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Objectives: The United Nations recognize the importance of balancing the needs of people and the planetary systems on which human health relies. This paper investigates the role that climate change has on human health via its influence on climate anxiety. Design: We conducted an intensive longitudinal study. Methods: Participants reported levels of climate anxiety, generalized anxiety and an array of health behaviours at 20 consecutive time points, 2 weeks apart. Results: A network analysis shows climate anxiety and generalized anxiety not to covary, and higher levels of climate anxiety not to covary with health behaviours, except for higher levels of alcohol consumption at the within‐participant level. Generalized anxiety showed completely distinct patterns of covariation with health behaviours compared with climate anxiety. Conclusions: Our findings imply that climate anxiety, as conceptualized and measured in the current study, is not in itself functionally impairing in terms of associations with unhealthy behaviours, and is distinct from generalized anxiety. The results also imply that interventions to induce anxiety about the climate might not always have significant impacts on health and well‐being. [ABSTRACT FROM AUTHOR]

Diffuse large B‐cell lymphoma (DLBCL) is the most common lymphoma entity, and its incidence increases with age. There is a paucity of data regarding use of biweekly R‐CHOP (R‐CHOP‐14) in patients ≥80 years of age. We performed a retrospective cohort study of patients with DLBCL aged ≥80 years treated with R‐CHOP‐14 and R‐miniCHOP in two academic tertiary centers in Germany between 01/01/2005 and 12/30/2019. Overall, 79 patients were included. Median age was 84 years (range 80–91). Despite higher CR rates with R‐CHOP‐14 (71.4% vs. 52.4%), no statistically significant difference could be found between patients treated with R‐CHOP‐14 and R‐miniCHOP regarding overall survival (OS) (p =.88, HR 0.94, 95% CI = 0.47–1.90) and progression‐free survival (PFS) (p =.26, HR 0.66, 95% CI = 0.32–1.36). At a median follow‐up of 40 months, the 2‐year OS rates were 56% with R‐CHOP‐14 and 53% with R‐miniCHOP. Two‐year PFS rates were 46% for R‐CHOP‐14 and 50% for R‐mini‐CHOP. Relative dose intensity of chemotherapy did not correlate with OS (p =.72). With the caveat of a retrospective cohort study, we conclude that lacking a difference in OS, R‐miniCHOP should be preferred for most patients with untreated DLBCL aged ≥80 years. [ABSTRACT FROM AUTHOR]

SUMMARY: Cyst nematodes establish permanent feeding structures called syncytia inside the host root vasculature, disrupting the flow of water and minerals. In response, plants form WOX11‐mediated adventitious lateral roots at nematode infection sites. WOX11 adventitious lateral rooting modulates tolerance to nematode infections; however, whether this also benefits nematode parasitism remains unknown. Here, we report on bioassays using a 35S::WOX11‐SRDX transcriptional repressor mutant to investigate whether WOX11 adventitious lateral rooting promotes syncytium development and thereby female growth and fecundity. Moreover, we chemically inhibited cellulose biosynthesis to verify if WOX11 directly modulates cell wall plasticity in syncytia. Finally, we performed histochemical analyses to test if WOX11 mediates syncytial cell wall plasticity via reactive oxygen species (ROS). Repression of WOX11‐mediated transcription specifically enhanced the radial expansion of syncytial elements, increasing both syncytium size and female offspring. The enhanced syncytial hypertrophy observed in the 35S::WOX11‐SRDX mutant could be phenocopied by chemical inhibition of cellulose biosynthesis and was associated with elevated levels of ROS at nematode infection sites. We, therefore, conclude that WOX11 restricts radial expansion of nematode‐feeding structures and female growth and fecundity, likely by modulating ROS‐mediated cell wall plasticity mechanisms. Remarkably, this novel role of WOX11 in plant cell size control is distinct from WOX11 adventitious lateral rooting underlying disease tolerance. Significance Statement: In this study, we uncover a novel role for WOX11 in Arabidopsis, which may help plants cope with infections by endoparasitic cyst nematodes in the field. By controlling plant cell size, WOX11 significantly limits the expansion of nematode feeding sites, ultimately reducing nematode offspring size. [ABSTRACT FROM AUTHOR]

The effective replication of microtubular structures in tissue engineering remains a great challenge. In this study, the temperature‐responsive characteristics of poly(N‐isopropylacrylamide) (pNIPAM) to create intricate, high‐resolution tubular structures through a shrinking mechanism is investigated by exploring 2 thermosensitive hydrogels–gelatin methacryloyl (gelMA) and silk fibroin methacryloyl (silkMA)–combined with pNIPAM. Systematic investigations revealed precise control of shrinking behavior at elevated temperatures (33–37 °C) as a function of polymer concentration. The hydrogel sizes reduce by ≈15% from room temperature (RT) to 33 °C and ≈40% from RT to 37 °C for both hydrogel types. The shrinking affects the mechanical properties, increasing the compressive modulus by ≈2.8‐fold for gelMA‐pNIPAM gels and ≈5.1‐fold for silkMA‐pNIPAM gels at 37 °C. Combined with volumetric printing, these materials achieve resolution enhancements of ≈20% for positive features and ≈70% for negative features, enabling the creation of complex, high‐resolution structures within seconds, with open channels (≈50 µm). GelMA‐pNIPAM hydrogels show better cell compatibility compared to silkMA‐pNIPAM hydrogels, promoting cell adhesion and viability. This study demonstrates the thermosensitive hydrogels' capability to engineer intricate, high‐resolution tubular structures with volumetric printing–an efficient route to fabricate microenvironments mimicking native tissues with potential for developing relevant in vitro models. [ABSTRACT FROM AUTHOR]

A crucial aspect of human social competence is the ability to spontaneously and rapidly infer from facial cues whether others are likely to approach us with friendliness or hostility—that is, trustworthiness. The rapid and automatic nature of these inferences has prompted the claim that they may originate from evolutionary pressures to detect potential threats, thus enhancing our chances of survival. However, the developmental origins of this social skill remain a topic of ongoing debate. Recent evidence shows that infants' brains and looking time behaviors differentiate between faces varying along the trustworthiness continuum, but the question about the nature of the facial cues they rely on remains open. In this review, we propose the spatial frequency (SF) filtering approach (i.e., the selective removal of spatial frequency bands from the image) as a useful tool for investigating this question, and specifically whether infants' discrimination of facial expressions of emotion share common visual and neural mechanisms with discrimination of facial cues associated with trustworthiness inferences. The SF filtering approach could shed light on the neural and perceptual mechanisms underlying trustworthiness perception in infancy, providing insights into whether and how these mechanisms change across development. The evidence gathered through this method would prove critical to the understanding of the developmental origins of trustworthiness perception. [ABSTRACT FROM AUTHOR]

