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ABSTRACT During oropharyngeal candidiasis, Candida albicans activates the epidermal growth factor receptor (EGFR), which induces oral epithelial cells to endocytose the fungus and synthesize proinflammatory mediators. To elucidate EGFR signaling pathways that are stimulated by C. albicans, we used proteomics to identify 1,214 proteins that were associated with EGFR in C. albicans-infected cells. Seven of these proteins were selected for additional study. Among these proteins, WW domain-binding protein 2, Toll-interacting protein, interferon-induced transmembrane protein 3 (IFITM3), and the globular C1q receptor (gC1qR) were found to associate with EGFR in viable oral epithelial cells. Each of these proteins was required for maximal endocytosis of C. albicans, and all regulated fungus-induced production of interleukin-1β (IL-1β) and/or IL-8, either positively or negatively. gC1qR was found to function as a key coreceptor with EGFR. Interacting with the C. albicans Als3 invasin, gC1qR was required for the fungus to induce autophosphorylation of both EGFR and the ephrin type A receptor 2. The combination of gC1qR and EGFR was necessary for maximal endocytosis of C. albicans and secretion of IL-1β, IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF) by human oral epithelial cells. In mouse oral epithelial cells, inhibition of gC1qR failed to block C. albicans-induced phosphorylation, and knockdown of IFITM3 did not inhibit C. albicans endocytosis, indicating that gC1qR and IFITM3 function differently in mouse versus human oral epithelial cells. Thus, this work provides an atlas of proteins that associate with EGFR and identifies several that play a central role in the response of human oral epithelial cells to C. albicans infection. IMPORTANCE Oral epithelial cells play a key role in the pathogenesis of oropharyngeal candidiasis. In addition to being target host cells for C. albicans adherence and invasion, they secrete proinflammatory cytokines and chemokines that recruit T cells and activated phagocytes to foci of infection. It is known that C. albicans activates EGFR on oral epithelial cells, which induces these cells to endocytose the organism and stimulates them to secrete proinflammatory mediators. To elucidate the EGFR signaling pathways that govern these responses, we analyzed the epithelial cell proteins that associate with EGFR in C. albicans-infected epithelial cells. We identified four proteins that physically associate with EGFR and that regulate different aspects of the epithelial response to C. albicans. One of these is gC1qR, which is required for C. albicans to activate EGFR, induce endocytosis, and stimulate the secretion of proinflammatory mediators, indicating that gC1qR functions as a key coreceptor with EGFR.

Background: While living kidney donation is considered safe in healthy individuals, perioperative complications can occur due to several factors. Objective: We explored associations between the incidence of perioperative complications and donor characteristics, surgical technique, and surgeon’s experience in a large contemporary cohort of living kidney donors. Design: Living kidney donors enrolled prospectively in a multicenter cohort study with some data collected retrospectively after enrollment was complete (eg, surgeon characteristics). Setting: Living kidney donor centers in Canada (n = 12) and Australia (n = 5). Patients: Living kidney donors who donated between 2004 and 2014 and the surgeons who performed the living kidney donor nephrectomies. Measurements: Operative and hospital discharge medical notes were collected prospectively, with data on perioperative (intraoperative and postoperative) information abstracted from notes after enrollment was complete. Complications were graded using the Clavien-Dindo system and further classified into minor and major. In 2016, surgeons who performed the nephrectomies were invited to fill an online survey on their training and experience. Methods: Multivariable logistic regression models with generalized estimating equations were used to compare perioperative complication rates between different groups of donors. The effect of surgeon characteristics on the complication rate was explored using a similar approach. Poisson regression was used to test rates of overall perioperative complications between high- and low-volume centers. Results: Of the 1421 living kidney donor candidates, 1042 individuals proceeded with donation, where 134 (13% [95% confidence interval (CI): 11%-15%]) experienced 142 perioperative complications (55 intraoperative; 87 postoperative). The most common intraoperative complication was organ injury and the most common postoperative complication was ileus. No donors died in the perioperative period. Most complications were minor (90% of 142 complications [95% CI: 86%-96%]); however, 12 donors (1% of 1042 [95% CI: 1%-2%]) experienced a major complication. No statistically significant differences were observed between donor groups and the rate of complications. A total of 43 of 48 eligible surgeons (90%) completed the online survey. Perioperative complication rates did not vary significantly by surgeon characteristics or by high- versus low-volume centers. Limitations: Operative and discharge reporting is not standardized and varies among surgeons. It is possible that some complications were missed. The online survey for surgeons was completed retrospectively, was based on self-report, and has not been validated. We had adequate statistical power only to detect large effects for factors associated with a higher risk of perioperative complications. Conclusions: This study confirms the safety of living kidney donation as evidenced by the low rate of major perioperative complications. We did not identify any donor or surgeon characteristics associated with a higher risk of perioperative complications. Trial registration(s): NCT00319579: A Prospective Study of Living Kidney Donation ( https://clinicaltrials.gov/ct2/show/NCT00319579 ) NCT00936078: Living Kidney Donor Study ( https://clinicaltrials.gov/ct2/show/NCT00936078 )

