The periodic Saffman-Delbrück (PSD) model, an extension of the Saffman-Delbrück model developed to describe the effects of periodic boundary conditions on the diffusion constants of lipids and ...proteins obtained from simulation, is tested using the coarse-grained Martini and all-atom CHARMM36 (C36) force fields. Simulations of pure Martini dipalmitoylphosphatidylcholine (DPPC) bilayers and those with one embedded gramicidin A (gA) dimer or one gA monomer with sizes ranging from 512 to 2048 lipids support the PSD model. Underestimates of D
(the value of the diffusion constant for an infinite system) from the 512-lipid system are 35% for DPPC, 45% for the gA monomer, and 70% for the gA dimer. Simulations of all-atom DPPC and dioleoylphosphatidylcholine (DOPC) bilayers yield diffusion constants not far from experiment. However, the PSD model predicts that diffusion constants at the sizes of the simulation should underestimate experiment by approximately a factor of 3 for DPPC and 2 for DOPC. This likely implies a deficiency in the C36 force field. A Bayesian method for extrapolating diffusion constants of lipids and proteins in membranes obtained from simulation to infinite system size is provided.
Artificial intelligence-based computer-aided polyp detection (CADe) systems are intended to address the issue of missed polyps during colonoscopy. The effect of CADe during screening and surveillance ...colonoscopy has not previously been studied in a United States (U.S.) population.
We conducted a prospective, multi-center, single-blind randomized tandem colonoscopy study to evaluate a deep-learning based CADe system (EndoScreener, Shanghai Wision AI, China). Patients were enrolled across 4 U.S. academic medical centers from 2019 through 2020. Patients presenting for colorectal cancer screening or surveillance were randomized to CADe colonoscopy first or high-definition white light (HDWL) colonoscopy first, followed immediately by the other procedure in tandem fashion by the same endoscopist. The primary outcome was adenoma miss rate (AMR), and secondary outcomes included sessile serrated lesion (SSL) miss rate and adenomas per colonoscopy (APC).
A total of 232 patients entered the study, with 116 patients randomized to undergo CADe colonoscopy first and 116 patients randomized to undergo HDWL colonoscopy first. After the exclusion of 9 patients, the study cohort included 223 patients. AMR was lower in the CADe-first group compared with the HDWL-first group (20.12% 34/169 vs 31.25% 45/144; odds ratio OR, 1.8048; 95% confidence interval CI, 1.0780-3.0217; P = .0247). SSL miss rate was lower in the CADe-first group (7.14% 1/14) vs the HDWL-first group (42.11% 8/19; P = .0482). First-pass APC was higher in the CADe-first group (1.19 standard deviation (SD), 2.03 vs 0.90 SD, 1.55; P = .0323). First-pass ADR was 50.44% in the CADe-first group and 43.64 % in the HDWL-first group (P = .3091).
In this U.S. multicenter tandem colonoscopy randomized controlled trial, we demonstrate a decrease in AMR and SSL miss rate and an increase in first-pass APC with the use of a CADe-system when compared with HDWL colonoscopy alone.
Abstract
The future of exoplanet science is bright, as
Transiting Exoplanet Survey Satellite
(
TESS
) once again demonstrates with the discovery of its longest-period confirmed planet to date. We ...hereby present HD 21749b (TOI 186.01), a sub-Neptune in a 36 day orbit around a bright (
V
= 8.1) nearby (16 pc) K4.5 dwarf.
TESS
measures HD 21749b to be
R
⊕
, and combined archival and follow-up precision radial velocity data put the mass of the planet at
M
⊕
. HD 21749b contributes to the
TESS
Level 1 Science Requirement of providing 50 transiting planets smaller than 4
R
⊕
with measured masses. Furthermore, we report the discovery of HD 21749c (TOI 186.02), the first Earth-sized (
) planet from
TESS
. The HD 21749 system is a prime target for comparative studies of planetary composition and architecture in multi-planet systems.