Background: Severely ill patients with coronavirus disease 2019 (COVID‐19) show an increased risk of new‐onset atrioventricular blocks (AVBs), associated with high rates of short‐term mortality. Recent data suggest that the uncontrolled inflammatory activation observed in these patients, specifically interleukin (IL)‐6 elevation, may play an important pathogenic role by directly affecting cardiac electrophysiology. The aim of our study was to assess the acute impact of IL‐6 changes on electrocardiographic indices of atrioventricular conduction in severe COVID‐19. Methods: We investigated (1) the behavior of PR‐interval and PR‐segment in patients with severe COVID‐19 during active phase and recovery, and (2) their association with circulating IL‐6 levels over time. Results: During active disease, COVID‐19 patients showed a significant increase of PR‐interval and PR‐segment. Such atrioventricular delay was transient as these parameters rapidly normalized during recovery. PR‐indices significantly correlated with circulating IL‐6 levels over time. All these changes and correlations persisted also in the absence of laboratory signs of cardiac strain/injury or concomitant treatment with PR‐prolonging drugs, repurposed or not. Conclusions: Our study provides evidence that in patients with severe COVID‐19 and high‐grade systemic inflammation, IL‐6 elevation is associated with a significant delay of atrioventricular conduction, independent of concomitant confounding factors. While transient, such alterations may enhance the risk of severe AVB and associated short‐term mortality. Our data provide further support to current anti‐inflammatory strategies for severe COVID‐19, including IL‐6 antagonists. [ABSTRACT FROM AUTHOR]

Objective: Women of childbearing age with juvenile absence epilepsy (JAE) face treatment challenges due to limited access to safe and effective anti‐seizure medications (ASMs). In a previous study we compared the effectiveness of levetiracetam (LEV) and lamotrigine (LTG) in women with idiopathic generalized epilepsy (IGE), highlighting a superiority of LEV in juvenile myoclonic epilepsy. In this study, we specifically reanalyzed, through a Bayesian approach and by expanding the previously published cohort, the comparative effectiveness of these ASMs as initial monotherapy in JAE. Methods: We conducted a multicenter, retrospective, comparative effectiveness study on women of childbearing age diagnosed with JAE and prescribed LEV or LTG as the initial ASM. Inverse probability treatment weighting (IPTW) Bayesian Cox proportional hazard models were employed to evaluate treatment failure (TF) due to ineffectiveness and ASM retention. The patients' center of provenance and year of prescription were considered as random effect factors. Posterior probabilities and relative log‐risk distribution were computed, and the distribution of posterior draws was analyzed to assess the evidence supporting LTG superiority over LEV. Results: Of 123 patients, those treated with LTG (n = 67) demonstrated lower TF and higher ASM retention than those treated with LEV (n = 56), with the IPTW‐weighted Bayesian Cox proportional hazards model showing a 99.2% posterior probability of LTG being superior on TF and a 99.5% probability on ASM retention. Additional analyses on ≥50% and ≥75% seizure reduction through IPTW‐weighted Bayesian logistic regression largely confirmed these findings, whereas the two ASMs did not show evident differences in terms of seizure freedom. The two ASMs showed comparable safety profiles, with only a minority of patients discontinuing treatment due to side effects. Significance: Bayesian reanalysis supports LTG as first‐line monotherapy for JAE in women of childbearing age, emphasizing the importance of individualized treatment strategies in women with IGE. This study underscores the value of Bayesian methods in refining clinical research and treatment decisions. [ABSTRACT FROM AUTHOR]

Aim: To explore parental perceptions of the consenting process and understanding of the study in a pilot randomised controlled trial wherein extremely premature infants (<29 weeks' gestation) were recruited either antenatally or by 4 h of life. Methods: We prospectively surveyed parents who had consented, declined consent or were eligible infants in the Positioning Preterm Infants for Neuroprotection study, a low‐risk intervention study in the first 72 h of life. Structured interview questions explored the process and acceptability of the consenting approach by the parents and their knowledge of the study. Additional comments made by the parents were transcribed verbatim. Results: Sixty‐two parents participated in the surveys; of those, 41 had provided their consent, 8 declined consent and 13 were parents of missed eligible infants. Overall, most parents reported they understood the study well before providing their consent and approaching them for consenting did not create a burden for them. A verbal explanation of the study by the study team, especially by the medical practitioners, was viewed as beneficial. Where consent was obtained in the birthing unit (imminent births and within 4 h of birthing), it was suggested that the 4‐h period for obtaining post‐natal consent may be too short. A deferred consent with a follow‐up opportunity for obtaining informed consent could be a suitable alternative. Conclusion: Parents found the consenting process acceptable and indicated they had sufficient understanding of the study to provide an informed consent. Deferred consent should be explored for future, low‐risk intervention studies as an alternative to prospective consent where extremely preterm infants need to be recruited in the immediate neonatal period. [ABSTRACT FROM AUTHOR]

Objective: Public health interventions promoted during the SARS‐CoV‐2 pandemic to control viral spread have impacted the occurrence of other communicable disease. Yet no studies have focused on perinatal infections with the potential for neonatal sequelae, including cytomegalovirus (CMV) and Toxoplasma gondii (TG). Here we investigate whether incidence rates of maternal primary CMV and TG infection in pregnancy were affected by the implementation of pandemic‐related public health measures. Methods: A retrospective study including all pregnant women with confirmed primary CMV or TG infection in pregnancy, managed between 2018 and 2021 at two university centers. The incidence rate was calculated as the number of CMV and TG infections per 100 consultations with a 95% confidence interval (CI). Data were compared between pre‐pandemic (2018–2019) and pandemic (2020 and 2021) years. The Newcombe Wilson with Continuity Correction method was employed to compare incidence rates. Results: The study population included 215 maternal primary CMV and 192 TG infections. Rate of maternal primary CMV infection decreased in 2021 compared with 2018–2019 (4.49% vs 6.40%, attributable risk [AR] 1.92, P = 0.019). By contrast, the rate of TG infection substantially increased in 2020 (6.95% vs 4.61%, AR 2.34, P = 0.006). Close contact with cats was more common among patients with TG infection in 2020 and 2021 than among pre‐pandemic TG‐infected women (26.3% and 24.4% vs 13.3%, P = 0.013). Conclusion: Pandemic‐related public health interventions and associated behavioral and lifestyle changes exerted a divergent effect on the incidence of primary CMV and TG infection in pregnancy, likely due to modulation of exposure to risk factors for these infections. Synopsis: Implementation of pandemic‐related public health measures and subsequent behavioral modifications exerted a divergent effect on the incidence of primary cytomegalovirus and Toxoplasma gondii infection in pregnancy. [ABSTRACT FROM AUTHOR]

