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Ensemble-based optimization (EnOpt), commonly used in reservoir management, can be seen as a special case of a natural evolution algorithm. Stein’s lemma gives a new interpretation of EnOpt. This interpretation enables us to study EnOpt in the context of general mutation distributions. In this paper, a non-Gaussian generalization of EnOpt (GenOpt) is proposed, where the control gradient is estimated using Stein’s lemma, and the mutation distribution is updated separately via natural evolution. For the multivariate case, a Gaussian copula is used to represent dependencies between the marginals. The correlation matrix is also iteratively optimized. It is shown that using beta distributions as marginals in the GenOpt algorithm addresses the truncation problem that sometimes arises when applying EnOpt on bounded optimization problems. The performance of the proposed optimization algorithm is evaluated on several test cases. The experiments indicate that GenOpt is less dependent on the chosen hyperparameters, and it is able to converge more quickly than EnOpt on a reservoir management test case.

Un homme de 48 ans atteint de trisomie 21 a ete transfere dans notre service de cardiologie en raison d'une dyspnee aigue. A l'arrivee, il presentait une pression arterielle de [...]

A 48-year-old man with trisomy 21 was transferred to our cardiology service because of acute dyspnea. At presentation, his blood pressure was 70/50 mm Hg, with a heart rate of [...]

Zusammenfassung: Passivrauchen ist weltweit die drittwichtigste vermeidbare Todesursache. Eine Passivrauchbelastung geht einher mit vermehrten obstruktiven Atemwegserkrankungen, Lungenkarzinomen und kardiovaskulären Erkrankungen. Bezüglich Atemwegserkrankungen zeigen sich überwiegend lineare Dosis-Wirkungs-Beziehungen, während bei den Herz-Kreislauf-Erkrankungen die Zusammenhänge nichtlinear sind. Es konnte vielfach gezeigt werden, dass sich passivrauchbedingte Morbidität und Mortalität durch öffentliche Rauchverbote deutlich reduzieren lassen.

ObjectiveTo assess the impact of COVID-19 on the palliative care (PC) publication trend in the last 10 years and the collaboration between countries and main topics that were discussed in the papers.MethodsWe used Scopus to identify publications on PC between 2012 and 2021 and publications about PC and COVID-19 between 2020 and 2021. We used VOSviewer to assess the main topics using the keywords from the papers and to assess country collaboration.Results1937 publications resulted. An increase in publications about PC was observed during the pandemic, only partially explained by OVID-19-related publications. Cancer-related PC publications were the ones with the most marked increase. We identified six clusters in the distribution of the keywords: bioethics, cancer, nursing home/telemedicine, public health, caring and PC following the WHO definition. The countries with higher number of publications were the United States and England.ConclusionWe showed an increase in the number of PC publications in the last 2 years that was only partially explained by COVID-19-related publications. Most of the publications increase was due to cancer-related publications, since, during the time of the pandemic, publications on cancer and PC increased markedly, while those on heart failure, lung disease and dementia, remained constant.

Abstract.Background:The enzyme glyoxalase1 (GLO1) is the main opponent in the degradation of the reactive metabolite methylglyoxal (MG), which by glycation of macromolecules is involved in atherogenesis. Reduced GLO1-activity in atherosclerotic tissue is known to be associated with diabetes. It has been shown that treatment of patients with type 2 diabetes with metformin leads to increased GLO1-activity in peripheral-blood-cells. The aim of this study was to evaluate whether metformin treatment increases GLO1-activity in atherosclerotic lesions of patients with type 2 diabetes. Patients and methods:Patients with type 2 diabetes and carotid artery disease were included into the study prospectively. Type of diabetes-medication was documented upon admission along with demographic and clinical history. Using shock frozen endarterectomy-derived carotid artery plaques, GLO1-activity as well as protein expression was measured by a spectophotometric assay and western-blotting respectively. Results:33 patients (76 % male, mean age 71 years) were included into the study and were divided according to treatment with metformin or not (15 vs. 18 patients). GLO1-activity was increased by the factor 1.36 when treated with metformin – however, not significantly (0.86 vs. 0.63 U/mg, p = 0.056). Normalisation of GLO1-activity onto GLO1-expression level lead to a significant increase by more than twofold (8.48 vs. 3.85, p = 0.044) while GLO1-protein levels did not differ significantly. GLO1-activity correlated positively with increasing HbA1c, especially under metformin treatment. Conclusions:Treatment with metformin in patients with type 2 diabetes is associated with enhanced GLO1-activity in atherosclerotic lesions. Regarding the macro- and microvascular complications in these patients further studies are needed to gain more insight into the effect of metformin on the GLO/MG system.

