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In this work, we extend previous results, demonstrating how complexity in an open quantum system can identify decoherence between two fields, even in the presence of an accelerating background. Using the curved-space Caldeira-Leggett two-field model in de Sitter as our toy model, we discover a distinctive feature in the growth of complexity of purification, providing an alternative diagnostic for studying decoherence when the adiabatic perturbation is coupled to a heavy field. This paper initiates a new pathway to explore the features of quantum complexity in an accelerating background, thereby expanding our understanding of the evolution of primordial cosmological perturbations in the early universe., Comment: 24 pages, 8 figures

A variety of scattering-based, microscopy-based, and mobility-based methods are frequently used to probe the size distributions of colloidal nanoparticles with transmission electron microscopy (TEM) often considered to be the "gold standard". Charge detection mass spectrometry (CDMS) is an alternative method for nanoparticle characterization that can rapidly measure the mass and charge of individual nanoparticle ions with high accuracy. Two low polydispersity, ∼100 nm diameter nanoparticle size standards with different compositions (polymethyl methacrylate/polystyrene copolymer and 100% polystyrene) were characterized using both TEM and CDMS to explore the merits and complementary aspects of both methods. Mass and diameter distributions are rapidly obtained from CDMS measurements of thousands of individual ions of known spherical shape, requiring less time than TEM sample preparation and image analysis. TEM image-to-image variations resulted in a ∼1-2 nm range in the determined mean diameters whereas the CDMS mass precision of ∼1% in these experiments leads to a diameter uncertainty of just 0.3 nm. For the 100% polystyrene nanoparticles with known density, the CDMS and TEM particle diameter distributions were in excellent agreement. For the copolymer nanoparticles with unknown density, the diameter from TEM measurements combined with the mass from CDMS measurements enabled an accurate measurement of nanoparticle density. Differing extents of charging for the two nanoparticle standards measured by CDMS show that charging is sensitive to nanoparticle surface properties. A mixture of the two samples was separated based on their different extents of charging despite having overlapping mass distributions centered at 341.5 and 331.0 MDa.

Anaplastic Wilms’ tumour has poor prognosis and is characterised by a high frequency of missense mutations in TP53. Despite these potential gain-of-function (GOF) mutations having been reported in the early 1990’s, the biological effects of GOF mutant p53 (mutp53) protein in anaplastic Wilms’ tumour has never been examined. In this study, we demonstrate that GOF mutp53 is critical to anaplastic Wilms’ tumour survival, with depletion causing growth arrest, autophagy induction, and apoptotic cell death. RNA sequencing following mutp53 depletion identifies putative downstream mutp53 targets. These include genes encoding several epigenetic writers and erasers, such as histone methyltransferase EHMT2/G9a; EHMT2 is overexpressed in Wilms’ tumour patient samples, with a positive correlation between staging and expression. Further analyses demonstrate that mutp53 co-opts G9a in a newly identified oncogenic axis to methylate and silence wtp53 target genes, including CDKN1A. Mutp53 is suggested to be a key driver mutation as it acts upstream of several reported Wilms’ tumour oncogenes and tumour suppressor genes; activities of mutp53 include transactivation of oncogene MYCN and repression of tumour suppressor gene REST. Genetic and pharmacological inhibition studies validated G9a as a potential therapeutic target in anaplastic Wilms’ tumour cell lines. G9a small molecule inhibitor UNC0638 promptly induced autophagy with regulation of induction genes, including GABARAPL1. However, autophagic flux is impaired as autophagosome-lysosome fusion is inhibited; this accumulation of autophagic vesicles is suggested to cause apoptosis. UNC0638 treatment also rapidly and effectively switches the activity of R248Q and G245S mutants to wtp53-like as wtp53 targets, such as CDKN1A, were derepressed. G9a inhibition causes transcriptional downregulation of TP53 demonstrating that G9a activity enhances mutp53 activity. RNA sequencing following UNC0638 treatment identified multiple ov

Background: The COVID-19 pandemic era had witnessed an upsurge of healthcare-associated infections (HAI) in COVID intensive care units (ICUs), which can be reduced by following proper hand hygiene (HH) practice. Performing HH auditing in COVID ICUs and providing timely feedback to the stake holders is crucial to reduce HAIs. Methods: From July 2021 to December 2021, HH auditing was conducted in COVID ICUs. Hand hygiene (HH) complete adherence rate (HHCAR), HH partial adherence rate (HHPAR) and HH total adherence rate (HHTAR) were analysed. Profession-specific HHTAR and moment-specific HHTAR (for each WHO moment) were also calculated.Results: HHCAR, HHPAR and HHTAR were found to be 47%, 19% and 66%, respectively. There was a significant increase in the monthly HHTAR from 62.2% to 72.2% (p<.001). The profession-specific hand-hygiene adherence rate (HHAR) was found to be highest among nurses (67%), and the moment-specific HHAR of WHO-moments 2 (90%) and 3 (94.8%) had the highest HH adherence.Conclusions: Auditing HH and providing timely feedback significantly improved HH adherence. The greatest need now is to regularly conduct HH auditing in COVID locations of all healthcare facilities to reduce the HAI rate among the COVID-19 infected patients in ICUs., Hintergrund: Während der COVID-19-Pandemie kam es auf COVID-Intensivstationen zu einem Anstieg Healthcare-assoziierter Infektionen (HAI), die durch ordnungsgemäße Händehygiene (HH) reduziert werden können. Die Durchführung von Hygienekontrollen auf COVID-Intensivstationen und die rechtzeitige Rückmeldung an die Beteiligten sind entscheidend für die Reduzierung von HAI.Methode: Von Juli 2021 bis Dezember 2021 wurde auf COVID-Intensivstationen ein HH-Audit durchgeführt. Analysiert wurden die HH-Komplettadhärenzrate (HHCAR), die HH-Teiladhärenzrate (HHPAR) und die HH-Gesamtadhärenzrate (HHTAR). Die berufsspezifische HHTAR und die momentenspezifische HHTAR (für jedes WHO-Moment) wurden ebenfalls berechnet.Ergebnisse: Die HHCAR, HHPAR und HHTAR wurden mit 47%, 19% bzw. 66% ermittelt. Es gab einen signifikanten Anstieg der monatlichen HHTAR von 62,2% auf 72,2% (p<.001). Die berufsspezifische HH-Adhärenzrate (HHAR) war bei Krankenschwestern und -pflegern am höchsten (67%). Die zeitpunktspezifische HHAR der WHO-Momente 2 (90%) und 3 (94,8%) wiesen die höchste HH-Adhärenz auf.Schlussfolgerung: Die Auditierung der HH und die rechtzeitige Rückmeldung haben die Einhaltung der HH deutlich verbessert. Das Gebot der Stunde ist die regelmäßige Durchführung von HH-Audits an COVID-Standorten in allen Gesundheitseinrichtungen, um die HAI-Rate unter den COVID-19-infizierten Patienten auf Intensivstationen zu senken.

We use high-resolution data from the millimetre-Wave Interferometric Survey of Dark Object Masses (WISDOM) project to investigate the connection between circumnuclear gas reservoirs and nuclear activity in a sample of nearby galaxies. Our sample spans a wide range of nuclear activity types including radio galaxies, Seyfert galaxies, low-luminosity active galactic nuclei (AGN) and inactive galaxies. We use measurements of nuclear millimetre continuum emission along with other archival tracers of AGN accretion/activity to investigate previous claims that at, circumnuclear scales (<100 pc), these should correlate with the mass of the cold molecular gas. We find that the molecular gas mass does not correlate with any tracer of nuclear activity. This suggests the level of nuclear activity cannot solely be regulated by the amount of cold gas around the supermassive black hole (SMBH). This indicates that AGN fuelling, that drives gas from the large-scale galaxy to the nuclear regions, is not a ubiquitous process and may vary between AGN type, with time-scale variations likely to be very important. By studying the structure of the central molecular gas reservoirs, we find our galaxies have a range of nuclear molecular gas concentrations. This could indicate that some of our galaxies may have had their circumnuclear regions impacted by AGN feedback, even though they currently have low nuclear activity. Alternatively, the nuclear molecular gas concentrations in our galaxies could instead be set by secular processes.

