bluuebunny/crossref_metadata_2025 huggingface dataset:
Involving Young People With Lived and Living Experience of Suicide in Suicide Research
Authors: Webb Marianne , Cooper Charlie , Hemming Laura , Dalton Alex , Unity Emily , Simmons Magenta B. , Bendall Sarah , Robinson Jo
Published: February 2024

Abstract: Background: Research into youth suicide prevention rarely involves young people with lived and living experiences as collaborators. Key barriers include a lack of guidelines or frameworks to inform collaboration, appropriate ethical approval processes, perceived risk, and recruitment. Aim: To develop guidelines for involving young people with lived and living experiences in suicide research as collaborators. Method: A Delphi expert consensus study was conducted with two expert panels: a youth lived and living experiences panel and a traditionally qualified researcher panel. Items rated as essential or important using a five-point Likert scale by more than 80% of both panels were included in the guidelines. Results: Forty-nine experts completed two consensus rounds. The guidelines are organized as follows: (1) preparation, (2) supporting safety and well-being, (3) evaluating involvement, and (4) tips for young people. Limitations: Participants were from English-speaking, Western countries only. Conclusion: These world-first guidelines address the unique challenges and opportunities for involving young people with lived and living experiences in suicide research.
The Development, Progress, and Impact of National Suicide Prevention Strategies Worldwide
Authors: Sinyor Mark , Ming Chan Prudence Po , Niederkrotenthaler Thomas , Scott Vanda , Platt Stephen
Published: February 2024

Abstract: National suicide prevention strategies have been identified as evidence-informed interventions that require multisectoral efforts by governments. This article reviews the rationale for national strategies, the need for a whole-of-government approach, and current progress on national strategies worldwide, including successes and challenges regarding implementation. We highlight the limitations of existing evidence and describe how future research may help to address knowledge gaps. We conclude that national strategies are an important tool for suicide prevention worldwide. However, a more robust evidence base evaluating the impact of strategies on suicide-related outcomes is needed.
The Role of Non‐Local Effects on Surface Sensible Heat Flux Under Different Types of Thermal Structures Over the Arctic Sea‐Ice Surface
Authors: Liu Changwei , Yang Qinghua , Gao Zhongming , Shupe Matthew D. , Han Bo , Zhang Huixian , Peng Shijie , Xi Xingya , Chen Dake
Published: February 2024

The effects of atmospheric thermal structure on the surface energy flux are poorly understood over the Arctic sea‐ice surface. Here, we explore the mechanism of sensible heat exchange under different types of thermal structures over the Arctic sea‐ice surface by using data collected during the Multidisciplinary drifting Observatory for the Study of Arctic Climate expedition. The quadrant analysis indicates that strong surface temperature inversions below 100 m enhance non‐local effects on the positive (upward) sensible heat flux () through entrainment of large eddies from the convective boundary layer aloft. However, strong surface inversions restrict the contributions of large eddies to the negative (downward) due to intensified surface stability. By inspecting the existing parameterization schemes, we found that the European Center for Medium‐Range Weather Forecasts Integrated Forecasting System scheme fails to predict the impacts of non‐local processes on the positive , and an adjustment term to correct the bias of parameterized is proposed.
Restoration and Transformation: The Response of Shocked and Oxidized Magnetite to Temperature
Authors: Mendes Bruno Daniel Leite , Kontny Agnes
Published: February 2024

Large impact craters on Earth are associated with prominent magnetic anomalies, residing in magnetite of the shocked target rocks and impactites. Shock experiments on magnetite suggest that up to 90% of magnetic susceptibility is lost at pressures >5 GPa, but can be partially restored by post‐shock thermal annealing. The magnetic property changes are caused by shock induced grain size reduction and fragmentation, as well as domain wall‐pinning at crystal lattice defects. A recent study of granitoids from the peak‐ring of the Chicxulub crater found that annealing may occur naturally, but can also be overprinted by high‐temperature hematite‐to‐magnetite transformation in non‐oxidizing environments. In this study, we isolate the effect of defect annealing and hematite‐to‐magnetite transformation using the evolution of hysteresis, isothermal remanent magnetization components and first order reversal curve (FORC) diagrams at different high‐temperature steps. We used a laboratory‐shocked magnetite‐quartz ore, a non‐shocked naturally oxidized granite, and a naturally shocked and oxidized granite. Our findings suggest that annealing of shock‐induced lattice defects partially restores some pre‐shock magnetic behavior and causes an apparent average bulk‐sample domain state increase. Hematite‐to‐magnetite transformation creates new fine‐grained magnetite that strongly overprints the original signal, and decreases the average bulk‐sample domain state. Where annealing and hematite‐to‐magnetite transformation both occur, the new magnetite masks the annealing‐induced property restoration and apparent domain state modification in the shocked magnetite. As magnetite oxidation is a ubiquitous process in surface rocks, these findings are fundamental to understand hematite‐to‐magnetite transformation as a potential overprint mechanism, and could have broad implications for paleomagnetic interpretations.
The Effect of Normal Stress Oscillations on Fault Slip Behavior Near the Stability Transition From Stable to Unstable Motion
Authors: Pignalberi Federico , Giorgetti Carolina , Noël Corentin , Marone Chris , Collettini Cristiano , Scuderi Marco Maria
Published: February 2024

