COVID-19 immune signatures reveal stable antiviral T cell function despite declining humoral responses.

Cellular and humoral immunity to SARS-CoV-2 is critical to control primary infection and correlates with severity of disease. The role of SARS-CoV-2-specific T cell immunity, its relationship to antibodies, and pre-existing immunity against endemic coronaviruses (huCoV), which has been hypothesized to be protective, were investigated in 82 healthy donors (HDs), 204 recovered (RCs), and 92 active COVID-19 patients (ACs). ACs had high amounts of anti-SARS-CoV-2 nucleocapsid and spike IgG but lymphopenia and overall reduced antiviral T cell responses due to the inflammatory milieu, expression of inhibitory molecules (PD-1, Tim-3) as well as effector caspase-3, -7, and -8 activity in T cells. SARS-CoV-2-specific T cell immunity conferred by polyfunctional, mainly interferon-γ-secreting CD4+ T cells remained stable throughout convalescence, whereas humoral responses declined. Immune responses toward huCoV in RCs with mild disease and strong cellular SARS-CoV-2 T cell reactivity imply a protective role of pre-existing immunity against huCoV.

The intramembrane COOH-terminal domain of PRRT2 regulates voltage-dependent Na+ channels.

Proline-rich transmembrane protein 2 (PRRT2) is the single causative gene for pleiotropic paroxysmal syndromes, including epilepsy, kinesigenic dyskinesia, episodic ataxia, and migraine. PRRT2 is a neuron-specific type-2 membrane protein with a COOH-terminal intramembrane domain and a long proline-rich NH2-terminal cytoplasmic region. A large array of experimental data indicates that PRRT2 is a neuron stability gene that negatively controls intrinsic excitability by regulating surface membrane localization and biophysical properties of voltage-dependent Na+ channels Nav1.2 and Nav1.6, but not Nav1.1. To further investigate the regulatory role of PRRT2, we studied the structural features of this membrane protein with molecular dynamics simulations, and its structure-function relationships with Nav1.2 channels by biochemical and electrophysiological techniques. We found that the intramembrane COOH-terminal region maintains a stable conformation over time, with the first transmembrane domain forming a helix-loop-helix motif within the bilayer. The unstructured NH2-terminal cytoplasmic region bound to the Nav1.2 better than the isolated COOH-terminal intramembrane domain, mimicking full-length PRRT2, while the COOH-terminal intramembrane domain was able to modulate Na+ current and channel biophysical properties, still maintaining the striking specificity for Nav1.2 versus Nav1.1. channels. The results identify PRRT2 as a dual-domain protein in which the NH2-terminal cytoplasmic region acts as a binding antenna for Na+ channels, while the COOH-terminal membrane domain regulates channel exposure on the membrane and its biophysical properties.

Outcomes of High-Grade Immune Checkpoint Inhibitor Hepatitis in Hospitalized and Nonhospitalized Patients.

BACKGROUND & AIMS: Guidelines recommend hospitalization for severe immune checkpoint inhibitor (ICI) hepatitis. We compared patient outcomes in the inpatient versus outpatient settings. METHODS: We conducted a multicenter, retrospective cohort study of 294 ICI-treated patients who developed grade 3-4 ICI hepatitis. The primary outcome was time to alanine aminotransferase (ALT) normalization (≤40); secondary outcomes included time to ALT ≤100 U/L and time to death. To account for confounding by indication, inverse probability of treatment weighting was applied to perform Cox regression. A sensitivity analysis was performed excluding patients with grade 4 hepatitis. RESULTS: One hundred and sixty-six patients (56.5%) were hospitalized for a median of 6 (interquartile range, 3-11) days. On inverse probability of treatment weighting Cox regression, hospitalization was not associated with time to ALT normalization (hazard ratio [HR], 1.11; 95% confidence interval [CI], 0.86-1.43; P = .436) or time to ALT ≤100 U/L (HR, 1.11; 95% CI, 0.86-1.43; P = .420). In the sensitivity analysis limited to patients with grade 3 hepatitis, hospitalization was also not associated with time to ALT normalization (HR, 1.11; 95% CI, 0.83-1.50; P = .474) or time to ALT ≤100 U/L (HR, 1.19; 95% CI, 0.90-1.58; P = .225). In a subgroup analysis of 152 patients with melanoma, hospitalization was not associated with reduced risk of all-cause death (HR, 0.93; 95% CI, 0.53-1.64; P = .798). Notably, despite their Common Terminology Criteria for Adverse Events classification of high-grade hepatitis, 94% of patients had "mild" liver injury based on International Drug-Induced Liver Injury Criteria. CONCLUSIONS: Hospitalization of patients with high-grade ICI hepatitis was not associated with faster hepatitis resolution and did not affect mortality. Routine hospitalization may not be necessary in all patients with high-grade ICI hepatitis and Common Terminology Criteria for Adverse Events criteria may overestimate severity of liver injury.

