The industrial revolution transformed the productive power of societies. It did so by vastly increasing the individual productivity, thus delivering whole populations from poverty. In this new ...account by one of the world's acknowledged authorities the central issue is not simply how the revolution began but still more why it did not quickly end. The answer lay in the use of a new source of energy. Pre-industrial societies had access only to very limited energy supplies. As long as mechanical energy came principally from human or animal muscle and heat energy from wood, the maximum attainable level of productivity was bound to be low. Exploitation of a new source of energy in the form of coal provided an escape route from the constraints of an organic economy but also brought novel dangers. Since this happened first in England, its experience has a special fascination, though other countries rapidly followed suit.
By the early nineteenth century England was very different economically from its continental neighbours. It was wealthier, growing more rapidly, more heavily urbanised, and far less dependent upon ...agriculture. A generation ago it was normal to attribute these differences to the 'industrial revolution' and to suppose that this was mainly the product of recent change, but no longer. Current estimates suggest only slow growth during the period from 1760–1840. This implies that the economy was much larger and more advanced by 1760 than had previously been supposed and suggests that growth in the preceding century or two must have been decisive in bringing about the 'divergence' of England. Sir E. A. Wrigley, the leading historian of industrial Britain, here examines the issues which arise in this connection from three viewpoints: economic growth; the transformation of the urban-rural balance; and demographic change in the seventeenth and eighteenth centuries.
Influenza is a major global public health threat as a result of its highly pathogenic variants, large zoonotic reservoir, and pandemic potential. Metagenomic viral sequencing offers the potential for ...a diagnostic test for influenza virus which also provides insights on transmission, evolution, and drug resistance and simultaneously detects other viruses. We therefore set out to apply the Oxford Nanopore Technologies sequencing method to metagenomic sequencing of respiratory samples. We generated influenza virus reads down to a limit of detection of 10
to 10
genome copies/ml in pooled samples, observing a strong relationship between the viral titer and the proportion of influenza virus reads (
= 4.7 × 10
). Applying our methods to clinical throat swabs, we generated influenza virus reads for 27/27 samples with mid-to-high viral titers (cycle threshold
values, <30) and 6/13 samples with low viral titers (
values, 30 to 40). No false-positive reads were generated from 10 influenza virus-negative samples. Thus, Nanopore sequencing operated with 83% sensitivity (95% confidence interval CI, 67 to 93%) and 100% specificity (95% CI, 69 to 100%) compared to the current diagnostic standard. Coverage of full-length virus was dependent on sample composition, being negatively influenced by increased host and bacterial reads. However, at high influenza virus titers, we were able to reconstruct >99% complete sequences for all eight gene segments. We also detected a human coronavirus coinfection in one clinical sample. While further optimization is required to improve sensitivity, this approach shows promise for the Nanopore platform to be used in the diagnosis and genetic analysis of influenza virus and other respiratory viruses.
Stressed cells shut down translation, release mRNA molecules from polysomes, and form stress granules (SGs) via a network of interactions that involve G3BP. Here we focus on the mechanistic ...underpinnings of SG assembly. We show that, under non-stress conditions, G3BP adopts a compact auto-inhibited state stabilized by electrostatic intramolecular interactions between the intrinsically disordered acidic tracts and the positively charged arginine-rich region. Upon release from polysomes, unfolded mRNAs outcompete G3BP auto-inhibitory interactions, engendering a conformational transition that facilitates clustering of G3BP through protein-RNA interactions. Subsequent physical crosslinking of G3BP clusters drives RNA molecules into networked RNA/protein condensates. We show that G3BP condensates impede RNA entanglement and recruit additional client proteins that promote SG maturation or induce a liquid-to-solid transition that may underlie disease. We propose that condensation coupled to conformational rearrangements and heterotypic multivalent interactions may be a general principle underlying RNP granule assembly.