Tumour oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state, but direct pharmacological inhibition of transcription factors has so ...far proven difficult. However, the transcriptional machinery contains various enzymatic cofactors that can be targeted for the development of new therapeutic candidates, including cyclin-dependent kinases (CDKs). Here we present the discovery and characterization of a covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell-line profiling indicates that a subset of cancer cell lines, including human T-cell acute lymphoblastic leukaemia (T-ALL), have exceptional sensitivity to THZ1. Genome-wide analysis in Jurkat T-ALL cells shows that THZ1 disproportionally affects transcription of RUNX1 and suggests that sensitivity to THZ1 may be due to vulnerability conferred by the RUNX1 super-enhancer and the key role of RUNX1 in the core transcriptional regulatory circuitry of these tumour cells. Pharmacological modulation of CDK7 kinase activity may thus provide an approach to identify and treat tumour types that are dependent on transcription for maintenance of the oncogenic state.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
All viruses with positive-sense RNA genomes replicate on membranous structures in the cytoplasm called replication complexes (RCs). RCs provide an advantageous microenvironment for viral replication, ...but it is unknown how the host immune system counteracts these structures. Here we show that interferon-gamma (IFNG) disrupts the RC of murine norovirus (MNV) via evolutionarily conserved autophagy proteins and the induction of IFN-inducible GTPases, which are known to destroy the membrane of vacuoles containing bacteria, protists, or fungi. The MNV RC was marked by the microtubule-associated-protein-1-light-chain-3 (LC3) conjugation system of autophagy and then targeted by immunity-related GTPases (IRGs) and guanylate-binding proteins (GBPs) upon their induction by IFNG. Further, the LC3 conjugation system and the IFN-inducible GTPases were necessary to inhibit MNV replication in mice and human cells. These data suggest that viral RCs can be marked and antagonized by a universal immune defense mechanism targeting diverse pathogens replicating in cytosolic membrane structures.
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•IFN-gamma inhibits murine norovirus replication complexes via the LC3 conjugation system•Degradative autophagy is not required to affect LC3-mediated RC restriction•LC3 and IFN-inducible GTPases are targeted to the RC membrane•IFN-inducible GTPases are required to inhibit MNV replication in mice and humans
The replication complexes (RCs) of positive-sense RNA viruses have been considered impenetrable to antiviral responses. Biering et al. discovered that viral RCs can be marked by the LC3 conjugation system of autophagy and targeted by IFN-inducible GTPases, demonstrating a universal effector mechanism against cytosolic vacuoles containing viruses, bacteria, protists, or fungi.
UHRF1 facilitates the establishment and maintenance of DNA methylation patterns in mammalian cells. The establishment domains are defined, including E3 ligase function, but the maintenance domains ...are poorly characterized. Here, we demonstrate that UHRF1 histone- and hemimethylated DNA binding functions, but not E3 ligase activity, maintain cancer-specific DNA methylation in human colorectal cancer (CRC) cells. Disrupting either chromatin reader activity reverses DNA hypermethylation, reactivates epigenetically silenced tumor suppressor genes (TSGs), and reduces CRC oncogenic properties. Moreover, an inverse correlation between high UHRF1 and low TSG expression tracks with CRC progression and reduced patient survival. Defining critical UHRF1 domain functions and its relationship with CRC prognosis suggests directions for, and value of, targeting this protein to develop therapeutic DNA demethylating agents.
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•UHRF1 maintains cancer-specific DNA methylation through its chromatin reader domains•PHD and SRA domain mutants phenocopy UHRF1 depletion to reverse DNA hypermethylation•Disrupting PHD or SRA domain functions impairs key oncogenic properties of CRC cells•The maintenance function of overexpressed UHRF1 in CRC has prognostic significance
Kong et al. show that histone and hemimethylated DNA reader domains are critical for UHRF1 to maintain aberrant DNA methylation in colorectal cancer (CRC) cells. Blocking either domain reverses DNA hypermethylation, reactivates epigenetically silenced tumor suppressor genes, and reduces CRC oncogenic properties.
The epigenetic inheritance of DNA methylation requires UHRF1, a histone- and DNA-binding RING E3 ubiquitin ligase that recruits DNMT1 to sites of newly replicated DNA through ubiquitylation of ...histone H3. UHRF1 binds DNA with selectivity towards hemi-methylated CpGs (HeDNA); however, the contribution of HeDNA sensing to UHRF1 function remains elusive. Here, we reveal that the interaction of UHRF1 with HeDNA is required for DNA methylation but is dispensable for chromatin interaction, which is governed by reciprocal positive cooperativity between the UHRF1 histone- and DNA-binding domains. HeDNA recognition activates UHRF1 ubiquitylation towards multiple lysines on the H3 tail adjacent to the UHRF1 histone-binding site. Collectively, our studies are the first demonstrations of a DNA-protein interaction and an epigenetic modification directly regulating E3 ubiquitin ligase activity. They also define an orchestrated epigenetic control mechanism involving modifications both to histones and DNA that facilitate UHRF1 chromatin targeting, H3 ubiquitylation, and DNA methylation inheritance.