Terrestrial enhanced weathering (EW) of silicate rocks, such as crushed basalt, on farmlands is a promising scalable atmospheric carbon dioxide removal (CDR) strategy that urgently requires performance assessment with commercial farming practices. We report findings from a large-scale replicated EW field trial across a typical maize-soybean rotation on an experimental farm in the heart of the United Sates Corn Belt over 4 y (2016 to 2020). We show an average combined loss of major cations (Ca2+ and Mg2+) from crushed basalt applied each fall over 4 y (50 t ha−1 y−1) gave a conservative time-integrated cumulative CDR potential of 10.5 ± 3.8 t CO2 ha−1. Maize and soybean yields increased significantly (P < 0.05) by 12 to 16% with EW following improved soil fertility, decreased soil acidification, and upregulation of root nutrient transport genes. Yield enhancements with EW were achieved with significantly (P < 0.05) increased key micro- and macronutrient concentrations (including potassium, magnesium, manganese, phosphorus, and zinc), thus improving or maintaining crop nutritional status. We observed no significant increase in the content of trace metals in grains of maize or soybean or soil exchangeable pools relative to controls. Our findings suggest that widespread adoption of EW across farming sectors has the potential to contribute significantly to net-zero greenhouse gas emissions goals while simultaneously improving food and soil security.

Proton exchange membrane fuel cells (PEMFCs) are expected to play a pivotal role in decarbonizing the transportation sector, and particularly heavy-duty vehicles (HDVs). However, improvements in durability are needed for PEMFCs to compete with state-of-the-art power sources for HDVs. Here, we examine how catalyst layer (CL) cracks that are engineered affect the CL durability by using patterned silicon templates to control the CL crack density at the micrometer scale. Electrochemical analyses show that the initial PEMFC performance is relatively unaffected by crack density, but the performance after durability testing was strongly affected. Specifically, CLs with high crack density showed higher performance relative to CLs without cracks after application of a carbon corrosion accelerated stress test. Electrochemical analyses coupled with X-ray computed tomography and scanning transmission electron microscopy with energy dispersive X-ray spectroscopy showed that the cracks provide shorter oxygen diffusion pathways to reaction sites, leading to decreased oxygen transport resistance. Additionally, we observed that the catalyst durability is unaffected by cracks. Our results provide a mechanistic explanation of the role of cracks in CL durability.

The flux ratios of strongly lensed quasars have previously been used to infer the properties of dark matter. In these analyses it is crucial to separate the effect of the main lensing galaxy and the low-mass dark matter halo population. In this work, we investigate flux-ratio perturbations resulting from general third- and fourth-order multipole perturbations to the main lensing galaxy's mass profile. We simulate four lens systems, each with a different lensing configuration, without multipoles. The simulated flux ratios are perturbed by 10-40 per cent by a population of low-mass haloes consistent with CDM and, in one case, also a satellite galaxy. This level of perturbation is comparable to the magnitude of flux-ratio anomalies in real data that has been previously analyzed. We then attempt to fit the simulated systems using multipoles instead of low-mass haloes. We find that multipoles with amplitudes of 0.01 or less can produce flux-ratio perturbations in excess of 40 per cent. In all cases, third- or fourth-order multipoles can individually reduce the magnitude of, if not eliminate, flux-ratio anomalies. When both multipole orders are jointly included, all simulated flux ratios can be fit to within the observational uncertainty. Our results indicate that low-mass haloes and multipoles are highly degenerate when modelling quadruply-imaged quasars based just on image positions and flux ratios. In the presence of this degeneracy, flux-ratio anomalies in lensed quasars alone cannot be used to place strong constraints on the properties of dark matter without additional information that can inform our priors., Comment: 13 pages, 9 figures, to be submitted to MNRAS; figures 2-7 updated for clarity

BACKGROUND: Resection of the contrast-enhancing (CE) tumor represents the standard of care in newly diagnosed glioblastoma. However, some tumors ultimately diagnosed as glioblastoma lack contrast enhancement and have a 'low grade appearance' on imaging (non-CE glioblastoma). We aimed to (I) volumetrically define the value of non-CE tumor resection in the absence of contrast enhancement, and to (II) delineate outcome differences between glioblastoma patients with and without contrast enhancement. METHODS: The RANO resect group retrospectively compiled a global, eight-center cohort of patients with newly diagnosed glioblastoma per WHO 2021 classification. The associations between post-operative tumor volumes and outcome were analyzed. Propensity score-matched analyses were constructed to compare glioblastomas with and without contrast enhancement. RESULTS: Among 1323 newly diagnosed IDH-wildtype glioblastomas, we identified 98 patients (7.4%) without contrast enhancement. In such patients, smaller post-operative tumor volumes were associated with more favourable outcome. There was an exponential increase in risk for death with larger residual non-CE tumor. Accordingly, extensive resection was associated with improved survival compared to lesion biopsy. These findings were retained on a multivariable analysis adjusting for demographic and clinical markers. Compared to CE glioblastoma, patients with non-CE glioblastoma had more favourable clinical profile and superior outcome as confirmed in propensity score analyses by matching the patients with non-CE glioblastoma to patients with CE glioblastoma using a large set of clinical variables. CONCLUSIONS: The absence of contrast enhancement characterizes a less aggressive clinical phenotype of IDH-wildtype glioblastomas. Maximal resection of non-CE tumors has prognostic implications and translates into favourable outcome.

INTRODUCTION: A greater extent of resection of the contrast-enhancing (CE) tumour part has been associated with improved outcomes in glioblastoma. Recent results suggest that resection of the non-contrast-enhancing (NCE) part might yield even better survival outcomes (supramaximal resection, SMR). Therefore, this study evaluates the efficacy and safety of SMR with and without mapping techniques in high-grade glioma (HGG) patients in terms of survival, functional, neurological, cognitive and quality of life outcomes. Furthermore, it evaluates which patients benefit the most from SMR, and how they could be identified preoperatively. METHODS AND ANALYSIS: This study is an international, multicentre, prospective, two-arm cohort study of observational nature. Consecutive glioblastoma patients will be operated with SMR or maximal resection at a 1:1 ratio. Primary endpoints are (1) overall survival and (2) proportion of patients with National Institute of Health Stroke Scale deterioration at 6 weeks, 3 months and 6 months postoperatively. Secondary endpoints are (1) residual CE and NCE tumour volume on postoperative T1-contrast and FLAIR (Fluid-attenuated inversion recovery) MRI scans; (2) progression-free survival; (3) receipt of adjuvant therapy with chemotherapy and radiotherapy; and (4) quality of life at 6 weeks, 3 months and 6 months postoperatively. The total duration of the study is 5 years. Patient inclusion is 4 years, follow-up is 1 year. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethics Committee (METC Zuid-West Holland/Erasmus Medical Center; MEC-2020-0812). The results will be published in peer-reviewed academic journals and disseminated to patient organisations and media.

Background The risk of recurrence is overestimated by the Kaplan–Meier method when competing events, such as death without recurrence, are present. Such overestimation can be avoided by using the Aalen-Johansen method, which is a direct extension of Kaplan–Meier that accounts for competing events. Meningiomas commonly occur in older individuals and have slow-growing properties, thereby warranting competing risk analysis. The extent to which competing events are considered in meningioma literature is unknown, and the consequences of using incorrect methodologies in meningioma recurrence risk analysis have not been investigated. Methods We surveyed articles indexed on PubMed since 2020 to assess the usage of competing risk analysis in recent meningioma literature. To compare recurrence risk estimates obtained through Kaplan–Meier and Aalen-Johansen methods, we applied our international database comprising ~ 8,000 patients with a primary meningioma collected from 42 institutions. Results Of 513 articles, 169 were eligible for full-text screening. There were 6,537 eligible cases from our PERNS database. The discrepancy between the results obtained by Kaplan–Meier and Aalen-Johansen was negligible among low-grade lesions and younger individuals. The discrepancy increased substantially in the patient groups associated with higher rates of competing events (older patients with high-grade lesions). Conclusion The importance of considering competing events in recurrence risk analysis is poorly recognized as only 6% of the studies we surveyed employed Aalen-Johansen analyses. Consequently, most of the previous literature has overestimated the risk of recurrence. The overestimation was negligible for studies involving low-grade lesions in younger individuals; however, overestimation might have been substantial for studies on high-grade lesions., Background: The risk of recurrence is overestimated by the Kaplan–Meier method when competing events, such as death without recurrence, are present. Such overestimation can be avoided by using the Aalen-Johansen method, which is a direct extension of Kaplan–Meier that accounts for competing events. Meningiomas commonly occur in older individuals and have slow-growing properties, thereby warranting competing risk analysis. The extent to which competing events are considered in meningioma literature is unknown, and the consequences of using incorrect methodologies in meningioma recurrence risk analysis have not been investigated. Methods: We surveyed articles indexed on PubMed since 2020 to assess the usage of competing risk analysis in recent meningioma literature. To compare recurrence risk estimates obtained through Kaplan–Meier and Aalen-Johansen methods, we applied our international database comprising ~ 8,000 patients with a primary meningioma collected from 42 institutions. Results: Of 513 articles, 169 were eligible for full-text screening. There were 6,537 eligible cases from our PERNS database. The discrepancy between the results obtained by Kaplan–Meier and Aalen-Johansen was negligible among low-grade lesions and younger individuals. The discrepancy increased substantially in the patient groups associated with higher rates of competing events (older patients with high-grade lesions). Conclusion: The importance of considering competing events in recurrence risk analysis is poorly recognized as only 6% of the studies we surveyed employed Aalen-Johansen analyses. Consequently, most of the previous literature has overestimated the risk of recurrence. The overestimation was negligible for studies involving low-grade lesions in younger individuals; however, overestimation might have been substantial for studies on high-grade lesions.