Defeating depolarizing fields with artificial flux closure in ultrathin ferroelectrics.

Material surfaces encompass structural and chemical discontinuities that often lead to the loss of the property of interest in so-called dead layers. It is particularly problematic in nanoscale oxide electronics, where the integration of strongly correlated materials into devices is obstructed by the thickness threshold required for the emergence of their functionality. Here we report the stabilization of ultrathin out-of-plane ferroelectricity in oxide heterostructures through the design of an artificial flux-closure architecture. Inserting an in-plane-polarized ferroelectric epitaxial buffer provides the continuity of polarization at the interface; despite its insulating nature, we observe the emergence of polarization in our out-of-plane-polarized model of ferroelectric BaTiO3 from the very first unit cell. In BiFeO3, the flux-closure approach stabilizes a 251° domain wall. Its unusual chirality is probably associated with the ferroelectric analogue to the Dzyaloshinskii-Moriya interaction. We, thus, see that in an adaptively engineered geometry, the depolarizing-field-screening properties of an insulator can even surpass those of a metal and be a source of functionality. This could be a useful insight on the road towards the next generation of oxide electronics.

A Solanum lycopersicoides reference genome facilitates insights into tomato specialized metabolism and immunity.

Wild relatives of tomato are a valuable source of natural variation in tomato breeding, as many can be hybridized to the cultivated species (Solanum lycopersicum). Several, including Solanum lycopersicoides, have been crossed to S. lycopersicum for the development of ordered introgression lines (ILs), facilitating breeding for desirable traits. Despite the utility of these wild relatives and their associated ILs, few finished genome sequences have been produced to aid genetic and genomic studies. Here we report a chromosome-scale genome assembly for S. lycopersicoides LA2951, which contains 37 938 predicted protein-coding genes. With the aid of this genome assembly, we have precisely delimited the boundaries of the S. lycopersicoides introgressions in a set of S. lycopersicum cv. VF36 × LA2951 ILs. We demonstrate the usefulness of the LA2951 genome by identifying several quantitative trait loci for phenolics and carotenoids, including underlying candidate genes, and by investigating the genome organization and immunity-associated function of the clustered Pto gene family. In addition, syntenic analysis of R2R3MYB genes sheds light on the identity of the Aubergine locus underlying anthocyanin production. The genome sequence and IL map provide valuable resources for studying fruit nutrient/quality traits, pathogen resistance, and environmental stress tolerance. We present a new genome resource for the wild species S. lycopersicoides, which we use to shed light on the Aubergine locus responsible for anthocyanin production. We also provide IL boundary mappings, which facilitated identifying novel carotenoid quantitative trait loci of which one was likely driven by an uncharacterized lycopene ß-cyclase whose function we demonstrate.

Hybrid Targeted/Untargeted Screening Method for the Determination of Wildfire and Water-Soluble Organic Tracers in Ice Cores and Snow.

