Natural short-lived halogens exert an indirect cooling effect on climate.

Observational evidence shows the ubiquitous presence of ocean-emitted short-lived halogens in the global atmosphere1-3. Natural emissions of these chemical compounds have been anthropogenically amplified since pre-industrial times4-6, while, in addition, anthropogenic short-lived halocarbons are currently being emitted to the atmosphere7,8. Despite their widespread distribution in the atmosphere, the combined impact of these species on Earth's radiative balance remains unknown. Here we show that short-lived halogens exert a substantial indirect cooling effect at present (-0.13 ± 0.03 watts per square metre) that arises from halogen-mediated radiative perturbations of ozone (-0.24 ± 0.02 watts per square metre), compensated by those from methane (+0.09 ± 0.01 watts per square metre), aerosols (+0.03 ± 0.01 watts per square metre) and stratospheric water vapour (+0.011 ± 0.001 watts per square metre). Importantly, this substantial cooling effect has increased since 1750 by -0.05 ± 0.03 watts per square metre (61 per cent), driven by the anthropogenic amplification of natural halogen emissions, and is projected to change further (18-31 per cent by 2100) depending on climate warming projections and socioeconomic development. We conclude that the indirect radiative effect due to short-lived halogens should now be incorporated into climate models to provide a more realistic natural baseline of Earth's climate system.

Anthropogenic short-lived halogens increase human exposure to mercury contamination due to enhanced mercury oxidation over continents.

Mercury (Hg) is a contaminant of global concern, and an accurate understanding of its atmospheric fate is needed to assess its risks to humans and ecosystem health. Atmospheric oxidation of Hg is key to the deposition of this toxic metal to the Earth's surface. Short-lived halogens (SLHs) can provide halogen radicals to directly oxidize Hg and perturb the budget of other Hg oxidants (e.g., OH and O3). In addition to known ocean emissions of halogens, recent observational evidence has revealed abundant anthropogenic emissions of SLHs over continental areas. However, the impacts of anthropogenic SLHs emissions on the atmospheric fate of Hg and human exposure to Hg contamination remain unknown. Here, we show that the inclusion of anthropogenic SLHs substantially increased local Hg oxidation and, consequently, deposition in/near Hg continental source regions by up to 20%, thereby decreasing Hg export from source regions to clean environments. Our modeling results indicated that the inclusion of anthropogenic SLHs can lead to higher Hg exposure in/near Hg source regions than estimated in previous assessments, e.g., with increases of 8.7% and 7.5% in China and India, respectively, consequently leading to higher Hg-related human health risks. These results highlight the urgent need for policymakers to reduce local Hg and SLHs emissions. We conclude that the substantial impacts of anthropogenic SLHs emissions should be included in model assessments of the Hg budget and associated health risks at local and global scales.

Arctic halogens reduce ozone in the northern mid-latitudes.

While the dominant role of halogens in Arctic ozone loss during spring has been widely studied in the last decades, the impact of sea-ice halogens on surface ozone abundance over the northern hemisphere (NH) mid-latitudes remains unquantified. Here, we use a state-of-the-art global chemistry-climate model including polar halogens (Cl, Br, and I), which reproduces Arctic ozone seasonality, to show that Arctic sea-ice halogens reduce surface ozone in the NH mid-latitudes (47°N to 60°N) by ~11% during spring. This background ozone reduction follows the southward export of ozone-poor and halogen-rich air masses from the Arctic through polar front intrusions toward lower latitudes, reducing the springtime tropospheric ozone column within the NH mid-latitudes by ~4%. Our results also show that the present-day influence of Arctic halogens on surface ozone destruction is comparatively smaller than in preindustrial times driven by changes in the chemical interplay between anthropogenic pollution and natural halogens. We conclude that the impact of Arctic sea-ice halogens on NH mid-latitude ozone abundance should be incorporated into global models to improve the representation of ozone seasonality.

Photocatalytic chlorine atom production on mineral dust-sea spray aerosols over the North Atlantic.