Background The risk of recurrence is overestimated by the Kaplan–Meier method when competing events, such as death without recurrence, are present. Such overestimation can be avoided by using the Aalen-Johansen method, which is a direct extension of Kaplan–Meier that accounts for competing events. Meningiomas commonly occur in older individuals and have slow-growing properties, thereby warranting competing risk analysis. The extent to which competing events are considered in meningioma literature is unknown, and the consequences of using incorrect methodologies in meningioma recurrence risk analysis have not been investigated. Methods We surveyed articles indexed on PubMed since 2020 to assess the usage of competing risk analysis in recent meningioma literature. To compare recurrence risk estimates obtained through Kaplan–Meier and Aalen-Johansen methods, we applied our international database comprising ~ 8,000 patients with a primary meningioma collected from 42 institutions. Results Of 513 articles, 169 were eligible for full-text screening. There were 6,537 eligible cases from our PERNS database. The discrepancy between the results obtained by Kaplan–Meier and Aalen-Johansen was negligible among low-grade lesions and younger individuals. The discrepancy increased substantially in the patient groups associated with higher rates of competing events (older patients with high-grade lesions). Conclusion The importance of considering competing events in recurrence risk analysis is poorly recognized as only 6% of the studies we surveyed employed Aalen-Johansen analyses. Consequently, most of the previous literature has overestimated the risk of recurrence. The overestimation was negligible for studies involving low-grade lesions in younger individuals; however, overestimation might have been substantial for studies on high-grade lesions., Background: The risk of recurrence is overestimated by the Kaplan–Meier method when competing events, such as death without recurrence, are present. Such overestimation can be avoided by using the Aalen-Johansen method, which is a direct extension of Kaplan–Meier that accounts for competing events. Meningiomas commonly occur in older individuals and have slow-growing properties, thereby warranting competing risk analysis. The extent to which competing events are considered in meningioma literature is unknown, and the consequences of using incorrect methodologies in meningioma recurrence risk analysis have not been investigated. Methods: We surveyed articles indexed on PubMed since 2020 to assess the usage of competing risk analysis in recent meningioma literature. To compare recurrence risk estimates obtained through Kaplan–Meier and Aalen-Johansen methods, we applied our international database comprising ~ 8,000 patients with a primary meningioma collected from 42 institutions. Results: Of 513 articles, 169 were eligible for full-text screening. There were 6,537 eligible cases from our PERNS database. The discrepancy between the results obtained by Kaplan–Meier and Aalen-Johansen was negligible among low-grade lesions and younger individuals. The discrepancy increased substantially in the patient groups associated with higher rates of competing events (older patients with high-grade lesions). Conclusion: The importance of considering competing events in recurrence risk analysis is poorly recognized as only 6% of the studies we surveyed employed Aalen-Johansen analyses. Consequently, most of the previous literature has overestimated the risk of recurrence. The overestimation was negligible for studies involving low-grade lesions in younger individuals; however, overestimation might have been substantial for studies on high-grade lesions.

We develop a new neural network architecture that strictly enforces constitutive constraints such as polyconvexity, frame-indifference, and the symmetry of the stress and material stiffness. Additionally, we show that the accuracy of the stress and material stiffness predictions is significantly improved for this neural network by using a Sobolev minimization strategy that includes derivative terms. Using our neural network, we model the constitutive behavior of fibrous-type discrete network material. With Sobolev minimization, we obtain a normalized mean square error of 0.15% for the strain energy density, 0.815% averaged across the components of the stress, and 5.4% averaged across the components of the stiffness tensor. This machine-learned constitutive model was deployed in a finite element simulation of a facet capsular ligament. The displacement fields and stress-strain curves were compared to a multiscale simulation that required running on a GPU-based supercomputer. The new approach maintained upward of 85% accuracy in stress up to 70% strain while reducing the computation cost by orders of magnitude., Comment: Data and code can be found at https://zenodo.org/doi/10.5281/zenodo.11205879

Fearful facial expressions are nonverbal and biologically salient signals of potential threat that automatically hold, capture, and direct observers' attention. They are characterized by enlarged eye whites and dilated pupils, and fearful eyes alone are sufficient to capture attention. The morphological properties of the eye region, such as sclera exposure, are thought to play an important role in nonverbal communication. Specifically, increased sclera exposure associated with fearful expressions has been shown to moderate how observers' shift their attention toward the direction of another's gaze. Yet, the extent to which variability in sclera exposure possibly impacts the capture and hold of attention by fearful faces is untested. To address this, a sample of 249 adults completed a dot-probe task of selective attention with fearful and neutral faces. The results suggested that (1) fearful faces were prioritized over neutral faces (i.e., they captured and held attention), (2) greater sclera exposure at target locations facilitated reaction times, and (3) attention was held by greater sclera exposure of fearful faces at task irrelevant locations resulting in delayed disengagement. Collectively, the results indicate that fearful facial expressions and sclera exposure modulate spatial attention through independent and interactive mechanisms. Sclera exposure appears to be an important facilitator of nonverbal communication and perhaps represents an understudied variable in social cognition more broadly.

Nanoelectrospray ionization emitters with submicron tip diameters have significant advantages for use in native mass spectrometry, including the ability to produce resolved charge-state distributions for proteins and macromolecular complexes from standard biochemical buffers that contain high concentrations of nonvolatile salts and to prevent nonspecific aggregation that can occur during droplet evaporation. We report on various factors affecting the tip morphology and provide suggestions for producing and using emitters with submicron tips. Effects of pulling parameters for a Sutter Instrument P-87 tip puller on the resulting tip diameter and morphology are shown. The "Pull" parameter has the largest effect on tip diameter, followed by "Velocity", "Pressure", and "Heat", whereas the "Time" parameter has minimal effect beyond a lower threshold. High "Pull" values generate emitters with multiple tapers, whereas high "Velocity" values generate a tip with only a single tapered region. A protocol for producing reproducible emitters in the submicron size range, as well as guidelines and tips for using these emitters with standard biochemical buffers that contain high concentrations of nonvolatile salts, is presented with the aim of expanding their use within the native mass spectrometry community.

Sensory neurons enable animals to detect environmental changes and avoid harm. An intriguing open question concerns how the various attributes of sensory neurons arise in development. Drosophila melanogaster larvae undergo a behavioral transition by robustly activating a thermal nociceptive escape behavior during the second half of larval development (third instar). The Class IV dendritic arborization (C4da) neurons are multimodal sensors which tile the body wall of Drosophila larvae and detect nociceptive temperature, light, and mechanical force. In contrast to the increase in nociceptive behavior in the third instar, we find that ultraviolet light-induced Ca2+ activity in C4da neurons decreases during the same period of larval development. Loss of ecdysone receptor has previously been shown to reduce nociception in third instar larvae. We find that ligand-dependent activation of ecdysone signaling is sufficient to promote nociceptive responses in second instar larvae and suppress expression of subdued (encoding a TMEM16 channel). Reduction of subdued expression in second instar C4da neurons not only increases thermal nociception but also decreases the response to ultraviolet light. Thus, steroid hormone signaling suppresses subdued expression to facilitate the sensory switch of C4da neurons. This regulation of a developmental sensory switch through steroid hormone regulation of channel expression raises the possibility that ion channel homeostasis is a key target for tuning the development of sensory modalities.