Plant thioredoxins (TRXs) are involved in numerous metabolic and signalling pathways, such as light‐dependent regulation of photosynthesis. The atypical TRX CDSP32, chloroplastic drought‐induced stress protein of 32 kDa, includes two TRX‐fold domains and participates in responses to oxidative stress as an electron donor to other thiol reductases. Here, we further characterised potato lines modified for CDSP32 expression to clarify the physiological roles of the TRX. Upon high salt treatments, modified lines displayed changes in the abundance and redox status of CDSP32 antioxidant partners, and exhibited sensitivity to combined saline‐alkaline stress. In non‐stressed plants overexpressing CDSP32, a lower abundance of photosystem II subunits and ATP‐synthase γ subunit was noticed. The CDSP32 co‐suppressed line showed altered chlorophyll a fluorescence induction and impaired regulation of the transthylakoid membrane potential during dark/light and light/dark transitions. These data, in agreement with the previously reported interaction between CDSP32 and ATP‐synthase γ subunit, suggest that CDSP32 affects the redox regulation of ATP‐synthase activity. Consistently, modelling of protein complex 3‐D structure indicates that CDSP32 could constitute a suitable partner of ATP‐synthase γ subunit. We discuss the roles of the TRX in the regulation of both photosynthetic activity and enzymatic antioxidant network in relation with environmental conditions. Summary Statement: The atypical CDSP32 thioredoxin participates in the response to saline‐alkaline stress and in the activation of photosynthesis in Solanum tuberosum, likely by affecting the redox regulation of the γ subunit of ATP‐synthase complex. [ABSTRACT FROM AUTHOR]

Biopolymers offer vast potential for renewable and sustainable devices. While nature mastered the use of biopolymers to create highly complex 3D structures and optimized their photonic response, artificially created structures still lack nature's diversity. To bridge this gap between natural and engineered biophotonic structures, fundamental questions such as the natural formation process and the interplay of structural order and disorder must be answered. Herein, biological photonic structures and their characterization techniques are reviewed, focusing on those structures not yet artificially manufactured. Then, employed and potential nanofabrication strategies for biomimetic, bio‐templated, and artificially created biopolymeric photonic structures are discussed. The discussion is extended to responsive biopolymer photonic structures and hybrid structures. Last, future fundamental physics, chemistry, and nanotechnology challenges related to biopolymer photonics are foreseen. [ABSTRACT FROM AUTHOR]

Structural color originates from the interference of light with periodic structures that feature characteristic length scales on the order of the wavelength of visible light. Long‐range order in photonic structures usually causes iridescence, and increasing disorder renders colors angle‐independent. Random disorder distributes scattering intensity over all wavelengths, producing white in the absence of absorption. Various non‐iridescent, vivid color patterns are found in Sternotomini longhorn beetles. Herein, Sternotomis virescens is investigated, where elytral scales produce a green‐blue color pattern on otherwise black elytra. Combining focused ion beam scanning electron microscopy (FIB‐SEM) tomography, ultra‐small‐angle X‐ray scattering (USAXS), structural modeling, and full‐wave optical simulations, it is found that the color originates from amorphous photonic networks based on sub‐units resembling the I‐WP unit cell, a triply‐periodic minimal surface with body‐centered‐cubic symmetry. This work provides insights into how quasi‐order produces stable colors in S. virescens longhorn beetles, highlights the advantages of volumetric imaging using FIB‐SEM tomography of porous nanostructured materials, and raises interesting questions about the formation mechanisms of amorphous structures in vivo. [ABSTRACT FROM AUTHOR]

Nucleoside and nucleotide analogues have proven to be transformative in the treatment of viral infections and cancer. One branch of structural modification to deliver new nucleoside analogue classes explores replacement of canonical ribose oxygen with a sulfur atom. Whilst biological activity of such analogues has been shown in some cases, widespread exploration of this compound class is hitherto hampered by the lack of a straightforward and universal nucleobase diversification strategy. Herein, we present a synergistic platform enabling both biocatalytic nucleobase diversification from 4′‐thiouridine in a one‐pot process, and chemical functionalization to access new entities. This methodology delivers entry across pyrimidine and purine 4′‐thionucleosides, paving a way for wider synthetic and biological exploration. We exemplify our approach by enzymatic synthesis of 5‐iodo‐4′‐thiouridine on multi‐milligram scale and from here switch to complete chemical synthesis of a novel nucleoside analogue probe, 5‐ethynyl‐4′‐thiouridine. Finally, we demonstrate the utility of this probe to monitor RNA synthesis in proliferating HeLa cells, validating its capability as a new metabolic RNA labelling tool. [ABSTRACT FROM AUTHOR]

Small molecule/polymer semiconductor blends are promising solutions for the development of high‐performing organic electronics. They are able to combine ease in solution processability, thanks to the tunable rheological properties of polymeric inks, with outstanding charge transport properties thanks to high crystalline phases of small molecules. However, because of charge injection issues, so far such good performances are only demonstrated in ad‐hoc device architectures, not suited for high‐frequency applications, where transistor dimensions require downscaling. Here, the successful integration of the most performing blend reported to date, based on 2,7‐dioctyl[1] benzothieno[3,2‐b][1]benzothiophene (C8‐BTBT) and poly(indacenodithiophene‐co‐benzothiadiazole) (C16IDT‐BT), in OFETs characterized by channel and overlap lengths equal to 1.3 and 1.9 µm, respectively, is demonstrated, enabling a transition frequency of 23 MHz at ‐8 V. Two key aspects allowed such result: molecular doping, leading to width‐normalized contact resistance of only 260 Ωcm, allowing to retain an apparent field‐effect mobility as high as 3 cm2/(Vs) in short channel devices, and the implementation of a high capacitance dielectric stack, enabling the reduction of operating voltages below 10 V and the overcoming of self‐heating issues. These results represent a fundamental step for the future development of low‐cost and high‐speed printed electronics for IoT applications. [ABSTRACT FROM AUTHOR]

The ongoing search for small molecule drugs that target ribonucleic acids (RNA) is complicated by a limited understanding of the principles that govern RNA‐small molecule interactions. Here we have used stoichiometry‐resolved native top‐down mass spectrometry (MS) to study the binding of neomycin B to small model hairpin RNAs, an unstructured RNA, and a viral RNA construct. For 15–22 nt model RNAs with hairpin structure, we found that neomycin B binding to hairpin loops relies on interactions with both the nucleobases and the 2′‐OH groups, and that a simple 5′ or 3′ overhang can introduce an additional binding motif. For a 47 nt RNA construct derived from stem IA of the human immunodeficiency virus 1 (HIV‐1) rev response element (RRE) RNA, native top‐down MS identified four different binding motifs, of which the purine‐rich internal loop showed the highest affinity for neomycin B. Stoichiometry‐resolved binding site mapping by native top‐down MS allows for a new perspective on binding specificity, and has the potential to reveal unexpected principles of small molecule binding to RNA. [ABSTRACT FROM AUTHOR]