Active chlorine in the atmosphere is poorly constrained and so is its role in the oxidation of the potent greenhouse gas methane, causing uncertainty in global methane budgets. We propose a photocatalytic mechanism for chlorine atom production that occurs when Sahara dust mixes with sea spray aerosol. The mechanism is validated by implementation in a global atmospheric model and thereby explaining the episodic, seasonal, and location-dependent 13C depletion in CO in air samples from Barbados [J.E. Mak, G. Kra, T. Sandomenico, P. Bergamaschi, J. Geophys. Res. Atmos. 108 (2003)], which remained unexplained for decades. The production of Cl can also explain the anomaly in the CO:ethane ratio found at Cape Verde [K. A. Read et al., J. Geophys. Res. Atmos. 114 (2009)], in addition to explaining the observation of elevated HOCl [M. J. Lawler et al., Atmos. Chem. Phys. 11, 7617-7628 (2011)]. Our model finds that 3.8 Tg(Cl) y-1 is produced over the North Atlantic, making it the dominant source of chlorine in the region; globally, chlorine production increases by 41%. The shift in the methane sink budget due to the increased role of Cl means that isotope-constrained top-down models fail to allocate 12 Tg y-1 (2% of total methane emissions) to 13C-depleted biological sources such as agriculture and wetlands. Since 2014, an increase in North African dust emissions has increased the 13C isotope of atmospheric CH4, thereby partially masking a much greater decline in this isotope, which has implications for the interpretation of the drivers behind the recent increase of methane in the atmosphere.

The influence of iodine on the Antarctic stratospheric ozone hole.

The catalytic depletion of Antarctic stratospheric ozone is linked to anthropogenic emissions of chlorine and bromine. Despite its larger ozone-depleting efficiency, the contribution of ocean-emitted iodine to ozone hole chemistry has not been evaluated, due to the negligible iodine levels previously reported to reach the stratosphere. Based on the recently observed range (0.77 ± 0.1 parts per trillion by volume [pptv]) of stratospheric iodine injection, we use the Whole Atmosphere Community Climate Model to assess the role of iodine in the formation and recent past evolution of the Antarctic ozone hole. Our 1980-2015 simulations indicate that iodine can significantly impact the lower part of the Antarctic ozone hole, contributing, on average, 10% of the lower stratospheric ozone loss during spring (up to 4.2% of the total stratospheric column). We find that the inclusion of iodine advances the beginning and delays the closure stages of the ozone hole by 3 d to 5 d, increasing its area and mass deficit by 11% and 20%, respectively. Despite being present in much smaller amounts, and due to faster gas-phase photochemical reactivation, iodine can dominate (∼73%) the halogen-mediated lower stratospheric ozone loss during summer and early fall, when the heterogeneous reactivation of inorganic chlorine and bromine reservoirs is reduced. The stratospheric ozone destruction caused by 0.77 pptv of iodine over Antarctica is equivalent to that of 3.1 (4.6) pptv of biogenic very short-lived bromocarbons during spring (rest of sunlit period). The relative contribution of iodine to future stratospheric ozone loss is likely to increase as anthropogenic chlorine and bromine emissions decline following the Montreal Protocol.

Metabolic shift underlies tumor progression and immune evasion in S-nitrosoglutathione reductase-deficient cancer.