Abstract: Introduction: The Comprehensive Autism Trait Inventory (CATI) comprises six subscales, including “social camouflage” and “sensory sensitivity,” developed to address the limitations of comprehensive evaluation (English et al., 2021). In this study, we report the development of the Japanese version of the CATI (CATI-j) for university students and validate its reliability and validity. Methods: All 43 items of the original CATI were translated into Japanese using a cognitive interview (N = 12) and back-translation method. The data from 509 participants were used to examine the item characteristics, the gender differences, and the factor structure. Results: Using samples of Japanese university students (N = 509), we found good reliability and validity for the CATI-j. Confirmatory factor analysis revealed that a bifactor model, assuming two general factors for “social communication and interaction” and “repetitive and restricted behavior,” along with six specific factors, best fit the data. However, in contrast to previous studies, no significant differences between men and women were observed for each scale. Limitations: Several limitations remain for future exploration, including examining samples beyond university students, determining cutoff values for distinguishing autism spectrum disorder, and investigating cultural differences. Discussion: The CATI-j is applicable to Japanese university students.

Objective:. To assess the relationship between postoperative opioid consumption and frailty status. Background:. Physiologic reserve can be assessed through both chronologic age as well as measures of frailty. Although prior studies suggest that older individuals may require less opioid following surgery, chronologic age, and frailty do not always align, and little is known regarding postoperative opioid consumption patterns by frailty. Methods:. We conducted a retrospective analysis of opioid-naïve adult patients undergoing common general, vascular, and gynecologic procedures across a statewide quality improvement program from November 6, 2017 to February 28, 2021. Our primary outcome was postoperative patient-reported opioid consumption within 30 days of surgery in oral morphine equivalents (OME). Our primary exposure was frailty status defined by the modified frailty index (mFi-5) criteria. Other covariates included patient demographic and clinical attributes, procedural factors, discharge opioid prescription size, and postoperative complications. Linear regression was performed to assess the association of frailty status and opioid consumption, stratified by age. Results:. In this cohort of 34,854 patients, 10,596 had an mFi-5 score of ≤1 and 3,635 had a score of >1. A score of >1 was associated with increased patient-reported opioid consumption (OMEs 3.3 greater; 95% CI = 1.5–5.1). This held true for individuals over 65 (OMEs 2.7 greater; 95% CI = 0.2–5.1). Frailty status, regardless of score, was negatively associated with an opioid prescription at discharge. Conclusions:. Frailty status is associated with increased opioid consumption after common operations. Future prescribing guidelines and outcomes analyses should consider this marker when reviewing opioid consumption data and related adverse outcomes.

Objective:. To evaluate opioid consumption for 21 procedures over 4 years from the Michigan Surgical Quality Collaborative (MSQC) registry and update post-discharge prescribing guidelines. Background:. Opioids remain a common treatment for postoperative pain of moderate-to-severe intensity not adequately addressed by nonopioid analgesics, but excessive prescribing correlates with increased usage. This analysis provides updates and compares patient-reported consumption in response to new guidelines. Methods:. We examined data from the MSQC registry for opioid-naive adult patients undergoing surgery between January 1, 2018, and October 31, 2021. The primary outcome was patient-reported opioid consumption in oxycodone 5 mg equivalents. Guidelines were anchored to the 75th percentile of consumption, updating previous guidelines from January 2020 based on data from January 1, 2018, to May 31, 2019. Results:. 39,493 opioid-naive surgical patients (average age 53.8 years [SD 16.4], 56.3% female, 19.1% non-White, 43.9% with public insurance) were included. Guidelines did not change for 7 of the 16 procedures including the most common procedures: minor hernia, laparoscopic cholecystectomy, laparoscopic appendectomy, and laparoscopic hysterectomy. Recommended prescribing ranges were lower for 9 procedures, with most (8) procedures having a reduction of 5 pills. Prescribing guidelines were developed for 5 new procedures. All procedures had upper-limit guidelines of 10 pills or less. Conclusions:. For most procedures, patient-reported opioid consumption decreased between 2018 and 2021 when compared to the period between 2018 and 2019. New guidelines were established for a dozen procedures to balance maximizing pain control with reducing harms from inappropriate prescribing.