Tectonic fault zones are subject to normal stress variations with a wide range of spatio‐temporal scales. Stress perturbations cover a wide range of frequencies and amplitudes from high frequency seismic waves generated by earthquakes to low frequency transients associated with solid Earth tides. These perturbations can reactivate critically stressed faults and trigger earthquakes. Here, we describe lab experiments to illuminate the physics of such changes in friction and the mechanics of earthquake triggering and fault reactivation. Friction tests were done in a double direct shear configuration for conditions near the stability transition from stable to unstable motion. We studied simulated fault gouge composed of quartz powder and conducted experiments at reference normal stress from 10 to 13.5 MPa. After shearing to steady state sliding, we applied sinusoidal normal stress oscillations of amplitude 0.5–2 MPa, and period of 0.5–50 s. We performed numerical simulations using measured values of rate and state friction (RSF) parameters to assess our data. Our results show that low frequency stress oscillations cause a Coulomb‐like response of shear strength that transitions from stable slip to slow lab earthquakes as frequency increases. At the critical frequency predicted by RSF we observe periodic stick‐slip behavior. Perturbations of high amplitude and short period weaken the fault, while lower amplitudes strengthen the fault. We find that a modified RSF formulation is able to accurately match our laboratory data. Our findings highlight the complex effects of stress perturbations on fault strength and the mode of fault slip.
Drivers of Marine Heatwaves in the Arctic Ocean
Authors: Richaud Benjamin , Hu Xianmin , Darmaraki Sofia , Fennel Katja , Lu Youyu , Oliver Eric C. J.
Published: February 2024

Among the documented consequences of anthropogenic global warming are the increased frequency and duration of marine heatwaves in the global ocean. The literature dedicated to Arctic marine heatwaves corroborates those results, but fails to identify the heat sources and sinks. Because of the numerous feedbacks impacting polar regions, understanding the processes triggering and dissipating those extreme events is particularly important to predict their occurrence in a fast changing ocean. A three‐dimensional regional ice‐ocean numerical model is used to calculate a surface mixed layer heat budget and to investigate mechanisms generating and dissipating marine heatwaves. The majority of the marine heatwaves are onset by surface heat fluxes and decayed by bottom and surface heat fluxes. The dominant processes are spatially and seasonally heterogeneous: lateral heat flux can become the primary process when advecting heat anomalies at the main Arctic gateways or by triggering temperature extremes in winter. Using a Reynolds decomposition, it can be determined that the shoaling of the surface mixed layer induced by ice melt can significantly lengthen and intensify Arctic marine heatwaves. In winter, the analysis of marine heatwaves poses unique challenges, with the long term freshening of the Arctic inducing a positive trend of 0.1°C per decade for the freezing point. Arctic marine heatwaves are expected to keep increasing in duration and intensity due to the increased trend of the primary process, the surface heat flux, and their dissipation by bottom heat flux provides a pathway for heat from the atmosphere to the Arctic subsurface water masses.
The Sensitive Area for Targeting Observations of Paired Mesoscale Eddies Associated With Sea Surface Height Anomaly Forecasts
Authors: Jiang Lin , Duan Wansuo , Wang Hui
Published: February 2024

For paired mesoscale eddies, the most sensitive initial errors in relation to sea surface height anomaly (SSHA) forecasts are investigated by utilizing the conditional nonlinear optimal perturbation (CNOP) method in a two‐layer quasigeostrophic model and then the sensitive areas are identified accordingly. For counter‐rotating eddies, the CNOP initial errors primarily occur within the eddies themselves, especially in areas characterized by clear high‐to low‐velocity gradients, accompanied by shear structures; while for co‐rotating eddies, besides sharing the feature of the former, their CNOP initial errors also concentrate between the two eddies and are obliquely tangential to their boundaries with a positive and negative shear structure. The utility of the CNOP initial errors in determining the sensitive areas for target observation is assessed through observing system simulation experiments (OSSEs). The OSSEs indicate that giving priority to the implementation of target observations in the sensitive areas identified by large CNOP initial errors, whether within eddies or between two co‐rotating eddies, particularly with a specific array guided by the shear structure of CNOP initial errors, leads to a notable improvement in SSHA forecasting. Finally, the effectiveness of the target observations, especially within the sensitive area situated between two co‐rotating eddies, is interpreted from the perspective of barotropic instability. The results of this study offer valuable scientific insights into the targeted observation of paired mesoscale eddies. These findings have the potential to provide important guidance for initializating paired mesoscale eddies, ultimately contributing to improvements in SSHA forecast accuracy.
Ice‐Ocean Interactions on Ocean Worlds Influence Ice Shell Topography
Authors: Lawrence J. D. , Schmidt B. E. , Buffo J. J. , Washam P. M. , Chivers C. , Miller S.
Published: February 2024

