Increasing evidence indicates the existence of selective autophagy pathways, but the manner in which substrates are recognized and targeted to the autophagy system is poorly understood. One strategy ...is transport of a particular substrate to the aggresome, a perinuclear compartment with high autophagic activity. In this paper, we identify a new cellular pathway that uses the specificity of heat‐shock protein 70 (Hsp70) to misfolded proteins as the basis for aggresome‐targeting and autophagic degradation. This pathway is regulated by the stress‐induced co‐chaperone Bcl‐2‐associated athanogene 3 (BAG3), which interacts with the microtubule‐motor dynein and selectively directs Hsp70 substrates to the motor and thereby to the aggresome. Notably, aggresome‐targeting by BAG3 is distinct from previously described mechanisms, as it does not depend on substrate ubiquitination.
Behl and colleagues report a novel cellular pathway utilizing the specificity of Hsp70 towards misfolded proteins as a basis for aggresome‐targeting and autophagic degradation and find that this pathway is regulated by the co‐chaperone BAG3.
Display omitted
•A solution has to be found rapidly against COVD-19.•From a set of 10 compounds of Aloe vera, 3 potential inhibitors of SARS-CoV-2 main protease were identified.•The binding affinity ...of ligand-protein interactions and the Lipinski’s rule of five based-on ADME analysis were used to confirm the best candidate.
SARS-CoV-2 is the pathogen agent of the new corona virus disease that appeared at the end of 2019 in China. There is, currently, no effective treatment against COVID-19. We report in this study a molecular docking study of ten Aloe vera molecules with the main protease (3CLpro) responsible for the replication of coronaviruses. The outcome of their molecular simulation and ADMET properties reveal three potential inhibitors of the enzyme (ligands 6, 1 and 8) with a clear preference of ligand 6 that has the highest binding energy (−7.9 kcal/mol) and fully obeys the Lipinski’s rule of five.
The most common form of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting adult motor neurons, is caused by dominant mutations in the ubiquitously expressed Cu-Zn Superoxide ...dismutase (SOD1). In chimeric mice that are mixtures of normal and SOD1 mutant-expressing cells, toxicity to motor neurons is shown to require damage from mutant SOD1 acting within nonneuronal cells. Normal motor neurons in SOD1 mutant chimeras develop aspects of ALS pathology. Most important, nonneuronal cells that do not express mutant SOD1 delay degeneration and significantly extend survival of mutant-expressing motor neurons.
An important constraint on the processes governing the geodynamo-the flow in the outer core responsible for generating Earth's magnetic field-is the duration of geomagnetic polarity reversals; that ...is, how long it takes for Earth's magnetic field to reverse. It is generally accepted that Earth's magnetic field strength drops to low levels during polarity reversals, and the field direction progresses through a 180° change while the field is weak. The time it takes for this process to happen, however, remains uncertain, with estimates ranging from a few thousand up to 28,000 years. Here I present an analysis of the available sediment records of the four most recent polarity reversals. These records yield an average estimate of about 7,000 years for the time it takes for the directional change to occur. The variation about this mean duration is not random, but instead varies with site latitude, with shorter durations observed at low-latitude sites, and longer durations observed at mid- to high-latitude sites. Such variation of duration with site latitude is predicted by simple geometrical reversal models, in which non-dipole fields are allowed to persist while the axial dipole decays through zero and then builds in the opposite direction, and provides a constraint on numerical dynamo models.
Abstract
Reversible protein phosphorylation is an important mechanism for regulating (dis)assembly of biomolecular condensates. However, condensate-specific phosphosites remain largely unknown, ...thereby limiting our understanding of the underlying mechanisms. Here, we combine solubility proteome profiling with phosphoproteomics to quantitatively map several hundred phosphosites enriched in either soluble or condensate-bound protein subpopulations, including a subset of phosphosites modulating protein–RNA interactions. We show that multi-phosphorylation of the C-terminal disordered segment of heteronuclear ribonucleoprotein A1 (HNRNPA1), a key RNA-splicing factor, reduces its ability to locate to nuclear clusters. For nucleophosmin 1 (NPM1), an essential nucleolar protein, we show that phosphorylation of S254 and S260 is crucial for lowering its partitioning to the nucleolus and additional phosphorylation of distal sites enhances its retention in the nucleoplasm. These phosphorylation events decrease RNA and protein interactions of NPM1 to regulate its condensation. Our dataset is a rich resource for systematically uncovering the phosphoregulation of biomolecular condensates.
