Explore the vast range of titles available.

The skin's barrier arises from proliferative cells that generate a perpetual upward flux of terminally differentiating epidermal cells. Cells nearing the body surface suddenly lose their organelles, becoming dead cellular ghosts called squames. Working in mouse tissue, Garcia Quiroz et al. found that as differentiation-specific proteins accumulate in the keratinocytes, they undergo a vinegar-in-oil type of phase separation that crowds the cytoplasm with increasingly viscous protein droplets (see the Perspective by Rai and Pelkmans). Upon approaching the acidic skin surface, the environmentally sensitive liquid-like droplets respond and dissipate, driving squame formation. These dynamics come into play in human skin barrier diseases, where mutations cause maladapted liquid-phase transitions. Science , this issue p. eaax9554 ; see also p. 1193 Phase-separation sensors reveal abundant liquid-like organelles at the crux of skin barrier formation. At the body surface, skin’s stratified squamous epithelium is challenged by environmental extremes. The surface of the skin is composed of enucleated, flattened surface squames. They derive from underlying, transcriptionally active keratinocytes that display filaggrin-containing keratohyalin granules (KGs) whose function is unclear. Here, we found that filaggrin assembles KGs through liquid-liquid phase separation. The dynamics of phase separation governed terminal differentiation and were disrupted by human skin barrier disease–associated mutations. We used fluorescent sensors to investigate endogenous phase behavior in mice. Phase transitions during epidermal stratification crowded cellular spaces with liquid-like KGs whose coalescence was restricted by keratin filament bundles. We imaged cells as they neared the skin surface and found that environmentally regulated KG phase dynamics drive squame formation. Thus, epidermal structure and function are driven by phase-separation dynamics.

It has been known for decades that the observed number of baryons in the local Universe falls about 30–40 per cent short 1 , 2 of the total number of baryons predicted 3 by Big Bang nucleosynthesis, as inferred 4 , 5 from density fluctuations of the cosmic microwave background and seen during the first 2–3 billion years of the Universe in the so-called ‘Lyman α forest’ 6 , 7 (a dense series of intervening H  i Lyman α absorption lines in the optical spectra of background quasars). A theoretical solution to this paradox locates the missing baryons in the hot and tenuous filamentary gas between galaxies, known as the warm–hot intergalactic medium. However, it is difficult to detect them there because the largest by far constituent of this gas—hydrogen—is mostly ionized and therefore almost invisible in far-ultraviolet spectra with typical signal-to-noise ratios 8 , 9 . Indeed, despite large observational efforts, only a few marginal claims of detection have been made so far 2 , 10 . Here we report observations of two absorbers of highly ionized oxygen (O  vii ) in the high-signal-to-noise-ratio X-ray spectrum of a quasar at a redshift higher than 0.4. These absorbers show no variability over a two-year timescale and have no associated cold absorption, making the assumption that they originate from the quasar’s intrinsic outflow or the host galaxy’s interstellar medium implausible. The O  vii systems lie in regions characterized by large (four times larger than average 11 ) galaxy overdensities and their number (down to the sensitivity threshold of our data) agrees well with numerical simulation predictions for the long-sought warm–hot intergalactic medium. We conclude that the missing baryons have been found. Observations of two absorbers of highly ionized oxygen in the X-ray spectrum of a quasar account for the missing baryons in the Universe.

Bright quasars, powered by accretion onto billion-solar-mass black holes, already existed at the epoch of reionization, when the Universe was 0.5–1 billion years old 1 . How these black holes formed in such a short time is the subject of debate, particularly as they lie above the correlation between black-hole mass and galaxy dynamical mass 2 , 3 in the local Universe. What slowed down black-hole growth, leading towards the symbiotic growth observed in the local Universe, and when this process started, has hitherto not been known, although black-hole feedback is a likely driver 4 . Here we report optical and near-infrared observations of a sample of quasars at redshifts 5.8 ≲  z  ≲ 6.6. About half of the quasar spectra reveal broad, blueshifted absorption line troughs, tracing black-hole-driven winds with extreme outflow velocities, up to 17% of the speed of light. The fraction of quasars with such outflow winds at z  ≳ 5.8 is ≈2.4 times higher than at z  ≈ 2–4. We infer that outflows at z  ≳ 5.8 inject large amounts of energy into the interstellar medium and suppress nuclear gas accretion, slowing down black-hole growth. The outflow phase may then mark the beginning of substantial black-hole feedback. The red optical colours of outflow quasars at z  ≳ 5.8 indeed suggest that these systems are dusty and may be caught during an initial quenching phase of obscured accretion 5 . A study reporting optical and near-infrared observations of quasars at redshifts 5.8–6.6 shows that about half have strong winds, up to 17% the speed of light, suppressing black-hole growth.