Atrial fibrillation (AF) and cancer often co-exist. Each has been associated with an increased risk of morbidity and mortality. The aim of this meta-analysis was to synthesize available data regarding the incidence of arterial thromboembolism (TE), bleeding, and all-cause mortality in patients with AF with or without cancer.

1,2,6-Thiadiazines treated with visible light and 3O2under ambient conditions are converted into difficult-to-access 1,2,5-thiadiazole 1-oxides (35 examples, yields of 39–100%). Experimental and theoretical studies reveal that 1,2,6-thiadiazines act as triplet photosensitizers that produce 1O2and then undergo a chemoselective [3 + 2] cycloaddition to give an endoperoxide that ring contracts with selective carbon atom excision and complete atom economy. The reaction was optimized under both batch and continuous-flow conditions and is also efficient in green solvents.

Drying of binary sessile droplets consisting of ethanol and octamethyltrisiloxane on a high-energy surface is investigated. During the process of evaporation, the droplets undergo liquid–liquid phase separation, resulting in the appearance of microdroplets at the liquid–air interface, which subsequently violently burst. This phase separation is attributed to water vapor transfer into the droplet, which modifies the solubility and leads to the formation of a ternary mixture. The newly formed ternary mixture may undergo nucleation and growth or spinodal decomposition, depending on the droplet composition path. By control of the relative humidity of air, phase separation can be mitigated or even eliminated. The droplets also display high mobility and complex wetting behavior due to phase separation, with two contracting and two spreading stages. The mass loss experiments reveal that the droplets undergo three distinct drying stages with an enhanced evaporation rate observed during the phase separation stage. A modified diffusion-limited model was employed to predict the evaporation rate, accounting for the physiochemical changes during evaporation and proved to be consistent with experimental observations. The findings of this work enhance our understanding of a coupled fundamental process involving the evaporation of multicomponent mixtures, wetting, and phase separation.

Vapor–liquid equilibria (VLE) of binary systems consisting of nitrogen and an n-alkane (n-tridecane, n-pentadecane, n-hexadecane, or n-heptadecane) were measured at a temperature range of T= 303–633 K and pressure range of p= 1.5–9 MPa. A microcapillary setup was employed, which was coupled with an in situ Raman spectroscopy unit. Calibration was performed inside the unsaturated vapor and liquid phase regime in order to link the Raman signal ratios of the saturated vapor and liquid phase spectra to mole fractions. Regarding the Raman evaluation of the saturated vapor phase spectra, a signal contribution from a liquid film can be successfully corrected by an indirect hard modeling (IHM) approach. The obtained experimental data of the binary system n-hexadecane/nitrogen were validated with the available literature data, where good agreement was found. By comparing the saturated compositions between the different binary systems, only small differences could be observed for the saturated liquid phase, while the compositions of the saturated vapor phase clearly deviated from each other. Moreover, the experimental results of all binary systems were compared with the calculated data obtained from different models: the predictive Peng-Robinson equation of state (PPR78) and the perturbed-chain statistical associating fluid theory (PC-SAFT). The data can be well described by the models, with the absolute average deviation (AAD) that is generally higher for the saturated vapor phase compared with the saturated liquid phase.

