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TBK1, or TANK-binding kinase 1, is an enzyme that functions as a serine/threonine protein kinase. It plays a crucial role in various cellular processes, including the innate immune response to viruses, cell proliferation, apoptosis, autophagy, and antitumor immunity. Dysregulation of TBK1 activity can lead to autoimmune diseases, neurodegenerative disorders, and cancer. Due to its central role in these critical pathways, TBK1 is a significant focus of research for therapeutic drug development. In this paper, we explore data from the CAS Content Collection regarding TBK1 and its implication in a large assortment of diseases and disorders. With the demand for developing efficient TBK1 inhibitors being outlined, we focus on utilizing a machine learning approach for developing predictive models for TBK1 inhibition, derived from the fragment-functional analysis descriptors. Using the extensive CAS Content Collection, we assembled a training set of TBK1 inhibitors with experimentally measured IC50 values. We explored several machine learning techniques combined with various molecular descriptors to derive and select the best TBK1 inhibitor QSAR models. Certain significant structural alerts that potentially contribute to inhibition of TBK1 are outlined and discussed. The merit of the article stems from identifying the most adequate TBK1 QSAR models and subsequent successful development of advanced positive training data to facilitate and enhance drug discovery for an important therapeutic target such as TBK1 inhibitors, based on an extensive, wide-ranging set of scientific information provided by the CAS Content Collection.

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Variants that alter gene splicing are estimated to comprise up to a third of all disease-causing variants, yet they are hard to predict from DNA sequencing data alone. To overcome this, many groups are incorporating RNA-based analyses, which are resource intensive, particularly for diagnostic laboratories. There are thousands of functionally validated variants that induce mis-splicing; however, this information is not consolidated, and they are under-represented in ClinVar, which presents a barrier to variant interpretation and can result in duplication of validation efforts. To address this issue, we developed SpliceVarDB, an online database consolidating over 50,000 variants assayed for their effects on splicing in over 8,000 human genes. We evaluated over 500 published data sources and established a spliceogenicity scale to standardize, harmonize, and consolidate variant validation data generated by a range of experimental protocols. According to the strength of their supporting evidence, variants were classified as "splice-altering" (∼25%), "not splice-altering" (∼25%), and "low-frequency splice-altering" (∼50%), which correspond to weak or indeterminate evidence of spliceogenicity. Importantly, 55% of the splice-altering variants in SpliceVarDB are outside the canonical splice sites (5.6% are deep intronic). These variants can support the variant curation diagnostic pathway and can be used to provide the high-quality data necessary to develop more accurate in silico splicing predictors. The variants are accessible through an online platform, SpliceVarDB, with additional features for visualization, variant information, in silico predictions, and validation metrics. SpliceVarDB is a very large collection of splice-altering variants and is available at https://splicevardb.org.

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Chloroplasts develop from undifferentiated plastids in response to light. In angiosperms, after the perception of light, the Elongated Hypocotyl 5 (HY5) transcription factor initiates photomorphogenesis, and two families of transcription factors known as GOLDEN2-LIKE (GLK) and GATA are considered master regulators of chloroplast development. In addition, the MIR171-targeted SCARECROW-LIKE GRAS transcription factors also impact chlorophyll biosynthesis. The extent to which these proteins carry out conserved roles in non-seed plants is not known. Using the model liverwort Marchantia polymorpha, we show that GLK controls chloroplast biogenesis, and HY5 shows a small conditional effect on chlorophyll content. Chromatin immunoprecipitation sequencing (ChIP-seq) revealed that MpGLK has a broader set of targets than has been reported in angiosperms. We also identified a functional GLK homolog in green algae. In summary, our data support the hypothesis that GLK carries out a conserved role relating to chloroplast biogenesis in land plants and green algae.

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Most heritable diseases are polygenic. To comprehend the underlying genetic architecture, it is crucial to discover the clinically relevant epistatic interactions (EIs) between genomic single nucleotide polymorphisms (SNPs) (1-3). Existing statistical computational methods for EI detection are mostly limited to pairs of SNPs due to the combinatorial explosion of higher-order EIs. With NeEDL (network-based epistasis detection via local search), we leverage network medicine to inform the selection of EIs that are an order of magnitude more statistically significant compared to existing tools and consist, on average, of five SNPs. We further show that this computationally demanding task can be substantially accelerated once quantum computing hardware becomes available. We apply NeEDL to eight different diseases and discover genes (affected by EIs of SNPs) that are partly known to affect the disease, additionally, these results are reproducible across independent cohorts. EIs for these eight diseases can be interactively explored in the Epistasis Disease Atlas (https://epistasis-disease-atlas.com). In summary, NeEDL demonstrates the potential of seamlessly integrated quantum computing techniques to accelerate biomedical research. Our network medicine approach detects higher-order EIs with unprecedented statistical and biological evidence, yielding unique insights into polygenic diseases and providing a basis for the development of improved risk scores and combination therapies.