IntroductionEvidence supports that enhanced recovery pathways (ERPs) reduce length of stay and complications; however, these measures may not reflect the perspective of patients who are the main stakeholders in the recovery process. This systematic review aimed to appraise the evidence regarding the impact of ERPs on patient-reported outcomes (PROs) after abdominal surgery.MethodsFive databases (Medline, Embase, Biosis, Cochrane, and Web of Science) were searched for randomized controlled trials (RCTs) addressing the impact of ERPs on PROs after abdominal surgery. We focused on distinct periods of recovery: early (within 7 days postoperatively) and late (beyond 7 days). Risk of bias was assessed using Cochrane’s RoB 2.0. Results were appraised descriptively as heterogeneity hindered meta-analysis. Certainty of evidence was evaluated using GRADE.ResultsFifty-six RCTs were identified [colorectal (n = 18), hepatopancreaticobiliary (HPB) (n = 11), upper gastrointestinal (UGI) (n = 10), gynecological (n = 7), urological (n = 7), general surgery (n = 3)]. Most trials had ‘some concerns’ (n = 30) or ‘high’ (n = 25) risk of bias. In the early postoperative period, ERPs improved patient-reported general health (colorectal, HPB, UGI, urological; very low to low certainty), physical health (colorectal, gynecological; very low to low certainty), mental health (colorectal, gynecological; very low certainty), pain (all specialties; very low to moderate certainty), and fatigue (colorectal; low certainty). In the late postoperative period, ERPs improved general health (HPB, UGI, urological; very low certainty), physical health (UGI, gynecological, urological; very low to low certainty), mental health (UGI, gynecological, urological; very low certainty), social health (gynecological; very low certainty), pain (gynecological, urological; very low certainty), and fatigue (gynecological; very low certainty).ConclusionThis review supports that ERPs may have a positive impact on patient-reported postoperative health status (i.e., general, physical, mental, and social health) and symptom experience (i.e., pain and fatigue) after abdominal surgery; however, data were largely derived from low-quality trials. Although these findings contribute important knowledge to inform evidence-based ERP implementation, there remains a great need to improve PRO assessment in studies focused on postoperative recovery.

Cyanobacteria are oxygenic phototrophic prokaryotes that have evolved to produce ultraviolet-screening mycosporine-like amino acids (MAAs) to lessen harmful effects from obligatory exposure to solar UV radiation. The cyanobacterial MAA biosynthetic cluster is formed by a gene encoding 2-epi-5-epi-valiolone synthase (EVS) located immediately upstream from an O-methyltransferase (OMT) encoding gene, which together biosynthesize the expected MAA precursor 4-deoxygadusol. Accordingly, these genes are typically absent in non-producers. In this study, the relationship between gene cluster architecture and constitutive production of MAAs was evaluated in cyanobacteria isolated from various Brazilian biomes. Constitutive production of MAAs was only detected in strains where genes formed a co-linear cluster. Expectedly, this production was enhanced upon exposure of the strains to UV irradiance and by using distinct culture media. Constitutive production of MAAs was not detected in all other strains and, unexpectedly, production could not be induced by exposure to UV irradiation or changing growth media. Other photoprotection strategies which might be employed by these MAA non-producing strains are discussed. The evolutionary and ecological significance of gene order conservation warrants closer experimentation, which may provide a first insight into regulatory interactions of genes encoding enzymes for MAA biosynthesis.