Wildfires can influence the earth's radiative forcing through the emission of biomass-burning aerosols. To better constrain the impacts of wildfires on climate and understand their evolution under future climate scenarios, reconstructing their chemical nature, assessing their past variability, and evaluating their influence on the atmospheric composition are essential. Ice cores are unique to perform such reconstructions representing archives not only of past biomass-burning events but also of concurrent climate and environmental changes. Here, we present a novel methodology for the quantification of five biomass-burning proxies (syringic acid, vanillic acid, vanillin, syringaldehyde, and p-hydroxybenzoic acid) and one biogenic emission proxy (pinic acid) using solid phase extraction (SPE) and ultrahigh-performance liquid chromatography coupled with high-resolution mass spectrometry. This method was also optimized for untargeted screening analysis to gain a broader knowledge about the chemical composition of organic aerosols in ice and snow samples. The method provides low detection limits (0.003-0.012 ng g-1), high recoveries (74 ± 10%), and excellent reproducibility, allowing the quantification of the six proxies and the identification of 313 different molecules, mainly constituted by carbon, hydrogen, and oxygen. The effectiveness of two different sample storage strategies, i.e., re-freezing of previously molten ice samples and freezing of previously loaded SPE cartridges, was also assessed, showing that the latter approach provides more reproducible results.

Effect of corticosteroid dosing on outcomes in high-grade immune checkpoint inhibitor hepatitis.

BACKGROUND AND AIMS: Consensus guidelines recommend high-dose corticosteroids (1-2 mg/kg/day methylprednisolone equivalents) for treating grade ≥3 immune checkpoint inhibitor (ICI) hepatitis. We examined the effect of corticosteroid dosing on time to alanine aminotransferase (ALT) normalization, need for additional immunosuppression, and steroid-related complications. APPROACH AND RESULTS: We conducted a retrospective cohort study of 215 ICI-treated patients from 2010 to 2020 who developed grade ≥3 (ALT > 200 U/L) ICI hepatitis. Patients were grouped by initial corticosteroid dose (≥1.5 mg/kg or <1.5 mg/kg methylprednisolone equivalents). Propensity scores were calculated predicting the risk of receiving the higher steroid dose and used in inverse probability of treatment weighted (IPTW) logistic or Cox regression. The 87 patients in the ≥1.5 mg/kg group received higher initial (2.0 vs. 0.8 mg/kg/day, p < 0.001) and maximum (2.0 vs. 1.0 mg/kg/day, p < 0.001) steroid doses than the 128 patients in the <1.5 mg/kg group. There was no difference between the higher versus lower-dose groups in development of steroid-refractory hepatitis (OR 1.22, 95% CI 0.79-1.89, p = 0.365) on IPTW-logistic regression. In patients with steroid-responsive disease, there was no difference between the two groups in time to ALT normalization using either standard Cox regression (HR 1.02, 95% CI 0.72-1.45, p = 0.903) or IPTW-Cox regression (HR 1.09, 95% CI 0.78-1.51, p = 0.610). The ≥1.5 mg/kg group had longer exposure to corticosteroids (median 60 vs. 44 days, p = 0.005) and higher incidences of infection (18.4% vs. 7.0%, relative risk [RR] 2.6, 95% CI 1.2-5.6, p = 0.011) and hyperglycemia requiring treatment (23.3% vs. 7.8%, RR 3.0, 95% CI 1.5-6.0, p = 0.001). CONCLUSIONS: In patients with high-grade ICI hepatitis, initial treatment with 1 mg/kg/day methylprednisolone equivalents provides similar hepatitis outcomes with reduced risk of steroid-related complications when compared with higher-dose regimens.

Early Liver Specialist Consultation is Associated With Faster Biochemical Resolution of Severe Immune Checkpoint Inhibitor-Induced Hepatitis.