Meningiomas are the most common non-metastatic brain tumors, and although the majority are relatively slow-growing and histologically benign, a subset of meningiomas are aggressive and remain challenging to treat. Despite a standard of care that includes surgical resection and radiotherapy, and recent advances in meningioma molecular grouping, there are no systemic medical options for patients with meningiomas that are resistant to standard interventions. Misactivation of the cell cycle at the level of CDK4/6 is common in high-grade or molecularly aggressive meningiomas, and CDK4/6 has emerged as a potential target for systemic meningioma treatments. In this review, we describe the preclinical evidence for CDK4/6 inhibitors as a treatment for high-grade meningiomas and summarize evolving clinical experience with these agents. Further, we highlight upcoming clinical trials for patients meningiomas, and discuss future directions aimed at optimizing the efficacy of these therapies and selecting patients most likely to benefit from their use.

Sensory neurons enable animals to detect environmental changes and avoid harm. An intriguing open question concerns how the various attributes of sensory neurons arise in development. Drosophila melanogaster larvae undergo a behavioral transition by robustly activating a thermal nociceptive escape behavior during the second half of larval development (third instar). The Class IV dendritic arborization (C4da) neurons are multimodal sensors which tile the body wall of Drosophila larvae and detect nociceptive temperature, light, and mechanical force. In contrast to the increase in nociceptive behavior in the third instar, we find that ultraviolet light-induced Ca2+ activity in C4da neurons decreases during the same period of larval development. Loss of ecdysone receptor has previously been shown to reduce nociception in third instar larvae. We find that ligand-dependent activation of ecdysone signaling is sufficient to promote nociceptive responses in second instar larvae and suppress expression of subdued (encoding a TMEM16 channel). Reduction of subdued expression in second instar C4da neurons not only increases thermal nociception but also decreases the response to ultraviolet light. Thus, steroid hormone signaling suppresses subdued expression to facilitate the sensory switch of C4da neurons. This regulation of a developmental sensory switch through steroid hormone regulation of channel expression raises the possibility that ion channel homeostasis is a key target for tuning the development of sensory modalities.

Meningiomas are the most common non-metastatic brain tumors, and although the majority are relatively slow-growing and histologically benign, a subset of meningiomas are aggressive and remain challenging to treat. Despite a standard of care that includes surgical resection and radiotherapy, and recent advances in meningioma molecular grouping, there are no systemic medical options for patients with meningiomas that are resistant to standard interventions. Misactivation of the cell cycle at the level of CDK4/6 is common in high-grade or molecularly aggressive meningiomas, and CDK4/6 has emerged as a potential target for systemic meningioma treatments. In this review, we describe the preclinical evidence for CDK4/6 inhibitors as a treatment for high-grade meningiomas and summarize evolving clinical experience with these agents. Further, we highlight upcoming clinical trials for patients meningiomas, and discuss future directions aimed at optimizing the efficacy of these therapies and selecting patients most likely to benefit from their use.

The Earth BioGenome Project (EBP) is an audacious endeavor to obtain whole-genome sequences of representatives from all eukaryotic species on Earth. In addition to the project's technical and organizational challenges, it also faces complicated ethical, legal, and social issues. This paper, from members of the EBP's Ethical, Legal, and Social Issues (ELSI) Committee, catalogs these ELSI concerns arising from EBP. These include legal issues, such as sample collection and permitting; the applicability of international treaties, such as the Convention on Biological Diversity and the Nagoya Protocol; intellectual property; sample accessioning; and biosecurity and ethical issues, such as sampling from the territories of Indigenous peoples and local communities, the protection of endangered species, and cross-border collections, among several others. We also comment on the intersection of digital sequence information and data rights. More broadly, this list of ethical, legal, and social issues for large-scale genomic sequencing projects may be useful in the consideration of ethical frameworks for future projects. While we do not-and cannot-provide simple, overarching solutions for all the issues raised here, we conclude our perspective by beginning to chart a path forward for EBP's work.

RationalePsychedelic research continues to garner significant public and scientific interest with a growing number of clinical studies examining a wide range of conditions and disorders. However, expectancy effects and effective condition masking have been raised as critical limitations to the interpretability of the research.ObjectiveIn this article, we review the many methodological challenges of conducting psychedelic clinical trials and provide recommendations for improving the rigor of future research.ResultsAlthough some challenges are shared with psychotherapy and pharmacology trials more broadly, psychedelic clinical trials have to contend with several unique sources of potential bias. The subjective effects of a high-dose psychedelic are often so pronounced that it is difficult to mask participants to their treatment condition; the significant hype from positive media coverage on the clinical potential of psychedelics influences participants' expectations for treatment benefit; and participant unmasking and treatment expectations can interact in such a way that makes psychedelic therapy highly susceptible to large placebo and nocebo effects. Specific recommendations to increase the success of masking procedures and reduce the influence of participant expectancies are discussed in the context of study development, participant recruitment and selection, incomplete disclosure of the study design, choice of active placebo condition, as well as the measurement of participant expectations and masking efficacy.ConclusionIncorporating the recommended design elements is intended to reduce the risk of bias in psychedelic clinical trials and thereby increases the ability to discern treatment-specific effects of psychedelic therapy.

The Sudan virus disease outbreak in Uganda in 2022 showed our vulnerability to viral haemorrhagic fevers (VHFs). Although there are regular outbreaks of VHFs with high morbidity and mortality, which disproportionally affect low-income settings, our understanding of how to treat them remains inadequate. In this systematic review, we aim to explore the availability, scope, standardisation, and quality of clinical management guidelines for VHFs. We identified 32 guidelines, 25 (78%) of which were low quality and did not have supporting evidence and eight (25%) of which had been produced or updated in the past 3 years. Guidance on supportive care and therapeutics had little detail and was sometimes contradictory. Guidelines based on uncertain evidence are a risk to patients, an ethical challenge for clinicians, and a challenge to implementing trials due to heterogeneous standards of care. We recommend a standard living guideline framework to improve the quality, scope, and applicability of guidelines. Furthermore, investments into trials should aim to identify optimal treatment strategies for VHFs and prioritise affordable and scalable interventions to improve outcomes globally.

Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. Here we develop a targeted gene expression biomarker that predicts meningioma outcomes and radiotherapy responses. Using a discovery cohort of 173 meningiomas, we developed a 34-gene expression risk score and performed clinical and analytical validation of this biomarker on independent meningiomas from 12 institutions across 3 continents (N = 1,856), including 103 meningiomas from a prospective clinical trial. The gene expression biomarker improved discrimination of outcomes compared with all other systems tested (N = 9) in the clinical validation cohort for local recurrence (5-year area under the curve (AUC) 0.81) and overall survival (5-year AUC 0.80). The increase in AUC compared with the standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval 0.07 to 0.17, P < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% confidence interval 0.37 to 0.78, P = 0.0001) and suggested postoperative management could be refined for 29.8% of patients. In sum, our results identify a targeted gene expression biomarker that improves discrimination of meningioma outcomes, including prediction of postoperative radiotherapy responses.

Proton exchange membrane fuel cells (PEMFCs) are leading candidates to decarbonize the transport sector, but widespread deployment will require improvements in lifetime, fuel economy and cost. Here we present the grooved electrode, an alternative electrode structure that enhances PEMFC performance and durability by coupling high ionomer (ion-conducting binder) content for improved H+ transport with grooves for rapid O2 transport. Grooved electrodes provide up to 50% higher performance than state-of-the-art conventional electrodes under standard operating conditions. Fuel cell diagnostics combined with multiphysics modelling demonstrate that grooved electrodes provide facile O2 transport despite their high ionomer content, enabling improved reaction rate uniformity. Grooved electrodes also provide improved durability, with less performance loss after carbon corrosion compared with baseline electrodes. Machine learning analysis demonstrates the potential to further optimize grooved structures for next-generation PEMFCs with enhanced performance and durability, enabling smaller and cheaper fuel cell stacks with higher fuel efficiency.

Polymer-electrolyte-membrane fuel cells (PEMFCs) hold great promise for applications in clean energy conversion, but cost and durability continue to limit commercialization. This work presents a new class of catalyst/electrode architecture that does not rely on Pt particles or carbon supports, eliminating the primary degradation mechanisms in conventional electrodes, and thereby enabling transformative durability improvements. The coaxial nanowire electrode (CANE) architecture consists of an array of vertically aligned nanowires, each comprising an ionomer core encapsulated by a nanoscale Pt film. This unique design eliminates the triple-phase boundary and replaces it with two double-phase boundaries, increasing Pt utilization. It also eliminates the need for carbon support and ionomer binder, enabling improved durability and faster mass transport. Fuel cell membrane electrode assemblies based on CANEs demonstrate extraordinary durability in accelerated stress tests (ASTs), with only 2% and 5% loss in performance after 5000 support AST cycles and 30000 catalysts AST cycles, respectively. The high power density and extremely high durability provided by CANEs can enable a paradigm shift from random electrodes based on unstable platinum nanoparticles dispersed on carbon to ordered electrodes based on durable Pt nanofilms, facilitating rapid deployment of fuel cells in transportation and other clean energy applications.