The freezing point of water is negatively dependent on pressure; therefore in any ocean without external forcing it is warmest at the surface and grows colder with depth. Below floating ice on Earth (e.g., ice shelves or sea ice), this pressure dependence combines with gradients in the ice draft to drive an ice redistribution process termed the “ice pump”: submerged ice melts, upwells, and then refreezes at shallower depths. Ice pumping is an exchange process between the ocean and overhead ice that results in unique ice compositions and textures and influences the distribution of sub‐ice habitats on Earth. Here, we scale recent observations from Earth's ice shelves to planetary conditions and find that ice pumping is expected for a wide range of possible sub‐ice shell pressures and salinity at other ocean worlds such as Europa and Enceladus. We show how ice pumping would affect hypothetical basal ice shell topography and ice thickness under varying ocean conditions and demonstrate how remote sensing of the ice shell draft can be used to estimate temperature gradients in the upper ocean ahead of in situ exploration. For example, the approximately 22 km gradient observed in Enceladus' ice shell draft between the south pole and the equator suggests a temperature differential of 0.18 K at the base of the ice shell. These concepts can extend the interpretation of observations from upcoming ocean world missions, and link ice shell topography to ice‐ocean material exchange processes that may prove important to overall ocean world habitability.
On‐Orbit Spatial Performance Characterization for Thermal Infrared Imagers of Landsat 7, 8, and 9, ECOSTRESS and CTI
Authors: Holmes T. R. H. , Poulter B. , McCorkel J. , Jennings D. E. , Wu D. L. , Efremova B. , Shiklomanov A. , Johnson W. R. , Jhabvala M. , Hook S. J.
Published: February 2024

In this analysis of the spatial resolving power of thermal imagery products we focus on four satellite instruments that are used in research and applications, for example, to monitor land surface temperature and derive evapotranspiration. These are thermal imagers on Landsat 7, Landsat 8, and Landsat 9, as well as the ECOsystem Spaceborne Thermal Radiometer Experiment on Space Station (ECOSTRESS). We compiled sets of close‐in‐time, day‐time images of bridges surrounded by open water bodies, captured by each of the satellite imagers during cloud‐free moments. Where possible, we also included some images captured by the Compact Thermal Imager (CTI), a technology demonstrator that was co‐located with ECOSTRESS on the International Space Station in 2019. Bridges were found to provide a sufficient thermal contrast with the water surface to quantify the line‐spread function of satellite‐based thermal products. The full‐width‐at‐half‐max of a gaussian beam model fitted to this transect quantifies the on‐orbit spatial resolution of different imagers. The results show some loss of spatial resolving power in the final product delivered to end‐users as compared to the at‐sensor characterization of spatial resolution. For Landsat 7, 8, and 9, the spatial resolution of the thermal bands is 1.5 times the ground sampling distance of 60 and 100 m respectively. For the ECOSTRESS the difference is up to twice the sampling distance of 78 by 69 m2. Since spatial resolution is a main driver for instrument design it is important to understand and communicate this discrepancy between pre‐flight design parameters and the characteristics of the surface imagery delivered to the user community. The goal of this research is to facilitate an improved fusion of current and future satellite observations into harmonized products with superior temporal and spatial characteristics.
Distinct characteristics of the DNA damage response in mammalian oocytes
Authors: Leem Jiyeon , Lee Crystal , Choi Da Yi , Oh Jeong Su
Published: February 2024

DNA damage is a critical threat that poses significant challenges to all cells. To address this issue, cells have evolved a sophisticated molecular and cellular process known as the DNA damage response (DDR). Among the various cell types, mammalian oocytes, which remain dormant in the ovary for extended periods, are particularly susceptible to DNA damage. The occurrence of DNA damage in oocytes can result in genetic abnormalities, potentially leading to infertility, birth defects, and even abortion. Therefore, understanding how oocytes detect and repair DNA damage is of paramount importance in maintaining oocyte quality and preserving fertility. Although the fundamental concept of the DDR is conserved across various cell types, an emerging body of evidence reveals striking distinctions in the DDR between mammalian oocytes and somatic cells. In this review, we highlight the distinctive characteristics of the DDR in oocytes and discuss the clinical implications of DNA damage in oocytes.
Analog spatiotemporal feature extraction for cognitive radio-frequency sensing with integrated photonics
Authors: Xu Shaofu , Liu Binshuo , Yi Sicheng , Wang Jing , Zou Weiwen
Published: February 2024

Analog feature extraction (AFE) is an appealing strategy for low-latency and efficient cognitive sensing systems since key features are much sparser than the Nyquist-sampled data. However, applying AFE to broadband radio-frequency (RF) scenarios is challenging due to the bandwidth and programmability bottlenecks of analog electronic circuitry. Here, we introduce a photonics-based scheme that extracts spatiotemporal features from broadband RF signals in the analog domain. The feature extractor structure inspired by convolutional neural networks is implemented on integrated photonic circuits to process RF signals from multiple antennas, extracting valid features from both temporal and spatial dimensions. Because of the tunability of the photonic devices, the photonic spatiotemporal feature extractor is trainable, which enhances the validity of the extracted features. Moreover, a digital-analog-hybrid transfer learning method is proposed for the effective and low-cost training of the photonic feature extractor. To validate our scheme, we demonstrate a radar target recognition task with a 4-GHz instantaneous bandwidth. Experimental results indicate that the photonic analog feature extractor tackles broadband RF signals and reduces the sampling rate of analog-to-digital converters to 1/4 of the Nyquist sampling while maintaining a high target recognition accuracy of 97.5%. Our scheme offers a promising path for exploiting the AFE strategy in the realm of cognitive RF sensing, with the potential to contribute to the efficient signal processing involved in applications such as autonomous driving, robotics, and smart factories.
Heterogeneity and tumoral origin of medulloblastoma in the single-cell era
Authors: Sheng Hui , Li Haotai , Zeng Han , Zhang Bin , Lu Yu , Liu Xixi , Xu Zhongwen , Zhang Jing , Zhang Liguo
Published: February 2024

