we no longer detect extraembryonic cells in the wild-type gut, whereas they persist and differentiate further in p53-mutant embryos. Our study provides key insights into the molecular and developmental fate of extraembryonic cells inside the embryo.

In the United States, copyright owners retain exclusive rights to their creative works. They alone have the legal right to reproduce, distribute, publicly perform, or publicly display their works or to construct derivative works. The recently enacted Digital Millennium Copyright Act has created several complex questions related to distance education for which higher education institutions must quickly search for procedural answers. This Digest poses and answers four questions that challenge basic knowledge of current copyright law and typify current concerns in institutions of higher education. Questions include whether or not movies may legally be shown as part of distance education course offerings, who holds intellectual property rights to a distance education course constructed by faculty, what intellectual property right individuals should pursue when creating distance education materials, and whether faculty may legally distribute to distance education students electronic copies of materials that would normally be placed on reserve for them in the school's library. (PW)

Developments due to the rapid expansion of technology have resulted in recent changes to U.S. copyright law. President Clinton signed the Digital Millennium Copyright Act into law in 1998, an action that reflects the growing interest our society, and especially higher education, is experiencing in copyright and other intellectual property issues. This digest offers a brief overview of some of the current intellectual property issues related to patents, licenses, and copyright. (JM)

We investigated the role of ligand clustering and density in the activation of natural killer (NK) cells. To that end, we designed reductionist arrays of nanopatterned ligands arranged with different cluster geometries and densities and probed their effects on NK cell activation. We used these arrays as an artificial microenvironment for the stimulation of NK cells and studied the effect of the array geometry on the NK cell immune response. We found that ligand density significantly regulated NK cell activation while ligand clustering had an impact only at a specific density threshold. We also rationalized these findings by introducing a theoretical membrane fluctuation model that considers biomechanical feedback between ligand–receptor bonds and the cell membrane. These findings provide important insight into NK cell mechanobiology, which is fundamentally important and essential for designing immunotherapeutic strategies targeting cancer.

Iatrogenic bile duct injury (BDI) during cholecystectomy is associated with a complex and heterogeneous management owing to the burden of morbidity until their definitive treatment. This study aimed to define the textbook outcomes (TOs) after BDI with the purpose to indicate the ideal treatment and to improve it management.

Copyright of Sächsische Verwaltungsblätter (SächsVBl.) is the property of Richard Boorberg Verlag GmbH & Co KG and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Fuel-driven dissipative formation of disulfide bonds using competing oxidative activation and reductive deactivation presents a possibly very versatile avenue for autonomous materials design. However, this is challenging to realize because of the direct annihilation of oxidizing fuel and a deactivating reducing agent. We overcome this challenge by introducing a redox-based enzymatic reaction network (ERN), enabling the dissipative disulfide formation for molecularly dissolved thiols in a fully autonomous manner. Moreover, the ERN allows for programming hydrogel lifetimes by utilizing thiol-terminated star polymers (sPEG-SH). The ERN can be customized to operate with aliphatic and aromatic thiols and should thus be broadly applicable to functional thiols.

Introduction Irregular warfare presents unique challenges for intelligence professionals who support efforts at the tactical, operational, and strategic levels. U.S. doctrine defines irregular warfare as a 'violent struggle among state [...]

(Abstracted from Prenatal Diagnosis2023;43:1622–1637)Congenital diseases often have a significant impact on individuals both prenatally and postbirth, and treatment options are quite limited until after delivery. In utero stem cell transplantation (IUSCT) is one method that can be used to treat congenital diseases prenatally, and primarily use hematopoietic or mesenchymal stem cells.