BackgroundTerminology to describe extent of resection in glioblastoma is inconsistent across clinical trials. A surgical classification system was previously proposed based upon residual contrast-enhancing (CE) tumor. We aimed to (1) explore the prognostic utility of the classification system and (2) define how much removed non-CE tumor translates into a survival benefit.MethodsThe international RANO resect group retrospectively searched previously compiled databases from 7 neuro-oncological centers in the USA and Europe for patients with newly diagnosed glioblastoma per WHO 2021 classification. Clinical and volumetric information from pre- and postoperative MRI were collected.ResultsWe collected 1,008 patients with newly diagnosed IDHwt glioblastoma. 744 IDHwt glioblastomas were treated with radiochemotherapy per EORTC-26981/22981 (TMZ/RT→TMZ) following surgery. Among these homogenously treated patients, lower absolute residual tumor volumes (in cm3) were favorably associated with outcome: patients with "maximal CE resection" (class 2) had superior outcome compared to patients with "submaximal CE resection" (class 3) or "biopsy" (class 4). Extensive resection of non-CE tumor (≤5 cm3 residual non-CE tumor) was associated with better survival among patients with complete CE resection, thus defining class 1 ("supramaximal CE resection"). The prognostic value of the resection classes was retained on multivariate analysis when adjusting for molecular and clinical markers.ConclusionsThe proposed "RANO categories for extent of resection in glioblastoma" are highly prognostic and may serve for stratification within clinical trials. Removal of non-CE tumor beyond the CE tumor borders may translate into additional survival benefit, providing a rationale to explicitly denominate such "supramaximal CE resection."

The National Institute of Allergy and Infectious Diseases (NIAID) established the Bioinformatics Resource Center (BRC) program to assist researchers with analyzing the growing body of genome sequence and other omics-related data. In this report, we describe the merger of the PAThosystems Resource Integration Center (PATRIC), the Influenza Research Database (IRD) and the Virus Pathogen Database and Analysis Resource (ViPR) BRCs to form the Bacterial and Viral Bioinformatics Resource Center (BV-BRC) https://www.bv-brc.org/. The combined BV-BRC leverages the functionality of the bacterial and viral resources to provide a unified data model, enhanced web-based visualization and analysis tools, bioinformatics services, and a powerful suite of command line tools that benefit the bacterial and viral research communities.

Redox flow batteries (RFBs) are a promising stationary energy storage technology for leveling power supply from intermittent renewable energy sources with demand. A central objective for the development of practical, scalable RFBs is to identify affordable and high-performance redox-active molecules as storage materials. Herein, we report the design, synthesis, and evaluation of a new organic scaffold, indolo[2,3-b]quinoxaline, for highly stable, low-reduction potential, and high-solubility anolytes for nonaqueous redox flow batteries (NARFBs). The mixture of 2- and 3-(tert-butyl)-6-(2-methoxyethyl)-6H-indolo[2,3-b]quinoxaline exhibits a low reduction potential (-2.01 V vs Fc/Fc+), high solubility (>2.7 M in acetonitrile), and remarkable stability (99.86% capacity retention over 49.5 h (202 cycles) of H-cell cycling). This anolyte was paired with N-(2-(2-methoxyethoxy)-ethyl)phenothiazine (MEEPT) to achieve a 2.3 V all-organic NARFB exhibiting 95.8% capacity retention over 75.1 h (120 cycles) of cycling.

BackgroundWhile genetic alterations in brain metastases (BMs) have been previously explored, there are limited data examining their association with recurrence after surgical resection. This study aimed to identify genetic alterations within BMs associated with CNS recurrence after surgery across multiple cancer types.MethodsA retrospective, single-center study was conducted with patients who underwent resection of a BM with available clinical and gene sequencing data available. Local and remote CNS recurrence were the primary study outcomes. Next-generation sequencing of the coding regions in over 500 oncogenes was performed in brain metastasis specimens. Cox proportional hazards analyses were performed to identify clinical features and genomic alterations associated with CNS recurrence.ResultsA total of 90 patients undergoing resection of 91 BMs composed the cohort. Genes most frequently mutated in the cohort included TP53 (64%), CDKN2A (37%), TERT (29%), CDKN2B (23%), NF1 (14%), KRAS (14%), and PTEN (13%), all of which occurred across multiple cancer types. CDKN2A/B co-deletion was seen in 21 (23.1%) brain metastases across multiple cancer types. In multivariate Cox proportional hazard analyses including patient, tumor, and treatment factors, CDKN2A/B co-deletion in the brain metastasis was associated with increased risk of local (HR 4.07, 95% CI 1.32-12.54, P = 0.014) and remote (HR 2.28, 95% CI 1.11-4.69, P = 0.025) CNS progression. Median survival and length of follow-up were not different based on CDKN2A/B mutation status.ConclusionsCDKN2A/B co-deletion detected in BMs is associated with increased CNS recurrence after surgical resection. Additional work is needed to determine whether more aggressive treatment in patients with this mutation may improve outcomes.

Idaho Dept. of Fish and Game, Div. of Fisheries IDFG Report Number 23-08, published April 2023.

Biocatalysis has revolutionized chemical synthesis, providing sustainable methods for preparing various organic molecules. In enzyme-mediated organic synthesis, most reactions involve molecules operating from their ground states. Over the past 25 years, there has been an increased interest in enzymatic processes that utilize electronically excited states accessed through photoexcitation. These photobiocatalytic processes involve a diverse array of reaction mechanisms that are complementary to one another. This comprehensive review will describe the state-of-the-art strategies in photobiocatalysis for organic synthesis until December 2022. Apart from reviewing the relevant literature, a central goal of this review is to delineate the mechanistic differences between the general strategies employed in the field. We will organize this review based on the relationship between the photochemical step and the enzymatic transformations. The review will include mechanistic studies, substrate scopes, and protein optimization strategies. By clearly defining mechanistically-distinct strategies in photobiocatalytic chemistry, we hope to illuminate future synthetic opportunities in the area.

We present a study of the molecular gas of seven early-type galaxies with high angular resolution data obtained as part of the mm-Wave Interferometric Survey of Dark Object Masses (WISDOM) project with the Atacama Large Millimeter/submillimeter Array. Using a fixed spatial scale approach, we study the mass surface density ($\Sigma$) and velocity dispersion ($\sigma$) of the molecular gas on spatial scales ranging from $60$ to $120$pc. Given the spatial resolution of our data ($20$ - $70$pc), we characterise these properties across many thousands of individual sight lines ($\approx50,000$ at our highest physical resolution). The molecular gas along these sight lines has a large range ($\approx2$dex) of mass surface densities and velocity dispersions $\approx40\%$ higher than those of star-forming spiral galaxies. It has virial parameters $\alpha_\mathrm{vir}$ that depend weakly on the physical scale observed, likely due to beam smearing of the bulk galactic rotation, and is generally super-virial. Comparing the internal turbulent pressure ($P_\mathrm{turb}$) to the pressure required for dynamic equilibrium ($P_\mathrm{DE}$), the ratio $P_\mathrm{turb}$/$P_\mathrm{DE}$ is significantly less than unity in all galaxies, indicating that the gas is not in dynamic equilibrium and is strongly compressed, in apparent contradiction to the virial parameters. This may be due to our neglect of shear and tidal forces, and/or the combination of three-dimensional and vertical diagnostics. Both $\alpha_\mathrm{vir}$ and $P_\mathrm{turb}$ anti-correlate with the global star-formation rate of our galaxies. We therefore conclude that the molecular gas in early-type galaxies is likely unbound, and that large-scale dynamics likely plays a critical role in its regulation. This contrasts to the giant molecular clouds in the discs of late-type galaxies, that are much closer to dynamical equilibrium., Comment: 32 pages (16 of Appendices), 39 Figures (27 in Appendices). Accepted for publication in MNRAS