Medulloblastoma is one of the most common malignant pediatric brain tumors derived from posterior fossa. The current treatment includes maximal safe surgical resection, radiotherapy, whole cranio-spinal radiation and adjuvant with chemotherapy. However, it can only limitedly prolong the survival time with severe side effects and relapse. Defining the intratumoral heterogeneity, cellular origin and identifying the interaction network within tumor microenvironment are helpful for understanding the mechanisms of medulloblastoma tumorigenesis and relapse. Due to technological limitations, the mechanisms of cellular heterogeneity and tumor origin have not been fully understood. Recently, the emergence of single-cell technology has provided a powerful tool for achieving the goal of understanding the mechanisms of tumorigenesis. Several studies have demonstrated the intratumoral heterogeneity and tumor origin for each subtype of medulloblastoma utilizing the single-cell RNA-seq, which has not been uncovered before using conventional technologies. In this review, we present an overview of the current progress in understanding of cellular heterogeneity and tumor origin of medulloblastoma and discuss novel findings in the age of single-cell technologies.
Infectious eye disease in the 21st century—an overview
Authors: Clare Gerry , Kempen John H. , Pavésio Carlos
Published: February 2024

Infectious diseases affecting the eye often cause unilateral or asymmetric visual loss in children and people of working age. This group of conditions includes viral, bacterial, fungal and parasitic diseases, both common and rare presentations which, in aggregate, may account for a significant portion of the global visual burden. Diagnosis is frequently challenging even in specialist centres, and many disease presentations are highly regional. In an age of globalisation, an understanding of the various modes of transmission and the geographic distribution of infections can be instructive to clinicians. The impact of eye infections on global disability is currently not sufficiently captured in global prevalence studies on visual impairment and blindness, which focus on bilateral disease in the over-50s. Moreover, in many cases it is hard to differentiate between infectious and immune-mediated diseases. Since infectious eye diseases can be preventable and frequently affect younger people, we argue that in future prevalence studies they should be considered as a separate category, including estimates of disability-adjusted life years (DALY) as a measure of overall disease burden. Numbers of ocular infections are uniquely affected by outbreaks as well as endemic transmission, and their control frequently relies on collaborative partnerships that go well beyond the remit of ophthalmology, encompassing domains as various as vaccination, antibiotic development, individual healthcare, vector control, mass drug administration, food supplementation, environmental and food hygiene, epidemiological mapping, and many more. Moreover, the anticipated impacts of global warming, conflict, food poverty, urbanisation and environmental degradation are likely to magnify their importance. While remote telemedicine can be a useful aide in the diagnosis of these conditions in resource-poor areas, enhanced global reporting networks and artificial intelligence systems may ultimately be required for disease surveillance and monitoring.
Low on-treatment blood pressure and cardiovascular events in patients without elevated risk: a nationwide cohort study
Authors: Mori Yuichiro , Mizuno Atsushi , Fukuma Shingo
Published: February 2024

Abstracts

Insufficient blood pressure control among patients with hypertension without elevated risk is a global concern, suggesting the need for treatment optimization. However, the potential harm of excessive blood pressure lowering among these patients is understudied. This study addressed this evidence gap by using nationally representative public health insurer database covering 30 million working-age population. Patients who were continuously using antihypertensive drugs with 10-year cardiovascular risk <10% were identified. They were categorized by on-treatment systolic and diastolic blood pressures. The primary outcome was a composite of myocardial infarction, stroke, heart failure hospitalization, and peripheral artery disease. Of 920,533 participants (mean age, 57.3 years; female, 48.3%; mean follow-up, 2.75 years), the adjusted hazard ratios for systolic blood pressure of <110, 110–119, 120–129 (reference), 130–139, 140–149, 150–159, and ≥160 mmHg were 1.05 (95% confidence interval: 0.99–1.12), 0.97 (0.93–1.02), 1 (reference), 1.05 (1.01–1.09), 1.15 (1.11–1.20), 1.30 (1.23–1.37), and 1.76 (1.66–1.86), respectively; and for diastolic blood pressure of <60, 60–69, 70–79 (reference), 80–89, 90–99, and ≥100 mmHg were 1.25 (1.14–1.38), 0.99 (0.95–1.04), 1 (reference), 1.00 (0.96–1.03), 1.13 (1.09–1.18), and 1.66 (1.58–1.76), respectively. Among low-risk patients with hypertension, diastolic blood pressure <60 mmHg was associated with increased cardiovascular events, while systolic blood pressure <110 mmHg was not. Compared to previous investigations in high-risk patients, the potential harm of excessive blood pressure lowering was less pronounced in low-risk patients with hypertension.
The IL6/JAK/STAT3 signaling axis is a therapeutic vulnerability in SMARCB1-deficient bladder cancer
Authors: Amara Chandra Sekhar , Kami Reddy Karthik Reddy , Yuntao Yang , Chan Yuen San , Piyarathna Danthasinghe Waduge Badrajee , Dobrolecki Lacey Elizabeth , Shih David J. H. , Shi Zhongcheng , Xu Jun , Huang Shixia , Ellis Matthew J. , Apolo Andrea B. , Ballester Leomar Y. , Gao Jianjun , Hansel Donna E. , Lotan Yair , Hodges H. Courtney , Lerner Seth P. , Creighton Chad J. , Sreekumar Arun , Zheng W. Jim , Msaouel Pavlos , Kavuri Shyam M. , Putluri Nagireddy
Published: February 2024