Display omitted
•Under non-stressed conditions, G3BP adopts a compact auto-inhibited state•Conformational expansion of G3BP increases the interaction valences•G3BP clusters crosslink RNA to assemble stress granules upon cellular stress•G3BP condensates prevent RNA entanglement
Reconstitution of stress granule assembly reveals an autoinhibitory conformation of G3BP that is alleviated by RNA binding, demonstrating how this central node of the stress granule network phase-separates in response to rising cellular RNA concentrations.
A marked ocean acidification event and elevated atmospheric carbon dioxide concentrations following the extreme environmental conditions of the younger Cryogenian glaciation have been inferred from ...boron isotope measurements. Calcium and magnesium isotope analyses offer additional insights into the processes occurring during this time. Data from Neoproterozoic sections in Namibia indicate that following the end of glaciation the continental weathering flux transitioned from being of mixed carbonate and silicate character to a silicate-dominated one. Combined with the effects of primary dolomite formation in the cap dolostones, this caused the ocean to depart from a state of acidification and return to higher pH after climatic amelioration. Differences in the magnitude of stratigraphic isotopic changes across the continental margin of the southern Congo craton shelf point to local influences modifying and amplifying the global signal, which need to be considered in order to avoid overestimation of the worldwide chemical weathering flux.
•We investigate Earth system response and recovery to extreme environmental conditions in the Neoproterozoic.•Calcium and magnesium isotopes indicate an enhanced continental weathering flux after a global glaciation.•Continental weathering enabled the ocean to recover from an ocean acidification state.
The Boudouard reaction, which is the reaction of carbon and carbon dioxide to produce carbon monoxide, represents a simple and straightforward method for the remediation of carbon dioxide in the ...environment through reduction: CO2(g) + C(s) ⇌ 2CO. However, due to the large positive enthalpy, typically reported to be 172 kJ/mol under standard conditions at 298 K, the equilibrium does not favor CO production until temperatures >700 °C, when the entropic term, −TΔS, begins to dominate and the free energy becomes negative. We have found that, under microwave irradiation to selectively heat the carbon, dramatically different thermodynamics for the reaction are observed. During kinetic studies of the reaction under conditions of flowing CO2, the apparent activation energy dropped from 118.4 kJ/mol under conventional convective heating to 38.5 kJ/mol under microwave irradiation. From measurement of the equilibrium constants as a function of temperature, the enthalpy of the reaction dropped from 183.3 kJ/mol at ∼1100 K to 33.4 kJ/mol at the same temperature under microwave irradiation. This changes the position of the equilibrium so that the temperature at which CO becomes the major product drops from 643 °C in the conventional thermal reaction to 213 °C in the microwave. The observed reduction in the apparent enthalpy of the microwave driven reaction, compared to what is determined for the thermal reaction from standard heats of formation, can be thought of as arising from additional energy being put into the carbon by the microwaves, effectively increasing its apparent standard enthalpy. Mechanistically, it is hypothesized that the enhanced reactivity arises from the interaction of CO2 with the steady-state concentration of electron–hole pairs that are present at the surface of the carbon due to the space-charge mechanism, by which microwaves are known to heat carbon. Such a mechanism is unique to microwave-induced heating and, given the effect it has on the thermodynamics of the Boudouard reaction, suggests that its use may yield energy savings in driving the general class of gas–carbon reactions.
We explored the effects of aging on 2 large-scale brain networks, the default mode network (DMN) and the task-positive network (TPN). During functional magnetic resonance imaging scanning, young and ...older participants carried out 4 visual tasks: detection, perceptual matching, attentional cueing, and working memory. Accuracy of performance was roughly matched at 80% across tasks and groups. Modulations of activity across conditions were assessed, as well as functional connectivity of both networks. Younger adults showed a broader engagement of the DMN and older adults a more extensive engagement of the TPN. Functional connectivity in the DMN was reduced in older adults, whereas the main pattern of TPN connectivity was equivalent in the 2 groups. Age-specific connectivity also was seen in TPN regions. Increased activity in TPN areas predicted worse accuracy on the tasks, but greater expression of a connectivity pattern associated with a right dorsolateral prefrontal TPN region, seen only in older adults, predicted better performance. These results provide further evidence for age-related differences in the DMN and new evidence of age differences in the TPN. Increased use of the TPN may reflect greater demand on cognitive control processes in older individuals that may be partially offset by alterations in prefrontal functional connectivity.