S-nitrosoglutathione reductase (GSNOR) is a denitrosylase enzyme that has been suggested to play a tumor suppressor role, although the mechanisms responsible are still largely unclear. In this study, we show that GSNOR deficiency in tumors is associated with poor prognostic histopathological features and poor survival in patients with colorectal cancer (CRC). GSNOR-low tumors were characterized by an immunosuppressive microenvironment with exclusion of cytotoxic CD8+ T cells. Notably, GSNOR-low tumors exhibited an immune evasive proteomic signature along with an altered energy metabolism characterized by impaired oxidative phosphorylation (OXPHOS) and energetic dependence on glycolytic activity. CRISPR-Cas9-mediated generation of GSNOR gene knockout (KO) CRC cells confirmed in vitro and in vivo that GSNOR-deficiency conferred higher tumorigenic and tumor-initiating capacities. Moreover, GSNOR-KO cells possessed enhanced immune evasive properties and resistance to immunotherapy, as revealed following xenografting them into humanized mouse models. Importantly, GSNOR-KO cells were characterized by a metabolic shift from OXPHOS to glycolysis to produce energy, as indicated by increased lactate secretion, higher sensitivity to 2-deoxyglucose (2DG), and a fragmented mitochondrial network. Real-time metabolic analysis revealed that GSNOR-KO cells operated close to their maximal glycolytic rate, as a compensation for lower OXPHOS levels, explaining their higher sensitivity to 2DG. Remarkably, this higher susceptibility to glycolysis inhibition with 2DG was validated in patient-derived xenografts and organoids from clinical GSNOR-low tumors. In conclusion, our data support the idea that metabolic reprogramming induced by GSNOR deficiency is an important mechanism for tumor progression and immune evasion in CRC and that the metabolic vulnerabilities associated with the deficiency of this denitrosylase can be exploited therapeutically. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Flow starvation during square-flow assisted ventilation detected by supervised deep learning techniques.

BACKGROUND: Flow starvation is a type of patient-ventilator asynchrony that occurs when gas delivery does not fully meet the patients' ventilatory demand due to an insufficient airflow and/or a high inspiratory effort, and it is usually identified by visual inspection of airway pressure waveform. Clinical diagnosis is cumbersome and prone to underdiagnosis, being an opportunity for artificial intelligence. Our objective is to develop a supervised artificial intelligence algorithm for identifying airway pressure deformation during square-flow assisted ventilation and patient-triggered breaths. METHODS: Multicenter, observational study. Adult critically ill patients under mechanical ventilation > 24 h on square-flow assisted ventilation were included. As the reference, 5 intensive care experts classified airway pressure deformation severity. Convolutional neural network and recurrent neural network models were trained and evaluated using accuracy, precision, recall and F1 score. In a subgroup of patients with esophageal pressure measurement (ΔPes), we analyzed the association between the intensity of the inspiratory effort and the airway pressure deformation. RESULTS: 6428 breaths from 28 patients were analyzed, 42% were classified as having normal-mild, 23% moderate, and 34% severe airway pressure deformation. The accuracy of recurrent neural network algorithm and convolutional neural network were 87.9% [87.6-88.3], and 86.8% [86.6-87.4], respectively. Double triggering appeared in 8.8% of breaths, always in the presence of severe airway pressure deformation. The subgroup analysis demonstrated that 74.4% of breaths classified as severe airway pressure deformation had a ΔPes > 10 cmH2O and 37.2% a ΔPes > 15 cmH2O. CONCLUSIONS: Recurrent neural network model appears excellent to identify airway pressure deformation due to flow starvation. It could be used as a real-time, 24-h bedside monitoring tool to minimize unrecognized periods of inappropriate patient-ventilator interaction.

Characterization of postintensive care syndrome in a prospective cohort of survivors of COVID-19 critical illness: a 12-month follow-up study.