The JWST Advanced Deep Extragalactic Survey (JADES) is a multicycle JWST program that has taken among the deepest near- and mid-infrared images to date (down to ∼30 AB mag) over ∼25 arcmin ^2 in the GOODS-S field in two sets of observations with 1 yr of separation. This presented the first opportunity to systematically search for transients, mostly supernovae (SNe), out to z > 2. We found 79 SNe: 38 at z < 2, 23 at 2 < z < 3, 8 at 3 < z < 4, 7 at 4 < z < 5, and 3 with undetermined redshifts, where the redshifts are predominantly based on spectroscopic or highly reliable JADES photometric redshifts of the host galaxies. At this depth, the detection rate is ∼1–2 arcmin ^–2 yr ^–1 , demonstrating the power of JWST as an SN discovery machine. We also conducted multiband follow-up NIRCam observations of a subset of the SNe to better constrain their light curves and classify their types. Here, we present the survey, sample, search parameters, spectral energy distributions, light curves, and classifications. Even at z ≥ 2, the NIRCam data quality is high enough to allow SN classification via multiepoch light-curve fitting with confidence. The multiepoch SN sample includes a Type Ia SN at z _spec = 2.90, a Type IIP SN at z _spec = 3.61, and a Type Ic-BL SN at z _spec = 2.83. We also found that two z ∼ 16 galaxy candidates from the first imaging epoch were actually transients that faded in the second epoch, illustrating the possibility that moderate/high-redshift SNe could mimic high-redshift dropout galaxies.

Objective: Intermittent claudication (IC) is known to be associated with impaired gait parameters, with a higher incidence of falls and higher oxygen consumption due to uneconomic walking. However, the influence of arterial disobliteration in patients with IC on their gait pattern has rarely been investigated to date. The aim of this study was to examine the gait patterns before and after inflow revascularization by surgical disobliteration of pelvic and inguinal arteries (ie, common iliac artery, external iliac artery, common femoral artery, profound femoral artery, superficial femoral artery) in IC patients. Successful surgical disobliteration of inflow arteries (improvement of ankle brachial pressure index of ≥0.2 and patent common iliac, external iliac, common femoral, profound femoral, and superficial femoral arteries) is known to improve the painless walking distance for patients with IC due to peripheral arterial disease; however, its influence on gait parameters is unclear. We hypothesized that the gait parameters would also improve after surgery. Improved gait parameters can lead to a more economic walking process, lower oxygen consumption, a lower risk of falls, and a higher quality of life. Methods: In a single-center, exploratory, longitudinal study, we examined the gait parameters of 20 IC inpatients of our hospital before and after surgical disobliteration of pelvic and inguinal arteries. Spatiotemporal parameters such as range of motion of the hip and knee joint, stance phase, cadence, and foot rotation were obtained using the Diers 4Dmotion Lab (Diers International). The gait parameters were obtained under painful walking conditions preoperatively and with the patients walking pain free at the same speed postoperatively. Results: A total of 20 patients were examined. Surgical revascularization led to a higher walking cadence (mean, plus 7.88 steps; 95.5 steps/min vs 87.6 steps/min; P = .024), an increased range of motion of the hip joint (mean, plus 2.0°; 35.1° vs 33.1°; P = .038), and improved foot rotation (mean, plus 2.0°; 11.0° vs 9.0°; P = .02). Regarding other parameters such as step length, stance phase, and step duration, smaller differences were detected in this study. Conclusions: In this exploratory study, we found that surgical revascularization of pelvic and inguinal arteries in IC patients improved certain gait parameters. Further studies with larger patient numbers are needed to confirm these data and provide more evidence on this subject. : Clinical Relevance: Intermittent claudication (IC) includes impaired gait parameters. The influence of arterial disobliteration has rarely been investigated. We examined the gait patterns before and after surgical disobliteration of pelvic and inguinal arteries. Disobliteration improves the painless walking distance; however, its influence on gait parameters is unclear. We hypothesized that the gait parameters would also improve after surgery. Improved parameters could lead to more economic walking, lower oxygen consumption, a lower risk of falls, and a higher quality of life. Revascularization of 20 patients with IC resulted in improved walking cadence (mean, plus 7.88 steps; 95.5 steps/min vs 87.6 steps/min), hip joint mobility (mean, plus 2.0°; 35.1° vs 33.1°), and foot rotation (mean, plus 2.0°; 11.0° vs 9.0°).