SMARCB1 loss has long been observed in many solid tumors. However, there is a need to elucidate targetable pathways driving growth and metastasis in SMARCB1-deficient tumors. Here, we demonstrate that SMARCB1 deficiency, defined as genomic SMARCB1 copy number loss associated with reduced mRNA, drives disease progression in patients with bladder cancer by engaging STAT3. SMARCB1 loss increases the chromatin accessibility of the STAT3 locus in vitro. Orthotopically implanted SMARCB1 knockout (KO) cell lines exhibit increased tumor growth and metastasis. SMARCB1-deficient tumors show an increased IL6/JAK/STAT3 signaling axis in in vivo models and patients. Furthermore, a pSTAT3 selective inhibitor, TTI-101, reduces tumor growth in SMARCB1 KO orthotopic cell line-derived xenografts and a SMARCB1-deficient patient derived xenograft model. We have identified a gene signature generated from SMARCB1 KO tumors that predicts SMARCB1 deficiency in patients. Overall, these findings support the clinical evaluation of STAT3 inhibitors for the treatment of SMARCB1-deficient bladder cancer.
Choreographing root architecture and rhizosphere interactions through synthetic biology
Authors: Ragland Carin J. , Shih Kevin Y. , Dinneny José R.
Published: February 2024

Climate change is driving extreme changes to the environment, posing substantial threats to global food security and bioenergy. Given the direct role of plant roots in mediating plant-environment interactions, engineering the form and function of root systems and their associated microbiota may mitigate these effects. Synthetic genetic circuits have enabled sophisticated control of gene expression in microbial systems for years and a surge of advances has heralded the extension of this approach to multicellular plant species. Targeting these tools to affect root structure, exudation, and microbe activity on root surfaces provide multiple strategies for the advancement of climate-ready crops.
In vitro induction of patterned branchial arch-like aggregate from human pluripotent stem cells
Authors: Seto Yusuke , Ogihara Ryoma , Takizawa Kaori , Eiraku Mototsugu
Published: February 2024

Early patterning of neural crest cells (NCCs) in the craniofacial primordium is important for subsequent development of proper craniofacial structures. However, because of the complexity of the environment of developing tissues, surveying the early specification and patterning of NCCs is difficult. In this study, we develop a simplified in vitro 3D model using human pluripotent stem cells to analyze the early stages of facial development. In this model, cranial NCC-like cells spontaneously differentiate from neural plate border-like cells into maxillary arch-like mesenchyme after a long-term culture. Upon the addition of EDN1 and BMP4, these aggregates are converted into a mandibular arch-like state. Furthermore, temporary treatment with EDN1 and BMP4 induces the formation of spatially separated domains expressing mandibular and maxillary arch markers within a single aggregate. These results suggest that this in vitro model is useful for determining the mechanisms underlying cell fate specification and patterning during early facial development.
Navigating the 16-dimensional Hilbert space of a high-spin donor qudit with electric and magnetic fields
Authors: Fernández de Fuentes Irene , Botzem Tim , Johnson Mark A. I. , Vaartjes Arjen , Asaad Serwan , Mourik Vincent , Hudson Fay E. , Itoh Kohei M. , Johnson Brett C. , Jakob Alexander M. , McCallum Jeffrey C. , Jamieson David N. , Dzurak Andrew S. , Morello Andrea
Published: February 2024

Efficient scaling and flexible control are key aspects of useful quantum computing hardware. Spins in semiconductors combine quantum information processing with electrons, holes or nuclei, control with electric or magnetic fields, and scalable coupling via exchange or dipole interaction. However, accessing large Hilbert space dimensions has remained challenging, due to the short-distance nature of the interactions. Here, we present an atom-based semiconductor platform where a 16-dimensional Hilbert space is built by the combined electron-nuclear states of a single antimony donor in silicon. We demonstrate the ability to navigate this large Hilbert space using both electric and magnetic fields, with gate fidelity exceeding 99.8% on the nuclear spin, and unveil fine details of the system Hamiltonian and its susceptibility to control and noise fields. These results establish high-spin donors as a rich platform for practical quantum information and to explore quantum foundations.
Modeling early pathophysiological phenotypes of diabetic retinopathy in a human inner blood-retinal barrier-on-a-chip
Authors: Maurissen Thomas L. , Spielmann Alena J. , Schellenberg Gabriella , Bickle Marc , Vieira Jose Ricardo , Lai Si Ying , Pavlou Georgios , Fauser Sascha , Westenskow Peter D. , Kamm Roger D. , Ragelle Héloïse
Published: February 2024

Diabetic retinopathy (DR) is a microvascular disorder characterized by inner blood-retinal barrier (iBRB) breakdown and irreversible vision loss. While the symptoms of DR are known, disease mechanisms including basement membrane thickening, pericyte dropout and capillary damage remain poorly understood and interventions to repair diseased iBRB microvascular networks have not been developed. In addition, current approaches using animal models and in vitro systems lack translatability and predictivity to finding new target pathways. Here, we develop a diabetic iBRB-on-a-chip that produces pathophysiological phenotypes and disease pathways in vitro that are representative of clinical diagnoses. We show that diabetic stimulation of the iBRB-on-a-chip mirrors DR features, including pericyte loss, vascular regression, ghost vessels, and production of pro-inflammatory factors. We also report transcriptomic data from diabetic iBRB microvascular networks that may reveal drug targets, and examine pericyte-endothelial cell stabilizing strategies. In summary, our model recapitulates key features of disease, and may inform future therapies for DR.
Molecular basis of VEGFR1 autoinhibition at the plasma membrane
Authors: Chakraborty Manas Pratim , Das Diptatanu , Mondal Purav , Kaul Pragya , Bhattacharyya Soumi , Kumar Das Prosad , Das Rahul
Published: February 2024