PURPOSE: Studies integrating an exhaustive longitudinal long-term follow-up of postintensive care syndrome (PICS) in critically ill COVID-19 survivors are scarce. We aimed to 1) describe PICS-related sequelae over a 12-month period after intensive care unit (ICU) discharge, 2) identify relevant demographic and clinical factors related to PICS, and 3) explore how PICS-related sequelae may influence health-related quality of life (HRQoL) in critically ill COVID-19 survivors. METHODS: We conducted a prospective cohort study in adult critically ill survivors of SARS-CoV-2 infection that did or did not need invasive mechanical ventilation (IMV) during the COVID-19 pandemic in Spain (March 2020 to January 2021). We performed a telemedicine follow-up of PICS-related sequelae (physical/functional, cognitive, and mental health) and HRQoL with five data collection points. We retrospectively collected demographic and clinical data. We used multivariable mixed-effects models for data analysis. RESULTS: We included 142 study participants in the final analysis, with a median [interquartile range] age of 61 [53-68] yr; 35% were female and 59% needed IMV. Fatigue/dyspnea, pain, impaired muscle function, psychiatric symptomatology and reduced physical HRQoL were prominent sequelae early after ICU discharge. Over the 12-month follow-up, functionality and fatigue/dyspnea improved progressively, while pain remained stable. We observed slight fluctuations in anxiety symptoms and perception of cognitive deficit, whereas posttraumatic stress disorder (PTSD) and depressive symptoms improved, with a mild rebound at the end of the follow-up. Female sex, younger age, and the need for IMV were risk factors for PICS, while having higher cognitive reserve was a potential protective factor. Physical HRQoL scores showed a general improvement over time, whereas mental HRQoL remained stable. Shorter ICU stay, better functionality, and lower scores for fatigue/dyspnea and pain were associated with better physical HRQoL, while lower scores for anxiety, depression, and PTSD were associated with better mental HRQoL. CONCLUSIONS: Postintensive care syndrome was common in COVID-19 critical illness survivors and persisted in a significant proportion of patients one year after ICU discharge, impacting HRQoL. The presence of risk factors for PICS may identify patients who are more likely to develop the condition and who would benefit from more specific and closer follow-up after ICU admission. STUDY REGISTRATION: ClinicalTrials.gov ( NCT04422444 ); first submitted 9 June 2020.

RéSUMé: OBJECTIF: Les études intégrant un suivi longitudinal exhaustif à long terme des syndromes post-soins intensifs (SPSI) chez les survivant·es gravement malades de la COVID-19 sont rares. Notre objectif était 1) de décrire les séquelles liées au SPSI sur une période de 12 mois après la sortie de l'unité de soins intensifs (USI), 2) d'identifier les facteurs démographiques et cliniques pertinents liés au SPSI, et 3) d'explorer comment les séquelles liées au SPSI peuvent influencer la qualité de vie liée à la santé (QVLS) chez les survivant·es gravement malades de la COVID-19. MéTHODE: Nous avons mené une étude de cohorte prospective chez des adultes gravement malades survivant·es d'une infection par le SRAS-CoV-2 qui ont eu ou non besoin d'une ventilation mécanique invasive (VMI) pendant la pandémie de COVID-19 en Espagne (mars 2020 à janvier 2021). Nous avons effectué un suivi par télémédecine des séquelles liées au SPSI (santé physique/fonctionnelle, cognitive et mentale) et à la QVLS avec cinq points de collecte de données. Nous avons rétrospectivement colligé des données démographiques et cliniques. Des modèles multivariés à effets mixtes ont été utilisés pour l'analyse des données. RéSULTATS: Nous avons inclus 142 participant·es à l'étude dans l'analyse finale, avec un âge médian [intervalle interquartile] de 61 [53-68] ans; 35 % étaient des femmes et 59 % avaient besoin de VMI. La fatigue/dyspnée, la douleur, l'altération de la fonction musculaire, la symptomatologie psychiatrique et la réduction de la QVLS physique étaient des séquelles importantes peu après la sortie de l'USI. Au cours du suivi de 12 mois, la fonctionnalité et la fatigue/dyspnée se sont améliorées progressivement, tandis que la douleur est restée stable. Nous avons observé de légères fluctuations des symptômes d'anxiété et de perception du déficit cognitif, tandis que le trouble de stress post-traumatique (ESPT) et les symptômes dépressifs se sont améliorés, avec un léger rebond à la fin du suivi. Le sexe féminin, un jeune âge et le besoin de VMI étaient des facteurs de risque de SPSI, tandis qu'une réserve cognitive plus élevée était un facteur potentiel de protection. Les scores physiques de la QVLS ont montré une amélioration générale au fil du temps, tandis que la QVLS mentale est restée stable. Un séjour plus court aux soins intensifs, une meilleure fonctionnalité et des scores plus faibles pour la fatigue/dyspnée et la douleur étaient associés à une meilleure QVLS physique, tandis que des scores plus faibles pour l'anxiété, la dépression et le ESPT étaient associés à une meilleure QVLS mentale. CONCLUSION: Le syndrome post-soins intensifs était fréquent chez les survivant·es d'une maladie grave de la COVID-19 et a persisté chez une proportion importante de patient·es un an après leur sortie de l'unité de soins intensifs, ce qui a eu un impact sur la QVLS. La présence de facteurs de risque de SPSI peut identifier les patient·es qui sont plus susceptibles de développer la maladie et qui bénéficieraient d'un suivi plus spécifique et plus étroit après leur admission aux soins intensifs. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov ( NCT04422444 ); première soumission le 9 juin 2020.