Fast and reliable evaluation of degradation and performance of cathode active materials (CAMs) for solid-state batteries (SSBs) is crucial to help better understand these systems and enable the synthesis of well-performing CAMs. However, there is a lack of well-thought-out procedures to reliably evaluate CAMs in SSBs. Current approaches often rely on X-ray photoelectron spectroscopy (XPS) for the evaluation of degradation. Unfortunately, XPS sensitivity is not very high, and minor but relevant degradation products may not be detected and distinguished. Furthermore, degradation caused by the current collector (CC) itself is usually not distinguished from CAM-induced degradation. This study uses a modified CC, which allows us to separate electrochemical degradation caused by the CC from degradation at the CAM itself. Using this CC, we present an approach using time-of-flight secondary ions mass spectrometry (ToF-SIMS) that offers high sensitivity and reliability. Principal component analysis (PCA) is applied to differentiate secondary ions as well as identify those mass fragments that correlate with degradation products. This approach also enables distinguishing between different pathways of degradation. To evaluate the kinetic performance of the samples, three-electrode rate tests are performed. Electrochemical characterization evaluates the kinetic performance of the samples under investigation. The samples are finally rated with a score that allows a reliable comparison between the different materials and offers a complete picture of the materials′ characteristics in terms of electrochemical performance and degradation.

The Coulomb interactions in molecular simulations are inherently approximated due to the finite size of the molecular box sizes amenable to current-day compute power. Several methods exist for treating long-range electrostatic interactions, yet these approaches are subject to various finite-size-related artifacts. Lattice-sum methods are frequently used to approximate long-range interactions; however, these approaches also suffer from artifacts which become particularly pronounced for free-energy calculations that involve charge changes. The artifacts, however, also affect the sampling when plain simulations are performed, leading to a biased ensemble. Here, we investigate two previously described model systems to determine if artifacts continue to play a role when overall neutral boxes are considered, in the context of both free-energy calculations and sampling. We find that ensuring that no net-charge changes take place, while maintaining a neutral simulation box, may be sufficient provided that the simulation boxes are large enough. Addition of salt to the solution (when appropriate) can further alleviate the remaining artifacts in the sampling or the calculated free-energy differences. We provide practical guidelines to avoid finite-size artifacts.

SARS-CoV-2 vaccination has reduced hospitalization and mortality for nursing home residents (NHRs) but emerging variants and waning immunity challenge vaccine effectiveness. This study assesses the immunogenicity of the most recent XBB.1.5 monovalent vaccine to variant strains among NHRs. Participants were subset of a longitudinal study of consented NHRs and Healthcare workers (HCWs) who have received serial blood draws to assess immunogenicity with each SARS-CoV-2 mRNA vaccine dose. We report data on participants who received the XBB.1.5 monovalent vaccine post-FDA approval in Fall 2023. NHRs were categorized by whether they had an interval SARS-CoV-2 infection between their first bivalent vaccine dose and their XBB.1.5 monovalent vaccination. The sample included 61 NHRs [median age 76 (IQR 68–86), 51% female] and 28 HCWs [median age 45 (IQR 31–58), 46% female). After XBB.1.5 vaccination, a robust geometric mean fold rise (GMFR) in XBB.1.5-specific neutralizing antibody titers was observed:17.3 (95% confidence interval [CI] 9.3, 32.4) and NHRs with interval infection and 11.3 (95% CI 5, 25.4) in those without and 13.6 (95% CI 8.4,22) in HCWs. For JN.1-specific titers, GMFRs were 14.9 (95% CI 7.9, 28) and 6.5 (95% CI 3.3, 13.1) in NHRs with and without interval infection, and 11.4 (95% CI 6.2, 20.9) in HCWs. NHRs with interval SARS-CoV-2 infection had higher titers across all analyzed strains analyzed. The XBB.1.5 vaccine significantly elevates Omicron-specific neutralizing antibody titers to XBB.1.5 and JN.1 strains in both NHRs and HCWs with more pronounced in those previously infected with SARS-CoV-2 since bivalent vaccination.