The mechanical properties of the extracellular matrix have recently been shown to promote myofibroblast differentiation and lung fibrosis. Mechanisms by which matrix stiffness regulates myofibroblast differentiation are not fully understood. The goal of this study was to determine the intrinsic mechanisms of mechanotransduction in the regulation of matrix stiffness–induced myofibroblast differentiation. A well established polyacrylamide gel system with tunable substrate stiffness was used in this study. Megakaryoblastic leukemia factor-1 (MKL1) nuclear translocation was imaged by confocal immunofluorescent microscopy. The binding of MKL1 to the α-smooth muscle actin (α-SMA) gene promoter was quantified by quantitative chromatin immunoprecipitation assay. Normal human lung fibroblasts responded to matrix stiffening with changes in actin dynamics that favor filamentous actin polymerization. Actin polymerization resulted in nuclear translocation of MKL1, a serum response factor coactivator that plays a central role in regulating the expression of fibrotic genes, including α-SMA, a marker for myofibroblast differentiation. Mouse lung fibroblasts deficient in Mkl1 did not respond to matrix stiffening with increased α-SMA expression, whereas ectopic expression of human MKL1 cDNA restored the ability of Mkl1 null lung fibroblasts to express α-SMA. Furthermore, matrix stiffening promoted production and activation of the small GTPase RhoA, increased Rho kinase (ROCK) activity, and enhanced fibroblast contractility. Inhibition of RhoA/ROCK abrogated stiff matrix–induced actin cytoskeletal reorganization, MKL1 nuclear translocation, and myofibroblast differentiation. This study indicates that actin cytoskeletal remodeling–mediated activation of MKL1 transduces mechanical stimuli from the extracellular matrix to a fibrogenic program that promotes myofibroblast differentiation, suggesting an intrinsic mechanotransduction mechanism.

In a prospective, randomized trial involving patients with resected pancreatic cancer, adjuvant combination chemotherapy with FOLFIRINOX resulted in a median disease-free survival of 21.6 months, as compared with 12.8 months with gemcitabine therapy. Overall survival was also longer with FOLFIRINOX.

Excessive opioid prescribing after surgery has contributed to the current opioid crisis; however, the value of prescribing opioids at surgical discharge remains uncertain. We aimed to estimate the extent to which opioid prescribing after discharge affects self-reported pain intensity and adverse events in comparison with an opioid-free analgesic regimen. In this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Library, Scopus, AMED, Biosis, and CINAHL from Jan 1, 1990, until July 8, 2021. We included multidose randomised controlled trials comparing opioid versus opioid-free analgesia in patients aged 15 years or older, discharged after undergoing a surgical procedure according to the Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity definition (minor, moderate, major, and major complex). We screened articles, extracted data, and assessed risk of bias (Cochrane's risk-of-bias tool for randomised trials) in duplicate. The primary outcomes of interest were self-reported pain intensity on day 1 after discharge (standardised to 0–10 cm visual analogue scale) and vomiting up to 30 days. Pain intensity at further timepoints, pain interference, other adverse events, risk of dissatisfaction, and health-care reutilisation were also assessed. We did random-effects meta-analyses and appraised evidence certainty using the Grading of Recommendations, Assessment, Development, and Evaluations scoring system. The review was registered with PROSPERO (ID CRD42020153050). 47 trials (n=6607 patients) were included. 30 (64%) trials involved elective minor procedures (63% dental procedures) and 17 (36%) trials involved procedures of moderate extent (47% orthopaedic and 29% general surgery procedures). Compared with opioid-free analgesia, opioid prescribing did not reduce pain on the first day after discharge (weighted mean difference 0·01cm, 95% CI –0·26 to 0·27; moderate certainty) or at other postoperative timepoints (moderate-to-very-low certainty). Opioid prescribing was associated with increased risk of vomiting (relative risk 4·50, 95% CI 1·93 to 10·51; high certainty) and other adverse events, including nausea, constipation, dizziness, and drowsiness (high-to-moderate certainty). Opioids did not affect other outcomes. Findings from this meta-analysis support that opioid prescribing at surgical discharge does not reduce pain intensity but does increase adverse events. Evidence relied on trials focused on elective surgeries of minor and moderate extent, suggesting that clinicians can consider prescribing opioid-free analgesia in these surgical settings. Data were largely derived from low-quality trials, and none involved patients having major or major-complex procedures. Given these limitations, there is a great need to advance the quality and scope of research in this field. The Canadian Institutes of Health Research.