BACKGROUND: We evaluated the impact of gastroenterology/hepatology consultation, as recommended by guidelines, on the management of severe immune checkpoint inhibitor (ICI)-induced hepatitis. METHODS: We conducted a multicenter, retrospective cohort study of 294 patients who developed grade ≥3 (alanine aminotransferase [ALT] >200 U/L) ICI-induced hepatitis, with early gastroenterology/hepatology consultation defined as occurring within 7 days of diagnosis. The primary outcome was time to ALT normalization (≤40 U/L), and the secondary outcome was time to ALT improvement to ≤100 U/L. RESULTS: A total of 117 patients received early consultation. In the 213 patients with steroid-responsive hepatitis, early consultation was not associated with faster ALT normalization (hazard ratio [HR], 1.12; 95% CI, 0.83-1.51; P=.453). A total of 81 patients developed steroid-refractory hepatitis, with 44 (54.3%) receiving early consultation. In contrast to the patients whose hepatitis responded to steroid treatment, early consultation in those with steroid-refractory disease was associated with faster ALT normalization (HR, 1.89; 95% CI, 1.12-3.19; P=.017) and ALT improvement to ≤100 U/L (HR, 1.72; 95% CI, 1.04-2.84; P=.034). Notably, additional immunosuppressive therapy for steroid-refractory disease was initiated sooner after diagnosis in the early consult group (median 7.5 vs 13.0 days; log-rank P=.001). When time to additional immunosuppression was added as a covariate to the Cox model in mediation analysis, early consultation was no longer associated with time to ALT normalization (HR, 1.39; 95% CI, 0.82-2.38; P=.226) or with time to ALT improvement to ≤100 U/L (HR, 1.25; 95% CI, 0.74-2.11; P=.404). Time to additional immunosuppression remained associated with faster ALT normalization and faster ALT improvement to ≤100 U/L in the model, suggesting that the faster hepatitis resolution in the early consultation group was primarily attributable to earlier initiation of additional immunosuppression. CONCLUSIONS: Early gastroenterology/hepatology consultation is associated with faster resolution of biochemical abnormalities in patients with steroid-refractory hepatitis. This beneficial effect appears to be mediated by earlier initiation of additional immunosuppressive therapy in those receiving early consultation.

Synthesis and Characterization of High-Entropy Dawsonite-Type Structures.

High-entropy hydroxides are an emerging subcategory of high-entropy materials (HEMs), not only because they can serve as tailorable precursors to high-entropy oxides (HEOs) but also because they can have unique high-entropy properties themselves. Many hydroxide crystal structures that are important for various applications are yet to be studied within the context of high-entropy materials, and it is unknown if they can take a high-entropy form (typically five or more incorporated cations). One such material is the dawsonite-type structure, which is a material with applications in both catalysis and ceramics. This work focuses on the adaptation of a dawsonite-type structure (NH4M(OH)2CO3) into a high-entropy material. Through a coprecipitation synthesis method, dawsonite-type materials readily took a high-entropy form with five cations that were equimolar and homogeneously distributed. The specific chemistries investigated were Al, Cr, Fe, and Ga with a fifth cation that was varied with increasing ionic radius (In, Er, Ho, Y, Eu, Ce, La). High-entropy dawsonites also exhibit the ″memory effects″ of non-high-entropy dawsonites. This work extends the field of high-entropy materials to include a structure that can serve as a material platform for the synthesis of high-entropy catalytic materials and ceramic powders.

Role of Soil Biofilms in Clogging and Fate of Pharmaceuticals: A Laboratory-Scale Column Experiment.

Contamination of groundwater with pharmaceutical active compounds (PhACs) increased over the last decades. Potential pathways of PhACs to groundwater include techniques such as irrigation, managed aquifer recharge, or bank filtration as well as natural processes such as losing streams of PhACs-loaded source waters. Usually, these systems are characterized by redox-active zones, where microorganisms grow and become immobilized by the formation of biofilms, structures that colonize the pore space and decrease the infiltration capacities, a phenomenon known as bioclogging. The goal of this work is to gain a deeper understanding of the influence of soil biofilms on hydraulic conductivity reduction and the fate of PhACs in the subsurface. For this purpose, we selected three PhACs with different physicochemical properties (carbamazepine, diclofenac, and metoprolol) and performed batch and column experiments using a natural soil, as it is and with the organic matter removed, under different biological conditions. We observed enhanced sorption and biodegradation for all PhACs in the system with higher biological activity. Bioclogging was more prevalent in the absence of organic matter. Our results differ from works using artificial porous media and thus reveal the importance of utilizing natural soils with organic matter in studies designed to assess the role of soil biofilms in bioclogging and the fate of PhACs in soils.

Sulfate Formation by Photosensitization in Mixed Incense Burning-Sodium Chloride Particles: Effects of RH, Light Intensity, and Aerosol Aging.