The development of transgenic mouse models that express genes of interest in specific cell types has transformed our understanding of basic biology and disease. However, generating these models is time- and resource-intensive. Here we describe a model system, SELective Expression and Controlled Transduction In Vivo (SELECTIV), that enables efficient and specific expression of transgenes by coupling adeno-associated virus (AAV) vectors with Cre-inducible overexpression of the multi-serotype AAV receptor, AAVR. We demonstrate that transgenic AAVR overexpression greatly increases the efficiency of transduction of many diverse cell types, including muscle stem cells, which are normally refractory to AAV transduction. Superior specificity is achieved by combining Cre-mediated AAVR overexpression with whole-body knockout of endogenous Aavr, which is demonstrated in heart cardiomyocytes, liver hepatocytes and cholinergic neurons. The enhanced efficacy and exquisite specificity of SELECTIV has broad utility in development of new mouse model systems and expands the use of AAV for gene delivery in vivo.

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How do mitochondrial organelles remove damaged parts of inner membrane for recycling in the cytoplasm? The discovery of an exit route that flips inner membrane outside the organelle provides some answers.

Supplemental Digital Content is Available in the Text.Heart failure (HF) and atrial fibrillation (AF) commonly coexist in real-life clinical practice. Among patients with HF with reduced ejection fraction (HFrEF) or HF with mildly reduced ejection fraction (HFmrEF), guidelines call for evidence-based target doses of renin–angiotensin–aldosterone system inhibitors and beta-blockers. However, target doses of guideline-directed medical treatment (GDMT) are often underused in real-world conditions, including HF–AF comorbidity. This retrospective cohort study of a randomized trial (Motivational Interviewing to Support Oral AntiCoagulation adherence in patients with nonvalvular AF) included hospitalized patients with AF and HFrEF or HFmrEF. Optimally targeted GDMT was defined as intake of evidence-based target doses of renin–angiotensin–aldosterone system and beta-blockers at 3 months after discharge. Rates of optimally targeted GDMT achievement across the baseline estimated glomerular filtration rate (eGFR) were assessed. Independent predictors of nontargeted GDMT and its association with all-cause mortality and the composite of cardiovascular death or HF hospitalization were assessed by regression analyses. In total, 374 patients with AF and HFrEF or HFmrEF were studied. At 3 months after discharge, 30.7% received target doses of GDMT medications. The rate of optimally targeted GDMT was reduced by 11% for every 10 mg/min/1.73 m2decrease in baseline eGFR [adjusted β = 0.99; 95% confidence interval (CI), 0.98–0.99] levels. After a median 31-month follow-up period, 37.8% patients in the optimally targeted GDMT group died, as compared with 67.8% (adjusted hazard ratio: 1.49; 95% CI, 1.05–2.13) in the nontargeted GDMT group. The risk of cardiovascular death or HF hospitalization was also higher in these patients (adjusted hazard ratio: 1.60; 95% CI, 1.17–2.20). Target doses of all HF drugs were reached in roughly one-third of patients with AF and HFrEF or HFmrEF 3 months after hospital discharge. Nontargeted GDMT was more frequent across lower eGFR levels and was associated with worse outcomes.

Impaired proinsulin-to-insulin processing in pancreatic β-cells is a key defective step in both type 1 diabetes and type 2 diabetes (T2D) (refs. 1,2), but the mechanisms involved remain to be defined. Altered metabolism of sphingolipids (SLs) has been linked to development of obesity, type 1 diabetes and T2D (refs. 3–8); nonetheless, the role of specific SL species in β-cell function and demise is unclear. Here we define the lipid signature of T2D-associated β-cell failure, including an imbalance of specific very-long-chain SLs and long-chain SLs. β-cell-specific ablation of CerS2, the enzyme necessary for generation of very-long-chain SLs, selectively reduces insulin content, impairs insulin secretion and disturbs systemic glucose tolerance in multiple complementary models. In contrast, ablation of long-chain-SL-synthesizing enzymes has no effect on insulin content. By quantitatively defining the SL–protein interactome, we reveal that CerS2 ablation affects SL binding to several endoplasmic reticulum–Golgi transport proteins, including Tmed2, which we define as an endogenous regulator of the essential proinsulin processing enzyme Pcsk1. Our study uncovers roles for specific SL subtypes and SL-binding proteins in β-cell function and T2D-associated β-cell failure.