Women in North America have a one in eight lifetime risk of developing breast cancer (BC), and a significant proportion of these individuals will develop recurrent BC and will eventually succumb to ...the disease. Metastatic, therapy-resistant BC cells are refractory to cell death induced by multiple stresses. Here, we document that the vitamin D receptor (VDR) acts as a master transcriptional regulator of autophagy. Activation of the VDR by vitamin D induces autophagy and an autophagic transcriptional signature in BC cells that correlates with increased survival in patients; strikingly, this signature is present in the normal mammary gland and is progressively lost in patients with metastatic BC. A number of epidemiological studies have shown that sufficient vitamin D serum levels might be protective against BC. We observed that dietary vitamin D supplementation in mice increases basal levels of autophagy in the normal mammary gland, highlighting the potential of vitamin D as a cancer-preventive agent. These findings point to a role of vitamin D and the VDR in modulating autophagy and cell death in both the normal mammary gland and BC cells.
Abstract
Background
Patients in the intensive care unit (ICU) are known to be at increased risk of developing delirium, but the risk of subsequent neuropsychiatric disorders is unclear. We therefore ...sought to examine the association between the presence of delirium in the ICU and incident neuropsychiatric disorders (including depressive, anxiety, trauma-and-stressor-related, and neurocognitive disorders) post-ICU stay among adult medical-surgical ICU patients.
Methods
Retrospective cohort study utilizing clinical and administrative data from both inpatient and outpatient healthcare visits to identify the ICU cohort and diagnostic information 5 years prior to and 1 year post-ICU stay. Patients ≥ 18 years of age admitted to one of 14 medical-surgical ICUs across Alberta, Canada, January 1, 2014–June 30, 2016, and survived to hospital discharge were included. The main outcome of interest was a new diagnosis of any neuropsychiatric disorder 1 year post-ICU stay. The exposure variable was delirium during the ICU stay identified through any positive delirium screen by the Intensive Care Unit Delirium Screening Checklist (ICDSC) during the ICU stay.
Results
Of 16,005 unique patients with at least one ICU admission, 4033 patients were included in the study of which 1792 (44%) experienced delirium during their ICU stay. The overall cumulative incidence of any neuropsychiatric disorder during the subsequent year was 19.7% for ICU patients. After adjusting for hospital characteristics using log-binomial regression, patients with delirium during the ICU stay had a risk ratio (RR) of 1.14 (95% confidence interval CI 0.98–1.33) of developing any neuropsychiatric disorder within 1 year post-ICU compared to those who did not experience delirium. Delirium was significantly associated with neurocognitive disorders (RR 1.59, 95% CI 1.08–2.35), but not depressive disorders (RR 1.16, 95% CI 0.92–1.45), anxiety (RR 1.16, 95% CI 0.92–1.47), and trauma-and-stressor-related (RR 0.82, 95% CI 0.53–1.28) disorders.
Conclusions
The diagnosis of new onset of neurocognitive disorders is associated with ICU-acquired delirium. In this study, significant associations were not observed for depressive, anxiety, and trauma-and-stressor-related disorders.
The severity of disease following infection with SARS-CoV-2 is determined by viral replication kinetics and host immunity, with early T cell responses and/or suppression of viraemia driving a ...favourable outcome. Recent studies uncovered a role for cholesterol metabolism in the SARS-CoV-2 life cycle and in T cell function. Here we show that blockade of the enzyme Acyl-CoA:cholesterol acyltransferase (ACAT) with Avasimibe inhibits SARS-CoV-2 pseudoparticle infection and disrupts the association of ACE2 and GM1 lipid rafts on the cell membrane, perturbing viral attachment. Imaging SARS-CoV-2 RNAs at the single cell level using a viral replicon model identifies the capacity of Avasimibe to limit the establishment of replication complexes required for RNA replication. Genetic studies to transiently silence or overexpress ACAT isoforms confirmed a role for ACAT in SARS-CoV-2 infection. Furthermore, Avasimibe boosts the expansion of functional SARS-CoV-2-specific T cells from the blood of patients sampled during the acute phase of infection. Thus, re-purposing of ACAT inhibitors provides a compelling therapeutic strategy for the treatment of COVID-19 to achieve both antiviral and immunomodulatory effects. Trial registration: NCT04318314.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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