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Time-to-event prediction is a key task for biological discovery, experimental medicine, and clinical care. This is particularly true for neurological diseases where development of reliable biomarkers is often limited by difficulty visualising and sampling relevant cell and molecular pathobiology. To date, much work has relied on Cox regression because of ease-of-use, despite evidence that this model includes incorrect assumptions. We have implemented a set of deep learning and spline models for time-to-event modelling within a fully customizable 'app' and accompanying online portal, both of which can be used for any time-to-event analysis in any disease by a non-expert user. Our online portal includes capacity for end-users including patients, Neurology clinicians, and researchers, to access and perform predictions using a trained model, and to contribute new data for model improvement, all within a data-secure environment. We demonstrate a pipeline for use of our app with three use-cases including imputation of missing data, hyperparameter tuning, model training and independent validation. We show that predictions are optimal for use in downstream applications such as genetic discovery, biomarker interpretation, and personalised choice of medication. We demonstrate the efficiency of an ensemble configuration, including focused training of a deep learning model. We have optimised a pipeline for imputation of missing data in combination with time-to-event prediction models. Overall, we provide a powerful and accessible tool to develop, access and share time-to-event prediction models; all software and tutorials are available at www.predictte.org.

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Cells must adapt to environmental changes to maintain homeostasis. One of the most striking environmental adaptations is entry into hibernation during which core body temperature can decrease from 37°C to as low at 4°C. How mammalian cells, which evolved to optimally function within a narrow range of temperatures, adapt to this profound decrease in temperature remains poorly understood. In this study, we conducted the first genome-scale CRISPR-Cas9 screen in cells derived from Syrian hamster, a facultative hibernator, as well as human cells to investigate the genetic basis of cold tolerance in a hibernator and a non-hibernator in an unbiased manner. Both screens independently revealed glutathione peroxidase 4 (GPX4), a selenium-containing enzyme, and associated proteins as critical for cold tolerance. We utilized genetic and pharmacological approaches to demonstrate that GPX4 is active in the cold and its catalytic activity is required for cold tolerance. Furthermore, we show that the role of GPX4 as a suppressor of cold-induced cell death extends across hibernating species, including 13-lined ground squirrels and greater horseshoe bats, highlighting the evolutionary conservation of this mechanism of cold tolerance. This study identifies GPX4 as a central modulator of mammalian cold tolerance and advances our understanding of the evolved mechanisms by which cells mitigate cold-associated damage-one of the most common challenges faced by cells and organisms in nature.

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INTRODUCTION: The need for remote ventilator control has been highlighted by the COVID-19 Public Health Emergency. Remote ventilator control from outside a patient's room can improve response time to patient needs, protect health care workers, and reduce personal protective equipment (PPE) consumption. Extending remote control to distant locations can expand the capabilities of frontline health care workers by delivering specialized clinical expertise to the point of care, which is much needed in diverse health care settings, such as tele-critical care and military medicine. However, the safety and effectiveness of remote ventilator control can be affected by many risk factors, including communication failures and network disruptions. Consensus safety requirements and test methods are needed to assess the resilience and safety of remote ventilator control under communication failures and network disruptions. MATERIALS AND METHODS: We designed two test methods to assess the robustness, usability, and safety of a remote ventilator control prototype system jointly developed by Nihon Kohden OrangeMed, Inc. and DocBox, Inc. ("the NK-DocBox system") to control the operation of an NKV-550 critical care ventilator under communication failures and network disruptions. First, the robustness of the NKV-550 ventilator was tested using a remote-control application developed on OpenICE - an open-source medical device interoperability platform - to transmit customized high-frequency and erroneous remote-control commands that could be caused by communication failures in a real-world environment. The second method utilized a network emulator to create different types and severity of network quality of service (QoS) degradation, including bandwidth throttling, network delay and jitter, packet drop and reordering, and bit errors, in the NKV-DocBox system to quantitatively assess the impact on system usability and safety. RESULTS: The NKV-550 ventilator operated as expected when remote-control commands arrived as fast as once per second. It ignored erroneous commands attempting to adjust invalid ventilation parameters. When facing commands that set the ventilation mode and parameters to invalid values, it reset the ventilation mode or parameters to default values, the safety implication of which may merit further evaluation. When any network QoS attribute (except for packet reordering) started to degrade, the NK-DocBox System experienced interference to its remote-control function, such as delays in the transmission of ventilator data and remote-control commands within the system. When the network QoS was worse than 500 ms network delay, 100 ms network jitter, 1% data drop rate, 12 Mbps minimal bandwidth, or 1e-6 bit error rate, the system became unsafe to use. For example, ventilator waveforms visualized on the remote-control application demonstrated freezes, out-of-synchronization, and moving backwards; and the connection between the ventilator and the remote-control application became unstable. CONCLUSION: The presented test methods confirmed the robustness of the NKV-550 ventilator against high-frequency and erroneous remote control, quantified the impact of network disruptions on the usability, reliability, and safety of the NK-DocBox system and identified the minimum network QoS requirements for it to function safely. These generalizable test methods can be customized to evaluate other remote ventilator control technologies and remote control of other types of medical devices against communication failures and network disruptions.