Ligand-independent activation of VEGFRs is a hallmark of diabetes and several cancers. Like EGFR, VEGFR2 is activated spontaneously at high receptor concentrations. VEGFR1, on the other hand, remains constitutively inactive in the unligated state, making it an exception among VEGFRs. Ligand stimulation transiently phosphorylates VEGFR1 and induces weak kinase activation in endothelial cells. Recent studies, however, suggest that VEGFR1 signaling is indispensable in regulating various physiological or pathological events. The reason why VEGFR1 is regulated differently from other VEGFRs remains unknown. Here, we elucidate a mechanism of juxtamembrane inhibition that shifts the equilibrium of VEGFR1 towards the inactive state, rendering it an inefficient kinase. The juxtamembrane inhibition of VEGFR1 suppresses its basal phosphorylation even at high receptor concentrations and transiently stabilizes tyrosine phosphorylation after ligand stimulation. We conclude that a subtle imbalance in phosphatase activation or removing juxtamembrane inhibition is sufficient to induce ligand-independent activation of VEGFR1 and sustain tyrosine phosphorylation.
Resolving the topology of encircling multiple exceptional points
Authors: Guria Chitres , Zhong Qi , Ozdemir Sahin Kaya , Patil Yogesh S. S. , El-Ganainy Ramy , Harris Jack Gwynne Emmet
Published: February 2024

Non-Hermiticity has emerged as a new paradigm for controlling coupled-mode systems in ways that cannot be achieved with conventional techniques. One aspect of this control that has received considerable attention recently is the encircling of exceptional points (EPs). To date, most work has focused on systems consisting of two modes that are tuned by two control parameters and have isolated EPs. While these systems exhibit exotic features related to EP encircling, it has been shown that richer behavior occurs in systems with more than two modes. Such systems can be tuned by more than two control parameters, and contain EPs that form a knot-like structure. Control loops that encircle this structure cause the system’s eigenvalues to trace out non-commutative braids. Here we consider a hybrid scenario: a three-mode system with just two control parameters. We describe the relationship between control loops and their topology in the full and two-dimensional parameter space. We demonstrate this relationship experimentally using a three-mode mechanical system in which the control parameters are provided by optomechanical interaction with a high-finesse optical cavity.
A deep-learning-based framework for identifying and localizing multiple abnormalities and assessing cardiomegaly in chest X-ray
Authors: Fan Weijie , Yang Yi , Qi Jing , Zhang Qichuan , Liao Cuiwei , Wen Li , Wang Shuang , Wang Guangxian , Xia Yu , Wu Qihua , Fan Xiaotao , Chen Xingcai , He Mi , Xiao JingJing , Yang Liu , Liu Yun , Chen Jia , Wang Bing , Zhang Lei , Yang Liuqing , Gan Hui , Zhang Shushu , Liu Guofang , Ge Xiaodong , Cai Yuanqing , Zhao Gang , Zhang Xi , Xie Mingxun , Xu Huilin , Zhang Yi , Chen Jiao , Li Jun , Han Shuang , Mu Ke , Xiao Shilin , Xiong Tingwei , Nian Yongjian , Zhang Dong
Published: February 2024

Accurate identification and localization of multiple abnormalities are crucial steps in the interpretation of chest X-rays (CXRs); however, the lack of a large CXR dataset with bounding boxes severely constrains accurate localization research based on deep learning. We created a large CXR dataset named CXR-AL14, containing 165,988 CXRs and 253,844 bounding boxes. On the basis of this dataset, a deep-learning-based framework was developed to identify and localize 14 common abnormalities and calculate the cardiothoracic ratio (CTR) simultaneously. The mean average precision values obtained by the model for 14 abnormalities reached 0.572-0.631 with an intersection-over-union threshold of 0.5, and the intraclass correlation coefficient of the CTR algorithm exceeded 0.95 on the held-out, multicentre and prospective test datasets. This framework shows an excellent performance, good generalization ability and strong clinical applicability, which is superior to senior radiologists and suitable for routine clinical settings.
Genomic epidemiology reveals geographical clustering of multidrug-resistant Escherichia coli ST131 associated with bacteraemia in Wales
Authors: White Rhys T. , Bull Matthew J. , Barker Clare R. , Arnott Julie M. , Wootton Mandy , Jones Lim S. , Howe Robin A. , Morgan Mari , Ashcroft Melinda M. , Forde Brian M. , Connor Thomas R. , Beatson Scott A.
Published: February 2024