Background and aims: Serum eye drops alleviate ocular symptoms of diseases such as sicca syndrome, or chronic graft‐versus‐host disease. This study was designed for good manufacturing practice validation of our standard manufacturing, storage and transport processes for both autologous and allogenic SEDs. Specifications of quality parameters are lacking and were aimed to be defined. Methods: Using sterile collected, coagulated whole blood, serum was separated by centrifugation and filled into single‐use eye drop applicator vials. Quality control tests included visual inspection, sterility, leukocyte concentration, pH, vitamin A, TGF‐ß and VEGF‐A. Samples were collected after manufacture and after 24 h and 6 months of frozen storage (−20°C). Sterility testing was performed after opening the SED applicators at specified intervals. For transport validation, SEDs were packed in insulated transport bags and stored at 20–24°C and 30–32°C for 8 h. Results: Vitamin A, TGF‐ß and VEGF‐A assays showed no difference in concentration between fresh and 24 h frozen serum. All specifications for pH (aim 7.4) and cellular contamination were met and microbiological contamination tests were negative. Shelf‐life was defined as 6 months at −20°C. Once opened, the product must be used within 24 h to avoid bacterial outgrowth. Transporting frozen SEDs from the manufacturer via a local pharmacy to the patient within a maximum of 4 h was demonstrated. Conclusions: The GMP compliance of our production, storage and transport processes for autologous and allogenic SEDs was successfully validated. 100% serum eye drops in single‐use applicators can be safely used for up to 24 h after opening. [ABSTRACT FROM AUTHOR]

Objectives: Surgical guides are frequently used for dental implant placement. The aim of this study was to evaluate the impact of the 3D printing process itself and subsequent steam autoclaving on the dimensional stability of five different resin/printer combinations (RPCs). Materials and Methods: Fifty identical surgical guides (10 per group) were produced consisting of five RPCs. Half of the guides (5 per group) were steam autoclaved with cycle 1 (121°C, 1 bar, 20.5 min) and the other half with cycle 2 (134°C, 2 bar, 5.5 min). All guides were scanned with a structured‐light (SL) 3D scanner before (T0) and after (T1) autoclaving. Linear measurements along the x‐, y‐, and z‐axes were performed at landmarks on the original STL file and on SL scans at T0 and T1, respectively. Wilcoxon signed‐rank test, Kruskal–Wallis test, and linear mixed‐effects models were performed, depending on the analysis. Results: Three‐dimensional printing was associated with significant dimensional alterations for all RPCs. Steam autoclaving using cycle 1 was associated with significant shrinkage in x‐ (1 RPC), y‐ (2 RPCs), and z‐direction (2 RPCs), while cycle 2 was also associated with shrinkage in x‐ (2 RPCs), y‐ (1 RPC), and z‐direction (1 RPC). One resin did not present any dimensional changes independently of the cycle. Conclusions: The majority of the guides presented minor but significant shrinkage due to 3D printing itself and both steam autoclaving cycles, the extent varied between different RPCs. Whether these changes compromise implant placement accuracy remains to be investigated. [ABSTRACT FROM AUTHOR]

Background: The term temporomandibular disorder (TMD) indicates a set of musculoskeletal conditions involving temporomandibular joint (TMJ), masticatory musculature, and related anatomical structures. Pain is the most common clinical manifestation of TMD, and the auditory system might be involved and affected, through tinnitus, dizziness, otalgia and ear fullness sensation. Objectives: The aim of this systematic review of randomised controlled trails (RCTs) was to evaluate the efficacy of rehabilitative approaches on otologic symptoms in patients with TMD. Methods: PubMed, Scopus and Web of Science were systematically searched from the inception until 8th October 2023 to identify RCTs presenting participants with a diagnosis of TMD associated with otologic signs and symptoms, rehabilitative approaches as interventions, and modification of the otological symptoms as outcome. Results: Out of 931 papers suitable for title/abstract screening, 627 articles were assessed for eligibility. Five studies were included reporting the efficacy of occlusal splint therapy, low‐level laser therapies, and physical therapy in patients diagnosed whit secondary otalgia or tinnitus associated with TMD. No RCTs evaluating other otologic symptoms, ear fullness, dizziness or vertigo were found. Conclusions: Results of this systematic review suggested that rehabilitative approaches might be effective in improving secondary otalgia and tinnitus in TMD patients. Thus, further RCTs with a higher level of evidence and more representative samples should be conducted to better understand the effects of TMD therapy on otologic complains. [ABSTRACT FROM AUTHOR]

3D bioprinting enables the fabrication of human organ models that can be used for various fields of biomedical research, including oncology and infection biology. An important challenge, however, remains the generation of vascularized, perfusable 3D models that closely simulate natural physiology. Here, a novel direct ink writing (DIW) approach is described that can produce vascularized organ models without using sacrificial materials during fabrication. The high resolution of the method allows the one‐step generation of various sophisticated hollow geometries. This sacrificial‐free DIW (SF‐DIW) approach is used to fabricate hepatic metastasis models of various cancer types and different formats for investigating the cytostatic activity of anti‐cancer drugs. To this end, the models are incorporated into a newly developed perfusion system with integrated micropumps and an agar casting step that improves the physiological features of the bioprinted tissues. It is shown that the hepatic environment of the tumor models is capable of activating a prodrug, which inhibits breast cancer growth. This versatile SF‐DIW approach is able to fabricate complicated perfusable constructs or microfluidic chips in a straightforward and cost‐efficient manner. It can also be easily adapted to other cell types for generating vascularized organ tissues or cancer models that may support the development of new therapeutics. [ABSTRACT FROM AUTHOR]

Pancreatic cancer, ranking as the third factor in cancer‐related deaths, necessitates enhanced diagnostic measures through early detection. In response, SiMoT‐Single‐molecule with a large Transistor multiplexing array, achieving a Technology Readiness Level of 5, is proposed for a timely identification of pancreatic cancer precursor cysts and is benchmarked against the commercially available chemiluminescent immunoassay SIMOA (Single molecule array) SP‐X System. A cohort of 39 samples, comprising 33 cyst fluids and 6 blood plasma specimens, undergoes detailed examination with both technologies. The SiMoT array targets oncoproteins MUC1 and CD55, and oncogene KRAS, while the SIMOA SP‐X planar technology exclusively focuses on MUC1 and CD55. Employing Principal Component Analysis (PCA) for multivariate data processing, the SiMoT array demonstrates effective discrimination of malignant/pre‐invasive high‐grade or potentially malignant low‐grade pancreatic cysts from benign non‐mucinous cysts. Conversely, PCA analysis applied to SIMOA assay reveals less effective differentiation ability among the three cyst classes. Notably, SiMoT unique capability of concurrently analyzing protein and genetic markers with the threshold of one single molecule in 0.1 mL positions it as a comprehensive and reliable diagnostic tool. The electronic response generated by the SiMoT array facilitates direct digital data communication, suggesting potential applications in the development of field‐deployable liquid biopsy. [ABSTRACT FROM AUTHOR]