In the building industry, different types of glass edges are used depending on their application and function. A widespread assumption is that the edge strength increases with the degree of optical finishing. This corresponds with the European standardisation, which targets an adjustment of the bending strength in form of edge finishing factors. Thereby the highest edge strength is set with polished edges. This article presents research which shows that the recommended edge finishing factors of annealed glass can be insufficient, particularly for the polished edge. Comparison with previous scientific studies confirms a high scatter in the edge strengths of different manufacturers. However, there are no generally valid grinding process parameters that can be associated with a high edge strength. Consequently, general edge strength values have to be questioned, as they potentially lead to safety concerns. Thus, the processes have to be investigated individually. For this purpose, an examination method with fracture tests and a microscopic defect analysis for process optimisation is introduced. Based on the results of two different edge grinding machines, the formation of defects is presented and their potential of causing early breakage is discussed. In an overall evaluation, approaches are proposed on how the manufacturing of glass edges with high edge strength can be verified and included in the design.

The demand for versatile and visually appealing glazed structures has been increasing in recent years. To meet contemporary architectural needs, a wider range of functionalities is required, including smart, bendable and thin laminated glazing. In particular, cold poured liquid interlayers are gaining prominence for complex curved cold bending and smart interlayers, where conventional interlayer films impose limitations. This paper presents research on several liquid optically clear adhesives (LOCA) for application as interlayers in laminated glass. Within a comprehensive experimental study essential material properties were investigated. The research focuses on the viscoelastic, tensile, and creep properties of the LOCA. Additionally, the study considers how the materials age under radiation, high temperature and high moisture in accordance with the product standard for laminated glass. All results are summarized to provide a wide-ranging data base for dimensioning laminated glass made with LOCA. Finally, the properties of the materials are compared with conventional interlayers and their potential for use in laminated glass applications is discussed.

High temperatures, especially non-uniform temperatures distributions, on glass structures can induce stress relaxation, viscous material behaviour and glass fracture. Temperature exposure of toughened glass to 290°C and above can result in a partial reduction in strength of the glass component and, in case of fracture, a change in the fracture pattern due to stress relaxation. To achieve a better understanding of the heat transfer in monolithic and laminated glass, test series in an electric furnace on different glass specimens were carried out. The specimens were made of monolithic and laminated soda-lime silicate glass in different components. The test set-up was chosen in a way to create an inhomogeneous temperature distribution from the heat source through the glass in order to create a more realistic load case than an assumption of homogeneity. The results of the experimental examinations were used to develop a first numerical model that was used to visualise details (e.g. temperature and stress distribution). In addition, the paper presents results of experimental and numerical examinations to the determination of the temperature distribution in different glass components, which leads to stress relaxation during high temperature exposure and affects fracture pattern in thermally toughened glass plates. This will pave the way towards understand of glass structures exposed to heat and fire and, as a vision, will form the fundamentals of a design concept.

Laminated safety glass is an important component of modern façade structures and is used when higher safety requirements are demanded. The interlayer increases the stiffness due to the available shear action, ensures the residual load-bearing capacity of the structure in the event of failure and holds broken pieces of glass in place. However, the stiffness and tensile strength of conventional interlayers such as EVA or PVB are known to strongly depend on time and temperature. This phenomenon is particularly critical for the behavior of glass panes during impact and after breakage when high tensile stresses occur in the interlayer. A film with higher stiffness, lower time and temperature dependence can be laminated between two layers of interlayer material to improve laminated glass behavior. Given the need to conserve resources and reduce weight, the question arises as to whether such an interlayer could also be used to meet the safety requirements for laminated glass made out of thin glass. In this study, the influence of a multilayer interlayer of EVA and a stiff core film of modified polyester (MPE) in glass laminates was examined. For this purpose, the material and composite behaviors were experimentally studied and evaluated. This article presents the test setup and the results. The focus is on comparing the properties of interlayers with and without MPE films. The results show that the impact strength of thin glass laminates is improved by the multilayer interlayer.