A quantitative description of nuclear mechanics is crucial for understanding its role in force sensing within eukaryotic cells. Recent studies indicate that the chromatin within the nucleus cannot be treated as a homogeneous material. To elucidate its material properties, we combine optical tweezers manipulation of isolated nuclei with multi-color fluorescence imaging of lamin and chromatin to map the response of nuclei to local deformations. Force spectroscopy reveals nuclear strain stiffening and an exponential force dependence, well described by a hierarchical chain model. Simultaneously, fluorescence data show a higher compliance of chromatin compared to the nuclear envelope at strains <30%. Micrococcal nuclease (MNase) digestion of chromatin results in nuclear softening and can be captured by our model. Additionally, we observe stretching responses showing a lipid tether signature, suggesting that these tethers originate from the nuclear membrane. Our combined approach allows us to elucidate the nuclear force response while mapping the deformation of lamin, (eu)chromatin, and membrane.

Patients with atrial fibrillation (AF) often receive multiple medications daily. The purpose of this study was to examine the prognostic implications of polypharmacy in patients with AF. This is a retrospective post hoc analysis of 1113 AF patients, enrolled in a randomized trial during an acute hospitalization (MISOAC-AF, NCT02941978). The presence of polypharmacy (use of >4 drugs daily) was assessed at hospital discharge. Regression analyses were performed to identify clinical predictors of polypharmacy and compare the outcomes of patients with or without confirmed polypharmacy. The coprimary outcomes were all-cause and cardiovascular (CV) mortality. Among patients with polypharmacy, the difference in the risk of mortality was also assessed per each added drug as a numeric variable. Polypharmacy was found in 36.9% of participants. Dyslipidemia, coronary artery disease, lower left ventricular ejection fraction, and higher glomerular filtration rates were independent predictors of polypharmacy. Polypharmacy was an independent predictor for all-cause death (adjusted hazard ratio [aHR]: 1.29, 95% confidence interval [CI]: 1.01–1.64) and CV death (aHR: 1.39, 95% CI: 1.05–1.84). Among patients with polypharmacy, each additional concomitant medication was independently associated with a 4% increased risk of all-cause mortality (aHR = 1.04, 95% CI: 1.00–1.08) and a 5% increased risk of CV mortality (aHR = 1.05, 95% CI: 1.00–1.10). Polypharmacy was common among patients with AF hospitalized in a tertiary hospital and was incrementally associated with higher rates of mortality.

Digoxin is widely used in atrial fibrillation (AF) and heart failure (HF). However, current evidence regarding its association with clinical outcomes is conflicting.

To increase computational flexibility, the processing of sensory inputs changes with behavioural context. In the visual system, active behavioural states characterized by motor activity and pupil dilation1,2enhance sensory responses, but typically leave the preferred stimuli of neurons unchanged2–9. Here we find that behavioural state also modulates stimulus selectivity in the mouse visual cortex in the context of coloured natural scenes. Using population imaging in behaving mice, pharmacology and deep neural network modelling, we identified a rapid shift in colour selectivity towards ultraviolet stimuli during an active behavioural state. This was exclusively caused by state-dependent pupil dilation, which resulted in a dynamic switch from rod to cone photoreceptors, thereby extending their role beyond night and day vision. The change in tuning facilitated the decoding of ethological stimuli, such as aerial predators against the twilight sky10. For decades, studies in neuroscience and cognitive science have used pupil dilation as an indirect measure of brain state. Our data suggest that, in addition, state-dependent pupil dilation itself tunes visual representations to behavioural demands by differentially recruiting rods and cones on fast timescales.

In this paper, we present a general framework for designing approximation schemes for combinatorial optimization problems in which the objective function is a combination of more than one function. Examples [...]

We study cooperative games with supermodular costs. We show that supermodular costs arise in a variety of situations; in particular, we show that the problem of minimizing a linear function [...]