Electronic immunosensors are indispensable tools for diagnostics, particularly in scenarios demanding immediate results. Conventionally, these sensors rely on the chemical immobilization of antibodies onto electrodes. However, globular proteins tend to adsorb and unfold on these surfaces. Therefore, self‐assembled monolayers (SAMs) of thiolated alkyl molecules are commonly used for indirect gold–antibody coupling. Here, a limitation associated with SAMs is revealed, wherein they curtail the longevity of protein sensors, particularly when integrated into the state‐of‐the‐art transducer of organic bioelectronics—the organic electrochemical transistor. The SpyDirect method is introduced, generating an ultrahigh‐density array of oriented nanobody receptors stably linked to the gold electrode without any SAMs. It is accomplished by directly coupling cysteine‐terminated and orientation‐optimized spyTag peptides, onto which nanobody‐spyCatcher fusion proteins are autocatalytically attached, yielding a dense and uniform biorecognition layer. The structure‐guided design optimizes the conformation and packing of flexibly tethered nanobodies. This biolayer enhances shelf‐life and reduces background noise in various complex media. SpyDirect functionalization is faster and easier than SAM‐based methods and does not necessitate organic solvents, rendering the sensors eco‐friendly, accessible, and amenable to scalability. SpyDirect represents a broadly applicable biofunctionalization method for enhancing the cost‐effectiveness, sustainability, and longevity of electronic biosensors, all without compromising sensitivity. [ABSTRACT FROM AUTHOR]

Intestinal edema is a common manifestation of numerous gastrointestinal diseases and is characterized by the accumulation of fluid in the interstitial space of the intestinal wall. Technical advances in laser capture microdissection and low‐biomass proteomics now allow us to specifically characterize the intestinal edema proteome. Using advanced proteomics, we identify peptides derived from antimicrobial factors with high signal intensity, but also highlight major contributions from the blood clotting system, extracellular matrix (ECM) and protease–protease inhibitor networks. The ECM is a complex fibrillar network of macromolecules that provides structural and mechanical support to the intestinal tissue. One abundant component of the ECM observed in Salmonella‐driven intestinal edema is the glycoprotein fibronectin, recognized for its structure–function interplay regulated by mechanical forces. Using mechanosensitive staining of fibronectin fibers reveals that they are tensed in the edema, despite the high abundance of proteases able to cleave fibronectin. In contrast, fibronectin fibers increasingly relax in other cecal tissue areas as the infection progresses. Co‐staining for fibrin(ogen) indicates the formation of a provisional matrix in the edema, similar to what is observed in response to skin injury, while collagen staining reveals a sparse and disrupted collagen fiber network. These observations plus the absence of low tensional fibronectin fibers and the additional finding of a high number of protease inhibitors in the edema proteome could indicate a critical role of stretched fibronectin fibers in maintaining tissue integrity in the severely inflamed cecum. Understanding these processes may also provide valuable functional diagnostic markers of intestinal disease progression in the future. [ABSTRACT FROM AUTHOR]

Driven by macro‐level investment and strategic competition, engagement between China and African countries has expanded significantly in recent years, giving rise to increased migration flows between the two regions. Wary of Beijing's growing influence on the continent, Western scholarship and media often portray China as extractive and neo‐colonialist, whereas Africa and Africans are depicted as passive and lacking agency. This study examines an important yet understudied group operating at the crux of contemporary Sino–African relations that challenges these assumptions: young, African student‐entrepreneurs studying and working in China. Drawing on data from 10 months of ethnographic fieldwork and interviews with African student‐traders, as well as Chinese university administrators, students, and officials, this study finds that African student‐traders have developed a set of strategies that allow them to navigate, exploit and reconfigure Chinese structures as they pursue their entrepreneurial aspirations, suggesting that the Sino–African relationship is far from one‐sided. [ABSTRACT FROM AUTHOR]

Background: In mice, intraperitoneal (ip) contrast agent (CA) administration is convenient for mapping microvascular parameters over a long‐time window. However, continuous quantitative MRI of CA accumulation in brain over hours is still missing. Purpose: To validate a quantitative time‐resolved MRI technique for mapping the CA kinetics in brain upon ip administration. Study Type: Prospective, animal model. Specimen: 25 C57Bl/6JRj mice underwent MRI. Field Strength/Sequence: 7‐T, gradient echo sequence. Assessment: Gd‐DOTA concentration was monitored by MRI (25 s/repetition) over 135 minutes with (N = 15) and without (N = 10) ip mannitol challenge (5 g/kg). After the final repetition, the brains were sampled to quantify gadolinium by mass spectrometry (MS). Upon manual brain segmentation, the average gadolinium concentration was compared with the MS quantification in transcardially perfused (N = 20) and unperfused (N = 5) mice. Precontrast T1‐maps were acquired in 8 of 25 mice. Statistical Tests: One‐tailed Spearman and Pearson correlation between gadolinium quantification by MRI and by MS, D'Agostino‐Pearson test for normal distribution, Bland–Altman analysis to evaluate the agreement between MRI and MS. Significance was set at P‐value <0.05. Results: MRI showed that ip administered CA reached the blood compartment (>5 mM) within 10 minutes and accumulated continuously for 2 hours in cerebrospinal fluid (>1 mM) and in brain tissue. The MRI‐derived concentration maps showed interindividual differences in CA accumulation (from 0.47 to 0.81 mM at 2 hours) with a consistent distribution resembling the pathways of the glymphatic system. The average in‐vivo brain concentration 2 hours post‐CA administration correlated significantly (r = 0.8206) with the brain gadolinium quantification by MS for N = 21 paired observations available. Data Conclusion: The presented experimental and imaging protocol may be convenient for monitoring the spatiotemporal pattern of CA uptake and clearance in the mouse brain over 2 hours. The quantification of the CA from the MRI signal in brain is corroborated by MS. Evidence Level: N/A Technical Efficacy: Stage 1 [ABSTRACT FROM AUTHOR]