Using glass elements as designated members of the structural design of buildings does not only require conscientious planning of structural redundancies, but also proof of safety for single components. In reality, random loads act in an unknown combination on a component, which is not directly resembled by the modelling process a priori. Hence, understanding the mechanical behaviour of glass components under probabilistic combination of static and dynamic loads is required. To serve this understanding best, the most critically loaded component of a glass shelter was examined experimentally by exposing extracted specimens to on-surface lateral loads and in-plane compressive loads simultaneously. Additionally, in-plane compressive loads were combined with soft-body impacts. This combination of static loads with short-term lateral loads is interesting in terms of stability and the residual load bearing capacity. The results show how compressive in-plane loads increase stress and deformation according to first and second order deformations and indicate that premature stability failure occurs due to soft-body impacting.

Fluids in the cavity can be used to integrate additional functions into insulating glazing. However, the high permanent load exerted by the fluid on the glazing and surrounding components is problematic. Conventional design methods result in large adhesive joints, which are not desirable from an aesthetic point of view. ETAG 002-1 is typically used for the design of structural adhesive bonds for use in structural glazing façades. However, the calculation is considered to be conservative. In particular, it is criticised for its deterministic safety concept. Therefore, in recent years, a number of researchers have looked at different methods for the design of adhesive joints. Such methods are presented by the Fachverband Konstruktiver Glasbau e.V. in the Technical Note FKG 01/2021. A further approach is presented by Drass & Kraus (2020, 2021a, 2021b), who proposes an approximation to the semi-probabilistic safety concept and thus to the current Eurocode 0 design standard by determining a material safety factor. This paper is concerned with the design of a load-bearing adhesive joint for use in a fluid-filled insulating glass unit. A specific façade element is used as an example for the calculations. Three dimensioning methods are compared: the analytical method according to ETAG 002-1, a numerical method according to Technical Note FKG 01/2021 and the approximation of a semi-probabilistic safety concept according to Drass & Kraus (2020, 2021a, 2021b). The results show significant differences between the design methods in terms of utilisation.

Background: High quality surgical care for colorectal cancer (CRC) includes obtaining a negative surgical margin. The Michigan Surgical Quality Collaborative (MSQC) is a statewide consortium of hospitals dedicated to quality improvement; a subset of MSQC hospitals abstract quality of care measures for CRC surgery, including positive margin rate. The purpose of this study was to determine whether positive margin rates vary significantly by hospital, and whether positive margin rates should be a target for quality improvement. Methods: We performed a retrospective cohort study of patients who underwent CRC resection from 2016 to 2020. The primary outcome was the presence of a positive margin. Univariate and multivariable analyses were performed to test the association of positive margins with patient, hospital, and tumor characteristics. Results: The cohort consisted of 4211 patients from 42 hospitals (85 % colon cancer and 15 % rectal cancer). The crude positive margin rate was 6.15 % (95 % CI 4.6–7.4 %); this ranged from 0 % to 22 % at individual hospitals. In multivariable analysis, factors independently associated with positive margins included male sex, underweight BMI, metastatic cancer, rectal cancer (vs. colon), T4 T-stage, N1c/N2 N-stage, and open surgical approach. After adjusting for these factors, there remained significant variation by hospital, with 8 hospitals being statistically-significant outliers. Conclusions: Positive margins rates for CRC vary by hospital in Michigan, even after rigorous adjustment for case-mix. Furthermore, several hospitals achieved near-zero positive margin rates, suggesting opportunities for quality improvement through the identification of best practices among CRC surgery centers.

Climate change and air pollution are two significant challenges facing our society and represent a major driver for new developments in the transport sector. As a consequence, automotive manufacturers have focused on the electrification of vehicle propulsion systems and offer a wide range of hybrid and full-electric vehicles in different classes. However, in the world’s most densely populated metropolitan areas, small and lightweight vehicles are key for the mobility of millions. Traditionally these vehicles have provided cost-effective transportation which is difficult to preserve with vehicle electrification. Many of these light vehicles, such as scooters and all-terrain vehicles, use internal combustion engines in combination with a continuously variable rubber belt transmission which provides a simple, comfortable and cost-effective transmission technology but with poor efficiency and high maintenance costs. In this contribution, a novel full hybrid powertrain concept is proposed that offers a similar driving experience to conventional continuously variable transmissions while providing significantly improved performance and fuel economy combined with low system complexity. In its basic configuration, the hybrid powertrain can operate without active actuators and even with mechanical throttle control of the internal combustion engine. This minimalist approach reduces system costs and helps to create a competitive solution for price-sensitive markets. The hybrid system is based on a planetary gear set that combines the internal combustion engine and an electric motor. It is complemented by a centrifugal clutch and one-way clutch, resulting in different operating modes for low and high speeds as well as for electric driving. This paper describes the mechanical design and control approach of the proposed hybrid powertrain layout. In order to evaluate the basic functionalities, a prototype vehicle was built and tested. This contribution shows the integration of the hybrid powertrain concept in a prototype vehicle and proves the fulfilment of all required full hybrid functionalities.