A change detection and thresholding methodology has been adapted from previous studies to determine the extent of flooding for 13 Sentinel‐1 synthetic aperture radar images captured during the floods ...of winter 2015–2016 in Yorkshire, UK. Both available polarisations, VH and VV, have been processed to allow for a comparison of their respective accuracy for delineating surface water. Peak flood extents are found on 29 December 2015 during the aftermath of storms Eva and Frank. Results have been validated against a Sentinel‐2 optical image, with both polarisations producing a total accuracy of 97%. Of the two polarisations, VV produces fewer misclassifications, mirroring the similar results reported in previous research. Mapped results are compared to the Environment Agency Flood Maps for Planning (EA FMP), with good correlation observed for inundation on the floodplains. Differences occur away from the floodplains, with the satellite data identifying pluvial flooding not highlighted by the EA FMP.
Summary Background No treatments are presently available to increase survival in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based ...chemotherapy. We aimed to assess efficacy and safety of zalutumumab, a human IgG1 monoclonal antibody targeting the epidermal growth factor receptor, for overall survival in such patients. Methods In our open-label, parallel-group, phase 3, randomised trial, we randomly allocated patients with squamous-cell carcinoma of the head and neck who were regarded as incurable with standard therapy, a WHO performance status of 0–2, and progressive disease within 6 months of platinum-based therapy in a 2:1 ratio to receive zalutumumab plus best supportive care (zalutumumab group) or best supportive care with optional methotrexate (control group) at medical centres in Europe, Brazil, and Canada. Randomisation was done via a centralised interactive voice-response system, stratified by performance status. Data were analysed when the randomisation code was broken, after the completion of the accrual and cleaning of the relevant data. An independent review committee, masked to treatment assignment, assessed tumour response and disease progression according to response evaluation criteria in solid tumours. Zalutumumab was given weekly by individual dose titration on the basis of skin rash. After a prespecified 231 deaths, we included all randomised patients in the survival analyses and all patients receiving at least one session of therapy in the safety analysis. The primary endpoint was overall survival, although progression-free survival was also assessed. This trial is registered with ClinicalTrials.gov , NCT00382031. Findings We randomly allocated 191 (67%) of 286 eligible patients to the zalutumumab group and 95 (33%) to the control group. Median overall survival was 6·7 months (95% CI 5·8–7·0) in the zalutumumab group and 5·2 months (4·1–6·4) in the control group (hazard ratio HR for death, stratified by WHO performance status, was 0·77, 97·06% CI 0·57–1·05; unadjusted p=0·0648). Progression-free survival was longer in the zalutumumab group than in the control group (HR for progression or death, stratified by WHO performance status, was 0·63, 95% CI 0·47–0·84; p=0·0012). 189 patients given zalutumumab and 94 controls were included in the safety analysis. The most common grade 3–4 adverse events were rash (39 21% patients in the zalutumumab group vs none in the control group), anaemia (11 6% vs five 5%), and pneumonia (nine 5% vs two 2%). 28 (15%) patients in the zalutumumab group had grade 3/4 infections compared with eight (9%) in the control group. The most common serious adverse events were tumour haemorrhage (28 15% patients given zalutumumab vs 13 14% controls), pneumonia (13 7% vs three 3%), and dysphagia (11 6% vs two 2%). Interpretation Although zalutumumab did not increase overall survival, progression-free survival was extended in patients with recurrent squamous-cell carcinoma of the head and neck who had failed platinum-based chemotherapy. Zalutumumab dose titration on the basis of rash is safe. Funding Genmab.