Summary: This S2k guideline on venous leg ulcers was created on the initiative and under the leadership of the German Society of Phlebology and Lymphology (DGPL). The guideline group also consisted of representatives from the German Society for Phlebology and Lymphology, German Dermatological Society, German Society for General Medicine, German Society for Angiology, German Society for Vascular Surgery and Vascular Medicine, German Society for Surgery, German Society for Dermatosurgery, German Society for Wound Healing and Wound Treatment, Professional Association of Phlebologists and Lymphologists and Initiative Chronische Wunden. The aim of this guideline is to combine the different approaches and levels of knowledge of the respective professional groups on the basis of consensus, so that a basic concept for the best possible treatment of patients with venous leg ulcers can be provided. A total of 70 specific recommendations were formulated and agreed upon, divided into the subject areas of diagnostics, therapy, prevention of recurrences, and everyday challenges. The guideline thus reflects the current state of scientific knowledge and is intended to be widely used as the best available document for the treatment of patients with venous leg ulcers in everyday clinical practice. [ABSTRACT FROM AUTHOR]

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Objective: To evaluate the impact of training quitline staff in lung cancer screening (LCS) on knowledge and attitudes towards connecting quitline callers to LCS educational materials. Methods: We conducted a pre‐post evaluation within a larger implementation project in the U.S. to support LCS among quitline callers. From July 2020 to June 2021, staff from four quitline service providers completed surveys before and after training on LCS knowledge. After training, staff completed the acceptability of intervention measure, intervention appropriateness measure, and feasibility of the intervention measure. Results: A total of 245 staff completed the initial demographic survey (analytic sample), 130 completed the pre‐training survey, and 225 completed the post‐training survey. Staff were on average 47.4 years old and 76.7% were female. LCS knowledge improved after the training (n = 120, mean difference = +26.5%, 95% CI 21.6, 31.4, p < 0.001). Overall, staff felt that connecting quitline callers to LCS education materials was acceptable (M = 4.0, SD = 0.8), appropriate (M = 4.1, SD = 0.7), and feasible (M = 4.0, SD = 0.7). Conclusions: Receiving training about LCS eligibility and the benefits and harms of screening improved LCS knowledge among quitline staff. Quitline staff found that connecting callers with LCS educational materials is acceptable, appropriate, and feasible, and aligned with their primary mission. [ABSTRACT FROM AUTHOR]

Objectives: This study's primary purpose was to demonstrate the correlation of preoperative right ventricular free‐wall longitudinal strain (RVFWLS) and pre‐/postsurgical variation in strain (delta strain) with the clinical and echocardiographic diagnosis of right ventricular dysfunction. Its secondary purpose was to determine the correlation of RVFWLS and delta strain with length of stay (LOS) in the intensive care unit (ICU), ventilation days, trend of natriuretic peptide test. (NT‐proBNP) and lactate in the first 48 h, incidence of acute renal failure, and 28‐day mortality. Design: Prospective observational study. Setting: Cardio‐thoracic and Vascular Anaesthesia Department and ICU of the University Hospital Integrated Trust of Verona. Participants: Patients scheduled for mitral surgery. Interventions: None. Measurements and Main Results: All clinical and transoesophageal echocardiographic (TEE) parameters were collected at baseline, before surgery (T1) and at admission in the ICU postsurgery (T2). During the postoperative period, the clinical and echocardiographic diagnoses of right, left, or biventricular dysfunction were evaluated. TEE parameters were evaluated by a cardiologist offline. The patients were divided into two subgroups according to the development of any type of ventricular dysfunction. No statistically significant differences emerged between the two groups. According to a logistic regression model, a T1‐RVFWLS value of −15% appeared to predict biventricular dysfunction (sensitivity: 100%; specificity: 91.3%). No correlation between T1‐ or T2‐RVFWLS and creatinine, hours of ventilation or ICU LOS was found. Conclusions: Our study introduces a new parameter that could be used in perioperative evaluations to identify patients at risk of postoperative biventricular dysfunction. [ABSTRACT FROM AUTHOR]

As a rule, an experiment carried out at school or in undergraduate study courses is rather simple and not very informative. However, when the experiments are to be performed using modern methods, they are often abstract and difficult to understand. Here, we describe a quick and simple experiment, namely the enzymatic characterization of ptyalin (human salivary amylase) using a starch degradation assay. With the experimental setup presented here, enzyme parameters, such as pH optimum, temperature optimum, chloride dependence, and sensitivity to certain chemicals can be easily determined. This experiment can serve as a good model for enzyme characterization in general, as modern methods usually follow the same principle: determination of the activity of the enzyme under different conditions. As different alleles occur in humans, a random selection of test subjects will be quite different with regard to ptyalin activities. Therefore, when the students measure their own ptyalin activity, significant differences will emerge, and this will give them an idea of the genetic diversity in human populations. The evaluation has shown that the pupils have gained a solid understanding of the topic through this experiment. [ABSTRACT FROM AUTHOR]

In the public and private spaces of Malaysia's capitalist cities, Malay women abide by a stricter Islamic dress code than they do in rural areas. Hence, in this local context, spatial public/private and ‘placial’ rural/urban order are of importance for gender identifications and practices. These orders imply influences on gendered forms of embodiment in the form of dress codes. This research examines the sociocultural constitutions of space and place in Malaysia regarding their relatedness to one another. The central argument states (1) that public space in Muslim contexts is defined as a social space in which men and women who are eligible to marry (non‐mahram) encounter each other; and (2) that these relations are perceived and practised differently in urban and rural public and private spaces. This implies that the public‐private divide is based significantly on gendered kinship relations: that is, concepts of family. [ABSTRACT FROM AUTHOR]

Autophagy, an essential cellular process for maintaining cellular homeostasis and eliminating harmful cytoplasmic objects, involves the de novo formation of double‐membraned autophagosomes that engulf and degrade cellular debris, protein aggregates, damaged organelles, and pathogens. Central to this process is the phagophore, which forms from donor membranes rich in lipids synthesized at various cellular sites, including the endoplasmic reticulum (ER), which has emerged as a primary source. The ER‐associated omegasomes, characterized by their distinctive omega‐shaped structure and accumulation of phosphatidylinositol 3‐phosphate (PI3P), play a pivotal role in autophagosome formation. Omegasomes are thought to serve as platforms for phagophore assembly by recruiting essential proteins such as DFCP1/ZFYVE1 and facilitating lipid transfer to expand the phagophore. Despite the critical importance of phagophore biogenesis, many aspects remain poorly understood, particularly the complete range of proteins involved in omegasome dynamics, and the detailed mechanisms of lipid transfer and membrane contact site formation. [ABSTRACT FROM AUTHOR]