Cereblon enhancer methylation and IMiD resistance in multiple myeloma.

Cereblon is the direct binding target of the immunomodulatory drugs (IMiDs) that are commonly used to treat multiple myeloma (MM), the second most frequent hematologic malignancy. Patients respond well to initial treatment with IMiDs, but virtually all patients develop drug resistance over time, and the underlying mechanisms are poorly understood. We identified an as yet undescribed DNA hypermethylation in an active intronic CRBN enhancer. Differential hypermethylation in this region was found to be increased in healthy plasma cells, but was more pronounced in IMiD-refractory MM. Methylation significantly correlated with decreased CRBN expression levels. DNA methyltransferase inhibitor (DNTMi) in vitro experiments induced CRBN enhancer demethylation, and sensitizing effects on lenalidomide treatment were observed in 2 MM cell lines. Thus, we provide first evidence that aberrant CRBN DNA methylation is a novel mechanism of IMiD resistance in MM and may predict IMiD response prior to treatment.

Objective and subjective cognition in survivors of COVID-19 one year after ICU discharge: the role of demographic, clinical, and emotional factors.

BACKGROUND: Intensive Care Unit (ICU) COVID-19 survivors may present long-term cognitive and emotional difficulties after hospital discharge. This study aims to characterize the neuropsychological dysfunction of COVID-19 survivors 12 months after ICU discharge, and to study whether the use of a measure of perceived cognitive deficit allows the detection of objective cognitive impairment. We also explore the relationship between demographic, clinical and emotional factors, and both objective and subjective cognitive deficits. METHODS: Critically ill COVID-19 survivors from two medical ICUs underwent cognitive and emotional assessment one year after discharge. The perception of cognitive deficit and emotional state was screened through self-rated questionnaires (Perceived Deficits Questionnaire, Hospital Anxiety and Depression Scale and Davidson Trauma Scale), and a comprehensive neuropsychological evaluation was carried out. Demographic and clinical data from ICU admission were collected retrospectively. RESULTS: Out of eighty participants included in the final analysis, 31.3% were women, 61.3% received mechanical ventilation and the median age of patients was 60.73 years. Objective cognitive impairment was observed in 30% of COVID-19 survivors. The worst performance was detected in executive functions, processing speed and recognition memory. Almost one in three patients manifested cognitive complaints, and 22.5%, 26.3% and 27.5% reported anxiety, depression and post-traumatic stress disorder (PTSD) symptoms, respectively. No significant differences were found in the perception of cognitive deficit between patients with and without objective cognitive impairment. Gender and PTSD symptomatology were significantly associated with perceived cognitive deficit, and cognitive reserve with objective cognitive impairment. CONCLUSIONS: One-third of COVID-19 survivors suffered objective cognitive impairment with a frontal-subcortical dysfunction 12 months after ICU discharge. Emotional disturbances and perceived cognitive deficits were common. Female gender and PTSD symptoms emerged as predictive factors for perceiving worse cognitive performance. Cognitive reserve emerged as a protective factor for objective cognitive functioning. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04422444; June 9, 2021.