Antibiotic resistance is a significant global public health concern. Uropathogenic Escherichia coli sequence type (ST)131, a widely prevalent multidrug-resistant clone, is frequently associated with bacteraemia. This study investigates third-generation cephalosporin resistance in bloodstream infections caused by E. coli ST131. From 2013-2014 blood culture surveillance in Wales, 142 E. coli ST131 genomes were studied alongside global data. All three major ST131 clades were represented across Wales, with clade C/H30 predominant (n = 102/142, 71.8%). Consistent with global findings, Welsh strains of clade C/H30 contain β-lactamase genes from the blaCTX-M-1 group (n = 65/102, 63.7%), which confer resistance to third-generation cephalosporins. Most Welsh clade C/H30 genomes belonged to sub-clade C2/H30Rx (58.3%). A Wales-specific sub-lineage, named GB-WLS.C2, diverged around 1996-2000. An introduction to North Wales around 2002 led to a localised cluster by 2009, depicting limited genomic diversity within North Wales. This investigation emphasises the value of genomic epidemiology, allowing the detection of genetically similar strains in local areas, enabling targeted and timely public health interventions.
Leukemic stem cells activate lineage inappropriate signalling pathways to promote their growth
Authors: Kellaway Sophie G. , Potluri Sandeep , Keane Peter , Blair Helen J. , Ames Luke , Worker Alice , Chin Paulynn S. , Ptasinska Anetta , Derevyanko Polina K. , Adamo Assunta , Coleman Daniel J. L. , Khan Naeem , Assi Salam A. , Krippner-Heidenreich Anja , Raghavan Manoj , Cockerill Peter N. , Heidenreich Olaf , Bonifer Constanze
Published: February 2024

Acute Myeloid Leukemia (AML) is caused by multiple mutations which dysregulate growth and differentiation of myeloid cells. Cells adopt different gene regulatory networks specific to individual mutations, maintaining a rapidly proliferating blast cell population with fatal consequences for the patient if not treated. The most common treatment option is still chemotherapy which targets such cells. However, patients harbour a population of quiescent leukemic stem cells (LSCs) which can emerge from quiescence to trigger relapse after therapy. The processes that allow such cells to re-grow remain unknown. Here, we examine the well characterised t(8;21) AML sub-type as a model to address this question. Using four primary AML samples and a novel t(8;21) patient-derived xenograft model, we show that t(8;21) LSCs aberrantly activate the VEGF and IL-5 signalling pathways. Both pathways operate within a regulatory circuit consisting of the driver oncoprotein RUNX1::ETO and an AP-1/GATA2 axis allowing LSCs to re-enter the cell cycle while preserving self-renewal capacity.
Elastic porous microspheres/extracellular matrix hydrogel injectable composites releasing dual bio-factors enable tissue regeneration
Authors: Li Yi , Liu Siyang , Zhang Jingjing , Wang Yumeng , Lu Hongjiang , Zhang Yuexi , Song Guangzhou , Niu Fanhua , Shen Yufan , Midgley Adam C. , Li Wen , Kong Deling , Zhu Meifeng
Published: February 2024

Injectable biomaterials have garnered increasing attention for their potential and beneficial applications in minimally invasive surgical procedures and tissue regeneration. Extracellular matrix (ECM) hydrogels and porous synthetic polymer microspheres can be prepared for injectable administration to achieve in situ tissue regeneration. However, the rapid degradation of ECM hydrogels and the poor injectability and biological inertness of most polymeric microspheres limit their pro-regenerative capabilities. Here, we develop a biomaterial system consisting of elastic porous poly(l-lactide-co-ε-caprolactone) (PLCL) microspheres mixed with ECM hydrogels as injectable composites with interleukin-4 (IL-4) and insulin-like growth factor-1 (IGF-1) dual-release functionality. The developed multifunctional composites have favorable injectability and biocompatibility, and regulate the behavior of macrophages and myogenic cells following injection into muscle tissue. The elicited promotive effects on tissue regeneration are evidenced by enhanced neomusle formation, vascularization, and neuralization at 2-months post-implantation in a male rat model of volumetric muscle loss. Our developed system provides a promising strategy for engineering bioactive injectable composites that demonstrates desirable properties for clinical use and holds translational potential for application as a minimally invasive and pro-regenerative implant material in multiple types of surgical procedures.
Epiallelic variation of non-coding RNA genes and their phenotypic consequences
Authors: Liu Jie , Zhong Xuehua
Published: February 2024

Epigenetic variations contribute greatly to the phenotypic plasticity and diversity. Current functional studies on epialleles have predominantly focused on protein-coding genes, leaving the epialleles of non-coding RNA (ncRNA) genes largely understudied. Here, we uncover abundant DNA methylation variations of ncRNA genes and their significant correlations with plant adaptation among 1001 natural Arabidopsis accessions. Through genome-wide association study (GWAS), we identify large numbers of methylation QTL (methylQTL) that are independent of known DNA methyltransferases and enriched in specific chromatin states. Proximal methylQTL closely located to ncRNA genes have a larger effect on DNA methylation than distal methylQTL. We ectopically tether a DNA methyltransferase MQ1v to miR157a by CRISPR-dCas9 and show de novo establishment of DNA methylation accompanied with decreased miR157a abundance and early flowering. These findings provide important insights into the genetic basis of epigenetic variations and highlight the contribution of epigenetic variations of ncRNA genes to plant phenotypes and diversity.
Observation of Josephson harmonics in tunnel junctions
Authors: Willsch Dennis , Rieger Dennis , Winkel Patrick , Willsch Madita , Dickel Christian , Krause Jonas , Ando Yoichi , Lescanne Raphaël , Leghtas Zaki , Bronn Nicholas T. , Deb Pratiti , Lanes Olivia , Minev Zlatko K. , Dennig Benedikt , Geisert Simon , Günzler Simon , Ihssen Sören , Paluch Patrick , Reisinger Thomas , Hanna Roudy , Bae Jin Hee , Schüffelgen Peter , Grützmacher Detlev , Buimaga-Iarinca Luiza , Morari Cristian , Wernsdorfer Wolfgang , DiVincenzo David P. , Michielsen Kristel , Catelani Gianluigi , Pop Ioan M.
Published: February 2024