Objective: This study investigates the mediating role of rumination in the relationship between work-related stress and sleep quality. Sleep quality is a critical component of mental health and wellbeing. Work-related stress is a potential risk factor for poor sleep quality, and this research focuses on how the constructs of rumination—affective rumination, detachment, and problem-solving rumination—may mediate this association. Methods: Data from the Dresden Burnout Study were analyzed cross-sectionally and longitudinally over three timepoints. The sample included 360 full- and parttime employees. Work-related stress was assessed using the effort–reward Imbalance Questionnaire, sleep quality using the Pittsburgh Sleep Quality Index, and rumination using the Work-Related Rumination Questionnaire. Results: The study found that work-related stress was positively correlated with reduced sleep quality, both cross-sectionally and longitudinally. In addition, work-related stress predicted increased levels of affective rumination and detachment but not of problem-solving rumination. Affective rumination and detachment partially mediated the relationship between work-related stress and sleep quality, suggesting that individuals who experience higher levels of work-related stress are more likely to engage in ruminative thoughts about their work experiences, which, in turn, leads to reduced sleep quality. Conclusion: These findings highlight the importance of considering cognitive processes such as rumination when addressing sleep disturbance related to work stress. Future research should include objective measures of sleep quality and consider shorter intervals to capture immediate changes in stress and sleep patterns. By addressing these factors, healthcare professionals can better support those suffering from sleep disturbance due to work-related stress. Ultimately, this may have a positive impact on their overall wellbeing and productivity at work.

Organoids are transformative in vitro model systems that mimic features of the corresponding tissue in vivo. However, across tissue types and species, organoids still often fail to reach full maturity and function because biochemical cues cannot be provided from within the organoid to guide their development. Here we introduce nanoengineered DNA microbeads with tissue mimetic tunable stiffness for implementing spatio-temporally controlled morphogen gradients inside of organoids at any point in their development. Using medaka retinal organoids and early embryos, we show that DNA microbeads can be integrated into embryos and organoids by microinjection and erased in a non-invasive manner with light. Coupling a recombinant surrogate Wnt to the DNA microbeads, we demonstrate the spatio-temporally controlled morphogen release from the microinjection site, which leads to morphogen gradients resulting in the formation of retinal pigmented epithelium while maintaining neuroretinal cell types. Thus, we bioengineered retinal organoids to more closely mirror the cell type diversity of in vivo retinae. Owing to the facile, one-pot fabrication process, the DNA microbead technology can be adapted to other organoid systems for improved tissue mimicry.

Cellulose-based biocomposites, such as Cottonid, are a promising class of materials to improve the carbon footprint of products during their service life. Cottonid has high technological potential due to its physical and mechanical similarities to engineering plastics and light metals. To replace traditional metallic materials in industry, cellulose-based semi-finished products need to be formed and cut. In particular, blanking is the most cost-effective and industrially common cutting method for metals. However, this study investigates the influence of various blanking process parameters on the quality and the fatigue strength of the resulting cutting edges of Cottonid. The presented results give insights on how the relationships between process parameters during cutting and resulting material properties known from conventional materials can be transferred to cellulose-based biocomposites like Cottonid. The relative clearance was varied between 4 and 10% and the cutting velocity between 0.05 and 10 m/s. It was evident that slower velocities and smaller clearances resulted in visibly better cutting edges. In order to relate this effect to the mechanical performance of Cottonid, new 3-point bend specimens were taken from the blanked strips for fatigue testing. It was found that the fatigue strength was significantly affected by the velocity and clearance. Further, similar to metallic materials, clean-cut (smooth area) and a fractured zone can be clearly distinguished. A good cutting edge quality results in a higher resistance of the Cottonid component against crack initiation at process-induced defects. The knowledge gained may enable an efficient cutting process for cellulose-based materials with higher fatigue strength in the future.

We demonstrate a novel transmitter concept for quantum key distribution based on the polarization-encoded BB84 protocol, which is sourced by the incoherent light of a forward-biased Ge-on-Si PIN junction. We investigate two architectures for quantum state preparation, including independent polarization encoding through multiple modulators and a simplified approach leveraging on an interferometric polarization modulator. We experimentally prove that the Ge-on-Si light source can accommodate for quantum key generation by accomplishing raw-key rates of 2.15 kbit/s at a quantum bit error ratio of 7.71% at a symbol rate of 1 GHz. We further investigate the impact of depolarization along fiber-based transmission channels in combination with the broadband nature of the incoherent light source. Our results prove the feasibility of a fully-integrated silicon quantum key distribution transmitter, including its light source, for possible short-reach applications in zero-trust intra-datacenter environments.