Abstract Bifurcations in kinetic pathways decide the evolution of a system. An example is crystallization, in which the thermodynamically stable polymorph may not form due to kinetic hindrance. Here, we use confined self-assembly to investigate the interplay of thermodynamics and kinetics in the crystallization pathways of finite clusters. We report the observation of decahedral clusters from colloidal particles in emulsion droplets and show that these decahedral clusters can be thermodynamically stable, just like icosahedral clusters. Our hard sphere simulations reveal how the development of the early nucleus shape passes through a bifurcation that decides the cluster symmetry. A geometric argument explains why decahedral clusters are kinetically hindered and why icosahedral clusters can be dominant even if they are not in the thermodynamic ground state.

Abstract Background In total knee arthroplasty, the normal kinematics of the knee may not be restored solely based on preoperative gait, fluoroscopic-based, and dynamic radiostereometric analyses. Surgical technique case presentation This note introduced a 69-year-old male patient who sustained post-traumatic osteoarthritis of his right knee. He underwent robot-assisted total knee arthroplasty based on anatomical reproduction of knee stability during the swing phase of gait. The kinematic alignment was simply achieved within an easy-to-identified range after preoperative radiographic assessment, intraoperative landmarking and pre-validated osteotomy, and intraoperative range of motion testing. Conclusions This novel technique allows personalized and imageless total knee arthroplasty. It provides a preliminary path in reproducing the anatomy alignment, natural collateral ligament laxity, and accurate component placement within safe-to-identified alignment boundaries.

Abstract Although surgical care has become safer, cheaper, and more efficient, it has only a modest impact on the overall health of society, which is driven primarily by health behaviors such as smoking, alcohol use, poor diet, and physical inactivity. Given the ubiquity of surgical care in the population, it represents a critical opportunity to screen for and address the health behaviors that drive premature mortality at a population level. Patients are especially receptive to behavior change around the time of surgery, and many health systems already have programs in place to address these issues. In this commentary, we present the case for integrating health behavior screening and intervention into the perioperative pathway as a novel and impactful way to improve the health of society.

Purpose: The etiopathogenesis of coronal nonsyndromic craniosynostosis (cNCS), a congenital condition defined by premature fusion of 1 or both coronal sutures, remains largely unknown. Methods: We conducted the largest genome-wide association study of cNCS followed by replication, fine mapping, and functional validation of the most significant region using zebrafish animal model. Results: Genome-wide association study identified 6 independent genome-wide-significant risk alleles, 4 on chromosome 7q21.3 SEM1-DLX5-DLX6 locus, and their combination conferred over 7-fold increased risk of cNCS. The top variants were replicated in an independent cohort and showed pleiotropic effects on brain and facial morphology and bone mineral density. Fine mapping of 7q21.3 identified a craniofacial transcriptional enhancer (eDlx36) within the linkage region of the top variant (rs4727341; odds ratio [95% confidence interval], 0.48[0.39-0.59]; P = 1.2E−12) that was located in SEM1 intron and enriched in 4 rare risk variants. In zebrafish, the activity of the transfected human eDlx36 enhancer was observed in the frontonasal prominence and calvaria during skull development and was reduced when the 4 rare risk variants were introduced into the sequence. Conclusion: Our findings support a polygenic nature of cNCS risk and functional role of craniofacial enhancers in cNCS susceptibility with potential broader implications for bone health.

IntroductionPhotogrammetric surface scans provide a radiation-free option to assess and classify craniosynostosis. Due to the low prevalence of craniosynostosis and high patient restrictions, clinical data are rare. Synthetic data could support or even replace clinical data for the classification of craniosynostosis, but this has never been studied systematically.MethodsWe tested the combinations of three different synthetic data sources: a statistical shape model (SSM), a generative adversarial network (GAN), and image-based principal component analysis for a convolutional neural network (CNN)–based classification of craniosynostosis. The CNN is trained only on synthetic data but is validated and tested on clinical data.ResultsThe combination of an SSM and a GAN achieved an accuracy of 0.960 and an F1 score of 0.928 on the unseen test set. The difference to training on clinical data was smaller than 0.01. Including a second image modality improved classification performance for all data sources.ConclusionsWithout a single clinical training sample, a CNN was able to classify head deformities with similar accuracy as if it was trained on clinical data. Using multiple data sources was key for a good classification based on synthetic data alone. Synthetic data might play an important future role in the assessment of craniosynostosis.