We report the discovery of the ``mm fundamental plane of black-hole accretion'', which is a tight correlation between the nuclear 1 mm luminosity ($L_{\rm \nu, mm}$), the intrinsic $2$ -- $10$~keV X-ray luminosity ($L_{\rm X,2-10}$) and the supermassive black hole (SMBH) mass ($M_{\rm BH}$) with an intrinsic scatter ($\sigma_{\rm int}$) of $0.40$ dex. The plane is found for a sample of 48 nearby galaxies, most of which are low-luminosity active galactic nuclei (LLAGN). Combining these sources with a sample of high-luminosity (quasar-like) nearby AGN, we find that the plane still holds. We also find that $M_{\rm BH}$ correlates with $L_{\rm \nu, mm}$ at a highly significant level, although such correlation is less tight than the mm fundamental plane ($\sigma_{\rm int}=0.51$ dex). Crucially, we show that spectral energy distribution (SED) models for both advection-dominated accretion flows (ADAFs) and compact jets can explain the existence of these relations, which are not reproduced by the standard torus-thin accretion disc models usually associated to quasar-like AGN. The ADAF models reproduces the observed relations somewhat better than those for compact jets, although neither provides a perfect prediction. Our findings thus suggest that radiatively-inefficient accretion processes such as those in ADAFs or compact (and thus possibly young) jets may play a key role in both low- and high-luminosity AGN. This mm fundamental plane also offers a new, rapid method to (indirectly) estimate SMBH masses., Comment: 9 pages, 5 figures

We present a CO dynamical estimate of the mass of the super-massive black hole (SMBH) in three nearby early-type galaxies: NGC0612, NGC1574 and NGC4261. Our analysis is based on Atacama Large Millimeter/submillimeter Array (ALMA) Cycle 3-6 observations of the $^{12}$CO(2-1) emission line with spatial resolutions of $14-58$ pc ($0.01"-0.26"$). We detect disc-like CO distributions on scales from $\lesssim200$ pc (NGC1574 and NGC4261) to $\approx10$ kpc (NGC0612). In NGC0612 and NGC1574 the bulk of the gas is regularly rotating. The data also provide evidence for the presence of a massive dark object at the centre of NGC1574, allowing us to obtain the first measure of its mass, $M_{\rm BH}=(1.0\pm0.2)\times10^{8}$ M$_{\odot}$ (1$\sigma$ uncertainty). In NGC4261, the CO kinematics is clearly dominated by the SMBH gravitational influence, allowing us to determine an accurate black hole mass of $(1.62{\pm 0.04})\times10^{9}$ M$_{\odot}$ ($1\sigma$ uncertainty). This is fully consistent with a previous CO dynamical estimate obtained using a different modelling technique. Signs of non-circular gas motions (likely outflow) are also identified in the inner regions of NGC4261. In NGC0612, we are only able to obtain a (conservative) upper limit of $M_{\rm BH}\lesssim3.2\times10^{9}$ M$_{\odot}$. This has likely to be ascribed to the presence of a central CO hole (with a radius much larger than that of the SMBH sphere of influence), combined with the inability of obtaining a robust prediction for the CO velocity curve. The three SMBH mass estimates are overall in agreement with predictions from the $M_{\rm BH}-\sigma_{\star}$ relation., Comment: Main text: 20 pages, 14 Figures; Appendix: 7 pages, 6 Figures. Accepted for publication in MNRAS on 2023 March 28

BACKGROUND: The value of re-resection in recurrent glioblastoma remains controversial as a randomized trial that specifies intentional incomplete resection cannot be justified ethically. Here, we aimed to (1) explore the prognostic role of extent of re-resection using the previously proposed Response Assessment in Neuro-Oncology (RANO) classification (based upon residual contrast-enhancing (CE) and non-CE tumor), and to (2) define factors consolidating the surgical effects on outcome. METHODS: The RANO resect group retrospectively compiled an 8-center cohort of patients with first recurrence from previously resected glioblastomas. The associations of re-resection and other clinical factors with outcome were analyzed. Propensity score-matched analyses were constructed to minimize confounding effects when comparing the different RANO classes. RESULTS: We studied 681 patients with first recurrence of Isocitrate Dehydrogenase (IDH) wild-type glioblastomas, including 310 patients who underwent re-resection. Re-resection was associated with prolonged survival even when stratifying for molecular and clinical confounders on multivariate analysis; ≤1 cm3 residual CE tumor was associated with longer survival than non-surgical management. Accordingly, "maximal resection" (class 2) had superior survival compared to "submaximal resection" (class 3). Administration of (radio-)chemotherapy in the absence of postoperative deficits augmented the survival associations of smaller residual CE tumors. Conversely, "supramaximal resection" of non-CE tumor (class 1) was not associated with prolonged survival but was frequently accompanied by postoperative deficits. The prognostic role of residual CE tumor was confirmed in propensity score analyses. CONCLUSIONS: The RANO resect classification serves to stratify patients with re-resection of glioblastoma. Complete resection according to RANO resect classes 1 and

This article provides an overview of the emerging field of American political economy (APE). Methodologically eclectic, this field seeks to understand the interaction of markets and government in America's unequal and polarized polity. Though situated within American politics research, APE draws from comparative political economy to develop a broad approach that departs from the American politics mainstream in two main ways. First, APE focuses on the interaction of markets and governance, a peripheral concern in much American politics research. Second, it invokes a theoretical orientation attentive to what we call meta politics—the processes of institution shaping, agenda setting, and venue shopping that unfold before and alongside the more visible processes of mass politics that figure so centrally in American politics research. These substantive and theoretical differences expand the study of American politics into neglected yet vital domains, generating fresh insights into the United States’ distinctive mix of capitalism and democracy.

Fungi often adapt to environmental stress by altering their size, shape, or rate of cell division. These morphological changes require reorganization of the cell wall, a structural feature external to the cell membrane composed of highly interconnected polysaccharides and glycoproteins. Lytic polysaccharide monooxygenases (LPMOs) are copper-dependent enzymes that are typically secreted into the extracellular space to catalyze initial oxidative steps in the degradation of complex biopolymers such as chitin and cellulose. However, their roles in modifying endogenous microbial carbohydrates are poorly characterized. The CEL1 gene in the human fungal pathogen Cryptococcus neoformans (Cn) is predicted by sequence homology to encode an LPMO of the AA9 enzyme family. The CEL1 gene is induced by host physiological pH and temperature, and it is primarily localized to the fungal cell wall. Targeted mutation of the CEL1 gene revealed that it is required for the expression of stress response phenotypes, including thermotolerance, cell wall integrity, and efficient cell cycle progression. Accordingly, a cel1 Delta deletion mutant was avirulent in two models of C. neoformans infection. Therefore, in contrast to LPMO activity in other microorganisms that primarily targets exogenous polysaccharides, these data suggest that CnCel1 promotes intrinsic fungal cell wall remodeling events required for efficient adaptation to the host environment.Author summaryFungi need to adapt quickly to environmental stresses to thrive. The fungal cell wall, which supplies support and integrity to the cell, is an essential compartment to react and interact with the surrounding environment. Rapid changes within the carbohydrate composition and architecture occur in response to environmental stresses. Lytic polysaccharide monooxygenases (LPMOs) are mononuclear copper-enzymes, secreted by microbes to assist in the first steps of remodeling and degradation of complex and recalcitrant carbohydrat

Fungi often adapt to environmental stress by altering their size, shape, or rate of cell division. These morphological changes require reorganization of the cell wall, a structural feature external to the cell membrane composed of highly interconnected polysaccharides and glycoproteins. Lytic polysaccharide monooxygenases (LPMOs) are copper-dependent enzymes that are typically secreted into the extracellular space to catalyze initial oxidative steps in the degradation of complex biopolymers such as chitin and cellulose. However, their roles in modifying endogenous microbial carbohydrates are poorly characterized. The CEL1 gene in the human fungal pathogen Cryptococcus neoformans (Cn) is predicted by sequence homology to encode an LPMO of the AA9 enzyme family. The CEL1 gene is induced by host physiological pH and temperature, and it is primarily localized to the fungal cell wall. Targeted mutation of the CEL1 gene revealed that it is required for the expression of stress response phenotypes, including thermotolerance, cell wall integrity, and efficient cell cycle progression. Accordingly, a cel1 Delta deletion mutant was avirulent in two models of C. neoformans infection. Therefore, in contrast to LPMO activity in other microorganisms that primarily targets exogenous polysaccharides, these data suggest that CnCel1 promotes intrinsic fungal cell wall remodeling events required for efficient adaptation to the host environment.Author summaryFungi need to adapt quickly to environmental stresses to thrive. The fungal cell wall, which supplies support and integrity to the cell, is an essential compartment to react and interact with the surrounding environment. Rapid changes within the carbohydrate composition and architecture occur in response to environmental stresses. Lytic polysaccharide monooxygenases (LPMOs) are mononuclear copper-enzymes, secreted by microbes to assist in the first steps of remodeling and degradation of complex and recalcitrant carbohydrat