The Psychiatric Genomics Consortium-Posttraumatic Stress Disorder group (PGC-PTSD) combined genome-wide case-control molecular genetic data across 11 multiethnic studies to quantify PTSD ...heritability, to examine potential shared genetic risk with schizophrenia, bipolar disorder, and major depressive disorder and to identify risk loci for PTSD. Examining 20 730 individuals, we report a molecular genetics-based heritability estimate (h
) for European-American females of 29% that is similar to h
for schizophrenia and is substantially higher than h
in European-American males (estimate not distinguishable from zero). We found strong evidence of overlapping genetic risk between PTSD and schizophrenia along with more modest evidence of overlap with bipolar and major depressive disorder. No single-nucleotide polymorphisms (SNPs) exceeded genome-wide significance in the transethnic (overall) meta-analysis and we do not replicate previously reported associations. Still, SNP-level summary statistics made available here afford the best-available molecular genetic index of PTSD-for both European- and African-American individuals-and can be used in polygenic risk prediction and genetic correlation studies of diverse phenotypes. Publication of summary statistics for ∼10 000 African Americans contributes to the broader goal of increased ancestral diversity in genomic data resources. In sum, the results demonstrate genetic influences on the development of PTSD, identify shared genetic risk between PTSD and other psychiatric disorders and highlight the importance of multiethnic/racial samples. As has been the case with schizophrenia and other complex genetic disorders, larger sample sizes are needed to identify specific risk loci.
Outcomes of children with high-risk (HR) relapsed acute lymphoblastic leukaemia (ALL) (N = 393), recruited to ALLR3 and ALL-REZ BFM 2002 trials, were analysed. Minimal residual disease (MRD) was ...assessed after induction and at predetermined time points until haematopoietic stem cell transplantation (SCT).
Genetic analyses included karyotype, copy-number alterations and mutation analyses. Ten-year survivals were analysed using Kaplan-Meier and Cox models for multivariable analyses.
Outcomes of patients were comparable in ALLR3 and ALL-REZ BFM 2002. The event-free survival of B-cell precursor (BCP) and T-cell ALL (T-ALL) was 22.6% and 26.2% (P = 0.94), respectively, and the overall survival (OS) was 32.6% and 28.2% (P = 0.11), respectively. Induction failures (38%) were associated with deletions of NR3C1 (P = 0.002) and BTG1 (P = 0.03) in BCP-ALL. The disease-free survival (DFS) and OS in patients with good vs poor MRD responses were 57.4% vs 22.6% (P < 0.0001) and 57.8% vs 32.0% (P = 0.0004), respectively. For BCP- and T-ALL, the post-SCT DFS and OS were 42.1% and 56.8% (P = 0.26) and 51.6% and 55.4% (P = 0.67), respectively. The cumulative incidences of post-SCT relapse for BCP- and T-ALL were 36.9% and 17.8% (P = 0.012) and of death were 10.7% and 25.5% (P = 0.013), respectively. Determinants of outcomes after SCT were acute graft versus host disease, pre-SCT MRD (≥10−3), HR cytogenetics and TP53 alterations in BCP-ALL.
Improvements in outcomes for HR ALL relapses require novel compounds in induction therapy to improve remission rates and immune targeted therapy after induction to maintain remission after SCT.
ALLR3: NCT00967057; ALL REZ-BFM 2002: NCT00114348
•Paediatric high-risk relapsed B- and T-cell leukaemias have comparably poor outcomes.•Determinants of induction failure in high-risk B-cell relapses were identified.•Molecular good responders had better outcomes after stem cell transplantation.•Benchmarks for evaluation of novel immune or targeted therapies were provided.
PDF