Cardiovascular disorders are the leading cause of death in the world. Many organ diseases (kidney, heart, and brain) are substantially more prone to develop in people with hypertension. In the treatment of hypertension, first‐line medications are recommended, while imidazoline receptor agonists are not first‐line antihypertensives. Our goal was to conduct a network meta‐analysis to assess the efficacy and safety of imidazoline receptor agonists. The meta‐analysis was performed following the PRISMA guidelines using the PICOS format, considering the CONSORT recommendations. Studies were collected from four databases: PubMed, Cochrane Library, Web of Science, and Embase. A total of 5960 articles were found. After filtering, 27 studies remained eligible for network meta‐analysis. Moxonidine reduced blood pressure in sitting position statistically significantly after 8 weeks of treatment (SBP MD: 23.80; 95% CI: 17.45–30.15; DBP MD: 10.90; 95% CI: 8.45–13.35) compared to placebo. Moreover, moxonidine reduced blood pressure more effectively than enalapril; however, this difference was not significant (SBP MD: 3.10; 95% CI: −2.60–8.80; DBP MD: 1.30; 95% CI: −1.25–3.85). Dry mouth was experienced as a side effect in the case of all imidazoline receptor agonists. After 8 weeks of treatment, the appearance of dry mouth was highest with clonidine (OR: 9.27 95% CI: 4.70–18.29) and lowest with rilmenidine (OR: 6.46 95% CI: 0.85–49.13) compared to placebo. Somnolence was less frequent with moxonidine compared to rilmenidine (OR: 0.63 95% CI: 0.17–2.31). Imidazoline receptor agonists were nearly as effective as the first‐line drugs in the examined studies. However, their utility as antihypertensives is limited due to their side effects. As a result, they are not first‐line antihypertensives and should not be used in monotherapy. However, in the case of resistant hypertension, they are a viable option. According to our findings, from the point of view of safety and efficacy, moxonidine appears to be the best choice among imidazoline receptor agonists. [ABSTRACT FROM AUTHOR]

This study reports the synthesis and crystal structure determination of a novel CrTe3 phase using various experimental and theoretical methods. The average stoichiometry and local phase separation of this quenched high‐pressure phase were characterized by ex situ synchrotron powder X‐ray diffraction and total scattering. Several structural models were obtained using simulated annealing, but all suffered from an imperfect Rietveld refinement, especially at higher diffraction angles. Finally, a novel stoichiometrically correct crystal structure model was proposed on the basis of electron diffraction data and refined against powder diffraction data using the Rietveld method. Scanning electron microscopy–energy‐dispersive X‐ray spectrometry (EDX) measurements verified the targeted 1:3 (Cr:Te) average stoichiometry for the starting compound and for the quenched high‐pressure phase within experimental errors. Scanning transmission electron microscopy (STEM)–EDX was used to examine minute variations of the Cr‐to‐Te ratio at the nanoscale. Precession electron diffraction (PED) experiments were applied for the nanoscale structure analysis of the quenched high‐pressure phase. The proposed monoclinic model from PED experiments provided an improved fit to the X‐ray patterns, especially after introducing atomic anisotropic displacement parameters and partial occupancy of Cr atoms. Atomic resolution STEM and simulations were conducted to identify variations in the Cr‐atom site‐occupancy factor. No significant variations were observed experimentally for several zone axes. The magnetic properties of the novel CrTe3 phase were investigated through temperature‐ and field‐dependent magnetization measurements. In order to understand these properties, auxiliary theoretical investigations have been performed by first‐principles electronic structure calculations and Monte Carlo simulations. The obtained results allow the observed magnetization behavior to be interpreted as the consequence of competition between the applied magnetic field and the Cr–Cr exchange interactions, leading to a decrease of the magnetization towards T = 0 K typical for antiferromagnetic systems, as well as a field‐induced enhanced magnetization around the critical temperature due to the high magnetic susceptibility in this region. [ABSTRACT FROM AUTHOR]

We study the effect of economic conditions early in life on the occurrence of type-2 diabetes in adulthood using contextual economic indicators and withinsibling pair variation. We use data from Lifelines: a longitudinal cohort study and biobank including 51,270 siblings born in the Netherlands from 1950 onward. Sibling fixed-effects account for selective fertility. To identify type-2 diabetes we use biomarkers on the hemoglobin A1c concentration and fasting glucose in the blood. We find that adverse economic conditions around birth increase the probability of type-2 diabetes later in life both in males and in females. Inference based on self-reported diabetes leads to biased results, incorrectly suggesting the absence of an effect. The same applies to inference that does not account for selective fertility. [ABSTRACT FROM AUTHOR]

The article discusses the diagnostic challenges of Atypical Spitz Tumor (AST), a rare melanocytic lesion that can be mistaken for spitzoid melanoma. The use of Line-field confocal optical coherence tomography (LC-OCT) is introduced as a non-invasive technique to aid in distinguishing AST from benign Spitz nevus, particularly in pediatric patients. LC-OCT provides 3D reconstructions of the skin at cellular resolution, highlighting architectural disorder and cytological atypia within melanocytic nests. Further studies are needed to differentiate AST from other entities, and patient consent was obtained for the publication of case details. [Extracted from the article]

Triple negative breast cancers (TNBC) are characterized by a poor prognosis and a lack of targeted treatments. Their progression depends on tumor cell intrinsic factors, the tumor microenvironment and host characteristics. Although adipocytes, the primary stromal cells of the breast, have been determined to be plastic in physiology and cancer, the tumor‐derived molecular mediators of tumor‐adipocyte crosstalk have not been identified yet. In this study, we report that the crosstalk between TNBC cells and adipocytes in vitro beyond adipocyte dedifferentiation, induces a unique transcriptional profile that is characterized by inflammation and pathways that are related to interaction with the tumor microenvironment. Accordingly, increased cancer stem‐like features and recruitment of pro‐tumorigenic immune cells are induced by this crosstalk through CXCL5 and IL‐8 production. We identified serum amyloid A1 (SAA1) as a regulator of the adipocyte reprogramming through CD36 and P2XR7 signaling. In human TNBC, SAA1 expression was associated with cancer‐associated adipocyte infiltration, inflammation, stimulated lipolysis, stem‐like properties, and a distinct tumor immune microenvironment. Our findings constitute evidence that the interaction between tumor cells and adipocytes through the release of SAA1 is relevant to the aggressiveness of TNBC. [ABSTRACT FROM AUTHOR]