Rett syndrome (RTT), mainly caused by mutations in methyl-CpG binding protein 2 (MeCP2), is one of the most prevalent intellectual disorders without effective therapies. Here, we used 2D and 3D human ...brain cultures to investigate MeCP2 function. We found that MeCP2 mutations cause severe abnormalities in human interneurons (INs). Surprisingly, treatment with a BET inhibitor, JQ1, rescued the molecular and functional phenotypes of MeCP2 mutant INs. We uncovered that abnormal increases in chromatin binding of BRD4 and enhancer-promoter interactions underlie the abnormal transcription in MeCP2 mutant INs, which were recovered to normal levels by JQ1. We revealed cell-type-specific transcriptome impairment in MeCP2 mutant region-specific human brain organoids that were rescued by JQ1. Finally, JQ1 ameliorated RTT-like phenotypes in mice. These data demonstrate that BRD4 dysregulation is a critical driver for RTT etiology and suggest that targeting BRD4 could be a potential therapeutic opportunity for RTT.
Display omitted
•MeCP2 mutation severely impairs human cortical interneurons•BRD4 dysregulation contributes to abnormal transcriptome in RTT interneurons•MeCP2 mutation causes cell-type-specific impairments in human brain organoids•BET inhibition rescues RTT-like phenotypes
Xiang et al. report that dysregulation of BRD4 function is a critical driver for the abnormal transcriptome in human RTT cells and that targeting BRD4 rescues molecular and functional deficiencies of human RTT cells and ameliorates RTT progression in mice.
To determine whether the supplementation of parenteral nutrition with ω-3 fatty acids confers treatment benefits to critically ill adult patients.
We performed computerized searches for relevant ...articles from 1996 to June 2011 on MEDLINE, EMBASE, and the Cochrane register of controlled trials and abstracts of scientific meetings from 2005 to 2011.
Randomized controlled trials of ω-3 fatty acid supplemented parenteral nutrition in critically ill adult patients admitted to the intensive therapy unit, given in addition to their routine care, compared with parenteral nutrition without ω-3 fatty acid supplementation.
Five fully published trials and three trials published in abstract form with 391 participants have been included. Overall trial quality was poor. Mortality data were pooled from eight studies with 391 participants. No differences were found with a risk ratio for death of 0.83 (95% confidence interval 0.57, 1.20; p = 0.32). Data for infectious complications were available from five studies with 337 participants. No differences were found, with a risk ratio for infection of 0.78 (95% confidence interval 0.43, 1.41; p = 0.41). Data for intensive therapy unit and hospital length of stay were available from six and three studies with 305 and 117 participants, respectively. With respect to intensive therapy unit length of stay, no differences were observed with a mean difference of 0.57 days in favor of the ω-3 fatty acid group (95% confidence interval -5.05, 3.90; p = 0.80). A significant reduction in hospital length of stay of 9.49 days (95% confidence interval -16.51, -2.47; p = 0.008) was observed for those receiving ω-3 fatty acid supplemented parenteral nutrition, but results were strongly influenced by one small study.
On the basis of this systematic review, it can be concluded that ω-3 fatty acid supplementation of parenteral nutrition does not improve mortality, infectious complications, and intensive therapy unit length of stay in comparison with standard parenteral nutrition. Although ω-3 fatty acids appear to reduce hospital length of stay, the poor methodology of the included studies and the absence of other outcome improvements mean they cannot be presently recommended.
In western North America, the current outbreak of the mountain pine beetle (MPB) and its microbial associates has destroyed wide areas of lodgepole pine forest, including more than 16 million ...hectares in British Columbia. Grosmannia clavigera (Gc), a critical component of the outbreak, is a symbiont of the MPB and a pathogen of pine trees. To better understand the interactions between Gc, MPB, and lodgepole pine hosts, we sequenced the ~30-Mb Gc genome and assembled it into 18 supercontigs. We predict 8,314 protein-coding genes, and support the gene models with proteome, expressed sequence tag, and RNA-seq data. We establish that Gc is heterothallic, and report evidence for repeat-induced point mutation. We report insights, from genome and transcriptome analyses, into how Gc tolerates conifer-defense chemicals, including oleoresin terpenoids, as they colonize a host tree. RNA-seq data indicate that terpenoids induce a substantial antimicrobial stress in Gc, and suggest that the fungus may detoxify these chemicals by using them as a carbon source. Terpenoid treatment strongly activated a ~100-kb region of the Gc genome that contains a set of genes that may be important for detoxification of these host-defense chemicals. This work is a major step toward understanding the biological interactions between the tripartite MPB/fungus/forest system.
PDF