Elevated particulate sulfate concentrations have been frequently observed in coastal areas when air masses are influenced by continental emissions, especially combustion sources like biomass burning. We studied the SO2 uptake by laboratory-generated droplets containing incense smoke extracts and sodium chloride (IS-NaCl) under irradiation and found enhanced sulfate production over pure NaCl droplets, attributable to photosensitization induced by constituents in IS. Low relative humidity and high light intensity facilitated sulfate formation and increased the SO2 uptake coefficient by IS-NaCl particles. Aging of the IS particles further enhanced sulfate production, attributable to the enhanced secondary oxidant production promoted by increased proportions of nitrogen-containing CHN and oxygen- and nitrogen-containing CHON species under light and air. Experiments using model compounds of syringaldehyde, pyrazine, and 4-nitroguaiacol verified the enhancements of CHN and CHON species in sulfate formation. This work provides experimental evidence of enhanced sulfate production in laboratory-generated IS-NaCl droplets via enhanced secondary oxidant production triggered by photosensitization in multiphase oxidation processes under light and air. Our results can shed light on the possible interactions between sea salt and biomass burning aerosols in enhancing sulfate production.

Towards Probing Conformational States of Y2 Receptor Using Hyperpolarized 129Xe NMR.

G protein-coupled receptors can adopt many different conformational states, each of them exhibiting different restraints towards downstream signaling pathways. One promising strategy to identify and quantify this conformational landscape is to introduce a cysteine at a receptor site sensitive to different states and label this cysteine with a probe for detection. Here, the application of NMR of hyperpolarized 129Xe for the detection of the conformational states of human neuropeptide Y2 receptor is introduced. The xenon trapping cage molecule cryptophane-A attached to a cysteine in extracellular loop 2 of the receptor facilitates chemical exchange saturation transfer experiments without and in the presence of native ligand neuropeptide Y. High-quality spectra indicative of structural states of the receptor-cage conjugate were obtained. Specifically, five signals could be assigned to the conjugate in the apo form. After the addition of NPY, one additional signal and subtle modifications in the persisting signals could be detected. The correlation of the spectroscopic signals and structural states was achieved with molecular dynamics simulations, suggesting frequent contact between the xenon trapping cage and the receptor surface but a preferred interaction with the bound ligand.

Analysis of the Dynamics of the Human Growth Hormone Secretagogue Receptor Reveals Insights into the Energy Landscape of the Molecule.

G protein-coupled receptors initiate signal transduction in response to ligand binding. Growth hormone secretagogue receptor (GHSR), the focus of this study, binds the 28 residue peptide ghrelin. While structures of GHSR in different states of activation are available, dynamics within each state have not been investigated in depth. We analyze long molecular dynamics simulation trajectories using "detectors" to compare dynamics of the apo and ghrelin-bound states yielding timescale-specific amplitudes of motion. We identify differences in dynamics between apo and ghrelin-bound GHSR in the extracellular loop 2 and transmembrane helices 5-7. NMR of the GHSR histidine residues reveals chemical shift differences in these regions. We evaluate timescale specific correlation of motions between residues of ghrelin and GHSR, where binding yields a high degree of correlation for the first 8 ghrelin residues, but less correlation for the helical end. Finally, we investigate the traverse of GHSR over a rugged energy landscape via principal component analysis.

Artificial intelligence to identify harmful alcohol use after early liver transplant for alcohol-associated hepatitis.

Early liver transplantation (LT) for alcohol-associated hepatitis (AH) is the fastest growing indication for LT, but prediction of harmful alcohol use post-LT remains limited. Among 10 ACCELERATE-AH centers, we examined psychosocial evaluations from consecutive LT recipients for AH from 2006 to 2017. A multidisciplinary panel used content analysis to develop a maximal list of psychosocial variables. We developed an artificial intelligence model to predict post-LT harmful alcohol use. The cohort included training (N = 91 among 8 centers) and external validation (N = 25 among 2 centers) sets, with median follow-up of 4.4 (IQR 3.0-6.0) years post-LT. In the training set, AUC was 0.930 (95%CI 0.862-0.998) with positive predictive value of 0.891 (95%CI 0.620-1.000), internally validated through fivefold cross-validation. In the external validation set, AUC was 0.692 (95%CI 0.666-0.718) with positive predictive value of 0.82 (95%CI 0.625-1.000). The model identified specific variables related to social support and substance use as highly important to predict post-LT harmful alcohol use. We retrospectively developed and validated a model that identified psychosocial profiles at LT predicting harmful alcohol use post-LT for AH. This preliminary model may inform selection and post-LT management for AH and warrants prospective evaluation in larger studies among all alcohol-associated liver disease being considered for early LT.