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Insect diversification has been catalyzed by widespread specialization on novel hosts - a process underlying exceptional radiations of phytophagous beetles, lepidopterans, parasitoid wasps, and inordinate lineages of symbionts, predators and other trophic specialists. The strict fidelity of many such interspecies associations is posited to hinge on sensory tuning to host-derived cues, a model supported by studies of neural function in host-specific model species. Here, we investigated the sensory basis of symbiotic interactions between a myrmecophile rove beetle and its single, natural host ant species. We show that host cues trigger analogous behaviors in both ant and symbiont. Cuticular hydrocarbons - the ant's nestmate recognition pheromones - elicit partner recognition by the beetle and execution of ant grooming behavior, integrating the beetle into the colony via chemical mimicry. The beetle also follows host trail pheromones, permitting inter-colony dispersal. Remarkably, the rove beetle also performs its symbiotic behaviors with ant species separated by ~95 million years, and shows minimal preference for its natural host over non-host ants. Experimentally validated agent-based modeling supports a scenario in which specificity is enforced by physiological constraints on symbiont dispersal, and negative fitness interactions with alternative hosts, rather than via sensory tuning. Enforced specificity may be a pervasive mechanism of host range restriction of specialists embedded within host niches. Chance realization of latent compatibilities with alternative hosts may facilitate host switching, enabling deep-time persistence of obligately symbiotic lineages.

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Chloroplast biogenesis is dependent on master regulators from the GOLDEN2-LIKE (GLK) family of transcription factors. However, glk mutants contain residual chlorophyll, indicating that other proteins must be involved. Here, we identify MYB-related transcription factors as regulators of chloroplast biogenesis in the liverwort Marchantia polymorpha and angiosperm Arabidopsis thaliana. In both species, double-mutant alleles in MYB-related genes show very limited chloroplast development, and photosynthesis gene expression is perturbed to a greater extent than in GLK mutants. Genes encoding enzymes of chlorophyll biosynthesis are controlled by MYB-related and GLK proteins, whereas those allowing CO2 fixation, photorespiration, and photosystem assembly and repair require MYB-related proteins. Regulation between the MYB-related and GLK transcription factors appears more extensive in A. thaliana than in M. polymorpha. Thus, MYB-related and GLK genes have overlapping as well as distinct targets. We conclude that MYB-related and GLK transcription factors orchestrate chloroplast development in land plants.