Serially improved GTOs for molecular applications (SIGMA): Basis sets from H to Ne.

A new approach for generating Gaussian basis sets is reported and tested for atoms from H to Ne. The basis sets thus calculated, named SIGMA basis sets, range from DZ to QZ sizes and have the same composition per shell as Dunning basis sets but with different treatment of the contractions. The standard SIGMA basis sets and their augmented versions have proven to be very suitable for providing good results in atomic and molecular calculations. The performance of the new basis sets is analyzed in terms of total, correlation, and atomization energies, equilibrium distances, and vibrational frequencies in several molecules, and the results are compared at several computational levels with those obtained with the corresponding Dunning and other basis sets.

Accurate Hellmann-Feynman forces from density functional calculations with augmented Gaussian basis sets.

The Hellmann-Feynman (HF) theorem provides a way to compute forces directly from the electron density, enabling efficient force calculations for large systems through machine learning (ML) models for the electron density. The main issue holding back the general acceptance of the HF approach for atom-centered basis sets is the well-known Pulay force which, if naively discarded, typically constitutes an error upward of 10 eV/Å in forces. In this work, we demonstrate that if a suitably augmented Gaussian basis set is used for density functional calculations, the Pulay force can be suppressed, and HF forces can be computed as accurately as analytical forces with state-of-the-art basis sets, allowing geometry optimization and molecular dynamics to be reliably performed with HF forces. Our results pave a clear path forward for the accurate and efficient simulation of large systems using ML densities and the HF theorem.

Quantitative detection of iodine in the stratosphere.

Oceanic emissions of iodine destroy ozone, modify oxidative capacity, and can form new particles in the troposphere. However, the impact of iodine in the stratosphere is highly uncertain due to the lack of previous quantitative measurements. Here, we report quantitative measurements of iodine monoxide radicals and particulate iodine (Iy,part) from aircraft in the stratosphere. These measurements support that 0.77 ± 0.10 parts per trillion by volume (pptv) total inorganic iodine (Iy) is injected to the stratosphere. These high Iy amounts are indicative of active iodine recycling on ice in the upper troposphere (UT), support the upper end of recent Iy estimates (0 to 0.8 pptv) by the World Meteorological Organization, and are incompatible with zero stratospheric iodine injection. Gas-phase iodine (Iy,gas) in the UT (0.67 ± 0.09 pptv) converts to Iy,part sharply near the tropopause. In the stratosphere, IO radicals remain detectable (0.06 ± 0.03 pptv), indicating persistent Iy,part recycling back to Iy,gas as a result of active multiphase chemistry. At the observed levels, iodine is responsible for 32% of the halogen-induced ozone loss (bromine 40%, chlorine 28%), due primarily to previously unconsidered heterogeneous chemistry. Anthropogenic (pollution) ozone has increased iodine emissions since preindustrial times (ca. factor of 3 since 1950) and could be partly responsible for the continued decrease of ozone in the lower stratosphere. Increasing iodine emissions have implications for ozone radiative forcing and possibly new particle formation near the tropopause.

The Effect of Clusters of Double Triggering and Ineffective Efforts in Critically Ill Patients.