Extensive Health Care Utilization and Costs of an Early Liver Transplantation Program for Alcoholic Hepatitis.

Early liver transplantation (LT) for severe alcoholic hepatitis (AH) is a rescue therapy for highly selected patients with favorable psychosocial profiles not responding to medical therapy. Given the expected increase of AH candidate referrals requiring complex care and comprehensive evaluations, increased workload and cost might be expected from implementing an early LT program for AH but have not been determined. Some centers may also view AH as a strategy to expeditiously increase LT volume and economic viability. The aim of this study was to determine the health care use and costs of an early LT program for AH. Analyses of prospective databases of AH, interhospital transfers, and the hospital accounting system at a single center were performed from July 2011 to July 2016. For 5 years, 193 patients with severe AH were evaluated at our center: 143 newly referred transfers and 50 direct admissions. Annual increases of 13% led to 2 to 3 AH transfers/month and AH becoming the top reason for transfer. There were 169 (88%) nonresponders who underwent psychosocial evaluations; 15 (9%) underwent early LT. The median cost of early LT was $297,422, which was highly correlated with length of stay (r = 0.83; P < 0.001). Total net revenue of the program from LT admission to 90 days after LT was -$630,305 (-5.0% revenue), which was inversely correlated with MELD score (r = -0.70; P = 0.004) and yielded lower revenue than a contemporaneous LT program for acute-on-chronic liver failure (ACLF; $118,168; 1.4% revenue; P = 0.001). The health care use and costs of an early LT program for AH are extensive and lifesaving with marginally negative net revenue. Significantly increasing care of severe AH patients over 5 years resulted in increased LT volume, but at a lower rate than ACLF, and without improving economic outcomes due to high MELD and prolonged length of stay.

A Symmetrically π-Expanded Carbazole Incorporating Fluoranthene Moieties.

A novel doubly cyclopentannulated carbazole which is accessible through a successive π-expansion of di(1-naphthylamine) is disclosed. The carbazole moiety is generated in the final step through intramolecular oxidative coupling. The π-expansion of carbazole resulted in strongly altered optoelectronic and electrochemical properties. The solid-state structure features an interesting packing motif with alternating face-to-face π⋅⋅⋅π and edge-to-face C-H⋅⋅⋅π interactions. The experimental findings were corroborated by theoretical calculations.

Nontarget Screening Exhibits a Seasonal Cycle of PM2.5 Organic Aerosol Composition in Beijing.

The molecular composition of atmospheric particulate matter (PM) in the urban environment is complex, and it remains a challenge to identify its sources and formation pathways. Here, we report the seasonal variation of the molecular composition of organic aerosols (OA), based on 172 PM2.5 filter samples collected in Beijing, China, from February 2018 to March 2019. We applied a hierarchical cluster analysis (HCA) on a large nontarget-screening data set and found a strong seasonal difference in the OA chemical composition. Molecular fingerprints of the major compound clusters exhibit a unique molecular pattern in the Van Krevelen-space. We found that summer OA in Beijing features a higher degree of oxidation and a higher proportion of organosulfates (OSs) in comparison to OA during wintertime, which exhibits a high contribution from (nitro-)aromatic compounds. OSs appeared with a high intensity in summer-haze conditions, indicating the importance of anthropogenic enhancement of secondary OA in summer Beijing. Furthermore, we quantified the contribution of the four main compound clusters to total OA using surrogate standards. With this approach, we are able to explain a small fraction of the OA (∼11-14%) monitored by the Time-of-Flight Aerosol Chemical Speciation Monitor (ToF-ACSM). However, we observe a strong correlation between the sum of the quantified clusters and OA measured by the ToF-ACSM, indicating that the identified clusters represent the major variability of OA seasonal cycles. This study highlights the potential of using nontarget screening in combination with HCA for gaining a better understanding of the molecular composition and the origin of OA in the urban environment.