Burkitt lymphoma cells (BL) exploit antigen-independent tonic signals transduced by the B-cell antigen receptor (BCR) for their survival, but the molecular details of the rewired BL-specific BCR signal network remain unclear. A loss of function screen revealed the SH2 domain-containing 5`-inositol phosphatase 2 (SHIP2) as a potential modulator of BL fitness. We characterized the role of SHIP2 in BL survival in several BL cell models and show that perturbing SHIP2 function renders cells more susceptible to apoptosis, while attenuating proliferation in a BCR-dependent manner. Unexpectedly, SHIP2 deficiency did neither affect PI3K survival signals nor MAPK activity, but attenuated ATP production. We found that an efficient energy metabolism in BL cells requires phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2), which is the enzymatic product of SHIP proteins. Consistently, interference with the function of SHIP1 and SHIP2 augments BL cell susceptibility to PI3K inhibition. Notably, we provide here a molecular basis of how tonic BCR signals are connected to energy supply, which is particularly important for such an aggressively growing neoplasia. These findings may help to improve therapies for the treatment of BL by limiting energy metabolism through the inhibition of SHIP proteins, which renders BL cells more susceptible to the targeting of survival signals.

A Type Ia supernova (SN) at z = 1.78 was discovered in James Webb Space Telescope Near Infrared Camera imaging of the galaxy cluster PLCK G165.7+67.0 (G165; z = 0.35). The SN is situated 1.5–2 kpc from the host-galaxy nucleus and appears in three different locations as a result of gravitational lensing by G165. These data can yield a value for Hubble’s constant using time delays from this multiply imaged SN Ia that we call “SN H0pe.” Over the cluster, we identified 21 image multiplicities, confirmed five of them using the Near-Infrared Spectrograph, and constructed a new lens model that gives a total mass within 600 kpc of (2.6 ± 0.3) × 10 ^14 M _⊙ . The photometry uncovered a galaxy overdensity coincident with the SN host galaxy. NIRSpec confirmed six member galaxies, four of which surround the SN host galaxy with relative velocity ≲900 km s ^−1 and projected physical extent ≲33 kpc. This compact galaxy group is dominated by the SN host galaxy, which has a stellar mass of (5.0 ± 0.1) × 10 ^11 M _⊙ . The group members have specific star formation rates of 2–260 Gyr ^−1 derived from the H α -line fluxes corrected for stellar absorption, dust extinction, and slit losses. Another group centered on a strongly lensed dusty star-forming galaxy is at z = 2.24. The total (unobscured and obscured) SFR of this second galaxy group is estimated to be (≳ 100 M _⊙ yr ^−1 ), which translates to a supernova rate of ∼1 SNe yr ^−1 , suggesting that regular monitoring of this cluster may yield additional SNe.

Asteroid collisions are one of the main processes responsible for the evolution of bodies in the main belt. Using observations of the Dimorphos impact by the DART spacecraft, we estimate how asteroid collisions in the main belt may look in the first hours after the impact. If the DART event is representative of asteroid collisions with a ∼1 m sized impactor, then the light curves of these collisions will rise on timescales of about ≳100 s and will remain bright for about 1 hr. Next, the light curve will decay on a few hours' timescale to an intermediate luminosity level in which it will remain for several weeks, before slowly returning to its baseline magnitude. This estimate suffers from several uncertainties due to, e.g., the diversity of asteroid composition, their material strength, and spread in collision velocities. We estimate that the rate of collisions in the main belt with energy similar to or larger than the DART impact is of the order of 7000 yr ^−1 (±1 dex). The large range is due to the uncertainty in the abundance of ∼1 m sized asteroids. We estimate the magnitude distribution of such events in the main belt, and we show that ∼6% of these events may peak at magnitudes brighter than 21. The detection of these events requires a survey with ≲1 hr cadence and may contribute to our understanding of the asteroids’ size distribution, collisional physics, and dust production. With an adequate survey strategy, new survey telescopes may regularly detect asteroid collisions.