Health informatics can inform decisions that practitioners, patients, policymakers, and researchers need to make about health and disease. Health informatics is built upon patient health data leading to the need to codify patient health information. Such standardization is required to compute population statistics (such as prevalence, incidence, etc.) that are common metrics used in fields such as epidemiology. Reliable decision-making about health and disease rests on our ability to organize, analyze, and assess data repositories that contain patient health data. While standards exist to structure and analyze patient data across patient data sources such as health information exchanges, clinical data repositories, and health data marketplaces, analogous best practices for rigorously defining patient populations in health informatics contexts do not exist. Codifying best practices for developing disease definitions could support the effective development of clinical guidelines, inform algorithms used in clinical decision support systems, and additional patient guidelines. In this paper, we present a workflow for the development of phenotype definitions. This workflow presents a series of recommendations for defining health and disease. Various examples within this paper are presented to demonstrate this workflow in health informatics contexts., Comment: IEEE Computer Based Medical Systems Conference

Landslides occur annually worldwide from natural and man-made influences with high levels of destruction. The prediction and mitigation of landslide occurrences can be largely beneficial in minimizing destruction and loss of life due to such occurrences. Observations on the causes of landslides, ranging from earthquakes, geological instabilities and human excavations and cuttings from slopes, have detailed rainfall of a prolonged or heavy nature has been deemed the primary cause, often occurring in mountainous terrain. Documented devastating occurrences of rainfall-induced landslides causing destruction to infrastructure and property, along with loss of human life, have occurred in many European countries, America, Taiwan, Japan, Hong Kong, Nepal and India. Australia is not free of landslide risk with a summarised cataloguing detailing over 114 known landslides causing injury or death and damage to infrastructure between 1842 to December 2011. One particularly devastating landslide in Australia occurred in Thredbo, New South Wales, in 1997, causing the death of 18 people as a result of heavy rainfall coupled with snowmelt. This historical evidence of landslide activity indicates a need for the monitoring of landslides within Australian mountainous regions. The mountainous regions between Mudgeeraba and the Currumbin Valley of south-east Queensland are particularly susceptible to shallow landslides during large rainfall weather events, due to the general steepness of slopes and weathered top layers of soil overlaying bedrock. As roadways are limited through these mountain passes, rainfall-induced shallow landslides can leave people stranded either in dire need of resources or medical aid. A prime example of a weather event leading to rainfall-induced shallow landslides in south-east Queensland was ex-Tropical Cyclone Debbie, on the 31st of March, 2017. Local government reported an excess of some 25 major landslides along road corridors of the mountainous areas. Rainf, Thesis (PhD Doctorate), Doctor of Philosophy (PhD), School of Eng & Built Env, Science, Environment, Engineering and Technology, Full Text

What enables strains of the same species to coexist in a microbiome? Here, we investigate whether host anatomy can explain strain co-residence of Cutibacterium acnes, the most abundant species on human skin. We reconstruct on-person evolution and migration using whole-genome sequencing of C. acnes colonies acquired from healthy subjects, including from individual skin pores, and find considerable spatial structure at the level of pores. Although lineages (sets of colonies separated by <100 mutations) with in vitro fitness differences coexist within centimeter-scale regions, each pore is dominated by a single lineage. Moreover, colonies from a pore typically have identical genomes. An absence of adaptive signatures suggests a genotype-independent source of low within-pore diversity. We therefore propose that pore anatomy imposes random single-cell bottlenecks; the resulting population fragmentation reduces competition and promotes coexistence. Our findings suggest that therapeutic interventions involving pore-dwelling species might focus on removing resident populations over optimizing probiotic fitness.

Background Terminology to describe extent of resection in glioblastoma is inconsistent across clinical trials. A surgical classification system was previously proposed based upon residual contrast-enhancing (CE) tumor. We aimed to (1) explore the prognostic utility of the classification system and (2) define how much removed non-CE tumor translates into a survival benefit. Methods The international RANO resect group retrospectively searched previously compiled databases from 7 neuro-oncological centers in the USA and Europe for patients with newly diagnosed glioblastoma per WHO 2021 classification. Clinical and volumetric information from pre- and postoperative MRI were collected. Results We collected 1,008 patients with newly diagnosed IDHwt glioblastoma. 744 IDHwt glioblastomas were treated with radiochemotherapy per EORTC-26981/22981 (TMZ/RT -> TMZ) following surgery. Among these homogenously treated patients, lower absolute residual tumor volumes (in cm(3)) were favorably associated with outcome: patients with "maximal CE resection" (class 2) had superior outcome compared to patients with "submaximal CE resection" (class 3) or "biopsy" (class 4). Extensive resection of non-CE tumor (<= 5 cm(3) residual non-CE tumor) was associated with better survival among patients with complete CE resection, thus defining class 1 ("supramaximal CE resection"). The prognostic value of the resection classes was retained on multivariate analysis when adjusting for molecular and clinical markers. Conclusions The proposed "RANO categories for extent of resection in glioblastoma" are highly prognostic and may serve for stratification within clinical trials. Removal of non-CE tumor beyond the CE tumor borders may translate into additional survival benefit, providing a rationale to explicitly denominate such "supramaximal CE resection."

While significant advances have been made and early commercial fuel cell light-duty vehicles (LDVs) are starting to be produced, fuel cells in the heavy-duty-vehicle (HDV) transportation sector (including trucks, long-haul semitrailers, maritime, trains, etc.) are nascent, despite the fact that advantages of fuel cells compared to both diesel and electric powertrains are very compelling in terms of emissions, charging time, efficiency, power-to-weight ratio, among others. However, the fuel-cell technology for HDVs requires a paradigm shift in fuel-cell research and development compared to LDVs, where the emphasis becomes efficiency and improvements in durability instead of a focus on increased power densities and lower cell costs. Heavy-duty applications require significantly longer vehicle lifetimes (>25,000 hours/1,000,000 miles for heavy-duty trucks), and therefore require improved fuel cell durability compared to light-duty vehicles. In 2020, HFTO formed the Million Mile Fuel Cell Truck Consortium (M2FCT) that includes a core team of five national laboratories to overcome durability and efficiency challenges in PEMFCs for heavy-duty applications with an initial focus on long-haul trucks. While targets and testing protocols have been developed for light-duty vehicles, the same level of targets and testing protocols have not been established for heavy-duty transportation. With operational times of greater than > 25,000 hours required, the need for well-developed accelerated stress tests (ASTs) is amplified. Results from these ASTs demonstrate the need for more durable electrode layers and well-controlled potential variations. This presentation will provide an overview of the DOE’s Fuel Cell R&D approach, highlighting past and current activities, as well as strategies to enable fuel cell competiveness for heavy-duty applications. Acknowledgments This work was funded through the DOE M2FCT Consortium with thanks to DOE EERE HFTO, Fuel Cell Technologies Offi

Correction to: Nature Energy. Published online 25 May 2023. This paper was originally published under a standard Springer Nature license (© The Author(s), under exclusive licence to Springer Nature Limited). It is now available as an open-access paper under a Creative Commons Attribution 4.0 International license, © The Author(s). The error has been corrected in the online version of the article.

PurposeIn patients with diffuse low-grade glioma (LGG), the extent of surgical tumor resection (EOR) has a controversial role, in part because a randomized clinical trial with different levels of EOR is not feasible.MethodsIn a 20-year retrospective cohort of 392 patients with IDH-mutant grade 2 glioma, we analyzed the combined effects of volumetric EOR and molecular and clinical factors on overall survival (OS) and progression-free survival by recursive partitioning analysis. The OS results were validated in two external cohorts (n = 365). Propensity score analysis of the combined cohorts (n = 757) was used to mimic a randomized clinical trial with varying levels of EOR.ResultsRecursive partitioning analysis identified three survival risk groups. Median OS was shortest in two subsets of patients with astrocytoma: those with postoperative tumor volume (TV) > 4.6 mL and those with preoperative TV > 43.1 mL and postoperative TV ≤ 4.6 mL. Intermediate OS was seen in patients with astrocytoma who had chemotherapy with preoperative TV ≤ 43.1 mL and postoperative TV ≤ 4.6 mL in addition to oligodendroglioma patients with either preoperative TV > 43.1 mL and residual TV ≤ 4.6 mL or postoperative residual volume > 4.6 mL. Longest OS was seen in astrocytoma patients with preoperative TV ≤ 43.1 mL and postoperative TV ≤ 4.6 mL who received no chemotherapy and oligodendroglioma patients with preoperative TV ≤ 43.1 mL and postoperative TV ≤ 4.6 mL. EOR ≥ 75% improved survival outcomes, as shown by propensity score analysis.ConclusionAcross both subtypes of LGG, EOR beginning at 75% improves OS while beginning at 80% improves progression-free survival. Nonetheless, maximal resection with preservation of neurological function remains the treatment goal. Our findings have implications for surgical strategies for LGGs, particularly oligodendroglioma.

