The ability of certain plants, invertebrates, and microorganisms to survive almost complete loss of water has long been recognized, but the molecular mechanisms of this phenomenon remain to be ...defined. One phylogenetically widespread adaptation is the presence of abundant, highly hydrophilic proteins in desiccation-tolerant organisms. The best characterized of these polypeptides are the late embryogenesis abundant (LEA) proteins, first described in plant seeds >20 years ago but recently identified in invertebrates and bacteria. The function of these largely unstructured proteins has been unclear, but we now show that a group 3 LEA protein from the desiccation-tolerant nematode Aphelenchus avenae is able to prevent aggregation of a wide range of other proteins both in vitro and in vivo. The presence of water is essential for maintenance of the structure of many proteins, and therefore desiccation stress induces unfolding and aggregation. The nematode LEA protein is able to abrogate desiccation-induced aggregation of the water-soluble proteomes from nematodes and mammalian cells and affords protection during both dehydration and rehydration. Furthermore, when coexpressed in a human cell line, the LEA protein reduces the propensity of polyglutamine and polyalanine expansion proteins associated with neurodegenerative diseases to form aggregates, demonstrating in vivo function of an LEA protein as an antiaggregant. Finally, human cells expressing LEA protein exhibit increased survival of dehydration imposed by osmotic upshift, consistent with a broad protein stabilization function of LEA proteins under conditions of water stress.
Extrachromosomal circular DNAs (eccDNAs) have emerged as important intra-cellular mobile genetic elements that affect gene copy number and exert in trans regulatory roles within the cell nucleus. ...Here, we describe scCircle-seq, a method for profiling eccDNAs and unraveling their diversity and complexity in single cells. We implement and validate scCircle-seq in normal and cancer cell lines, demonstrating that most eccDNAs vary largely between cells and are stochastically inherited during cell division, although their genomic landscape is cell type-specific and can be used to accurately cluster cells of the same origin. eccDNAs are preferentially produced from chromatin regions enriched in H3K9me3 and H3K27me3 histone marks and are induced during replication stress conditions. Concomitant sequencing of eccDNAs and RNA from the same cell uncovers the absence of correlation between eccDNA copy number and gene expression levels, except for a few oncogenes, including MYC, contained within a large eccDNA in colorectal cancer cells. Lastly, we apply scCircle-seq to one prostate cancer and two breast cancer specimens, revealing cancer-specific eccDNA landscapes and a higher propensity of eccDNAs to form in amplified genomic regions. scCircle-seq is a scalable tool that can be used to dissect the complexity of eccDNAs across different cell and tissue types, and further expands the potential of eccDNAs for cancer diagnostics.
We present the first real-time composition of submicron particulate matter
(PM1) in Old Delhi using high-resolution aerosol mass spectrometry
(HR-AMS). Old Delhi is one of the most polluted locations ...in the world, and
PM1 concentrations reached ∼ 750 µg m−3
during the most polluted period, the post-monsoon period, where PM1 increased
by 188 % over the pre-monsoon period. Sulfate contributes the largest
inorganic PM1 mass fraction during the pre-monsoon (24 %) and monsoon
(24 %) periods, with nitrate contributing most during the post-monsoon period
(8 %). The organics dominate the mass fraction (54 %–68 %) throughout the
three periods, and, using positive matrix factorisation (PMF) to perform
source apportionment analysis of organic mass, two burning-related factors
were found to contribute the most (35 %) to the post-monsoon increase. The
first PMF factor, semi-volatility biomass burning organic aerosol (SVBBOA),
shows a high correlation with Earth observation fire counts in surrounding
states, which links its origin to crop residue burning. The second is a
solid fuel OA (SFOA) factor with links to local open burning due to its high
composition of polyaromatic hydrocarbons (PAHs) and novel AMS-measured marker
species for polychlorinated dibenzodioxins (PCDDs) and polychlorinated
dibenzofurans (PCDFs). Two traffic factors were resolved: one
hydrocarbon-like OA (HOA) factor and another nitrogen-rich HOA (NHOA)
factor. The N compounds within NHOA were mainly nitrile species which have
not previously been identified within AMS measurements. Their PAH
composition suggests that NHOA is linked to diesel and HOA to compressed
natural gas and petrol. These factors combined make the largest relative
contribution to primary PM1 mass during the pre-monsoon and monsoon
periods while contributing the second highest in the post-monsoon period. A
cooking OA (COA) factor shows strong links to the secondary factor,
semi-volatility oxygenated OA (SVOOA). Correlations with co-located volatile
organic compound (VOC) measurements and AMS-measured organic nitrogen oxides
(OrgNO) suggest SVOOA is formed from aged COA. It is also found that a
significant increase in chloride concentrations (522 %) from pre-monsoon
to post-monsoon correlates well with SVBBOA and SFOA, suggesting that crop
residue burning and open waste burning are responsible. A reduction in
traffic emissions would effectively reduce concentrations across most of the
year. In order to reduce the post-monsoon peak, sources such as funeral
pyres, solid waste burning and crop residue burning should be considered
when developing new air quality policy.