We characterize the (regular) holonomicity of Horn systems of differential equations under a hypothesis that captures the most widely studied classical hypergeometric systems.

Human microbiomes, particularly in the gut, could have a major impact on the efficacy and toxicity of drugs. However, gut microbial metabolism is often neglected in the drug discovery and development process. Medicen, a Paris-based human health innovation cluster, has gathered more than 30 international leading experts from pharma, academia, biotech, clinical research organizations, and regulatory science to develop proposals to facilitate the integration of microbiome science into drug discovery and development. Seven subteams were formed to cover the complementary expertise areas of 1) pharma experience and case studies, 2) in silico microbiome–drug interaction, 3) in vitro microbial stability screening, 4) gut fermentation models, 5) animal models, 6) microbiome integration in clinical and regulatory aspects, and 7) microbiome ecosystems and models. Each expert team produced a state-of-the-art report of their respective field highlighting existing microbiome-related tools at every stage of drug discovery and development. The most critical limitations are the growing, but still limited, drug–microbiome interaction data to produce predictive models and the lack of agreed-upon standards despite recent progress. In this paper we will report on and share proposals covering 1) how microbiome tools can support moving a compound from drug discovery to clinical proof-of-concept studies and alert early on potential undesired properties stemming from microbiome-induced drug metabolism and 2) how microbiome data can be generated and integrated in pharmacokinetic models that are predictive of the human situation. Examples of drugs metabolized by the microbiome will be discussed in detail to support recommendations from the working group.SIGNIFICANCE STATEMENTGut microbial metabolism is often neglected in the drug discovery and development process despite growing evidence of drugs’ efficacy and safety impacted by their interaction with the microbiome. This paper will detail existing microbiome-related tools covering every stage of drug discovery and development, current progress, and limitations, as well as recommendations to integrate them into the drug discovery and development process.

Converging evidence indicates that deep neural network models that are trained on large datasets are biased toward color and texture information. Humans, on the other hand, can easily recognize objects and scenes from images as well as from bounding contours. Mid-level vision is characterized by the recombination and organization of simple primary features into more complex ones by a set of so-called Gestalt grouping rules. While described qualitatively in the human literature, a computational implementation of these perceptual grouping rules is so far missing. In this article, we contribute a novel set of algorithms for the detection of contour-based cues in complex scenes. We use the medial axis transform (MAT) to locally score contours according to these grouping rules. We demonstrate the benefit of these cues for scene categorization in two ways: (i) Both human observers and CNN models categorize scenes most accurately when perceptual grouping information is emphasized. (ii) Weighting the contours with these measures boosts performance of a CNN model significantly compared to the use of unweighted contours. Our work suggests that, even though these measures are computed directly from contours in the image, current CNN models do not appear to extract or utilize these grouping cues.

Der vorliegende Beitrag fokussiert psychosoziale Unterstützungsmöglichkeiten für an Krebs Erkrankte im Prozess ihrer Rückkehr oder ihrem Verbleib in Erwerbstätigkeit. Sozialrechtliche Fragestellungen spielen dabei eine wichtige Rolle – entsprechende Informationsdefizite können weitreichende, auch die finanzielle Existenz bedrohende Folgen nach sich ziehen. Im Folgenden wird skizziert, welche Unterstützungen Betroffene in den Institutionen Akutkrankenhaus, Rehabilitationseinrichtung und ambulante Beratungsstellen im Hinblick auf ihre berufliche Wiedereingliederung erhoffen können, aber auch, welche Herausforderungen sich jeweils stellen bzw. für eine verbesserte Unterstützung zwingend angegangen werden müssen.