Introduction Patients, clinicians and researchers seek an easy, reproducible and valid measure of postoperative recovery. The six-minute walk test (6MWT) is a low-cost measure of physical function, which is a relevant dimension of recovery. The aim of the present study was to contribute further evidence for the validity of the 6MWT as a measure of postoperative recovery after colorectal surgery. Methods This study involved a sample of 174 patients enrolled in three previous randomized controlled trials. Construct validity was assessed by testing the hypotheses that the distance walked in 6 min (6MWD) at 4 weeks after surgery is greater (1) in younger versus older patients, (2) in patients with higher preoperative physical status versus lower, (3) after laparoscopic versus open surgery, (4) in patients without postoperative complications versus with postoperative complications; and that 6MWD (5) correlates cross-sectionally with self-reported physical activity as measured with a questionnaire (CHAMPS). Statistical analysis was performed using linear regression and Spearman’s correlation. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist was used to guide the formulation of hypotheses and reporting of results. Results One hundred and fifty-one patients who completed the 6MWT at 4 weeks after surgery were included in the analysis. All hypotheses tested for construct validity were supported by the data. Older age, poorer physical status, open surgery and occurrence of postoperative complications were associated with clinically relevant reduction in 6MWD (>19 m). There was a moderate positive correlation between 6MWD and patient-reported physical activity ( r  = 0.46). Conclusions This study contributes further evidence for the construct validity of the 6MWT as a measure of postoperative recovery after colorectal surgery. Results from this study support the use of the 6MWT as an outcome measure in studies evaluating interventions aimed to improve postoperative recovery.

The 2021 Tajogaite eruption of Cumbre Vieja (La Palma, Spain) was typified by the emission of low viscosity lavas that flowed at high velocities and inundated a large area. We experimentally investigated the rheological evolution of melt feeding the eruption through concentric cylinder viscometry to understand the exceptional flowing ability of these lavas and constrain its emplacement dynamics. We conducted a set of cooling deformation experiments at different cooling rates (from 0.1 to 10 °C/min), and isothermal deformation experiments at subliquidus dwell temperatures between 1225 and 1175°C. All experiments were conducted at a shear rate of 10 s−1. Results show that disequilibrium crystallization and its timescale fundamentally control the rheological evolution of the melt, resulting in different rheological response to deformation of the crystal‐bearing magmatic suspension. Integrating rheological data with field observations allows us to shed light on the mechanisms that govern the high flowability of these lavas. Plain Language Summary Understanding and modeling the mechanisms controlling the inundation ability of lava flows is pivotal for hazard assessment and mitigation of related risk. Lavas flowing across the Earth's surface experience different cooling conditions. These conditions are related to the thermal gradients generated at various levels within the flow's thickness. Especially for extremely fluid magmas such as those erupted at Cumbre Vieja, the different cooling paths (and different disequilibrium conditions) that lava flows experience strongly influence the crystallization processes. Both cooling and crystallization produce an increase of lava viscosity, hindering lava flowability. If crystallization occurs over timescales shorter than those of cooling, the presence of crystals may give rise to more complex flow behavior and emplacement style, including flow rupture and separation. Such conditions may favor the development of flow decoupling and lava tunnel formation. In this study we experimentally investigate the viscosity evolution of the Tajogaite lavas and the transition from pure viscous flow to more complex responses to deformation. Then, we use our data set in concert with field observation to constrain the dynamics governing the emplacement style of these lavas. Key Points High‐T deformation experiments characterize the rheology of Cumbre Vieja lavas under both disequilibrium and equilibrium conditions Two different rheological responses are observed in relation to the increased disequilibrium conditions at which the melt is subjected Integration of experimental and field data permits to understand the mechanisms that enhance the flowing ability of these lavas