The multikinase inhibitor sorafenib improves event-free survival (EFS) when used with 7 + 3 in adults with newly-diagnosed acute myeloid leukemia (AML), irrespective of the FLT3-mutation status. Here, we evaluated adding sorafenib to cladribine, high-dose cytarabine, granulocyte colony–stimulating factor, and mitoxantrone (CLAG-M) in a phase 1/2 trial of 81 adults aged ≤60 years with newly diagnosed AML. Forty-six patients were treated in phase 1 with escalating doses of sorafenib and mitoxantrone. No maximum tolerated dose was reached, and a regimen including mitoxantrone 18 mg/m2 per day and sorafenib 400 mg twice daily was declared the recommended phase 2 dose (RP2D). Among 41 patients treated at RP2D, a measurable residual disease–negative complete remission (MRD– CR) rate of 83% was obtained. Four-week mortality was 2%. One-year overall survival (OS) and EFS were 80% and 76%, without differences in MRD– CR rates, OS, or EFS between patients with or without FLT3-mutated disease. Comparing outcomes using CLAG-M/sorafenib with those of a matched cohort of 76 patients treated with CLAG-M alone, multivariable-adjusted survival estimates were improved for 41 patients receiving CLAG-M/sorafenib at RP2D (OS: hazard ratio,0.24 [95% confidence interval, 0.07-0.82]; P = .023; EFS: hazard ratio, 0.16 [95% confidence interval, 0.05-0.53]; P = .003). Benefit was limited to patients with intermediate-risk disease (univariate analysis: P = .01 for OS; P = .02 for EFS). These data suggest that CLAG-M/sorafenib is safe and improves OS and EFS relative to CLAG-M alone, with benefits primarily in patients with intermediate-risk disease. The trial was registered at www.clinicaltrials.gov as #NCT02728050.

BACKGROUND Terminology to describe extent of resection in glioblastoma is inconsistent across clinical trials. A surgical classification system was previously proposed based upon residual contrast-enhancing (CE) tumor. We aimed to (I) explore the prognostic utility of the classification system and (II) define how much removed non-CE tumor translates into a survival benefit. METHODS The international RANO resect group retrospectively searched previously compiled databases from seven neuro-oncological centers in the USA and Europe for patients with newly diagnosed glioblastoma per WHO 2021 classification. Clinical and volumetric information from pre- and post-operative MRI were collected. RESULTS We collected 1008 patients with newly diagnosed IDHwt glioblastoma. 744 IDHwt glioblastomas were treated with radiochemotherapy per EORTC 26981/22981 (TMZ/RT→TMZ) following surgery. Among these homogenously treated patients, lower absolute residual tumor volumes (in cm 3) were favorably associated with outcome: patients with 'maximal CE resection' (class 2) had superior outcome compared to patients with 'submaximal CE resection' (class 3) or 'biopsy' (class 4). Extensive resection of non-CE tumor (≤5 cm 3 residual non-CE tumor) was associated with better survival among patients with complete CE resection, thus defining class 1 ('supramaximal CE resection'). The prognostic value of the resection classes was retained on multivariate analysis when adjusting for molecular and clinical markers. CONCLUSIONS The proposed "RANO categories for extent of resection in glioblastoma" are highly prognostic and may serve for stratification within clinical trials. Removal of non-CE tumor beyond the CE tumor borders may translate into additional survival benefit, providing a rationale to explicitly denominate such 'supramaximal CE resection'.

We use high-resolution data from the millimetre-Wave Interferometric Survey of Dark Object Masses (WISDOM) project to investigate the connection between circumnuclear gas reservoirs and nuclear activity in a sample of nearby galaxies. Our sample spans a wide range of nuclear activity types including radio galaxies, Seyfert galaxies, low-luminosity active galactic nuclei (AGN) and inactive galaxies. We use measurements of nuclear millimetre continuum emission along with other archival tracers of AGN accretion/activity to investigate previous claims that at, circumnuclear scales (<100 pc), these should correlate with the mass of the cold molecular gas. We find that the molecular gas mass does not correlate with any tracer of nuclear activity. This suggests the level of nuclear activity cannot solely be regulated by the amount of cold gas around the supermassive black hole (SMBH). This indicates that AGN fuelling, that drives gas from the large scale galaxy to the nuclear regions, is not a ubiquitous process and may vary between AGN type, with timescale variations likely to be very important. By studying the structure of the central molecular gas reservoirs, we find our galaxies have a range of nuclear molecular gas concentrations. This could indicate that some of our galaxies may have had their circumnuclear regions impacted by AGN feedback, even though they currently have low nuclear activity. On the other hand, the nuclear molecular gas concentrations in our galaxies could instead be set by secular processes., Comment: 15 pages plus 3 in the appendix, 8 figures plus 1 in the appendix, 3 tables plus 4 in the appendix

The co-evolution of galaxies and supermassive black holes (SMBHs) underpins our understanding of galaxy evolution, but different methods to measure SMBH masses have only infrequently been cross-checked. We attempt to identify targets to cross-check two of the most accurate methods, megamaser and cold molecular gas dynamics. Three promising galaxies are selected from all those with existing megamaser SMBH mass measurements. We present Atacama Large Millimeter/sub-millimeter Array (ALMA) 12CO(2-1) and 230-GHz continuum observations with angular resolutions of about 0.5". Every galaxy has an extended rotating molecular gas disc and 230-GHz continuum source(s), but all also have irregularities and/or non-axisymmetric features: NGC1194 is highly inclined and has disturbed and lopsided central 12CO(2-1) emission; NGC3393 has a nuclear disc with fairly regular but patchy 12CO(2-1) emission with little gas near the kinematic major axis, faint emission in the very centre and two brighter structures reminiscent of a nuclear ring and/or spiral; NGC5765B has a strong bar and very bright 12CO(2-1) emission concentrated along two bisymmetric offset dust lanes and two bisymmetric nuclear spiral arms. 12CO(2-1) and 12CO(3-2) observations with the James Clerk Maxwell Telescope are compared with the ALMA observations. Because of the disturbed gas kinematics and the impractically long integration times required for higher angular resolution observations, none of the three galaxies is suitable for a future SMBH mass measurement. Nonetheless, increasing the number of molecular gas observations of megamaser galaxies is valuable, and the ubiquitous disturbances suggest a link between large-scale gas properties and the existence of megamasers., Comment: 17 pages, 5 figures, accepted by MNRAS

BACKGROUND: Vestibular schwannomas (VSs) related to neurofibromatosis type 2 (NF2) are challenging tumors. The increasing use of stereotactic radiosurgery (SRS) necessitates further investigations of its role and safety. OBJECTIVE: To evaluate tumor control, freedom from additional treatment (FFAT), serviceable hearing preservation, and radiation-related risks of patients with NF2 after SRS for VS.METHODS: We performed a retrospective study of 267 patients with NF2 (328 VSs) who underwent single-session SRS at 12 centers participating in the International Radiosurgery Research Foundation. The median patient age was 31 years (IQR, 21-45 years), and 52% were male. RESULTS: A total of 328 tumors underwent SRS during a median follow-up time of 59 months (IQR, 23-112 months). At 10 and 15 years, the tumor control rates were 77% (95% CI: 69%-84%) and 52% (95% CI: 40%-64%), respectively, and the FFAT rate were 85% (95% CI: 79%-90%) and 75% (95% CI: 65%-86%), respectively. At 5 and 10 years, the serviceable hearing preservation rates were 64% (95% CI: 55%-75%) and 35% (95% CI: 25%-54%), respectively. In the multivariate analysis, age (hazards ratio: 1.03 [95% CI: 1.01-1.05]; P= .02) and bilateral VSs (hazards ratio: 4.56 [95% CI: 1.05-19.78]; P= .04) were predictors for serviceable hearing loss. Neither radiation-induced tumors nor malignant transformation were encountered in this cohort. CONCLUSION: Although the absolute volumetric tumor progression rate was 48% at 15 years, the rate of FFAT related to VS was 75% at 15 years after SRS. None of the patients with NF2-related VS developed a new radiation-related neoplasm or malignant transformation after SRS., NA