SN H0pe is a triply imaged supernova (SN) at redshift z = 1.78 discovered using the James Webb Space Telescope. In order to classify the SN spectroscopically and measure the relative time delays of its three images (designated A, B, and C), we acquired NIRSpec follow-up spectroscopy spanning 0.6–5 μ m. From the high signal-to-noise spectra of the two bright images B and C, we first classify the SN, whose spectra most closely match those of SN 1994D and SN 2013dy, as a Type Ia SN. We identify prominent blueshifted absorption features corresponding to Si ii λ 6355 and Ca ii H λ 3970 and K λ 3935. We next measure the absolute phases of the three images from our spectra, which allow us to constrain their relative time delays. The absolute phases of the three images, determined by fitting the three spectra to Hsiao07 SN templates, are ${6.5}_{-1.8}^{+2.4}$ days, ${24.3}_{-3.9}^{+3.9}$ days, and ${50.6}_{-15.3}^{+16.1}$ days for the brightest to faintest images. These correspond to relative time delays between Image A and Image B and between Image B and Image C of $-{122.3}_{-43.8}^{+43.7}$ days and ${49.3}_{-14.7}^{+12.2}$ days, respectively. The SALT3-NIR model yields phases and time delays consistent with these values. After unblinding, we additionally explored the effect of using Hsiao07 template spectra for simulations through 80 days instead of 60 days past maximum, and found a small (11.5 and 1.0 days, respectively) yet statistically insignificant (∼0.25 σ and ∼0.1 σ ) effect on the inferred image delays.

We analyze pre-explosion near- and mid-infrared (IR) imaging of the site of SN 2023ixf in the nearby spiral galaxy M101 and characterize the candidate progenitor star. The star displays compelling evidence of variability with a possible period of ≈1000 days and an amplitude of Δ m ≈ 0.6 mag in extensive monitoring with the Spitzer Space Telescope since 2004, likely indicative of radial pulsations. Variability consistent with this period is also seen in the near-IR J and K _s bands between 2010 and 2023, up to just 10 days before the explosion. Beyond the periodic variability, we do not find evidence for any IR-bright pre-supernova outbursts in this time period. The IR brightness ( ${M}_{{K}_{s}}=-10.7$ mag) and color ( J − K _s = 1.6 mag) of the star suggest a luminous and dusty red supergiant. Modeling of the phase-averaged spectral energy distribution (SED) yields constraints on the stellar temperature ( ${T}_{\mathrm{eff}}={3500}_{-1400}^{+800}$ K) and luminosity ( $\mathrm{log}L/{L}_{\odot }=5.1\pm 0.2$ ). This places the candidate among the most luminous Type II supernova progenitors with direct imaging constraints, with the caveat that many of these rely only on optical measurements. Comparison with stellar evolution models gives an initial mass of M _init = 17 ± 4 M _⊙ . We estimate the pre-supernova mass-loss rate of the star between 3 and 19 yr before explosion from the SED modeling at $\dot{M}\approx 3\times {10}^{-5}$ to 3 × 10 ^−4 M _⊙ yr ^−1 for an assumed wind velocity of v _w = 10 km s ^−1 , perhaps pointing to enhanced mass loss in a pulsation-driven wind.

Introduction Previous research demonstrated that medical scent detection dogs have the ability to distinguish SARS-CoV-2 positive from negative samples with high diagnostic accuracy. To deploy these dogs as a reliable screening method, it is mandatory to examine if canines maintain their high diagnostic accuracy in real-life screening settings. We conducted a study to evaluate the performance of medical scent detection dogs under real-life circumstances.Methods Eight dogs were trained to detect SARS-CoV-2 RT-qPCR-positive samples. Four concerts with a total of 2802 participants were held to evaluate canines’ performance in screening individuals for SARS-CoV-2 infection. Sweat samples were taken from all participants and presented in a line-up setting. In addition, every participant had been tested with a SARS-CoV-2 specific rapid antigen test and a RT-qPCR and they provided information regarding age, sex, vaccination status and medical disease history. The participants’ infection status was unknown at the time of canine testing. Safety measures such as mask wearing and distance keeping were ensured.Results The SARS-CoV-2 detection dogs achieved a diagnostic specificity of 99.93% (95% CI 99.74% to 99.99%) and a sensitivity of 81.58% (95% CI 66.58% to 90.78%), respectively. The overall rate of concordant results was 99.68%. The majority of the study population was vaccinated with varying vaccines and vaccination schemes, while several participants had chronic diseases and were under chronic medication. This did not influence dogs’ decisions.Conclusion Our results demonstrate that SARS-CoV-2 scent detection dogs achieved high diagnostic accuracy in a real-life scenario. The vaccination status, previous SARS-CoV-2 infection, chronic disease and medication of the participants did not influence the performance of the dogs in detecting the acute infection. This indicates that dogs provide a fast and reliable screening option for public events in which high-throughput screening is required.