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Virus-associated chronic inflammation may contribute to autoimmunity in a number of diseases. In the brain, autoimmune encephalitis appears related to fluctuating reactivation states of neurotropic viruses. In addition, viral miRNAs and proteins can be transmitted via exosomes, which constitute novel but highly relevant mediators of cellular communication. The current study questioned the role of HSV-1-encoded and host-derived miRNAs in cerebrospinal fluid (CSF)-derived exosomes, enriched from stress-induced neuroinflammatory diseases, mainly subarachnoid hemorrhage (SAH), psychiatric disorders (AF and SZ), and various other neuroinflammatory diseases. The results were compared with CSF exosomes from control donors devoid of any neuroinflammatory pathology. Serology proved positive, but variable immunity against herpesviruses in the majority of patients, except controls. Selective ultrastructural examinations identified distinct, herpesvirus-like particles in CSF-derived lymphocytes and monocytes. The likely release of extracellular vesicles and exosomes was most frequently observed from CSF monocytes. The exosomes released were structurally similar to highly purified stem-cell-derived exosomes. Exosomal RNA was quantified for HSV-1-derived miR-H2-3p, miR-H3-3p, miR-H4-3p, miR-H4-5p, miR-H6-3p, miR-H27 and host-derived miR-21-5p, miR-146a-5p, miR-155-5p, and miR-138-5p and correlated with the oxidative stress chemokine IL-8 and the axonal damage marker neurofilament light chain (NfL). Replication-associated miR-H27 correlated with neuronal damage marker NfL, and cell-derived miR-155-5p correlated with oxidative stress marker IL-8. Elevated miR-138-5p targeting HSV-1 latency-associated ICP0 inversely correlated with lower HSV-1 antibodies in CSF. In summary, miR-H27 and miR-155-5p may constitute neuroinflammatory markers for delineating frequent and fluctuating HSV-1 replication and NfL-related axonal damage in addition to the oxidative stress cytokine IL-8 in the brain. Tentatively, HSV-1 remains a relevant pathogen conditioning autoimmune processes and a psychiatric clinical phenotype.

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BACKGROUND: PSMA-PET is increasingly used for staging prostate cancer (PCA) patients. However, it is not clear if quantitative imaging parameters of positron emission tomography (PET) have an impact on disease progression and are thus important for the prognosis of localized PCA. METHODS: This is a monocenter retrospective analysis of 86 consecutive patients with localized intermediate or high-risk PCA and PSMA-PET before treatment The quantitative PET parameters maximum standardized uptake value (SUVmax), tumor asphericity (ASP), PSMA tumor volume (PSMA-TV), and PSMA total lesion uptake (PSMA-TLU = PSMA-TV × SUVmean) were assessed for their prognostic significance in patients with radiotherapy or surgery. Cox regression analyses were performed for biochemical recurrence-free survival, overall survival (OS), local control, and loco-regional control (LRC). RESULTS: 67% of patients had high-risk disease, 51 patients were treated with radiotherapy, and 35 with surgery. Analysis of metric PET parameters in the whole cohort revealed a significant association of PSMA-TV (p = 0.003), PSMA-TLU (p = 0.004), and ASP (p < 0.001) with OS. Upon binarization of PET parameters, several other parameters showed a significant association with clinical outcome. When analyzing high-risk patients according to the primary treatment approach, a previously published cut-off for SUVmax (8.6) showed a significant association with LRC in surgically treated (p = 0.048), but not in primary irradiated (p = 0.34) patients. In addition, PSMA-TLU (p = 0.016) seemed to be a very promising biomarker to stratify surgical patients. CONCLUSION: Our data confirm one previous publication on the prognostic impact of SUVmax in surgically treated patients with high-risk PCA. Our exploratory analysis indicates that PSMA-TLU might be even better suited. The missing association with primary irradiated patients needs prospective validation with a larger sample size to conclude a predictive potential. Trial registration Due to the retrospective nature of this research, no registration was carried out.

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Background: Helicopter emergency medical services (HEMS) play a fundamental role in prehospital care. However, the impact of HEMS on survival of patients with out-of-hospital cardiac arrest (OHCA) is widely unknown. Therefore, the purpose of this study was to assess demographics, treatment, and outcome of patients with OHCA attended by physician-staffed helicopters. Methods: Retrospective cohort study enrolling OHCA patients treated by HEMS during a ten-year period (2010-2019) in Austria. Patients were identified using electronic mission records of 13 HEMS bases run by the Austrian Automobile, Motorcycle and Touring Club (OEAMTC), and subsequently matched with the national register of deaths to determine 30-day and one-year survival rates. Results are reported according to the 2015 Utstein Style. Multivariable logistic regression analysis was used to identify factors associated with patient outcome. Results: In total, 9344 presumed OHCA missions were identified. Cardiopulmonary resuscitation was attempted or continued by HEMS in 3889 cases. Approximately 32.2% of patients achieved return of spontaneous circulation (ROSC) and 22.5% sustained ROSC until arrival at the emergency department. Thirty-day and one-year survival rates were 14.0% and 12.4% respectively. HEMS response time, on-scene time, age, pathogenesis, arrest location, witness-status, first monitored rhythm, bystander automated external defibrillator (AED) use, airway type and administration of adrenaline were independent predictors of 30-day survival. Conclusions: This study provides an extensive insight into the management of OHCA in an almost nationwide HEMS sample. Thirty-day and one-year survival rates are high, indicating high-quality care and systematic selection of patients with favorable prognosis.