Oxidative Cyclodehydrogenation of Trinaphthylamine: Selective Formation of a Nitrogen-Centered Polycyclic π-System Comprising 5- and 7-Membered Rings.

We describe a new type of nitrogen-centered polycyclic scaffold comprising a unique combination of 5-, 6-, and 7-membered rings. The compound is accessible through an intramolecular oxidative cyclodehydrogenation of tri(1-naphthyl)amine. To the best of our knowledge this is the very first example of a direct 3-fold cyclization of a triarylamine under oxidative conditions. The unusual ring fusion motif is confirmed by X-ray crystallography and the impact of cyclization on the electronic and photophysical properties is investigated both experimentally and theoretically based on density-functional theory (DFT) calculations. The formation of the unexpected product is rationalized by detailed mechanistic studies on the DFT level. The results suggest the cyclization to occur under kinetic control via a dicationic mechanism.

Predictors of Outcomes of COVID-19 in Patients With Chronic Liver Disease: US Multi-center Study.

BACKGROUND & AIMS: Chronic liver disease (CLD) represents a major global health burden. We undertook this study to identify the factors associated with adverse outcomes in patients with CLD who acquire the novel coronavirus-2019 (COVID-19). METHODS: We conducted a multi-center, observational cohort study across 21 institutions in the United States (US) of adult patients with CLD and laboratory-confirmed diagnosis of COVID-19 between March 1, 2020 and May 30, 2020. We performed survival analysis to identify independent predictors of all-cause mortality and COVID-19 related mortality, and multivariate logistic regression to determine the risk of severe COVID-19 in patients with CLD. RESULTS: Of the 978 patients in our cohort, 867 patients (mean age 56.9 ± 14.5 years, 55% male) met inclusion criteria. The overall all-cause mortality was 14.0% (n = 121), and 61.7% (n = 535) had severe COVID-19. Patients presenting with diarrhea or nausea/vomiting were more likely to have severe COVID-19. The liver-specific factors associated with independent risk of higher overall mortality were alcohol-related liver disease (ALD) (hazard ratio [HR] 2.42, 95% confidence interval [CI] 1.29-4.55), decompensated cirrhosis (HR 2.91 [1.70-5.00]) and hepatocellular carcinoma (HCC) (HR 3.31 [1.53-7.16]). Other factors were increasing age, diabetes, hypertension, chronic obstructive pulmonary disease and current smoker. Hispanic ethnicity (odds ratio [OR] 2.33 [1.47-3.70]) and decompensated cirrhosis (OR 2.50 [1.20-5.21]) were independently associated with risk for severe COVID-19. CONCLUSIONS: The risk factors which predict higher overall mortality among patients with CLD and COVID-19 are ALD, decompensated cirrhosis and HCC. Hispanic ethnicity and decompensated cirrhosis are associated with severe COVID-19. Our results will enable risk stratification and personalization of the management of patients with CLD and COVID-19. Clinicaltrials.gov number NCT04439084.

High light induces species specific changes in the membrane lipid composition of Chlorella.

Algae have evolved several mechanisms to adjust to changing environmental conditions. To separate from their surroundings, algal cell membranes form a hydrophobic barrier that is critical for life. Thus, it is important to maintain or adjust the physical and biochemical properties of cell membranes which are exposed to environmental factors. Especially glycerolipids of thylakoid membranes, the site of photosynthesis and photoprotection within chloroplasts, are affected by different light conditions. Since little is known about membrane lipid remodeling upon different light treatments, we examined light induced alterations in the glycerolipid composition of the two Chlorella species, C. vulgaris and C. sorokiniana, which differ strongly in their ability to cope with different light intensities. Lipidomic analysis and isotopic labeling experiments revealed differences in the composition of their galactolipid species, although both species likely utilize galactolipid precursors originated from the endoplasmic reticulum. However, in silico research of de novo sequenced genomes and ortholog mapping of proteins putatively involved in lipid metabolism showed largely conserved lipid biosynthesis pathways suggesting species specific lipid remodeling mechanisms, which possibly have an impact on the response to different light conditions.