The contribution of related donors to the globally rising number of allogeneic haematopoietic stem cell transplantations (HSCT) remains increasingly important, particularly because of the growing use of haploidentical HSCT. Compared with the strict recommendations on the suitability for unrelated donors, criteria for related donors allow for more discretion and vary between centres. In 2015, the donor outcome committee of the Worldwide Network for Blood and Marrow Transplantation (WBMT) proposed consensus recommendations of suitability criteria for paediatric and adult related donors. This Review provides updates and additions to these recommendations from a panel of experts with global representation, including the WBMT, the European Society for Blood and Marrow Transplantation donor outcome committee, the Center for International Blood and Marrow Transplant Research donor health and safety committee, the US National Marrow Donor Program, and the World Marrow Donor Association, after review of the current literature and guidelines. Sections on the suitability of related donors who would not qualify as unrelated donors have been updated. Sections on communicable diseases, clonal haematopoiesis of indeterminate potential, paediatric aspects including psychological issues, and reporting on serious adverse events have been added. The intention of this Review is to support decision making, with the goal of minimising the medical risk to the donor and protecting the recipient from transmissible diseases.

Rhythm control and rate control are both employed commonly in patients with atrial fibrillation (AF) and heart failure (HF), but limited real-world data exist on them. We aimed to compare outcomes between these two strategies across the left ventricular ejection fraction (LVEF) spectrum.

We study the problem of minimizing the maximum latency of flows in networks with congestion. We show that this problem is NP-hard, even when all arc latency functions are linear [...]

The design of route guidance systems faces a well-known dilemma. The approach that theoretically yields the system-optimal traffic pattern may discriminate against some users in favor of others. Proposed alternate [...]

A key feature of neurons in the primary visual cortex (V1) of primates is their orientation selectivity. Recent studies using deep neural network models showed that the most exciting input (MEI) for mouse V1 neurons exhibit complex spatial structures that predict non-uniform orientation selectivity across the receptive field (RF), in contrast to the classical Gabor filter model. Using local patches of drifting gratings, we identified heterogeneous orientation tuning in mouse V1 that varied up to 90° across sub-regions of the RF. This heterogeneity correlated with deviations from optimal Gabor filters and was consistent across cortical layers and recording modalities (calcium vs. spikes). In contrast, model-synthesized MEIs for macaque V1 neurons were predominantly Gabor like, consistent with previous studies. These findings suggest that complex spatial feature selectivity emerges earlier in the visual pathway in mice than in primates. This may provide a faster, though less general, method of extracting task-relevant information.

Background/Objectives: Religious fasting (RF) is practiced annually by millions of Christian and Muslim followers worldwide. Scarce data exist on the impact of RF on the metabolic and hematological profile of individuals with or without dyslipidemia. Subjects/Methods: The present study included: (i) 60 Greek Orthodox participants, 30 with dyslipidemia and 30 without dyslipidemia, who abstained from meat, fish and dairy products for seven consecutive weeks, and (ii) 15 young, non-dyslipidemic Muslim participants abstaining totally from food and liquid from dawn till sunset during 30 days. Biochemical (iron, ferritin, vitamin B12, calcium, low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol (TC), triglyceride and fasting glucose) and hematological (hemoglobin, hematocrit) serum blood test results of study participants were measured pre- and post- RF (at weeks 0 and 7 for Orthodox participants and at weeks 0 and 4 for Muslim participants). Results: In dyslipidemic and non-dyslipidemic Orthodox participants, a significant reduction of fasting glucose, HDL, LDL and TC levels was found post-RF. Hemoglobin, hematocrit, iron and ferritin levels were significantly increased, while post-RF vitamin B12 and calcium levels were substantially decreased. Subanalysis between dyslipidemic and non-dyslipidemic Orthodox participants revealed a greater decrease of cholesterol levels in the former. In Muslim participants, triglyceride, LDL and total cholesterol levels were increased post-RF (all pvalues &lt; 0.05). Conclusions: Our study adds to the existing literature evidence about the significant impact of RF on metabolic and hematological profiles of Orthodox and Muslim followers. The prevention of calcium and B12 deficiency during Orthodox RF by supplement consumption as well as the protection from dehydration and dysregulation of lipid metabolism during Ramadan RF should concern both clinicians and dietician nutritionists. Nevertheless, studies with larger sample size and/or long-term follow-up are warranted before reaching definite conclusions about the effects of RF on human health.