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BACKGROUND: Women respond more favorably to biventricular pacing (BIVP) than men. Sex differences in atrioventricular and interventricular conduction have been described in BIVP studies. Left bundle branch area pacing (LBBAP) offers advantages due to direct capture of the conduction system. We hypothesized that men could respond better to LBBAP than BIVP. OBJECTIVES: This study aims to describe the sex differences in response to LBBAP vs BIVP as the initial cardiac resynchronization therapy (CRT). METHODS: In this multicenter prospective registry, we included patients with left ventricular ejection fraction ≤35% and left bundle branch block or a left ventricular ejection fraction ≤40% with an expected right ventricular pacing exceeding 40% undergoing initial CRT with LBBAP or BIVP. The composite primary outcome was heart failure-related hospitalization and all-cause mortality. The primary safety outcome included all procedure-related complications. RESULTS: There was no significant difference in the primary outcome when comparing men and women receiving LBBAP (P = 0.46), whereas the primary outcome was less frequent in women in the BIVP group than men treated with BIVP (P = 0.03). The primary outcome occurred less frequently in men undergoing LBBAP (29.9%) compared to those treated with BIVP (46.5%) (P = 0.004). In women, the incidence of the primary endpoint was 24.14% in the LBBAP group and 36.2% in the BIVP group; however, this difference was not statistically significant (P = 0.23). Complication rates remained consistent across all groups. CONCLUSIONS: Men and women undergoing LBBAP for CRT had similar clinical outcomes. Men undergoing LBBAP showed a lower risk of heart failure-related hospitalizations and all-cause mortality compared to men undergoing BIVP, whereas there was no difference between LBBAP and BIVP in women.

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Hibernomas, rare benign tumors originating from brown adipose tissue, pose diagnostic challenges due to their infrequent occurrence and slow growth. We present a case of a 38-year-old woman with a progressively enlarging mass in her right lateral chest wall, initially stable in size but growing during pregnancy and causing pain and functional impairment. Radiological evaluation, including x-ray and MRI, provided inconclusive results, necessitating a biopsy for a definitive diagnosis. Ultrasound-guided needle aspiration biopsy revealed typical histopathological features consistent with hibernoma. A subsequent total surgical excision with negative margins was performed. The patient achieved complete recovery without recurrence during two years of follow-up. This case underscores the importance of considering hibernoma in the differential diagnosis of adipose tissue tumors, particularly in atypical clinical presentations. Moreover, it highlights the challenges in diagnosing and managing hibernomas and emphasizes the role of MRI and biopsy in achieving accurate diagnosis and optimal treatment outcomes. Continued reporting of such cases is crucial for increasing awareness and improving the management of this rare tumor.

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Extreme weather events across coastal environments are expected to increase in frequency under predicted climate change scenarios. These events can impact coastal recreational fisheries and their supporting ecosystems by influencing the productivity of fish stocks or altering behaviours and decision-making among fishers. Using off-site telephone/diary survey data on estuarine and oceanic recreational fishing activity in eastern Australia, we analyse interannual and geographic variability in bream (Acanthopagrus spp) and snapper (Chrysophrys auratus) catch, total effort and total catch per unit effort (CPUE) through a period (2013/2014, 2017/2018 and 2019/2020) that encompassed severe drought, bushfires and flooding. Interacting spatial and temporal differences were detected for bream and may reflect spatial variation in the intensity and extent of some of the extreme weather events. The catch of snapper did not change temporally, providing little evidence that this species' catch may be influenced by the extreme weather events. Independent bioregional and temporal effects on effort were detected, while CPUE only showed significant bioregional differences. Although adverse conditions created by the extreme weather events may have dissuaded fisher participation and impacted effort, we propose that the observed temporal patterns in effort reflect the early influence of socio-economic changes brought on by the COVID-19 pandemic on coastal recreational fishing, over and above the impacts of extreme weather events. This study demonstrates how interrelated ecological, social and economic factors can shape coastal recreational fisheries and facilitates development of management strategies to address future threats to the sector.

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How evolution at the cellular level potentiates macroevolutionary change is central to understanding biological diversification. The >66,000 rove beetle species (Staphylinidae) form the largest metazoan family. Combining genomic and cell type transcriptomic insights spanning the largest clade, Aleocharinae, we retrace evolution of two cell types comprising a defensive gland-a putative catalyst behind staphylinid megadiversity. We identify molecular evolutionary steps leading to benzoquinone production by one cell type via a mechanism convergent with plant toxin release systems, and synthesis by the second cell type of a solvent that weaponizes the total secretion. This cooperative system has been conserved since the Early Cretaceous as Aleocharinae radiated into tens of thousands of lineages. Reprogramming each cell type yielded biochemical novelties enabling ecological specialization-most dramatically in symbionts that infiltrate social insect colonies via host-manipulating secretions. Our findings uncover cell type evolutionary processes underlying the origin and evolvability of a beetle chemical innovation.