Recent reports suggest a link between positive regulation of the Hippo pathway with bipolar disorder (BD), and the Hippo pathway is known to interact with multiple other signaling pathways previously ...associated with BD and other psychiatric disorders. In this study, neuronal-like NT2 cells were treated with amisulpride (10 µM), aripiprazole (0.1 µM), clozapine (10 µM), lamotrigine (50 µM), lithium (2.5 mM), quetiapine (50 µM), risperidone (0.1 µM), valproate (0.5 mM), or vehicle control for 24 h. Genome-wide mRNA expression was quantified and analyzed using gene set enrichment analysis (GSEA), with genes belonging to Hippo, Wnt, Notch, TGF- β, and Hedgehog retrieved from the KEGG database. Five of the eight drugs downregulated the genes of the Hippo pathway and modulated several genes involved in the interacting pathways. We speculate that the regulation of these genes, especially by aripiprazole, clozapine, and quetiapine, results in a reduction of MAPK and NFκB pro-inflammatory signaling through modulation of Hippo, Wnt, and TGF-β pathways. We also employed connectivity map analysis to identify compounds that act on these pathways in a similar manner to the known psychiatric drugs. Thirty-six compounds were identified. The presence of antidepressants and antipsychotics validates our approach and reveals possible new targets for drug repurposing.
Accumulation of DNA lesions causing transcription stress is associated with natural and accelerated aging and culminates with profound metabolic alterations. Our understanding of the mechanisms ...governing metabolic redesign upon genomic instability, however, is highly rudimentary. Using Ercc1-defective mice and Xpg knock-out mice, we demonstrate that combined defects in transcription-coupled DNA repair (TCR) and in nucleotide excision repair (NER) directly affect bioenergetics due to declined transcription, leading to increased ATP levels. This in turn inhibits glycolysis allosterically and favors glucose rerouting through the pentose phosphate shunt, eventually enhancing production of NADPH-reducing equivalents. In NER/TCR-defective mutants, augmented NADPH is not counterbalanced by increased production of pro-oxidants and thus pentose phosphate potentiation culminates in an over-reduced redox state. Skin fibroblasts from the TCR disease Cockayne syndrome confirm results in animal models. Overall, these findings unravel a mechanism connecting DNA damage and transcriptional stress to metabolic redesign and protective antioxidant defenses.
Over the past 34 Million years, the Antarctic continental shelf has gradually deepened due to ice sheet loading, thermal subsidence, and erosion from repeated glaciations. The deepening that is ...recorded in the sedimentary deposits around the Antarctic margin indicates that after the mid-Miocene Climate Optimum (≈15 Ma), Antarctic Ice Sheet (AIS) dynamical response to climate conditions changed. We explore end-members for maximum AIS extent, based on ice-sheet simulations of a late-Pleistocene and a mid-Miocene glaciation. Fundamental dynamical differences emerge as a consequence of atmospheric forcing, eustatic sea level and continental shelf evolution. We show that the AIS contributed to the amplification of its own sensitivity to ocean forcing by gradually expanding and eroding the continental shelf, that probably changed its tipping points through time. The lack of past topographic and bathymetric reconstructions implies that so far, we still have an incomplete understanding of AIS fast response to past warm climate conditions, which is crucial to constrain its future evolution.
Transition quadrupole moments, Q sub(t), of two ultrahigh-spin, collective structures in super(154)Er have been measured for the first time using the Doppler Shift Attenuation Method (DSAM). Data ...were acquired at the ATLAS accelerator facility of Argonne National Laboratory, using the Gammasphere detector array. A thick, gold-backed super(110)Pd foil was bombarded by a beam of super(48)Ti ions at 215 MeV. The Q sub(t) for each band was determined from the Doppler shift of gamma rays emitted by the resulting recoil nuclei. The extracted transition quadrupole moments are significantly different in magnitude, suggesting the two structures in super(154)Er represent distinct exotic nuclear shapes, namely axial superdeformed (SD) with Q sub(t) approximately 20 eb, and triaxial strongly deformed (TSD) with Q sub(t) approximately 11 eb. Indeed, the results calibrate the quadrupole moments of TSD bands recently measured in light erbium nuclei, super(157,158)Er.
Objectives12-hour shifts worked by nurses on acute hospital wards have been associated with increased rates of missed care reported by nurses. This study aimed to measure the association between ...nurses working shifts of at least 12 hours and an objective measure of missed care: vital signs observations taken on time according to an acuity-based surveillance protocol.DesignA retrospective observational study using routinely collected data from March 2012 to March 2015.Setting32 general inpatient wards at a large acute hospital in England.Participants658 628 nursing shifts nested in 24 069 ward days.Outcome measuresThe rate of daily delayed and missed vital signs observations. We focused on situations where vital signs observations were required at least every 4 hours and measured the number of instances where observations were delayed or missed, per 24-hour period. For each ward and each day, shift patterns were characterised in terms of proportion of care hours per patient day deriving from ‘long’ shifts (≥12 hours) for both registered nurses and healthcare assistants.ResultsOn 99 043 occasions (53%), observations were significantly delayed, and on 81 568 occasions (44%), observations were missed. Observations were more likely to be delayed when a higher proportion of the hours worked by healthcare assistants were part of long shifts (IRR=1.05; 95% CI 1.00 to 1.10). No significant association was found in relation to the proportion of hours registered nurses worked as long shifts.ConclusionOn days when a higher proportion of hours worked by healthcare assistants are from long shifts, the risk of delaying vital signs observations is higher, suggesting lower job performance. While longer shifts are thought to require fewer staff resources to maintain nurse-to-patient ratios, any benefits may be lost if staff become less productive.
PDF