The number of cases of European foulbrood (EFB) increased massively in Switzerland since 2000. According to Swiss legislation, the health status of all colonies within one kilometer from a case needs to be identified by a bee inspector. This results in a workload too high to be handled in due time in areas with a high prevalence and high colony density. Therefore, the primary goal of this study was testing the hypothesis that the number of visual inspections could be reduced if brood nest bees sampled by owners were tested by real-time PCR for the presence of Melissococcus plutonius,and results were assigned to one of the three categories “negative”, “positive,” or “strong positive” depending on the amount of bacterial DNA. Only apiaries with strong positive results were inspected visually. Furthermore, the development of the bacterial load over time was analyzed on an apiary level to determine whether this would allow predicting the outcome of an infection. For this purpose, bee samples of 88 apiaries were assayed by real-time PCR and visually inspected in parallel over several months. Comparison of the two methods revealed a sensitivity of the real-time PCR of 93.5% and a specificity of 58.6% relative to visual inspection. One month after first sampling the bacterial load was still on the same level in 54%, had increased in 17%, and decreased in 29% of 35 apiaries. Establishing predictions on the basis of real-time PCR results is therefore not possible. In conclusion, due to its poor specificity, preliminary real-time PCR would not allow reducing the number of visual inspections sufficiently to compensate the costs of additional laboratory diagnosis. However, real-time PCR may be a valuable tool for identifying infected colonies in the context of trade and migratory beekeeping.

The design of biocatalytic reaction systems is highly complex owing to the dependency of the estimated kinetic parameters on the enzyme, the reaction conditions, and the modeling method. Consequently, reproducibility of enzymatic experiments and reusability of enzymatic data are challenging. We developed the XML-based markup language EnzymeML to enable storage and exchange of enzymatic data such as reaction conditions, the time course of the substrate and the product, kinetic parameters and the kinetic model, thus making enzymatic data findable, accessible, interoperable and reusable (FAIR). The feasibility and usefulness of the EnzymeML toolbox is demonstrated in six scenarios, for which data and metadata of different enzymatic reactions are collected and analyzed. EnzymeML serves as a seamless communication channel between experimental platforms, electronic lab notebooks, tools for modeling of enzyme kinetics, publication platforms and enzymatic reaction databases. EnzymeML is open and transparent, and invites the community to contribute. All documents and codes are freely available at https://enzymeml.org.

The papers in this special section focus on large-scale medical imaging and video analytics for clinical decision support systems. Biomedical images and videos are ubiquitous and overwhelming in volume, amounting to a database that can be measured in zettabytes.With increased access to open image and video datasets and the recent development of effective image and video analysis systems, there is a unique opportunity for the development of artificial intelligence (AI) systems that can be trained and tested on large-scale biomedical image and video databases. The special issue summarizes emerging methods associated with the development of computer-aided diagnostic systems. More specifically, the special issue discusses the development of methods for dealing with small or large or creating new datasets, biomedical image segmentation, and image classification. The development of new dataset methods allows us to develop methods for specific diseases, employ meta-learning for training on small datasets, or develop methods for reducing larger video datasets. Biomedical image segmentation is a primary focus of the special issue.

It is a major outstanding goal in nanotechnology to precisely position functional nanoparticles, such as quantum dots, inside a three-dimensional (3D) nanostructure in order to realize innovative functions. Once the 3D positioning is performed, the challenge arises how to nondestructively verify where the nanoparticles reside in the 3D nanostructure. Here, we study 3D photonic band gap crystals made of Si that are infiltrated with PbS nanocrystal quantum dots. The nanocrystals are covalently bonded to polymer brush layers that are grafted to the Si–air interfaces inside the 3D nanostructure using surface-initiated atom transfer radical polymerization (SI-ATRP). The functionalized 3D nanostructures are probed by synchrotron X-ray fluorescence (SXRF) tomography that is performed at 17 keV photon energy to obtain large penetration depths and efficient excitation of the elements of interest. Spatial projection maps were obtained followed by tomographic reconstruction to obtain the 3D atom density distribution with 50 nm voxel size for all chemical elements probed: Cl, Cr, Cu, Ga, Br, and Pb. The quantum dots are found to be positioned inside the 3D nanostructure, and their positions correlate with the positions of elements characteristic of the polymer brush layer and the ATRP initiator. We conclude that X-ray fluorescence tomography is very well suited to nondestructively characterize 3D nanomaterials with photonic and other functionalities.