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In recent decades, the development of new drugs has become increasingly expensive and inefficient, and the molecular mechanisms of most pharmaceuticals remain poorly understood. In response, computational systems and network medicine tools have emerged to identify potential drug repurposing candidates. However, these tools often require complex installation and lack intuitive visual network mining capabilities. To tackle these challenges, we introduce Drugst.One, a platform that assists specialized computational medicine tools in becoming user-friendly, web-based utilities for drug repurposing. With just three lines of code, Drugst.One turns any systems biology software into an interactive web tool for modeling and analyzing complex protein-drug-disease networks. Demonstrating its broad adaptability, Drugst.One has been successfully integrated with 21 computational systems medicine tools. Available at https://drugst.one, Drugst.One has significant potential for streamlining the drug discovery process, allowing researchers to focus on essential aspects of pharmaceutical treatment research.

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Cement production causes 7.5% of global anthropogenic CO2 emissions, arising from limestone decarbonation and fossil-fuel combustion1-3. Current decarbonation strategies include substituting Portland clinker with supplementary materials, but these mainly arise in emitting processes, developing alternative binders but none yet promises scale, or adopting carbon capture and storage that still releases some emissions4-8. However, used cement is potentially an abundant, decarbonated feedstock. Here we show that recovered cement paste can be reclinkered if used as a partial substitute for the lime-dolomite flux used in steel recycling nowadays. The resulting slag can meet existing specifications for Portland clinker and can be blended effectively with calcined clay and limestone. The process is sensitive to the silica content of the recovered cement paste, and silica and alumina that may come from the scrap, but this can be adjusted easily. We show that the proposed process may be economically competitive, and if powered by emissions-free electricity, can lead to zero emissions cement while also reducing the emissions of steel recycling by reducing lime flux requirements. The global supply of scrap steel for recycling may treble by 2050, and it is likely that more slag can be made per unit of steel recycled. With material efficiency in construction9,10, future global cement requirements could be met by this route.

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Hybrid zones are dynamic systems where natural selection, sexual selection, and other evolutionary forces can act on reshuffled combinations of distinct genomes. The movement of hybrid zones, individual traits, or both are of particular interest for understanding the interplay between selective processes. In a hybrid zone involving two lek-breeding birds, secondary sexual plumage traits of Manacus vitellinus, including bright yellow collar and olive belly color, have introgressed ~50 km asymmetrically across the genomic center of the zone into populations more genetically similar to Manacus candei. Males with yellow collars are preferred by females and are more aggressive than parental M. candei, suggesting that sexual selection was responsible for the introgression of male traits. We assessed the spatial and temporal dynamics of this hybrid zone using historical (1989-1994) and contemporary (2017-2020) transect samples to survey both morphological and genetic variation. Genome-wide single nucleotide polymorphism data and several male phenotypic traits show that the genomic center of the zone has remained spatially stable, whereas the olive belly color of male M. vitellinus has continued to introgress over this time period. Our data suggest that sexual selection can continue to shape phenotypes dynamically, independent of a stable genomic transition between species.

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Tunnel junctions comprising self-assembled monolayers (SAMs) from liquid crystal-inspired molecules show a pronounced hysteretic current-voltage response, due to electric field-driven dipole reorientation in the SAM. This renders these junctions attractive device candidates for emerging technologies such as in-memory and neuromorphic computing. Here, the novel molecular design, device fabrication, and characterization of such resistive switching devices with a largely improved performance, compared to the previously published work are reported. Those former devices suffer from a stochastic switching behavior limiting reliability, as well as from critically small read-out currents. The present progress is based on replacing Al/AlOx with TiN as a new electrode material and as a key point, on redesigning the active molecular material making up the SAM: a previously present, flexible aliphatic moiety has been replaced by a rigid aromatic linker, thereby introducing a molecular "ratchet". This restricts the possible molecular conformations to only two major states of opposite polarity. The above measures have resulted in an increase of the current density by five orders of magnitude as well as in an ON/OFF conductance ratio which is more than ten times higher than the individual scattering ranges of the high and low resistance states.