OBJECTIVES: To characterize clusters of double triggering and ineffective inspiratory efforts throughout mechanical ventilation and investigate their associations with mortality and duration of ICU stay and mechanical ventilation. DESIGN: Registry-based, real-world study. BACKGROUND: Asynchronies during invasive mechanical ventilation can occur as isolated events or in clusters and might be related to clinical outcomes. SUBJECTS: Adults requiring mechanical ventilation greater than 24 hours for whom greater than or equal to 70% of ventilator waveforms were available. INTERVENTIONS: We identified clusters of double triggering and ineffective inspiratory efforts and determined their power and duration. We used Fine-Gray's competing risk model to analyze their effects on mortality and generalized linear models to analyze their effects on duration of mechanical ventilation and ICU stay. MEASUREMENTS AND MAIN RESULTS: We analyzed 58,625,796 breaths from 180 patients. All patients had clusters (mean/d, 8.2 [5.4-10.6]; mean power, 54.5 [29.6-111.4]; mean duration, 20.3 min [12.2-34.9 min]). Clusters were less frequent during the first 48 hours (5.5 [2.5-10] vs 7.6 [4.4-9.9] in the remaining period [p = 0.027]). Total number of clusters/d was positively associated with the probability of being discharged alive considering the total period of mechanical ventilation (p = 0.001). Power and duration were similar in the two periods. Power was associated with the probability of being discharged dead (p = 0.03), longer mechanical ventilation (p < 0.001), and longer ICU stay (p = 0.035); cluster duration was associated with longer ICU stay (p = 0.027). CONCLUSIONS: Clusters of double triggering and ineffective inspiratory efforts are common. Although higher numbers of clusters might indicate better chances of survival, clusters with greater power and duration indicate a risk of worse clinical outcomes.

A mass spectrometry-based proteome map of drug action in lung cancer cell lines.

Mass spectrometry-based discovery proteomics is an essential tool for the proximal readout of cellular drug action. Here, we apply a robust proteomic workflow to rapidly profile the proteomes of five lung cancer cell lines in response to more than 50 drugs. Integration of millions of quantitative protein-drug associations substantially improved the mechanism of action (MoA) deconvolution of single compounds. For example, MoA specificity increased after removal of proteins that frequently responded to drugs and the aggregation of proteome changes across cell lines resolved compound effects on proteostasis. We leveraged these findings to demonstrate efficient target identification of chemical protein degraders. Aggregating drug response across cell lines also revealed that one-quarter of compounds modulated the abundance of one of their known protein targets. Finally, the proteomic data led us to discover that inhibition of mitochondrial function is an off-target mechanism of the MAP2K1/2 inhibitor PD184352 and that the ALK inhibitor ceritinib modulates autophagy.

Publisher Correction: A mass spectrometry-based proteome map of drug action in lung cancer cell lines.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Phosphine Ligand Binding and Catalytic Activity of Group 10-14 Heterobimetallic Complexes.

Heterobimetallic complexes have attracted much interest due to their broad range of structures and reactivities as well as unique catalytic abilities. Additionally, these complexes can be utilized as single-source precursors for the synthesis of binary intermetallic compounds. An example is the family of bis(pyridine-2-thiolato)dichloro-germanium and tin complexes of group 10 metals (Pd and Pt). The reactivity of these heterobimetallic complexes is highly tunable through substitution of the group 14 element and the neutral ligand bound to the transition metal. Here, we study the binding energies of three different phosphorous-based ligands, PR3 (R = Bu, Ph, and OPh) by density functional theory and restricted Hartree-Fock methods. The PR3 ligand-binding energies follow the trend of PBu3 > PPh3 > P(OPh)3, in agreement with their sigma-bonding ability. These results are confirmed by ligand exchange experiments monitored with 31P NMR spectroscopy, in which a weaker binding PR3 ligand is replaced with a stronger one. Furthermore, we demonstrate that the heterobimetallic complexes are active catalysts in the Negishi coupling reaction, where stronger binding PR3 ligands inhibit access to an active site at the metal center. Similar strategies could be applied to other complexes to better understand their ligand-binding energetics and predict their reactivity as both precursors and catalysts.

Role of Iodine Recycling on Sea-Salt Aerosols in the Global Marine Boundary Layer.