Abstract

New value‐adding applications of spent grain, a co‐product of brewhouse operations, are considered in the context of a sustainable circular economy. Previous studies have focused on the compounds remaining in the solid phase of the spent grain. However, depending on the dewatering process, the separated water also contains relevant fractions of nutritionally and physiologically valuable compounds including proteins, carbohydrates and polyphenols. Accordingly, the work reported here considers the two fractions and presents a detailed view of relevant substances especially those from liquor. The reported mass balance is the result of these investigations, supplemented by values from the literature. The potential value of these compounds for industrial biotechnology is examined in an economic assessment. © 2022 The Authors. Journal of the Institute of Brewingpublished by John Wiley & Sons Ltd on behalf of The Institute of Brewing & Distilling.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a range of symptoms in infected individuals, from mild respiratory illness to acute respiratory distress syndrome. A systematic understanding of host factors influencing viral infection is critical to elucidate SARS-CoV-2–host interactions and the progression of Coronavirus disease 2019 (COVID-19). Here, we conducted genome-wide CRISPR knockout and activation screens in human lung epithelial cells with endogenous expression of the SARS-CoV-2 entry factors ACE2and TMPRSS2. We uncovered proviral and antiviral factors across highly interconnected host pathways, including clathrin transport, inflammatory signaling, cell-cycle regulation, and transcriptional and epigenetic regulation. We further identified mucins, a family of high molecular weight glycoproteins, as a prominent viral restriction network that inhibits SARS-CoV-2 infection in vitro and in murine models. These mucins also inhibit infection of diverse respiratory viruses. This functional landscape of SARS-CoV-2 host factors provides a physiologically relevant starting point for new host-directed therapeutics and highlights airway mucins as a host defense mechanism.

ABSTRACTWhether macroautophagy/autophagy is physiologically relevant to regulate mitochondrial function for a rapid and dynamic adaptation of yeast cells to respiratory growth was not fully understood until recently. May et al. (2020. Nat Commun) report that bulk autophagy provides serine as a one-carbon (1C) metabolite that controls respiratory growth onset by initiating mitochondrial initiator tRNAMetmodification and mitochondrial translation linking autophagy mechanistically to mitochondrial function. We discuss the mechanistic interplay between autophagy, one-carbon-metabolism, and mitochondrial function and the possible implications in neurodegeneration, aging, and carcinogenesis.Abbreviations:10-formyl-THF: 10-formyl-tetrahydrofolate; OXPHOS: oxidative phosphorylation; PAS: phagophore assembly site

The combination of DNA force spectroscopy and polarization microscopy of fluorescent DNA intercalator dyes can provide valuable insights into the structure of DNA under tension. These techniques have previously been used to characterize S-DNA—an elongated DNA conformation that forms when DNA overstretches at forces ≥ 65 pN. In this way, it was deduced that the base pairs of S-DNA are highly inclined, relative to those in relaxed (B-form) DNA. However, it is unclear whether and how topological constraints on the DNA may influence the base-pair inclinations under tension. Here, we apply polarization microscopy to investigate the impact of DNA pulling geometry, torsional constraint, and negative supercoiling on the orientations of intercalated dyes during overstretching. In contrast to earlier predictions, the pulling geometry (namely, whether the DNA molecule is stretched viaopposite strands or the same strand) is found to have little influence. However, torsional constraint leads to a substantial reduction in intercalator tilting in overstretched DNA, particularly in AT-rich sequences. Surprisingly, the extent of intercalator tilting is similarly reduced when the DNA molecule is negatively supercoiled up to a critical supercoiling density (corresponding to ∼70% reduction in the linking number). We attribute these observations to the presence of P-DNA (an overwound DNA conformation). Our results suggest that intercalated DNA preferentially flanks regions of P-DNA rather than those of S-DNA and also substantiate previous suggestions that P-DNA forms predominantly in AT-rich sequences.