Approaches to developing large-scale superconducting quantum processors must cope with the numerous microscopic degrees of freedom that are ubiquitous in solid-state devices. State-of-the-art superconducting qubits employ aluminium oxide (AlOx) tunnel Josephson junctions as the sources of nonlinearity necessary to perform quantum operations. Analyses of these junctions typically assume an idealized, purely sinusoidal current–phase relation. However, this relation is expected to hold only in the limit of vanishingly low-transparency channels in the AlOx barrier. Here we show that the standard current–phase relation fails to accurately describe the energy spectra of transmon artificial atoms across various samples and laboratories. Instead, a mesoscopic model of tunnelling through an inhomogeneous AlOx barrier predicts percent-level contributions from higher Josephson harmonics. By including these in the transmon Hamiltonian, we obtain orders of magnitude better agreement between the computed and measured energy spectra. The presence and impact of Josephson harmonics has important implications for developing AlOx-based quantum technologies including quantum computers and parametric amplifiers. As an example, we show that engineered Josephson harmonics can reduce the charge dispersion and associated errors in transmon qubits by an order of magnitude while preserving their anharmonicity.
Smoking changes adaptive immunity with persistent effects
Authors: Saint-André Violaine , Charbit Bruno , Biton Anne , Rouilly Vincent , Possémé Céline , Bertrand Anthony , Rotival Maxime , Bergstedt Jacob , Patin Etienne , Albert Matthew L. , Quintana-Murci Lluis , Duffy Darragh ,   The Milieu Intérieur Consortium, Abel Laurent , Alcover Andres , Aschard Hugues , Bousso Philippe , Bourke Nollaig , Brodin Petter , Bruhns Pierre , Cerf-Bensussan Nadine , Cumano Ana , D’Enfert Christophe , Demangel Caroline , Deriano Ludovic , Dillies Marie-Agnès , Santo James Di , Eberl Gérard , Enninga Jost , Fellay Jacques , Gomperts-Boneca Ivo , Hasan Milena , Hedestam Gunilla Karlsson , Hercberg Serge , Ingersoll Molly A. , Lantz Olivier , Kenny Rose Anne , Ménager Mickaël , Michel Frédérique , Mouquet Hugo , O’Farrelly Cliona , Rausell Antonio , Rieux-Laucat Frédéric , Rogge Lars , Fontes Magnus , Sakuntabhai Anavaj , Schwartz Olivier , Schwikowski Benno , Shorte Spencer , Tangy Frédéric , Toubert Antoine , Touvier Mathilde , Ungeheuer Marie-Noëlle , Zimmer Christophe
Published: February 2024

Individuals differ widely in their immune responses, with age, sex and genetic factors having major roles in this inherent variability1–6. However, the variables that drive such differences in cytokine secretion—a crucial component of the host response to immune challenges—remain poorly defined. Here we investigated 136 variables and identified smoking, cytomegalovirus latent infection and body mass index as major contributors to variability in cytokine response, with effects of comparable magnitudes with age, sex and genetics. We find that smoking influences both innate and adaptive immune responses. Notably, its effect on innate responses is quickly lost after smoking cessation and is specifically associated with plasma levels of CEACAM6, whereas its effect on adaptive responses persists long after individuals quit smoking and is associated with epigenetic memory. This is supported by the association of the past smoking effect on cytokine responses with DNA methylation at specific signal trans-activators and regulators of metabolism. Our findings identify three novel variables associated with cytokine secretion variability and reveal roles for smoking in the short- and long-term regulation of immune responses. These results have potential clinical implications for the risk of developing infections, cancers or autoimmune diseases.
Room-temperature quantum optomechanics using an ultralow noise cavity
Authors: Huang Guanhao , Beccari Alberto , Engelsen Nils J. , Kippenberg Tobias J.
Published: February 2024

At room temperature, mechanical motion driven by the quantum backaction of light has been observed only in pioneering experiments in which an optical restoring force controls the oscillator stiffness1,2. For solid-state mechanical resonators in which oscillations are controlled by the material rigidity, the observation of these effects has been hindered by low mechanical quality factors, optical cavity frequency fluctuations3, thermal intermodulation noise4,5 and photothermal instabilities. Here we overcome these challenges with a phononic-engineered membrane-in-the-middle system. By using phononic-crystal-patterned cavity mirrors, we reduce the cavity frequency noise by more than 700-fold. In this ultralow noise cavity, we insert a membrane resonator with high thermal conductance and a quality factor (Q) of 180 million, engineered using recently developed soft-clamping techniques6,7. These advances enable the operation of the system within a factor of 2.5 of the Heisenberg limit for displacement sensing8, leading to the squeezing of the probe laser by 1.09(1) dB below the vacuum fluctuations. Moreover, the long thermal decoherence time of the membrane oscillator (30 vibrational periods) enables us to prepare conditional displaced thermal states of motion with an occupation of 0.97(2) phonons using a multimode Kalman filter. Our work extends the quantum control of solid-state macroscopic oscillators to room temperature.