Heterogeneous uptake of hypoiodous acid (HOI), the dominant inorganic iodine species in the marine boundary layer (MBL), on sea-salt aerosol (SSA) to form iodine monobromide and iodine monochloride has been adopted in models with assumed efficiency. Recently, field measurements have reported a much faster rate of this recycling process than previously assumed in models. Here, we conduct global model simulations to quantify the range of effects of iodine recycling within the MBL, using Conventional, Updated, and Upper-limit coefficients. When considering the Updated coefficient, iodine recycling significantly enhances gaseous inorganic iodine abundance (∼40%), increases halogen atom production rates (∼40% in I, >100% in Br, and ∼60% in Cl), and reduces oxidant levels (-7% in O3, -2% in OH, and -4% in HO2) compared to the simulation without the process. We appeal for further direct measurements of iodine species, laboratory experiments on the controlling factors, and multiscale simulations of iodine heterogeneous recycling.

Intra- or peri-procedural rupture in the endovascular treatment of intracranial aneurysms.

INTRODUCTION: Intra- or peri-procedural aneurysm rupture is one of the most feared adverse effects associated with embolization. Our aim was to report the characteristics of patients suffering intra- or peri-procedural ruptures during embolization of cerebral aneurysms. PATIENTS AND METHODS: Between March 1994 and October 2021, 648 consecutive cerebral aneurysms were treated by endovascular procedure at our facility. Medical records were reviewed retrospectively with emphasis on procedure description, potential risk factors, and clinical outcomes related to intra- or peri-procedural rupture. RESULTS: Of the 648 patients, 17 (2.6%) suffered an intra- or peri-procedural hemorrhagic event. The most common location was the anterior communicating artery. There was no significant difference between previously ruptured and unruptured aneurysms in the incidence of bleeding. In four patients, bleeding was evident within 24 h after the procedure. The clinical evolution at three months was poor and only four patients presented a positive evolution. There were 11 deaths (64.71%). Balloon remodeling was associated with an increased frequency of ruptures, while stenting was a safer treatment. CONCLUSION: Aneurysmal rupture during endovascular therapy is unpredictable, and its occurrence can be devastating. The incidence is quite low although the outcome is frequently poor. Early detection and proper management, including prompt occlusion of the aneurysm, are important to achieve a positive outcome. Anterior communicating artery aneurysms and those treated with balloon catheters have a higher incidence of rupture. A small number of ruptures of uncertain origin occur that go unnoticed in digital subtraction angiograms.

Non-invasive oxygenation support in acutely hypoxemic COVID-19 patients admitted to the ICU: a multicenter observational retrospective study.

BACKGROUND: Non-invasive oxygenation strategies have a prominent role in the treatment of acute hypoxemic respiratory failure during the coronavirus disease 2019 (COVID-19). While the efficacy of these therapies has been studied in hospitalized patients with COVID-19, the clinical outcomes associated with oxygen masks, high-flow oxygen therapy by nasal cannula and non-invasive mechanical ventilation in critically ill intensive care unit (ICU) patients remain unclear. METHODS: In this retrospective study, we used the best of nine covariate balancing algorithms on all baseline covariates in critically ill COVID-19 patients supported with > 10 L of supplemental oxygen at one of the 26 participating ICUs in Catalonia, Spain, between March 14 and April 15, 2020. RESULTS: Of the 1093 non-invasively oxygenated patients at ICU admission treated with one of the three stand-alone non-invasive oxygenation strategies, 897 (82%) required endotracheal intubation and 310 (28%) died during the ICU stay. High-flow oxygen therapy by nasal cannula (n = 439) and non-invasive mechanical ventilation (n = 101) were associated with a lower rate of endotracheal intubation (70% and 88%, respectively) than oxygen masks (n = 553 and 91% intubated), p < 0.001. Compared to oxygen masks, high-flow oxygen therapy by nasal cannula was associated with lower ICU mortality (hazard ratio 0.75 [95% CI 0.58-0.98), and the hazard ratio for ICU mortality was 1.21 [95% CI 0.80-1.83] for non-invasive mechanical ventilation. CONCLUSION: In critically ill COVID-19 ICU patients and, in the absence of conclusive data, high-flow oxygen therapy by nasal cannula may be the approach of choice as the primary non-invasive oxygenation support strategy.