Umhlatuzana rockshelter is known for its continuous record of Middle and Later Stone Age lithic assemblages. This study presents multiproxy geoarchaeological data (micromorphology, X‐ray diffraction and scanning electron microscopy with energy‐dispersive spectroscopy) to reconstruct the depositional and post‐depositional history of the site. Although the Stone Age deposits macroscopically appear homogeneous, micromorphological analysis reveals the existence of primary, unaltered depositional microlayering throughout the sequence. Sediments related to combustion activities on‐site are observed in both the Holocene and Pleistocene deposits. Post‐depositional geochemical alterations result in the formation of several phosphatic minerals that significantly affect the site's preservation conditions. One of those is vashegyite, a rare magnesium phosphate mineral related to acidic and moist sedimentary environments. Bioturbation features are prominent at the microscale, but sediment mixing does not seem to affect the vertical distribution of the artifacts. The observation of horizontal microlayering in both the Pleistocene and Holocene illuminates the dominant mechanism of sedimentation throughout the site's 70,000‐year occupational history. It moreover shows that the lithics can be analysed as coherent assemblages. [ABSTRACT FROM AUTHOR]

Deuterium metabolic imaging (DMI) is an emerging magnetic resonance technique, for non‐invasive mapping of human brain glucose metabolism following oral or intravenous administration of deuterium‐labeled glucose. Regional differences in glucose metabolism can be observed in various brain pathologies, such as Alzheimer's disease, cancer, epilepsy or schizophrenia, but the achievable spatial resolution of conventional phase‐encoded DMI methods is limited due to prolonged acquisition times rendering submilliliter isotropic spatial resolution for dynamic whole brain DMI not feasible. The purpose of this study was to implement non‐Cartesian spatial‐spectral sampling schemes for whole‐brain 2H FID‐MR Spectroscopic Imaging to assess time‐resolved metabolic maps with sufficient spatial resolution to reliably detect metabolic differences between healthy gray and white matter regions. Results were compared with lower‐resolution DMI maps, conventionally acquired within the same session. Six healthy volunteers (4 m/2 f) were scanned for ~90 min after administration of 0.8 g/kg oral [6,6′]‐2H glucose. Time‐resolved whole brain 2H FID‐DMI maps of glucose (Glc) and glutamate + glutamine (Glx) were acquired with 0.75 and 2 mL isotropic spatial resolution using density‐weighted concentric ring trajectory (CRT) and conventional phase encoding (PE) readout, respectively, at 7 T. To minimize the effect of decreased signal‐to‐noise ratios associated with smaller voxels, low‐rank denoising of the spatiotemporal data was performed during reconstruction. Sixty‐three minutes after oral tracer uptake three‐dimensional (3D) CRT‐DMI maps featured 19% higher (p =.006) deuterium‐labeled Glc concentrations in GM (1.98 ± 0.43 mM) compared with WM (1.66 ± 0.36 mM) dominated regions, across all volunteers. Similarly, 48% higher (p =.01) 2H‐Glx concentrations were observed in GM (2.21 ± 0.44 mM) compared with WM (1.49 ± 0.20 mM). Low‐resolution PE‐DMI maps acquired 70 min after tracer uptake featured smaller regional differences between GM‐ and WM‐dominated areas for 2H‐Glc concentrations with 2.00 ± 0.35 mM and 1.71 ± 0.31 mM, respectively (+16%; p =.045), while no regional differences were observed for 2H‐Glx concentrations. In this study, we successfully implemented 3D FID‐MRSI with fast CRT encoding for dynamic whole‐brain DMI at 7 T with 2.5‐fold increased spatial resolution compared with conventional whole‐brain phase encoded (PE) DMI to visualize regional metabolic differences. The faster metabolic activity represented by 48% higher Glx concentrations was observed in GM‐ compared with WM‐dominated regions, which could not be reproduced using whole‐brain DMI with the low spatial resolution protocol. Improved assessment of regional pathologic alterations using a fully non‐invasive imaging method is of high clinical relevance and could push DMI one step toward clinical applications. [ABSTRACT FROM AUTHOR]

Objective: The etiopathogenesis of systemic sclerosis (SSc) is unknown. Platelet‐derived growth factor receptors (PDGFRs) are overexpressed in patients with SSc. Because PDGFRα is targeted by the adeno‐associated virus type 5 (AAV5), we investigated whether AAV5 forms a complex with PDGFRα exposing epitopes that may induce the immune responses to the virus–PDGFRα complex. Methods: The binding of monomeric human PDGFRα to the AAV5 capsid was analyzed by in silico molecular docking, surface plasmon resonance (SPR), and genome editing of the PDGFRα locus. AAV5 was detected in SSc lungs by in situ hybridization, immunohistochemistry, confocal microscopy, and molecular analysis of bronchoalveolar lavage (BAL) fluid. Immune responses to AAV5 and PDGFRα were evaluated by SPR using SSc monoclonal anti‐PDGFRα antibodies and immunoaffinity‐purified anti‐PDGFRα antibodies from sera of patients with SSc. Results: AAV5 was detected in the BAL fluid of 41 of 66 patients with SSc with interstitial lung disease (62.1%) and in 17 of 66 controls (25.75%) (P < 0.001). In SSc lungs, AAV5 localized in type II pneumocytes and in interstitial cells. A molecular complex formed of spatially contiguous epitopes of the AAV5 capsid and of PDGFRα was identified and characterized. In silico molecular docking analysis and binding to the agonistic anti‐PDGFRα antibodies identified spatially contiguous epitopes derived from PDGFRα and AAV5 that interacted with SSc agonistic antibodies to PDGFRα. These peptides were also able to bind total IgG isolated from patients with SSc, not from healthy controls. Conclusion: These data link AVV5 with the immune reactivity to endogenous antigens in SSc and provide a novel element in the pathogenesis of SSc. [ABSTRACT FROM AUTHOR]

Bone fracture healing is regulated by mechanobiological cues. Both, extracellular matrix (ECM) deposition and microvascular assembly determine the dynamics of the regenerative processes. Mechanical instability as by inter‐fragmentary shear or compression is known to influence early ECM formation and wound healing. However, it remains unclear how these external cues shape subsequent ECM and microvascular network assembly. As transcriptional coactivators, the mechanotransducers yes‐associated protein 1 (YAP)/transcriptional coactivator with PDZ‐binding motif (TAZ) translate physical cues into downstream signaling events, yet their role in sprouting angiogenesis into the hematoma after injury is unknown. Using bone healing as model system for scar‐free regeneration, the role of endothelial YAP/TAZ in combination with tuning the extrinsic mechanical stability via fracture fixation is investigated. Extrinsically imposed shear across the gap delayed hematoma remodeling and shaped the morphology of early collagen fiber orientations and microvascular networks, suggesting that enhanced shear increased the nutrient exchange in the hematoma. In contrast, endothelial YAP/TAZ deletion has little impact on the overall vascularization of the fracture gap, yet slightly increases the collagen fiber deposition under semi‐rigid fixation. Together, these data provide novel insights into the respective roles of endothelial YAP/TAZ and extrinsic mechanical cues in orchestrating the process of bone regeneration. [ABSTRACT FROM AUTHOR]