Excess copper is poisonous to all forms of life, and copper overloading is responsible for several human pathologic processes. The primary mechanisms of toxicity are unknown. In this study, mutants ...of Escherichia coli that lack copper homeostatic systems (copA cueO cus) were used to identify intracellular targets and to test the hypothesis that toxicity involves the action of reactive oxygen species. Low micromolar levels of copper were sufficient to inhibit the growth of both WT and mutant strains. The addition of branched-chain amino acids restored growth, indicating that copper blocks their biosynthesis. Indeed, copper treatment rapidly inactivated isopropylmalate dehydratase, an iron-sulfur cluster enzyme in this pathway. Other enzymes in this iron-sulfur dehydratase family were similarly affected. Inactivation did not require oxygen, in vivo or with purified enzyme. Damage occurred concomitant with the displacement of iron atoms from the solvent-exposed cluster, suggesting that Cu(I) damages these proteins by liganding to the coordinating sulfur atoms. Copper efflux by dedicated export systems, chelation by glutathione, and cluster repair by assembly systems all enhance the resistance of cells to this metal.
For most immune-mediated diseases, the main determinant of patient well-being is not the diagnosis itself but instead the course that the disease takes over time (prognosis). Prognosis may vary ...substantially between patients for reasons that are poorly understood. Familial studies support a genetic contribution to prognosis, but little evidence has been found for a proposed association between prognosis and the burden of susceptibility variants. To better characterize how genetic variation influences disease prognosis, we performed a within-cases genome-wide association study in two cohorts of patients with Crohn's disease. We identified four genome-wide significant loci, none of which showed any association with disease susceptibility. Conversely, the aggregated effect of all 170 disease susceptibility loci was not associated with disease prognosis. Together, these data suggest that the genetic contribution to prognosis in Crohn's disease is largely independent of the contribution to disease susceptibility and point to a biology of prognosis that could provide new therapeutic opportunities.
To define the cell populations that drive joint inflammation in rheumatoid arthritis (RA), we applied single-cell RNA sequencing (scRNA-seq), mass cytometry, bulk RNA sequencing (RNA-seq) and flow ...cytometry to T cells, B cells, monocytes, and fibroblasts from 51 samples of synovial tissue from patients with RA or osteoarthritis (OA). Utilizing an integrated strategy based on canonical correlation analysis of 5,265 scRNA-seq profiles, we identified 18 unique cell populations. Combining mass cytometry and transcriptomics revealed cell states expanded in RA synovia: THY1(CD90)
HLA-DRA
sublining fibroblasts, IL1B
pro-inflammatory monocytes, ITGAX
TBX21
autoimmune-associated B cells and PDCD1
peripheral helper T (T
) cells and follicular helper T (T
) cells. We defined distinct subsets of CD8
T cells characterized by GZMK
, GZMB
, and GNLY
phenotypes. We mapped inflammatory mediators to their source cell populations; for example, we attributed IL6 expression to THY1
HLA-DRA
fibroblasts and IL1B production to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.
Concern over the economics of accessing fossil fuel reserves, and widespread acceptance of the anthropogenic origin of rising CO
2
emissions and associated climate change from combusting such carbon ...sources, is driving academic and commercial research into new routes to sustainable fuels to meet the demands of a rapidly rising global population. Here we discuss catalytic esterification and transesterification solutions to the clean synthesis of biodiesel, the most readily implemented and low cost, alternative source of transportation fuels to meet future societal demands.
Low temperature catalytic conversion of triglycerides and fatty acids sourced from renewable feedstocks represents a key enabling technology for the sustainable production of biodiesel through energy efficient, intensified processes.
Higher-order chromatin structure is emerging as an important regulator of gene expression. Although dynamic chromatin structures have been identified in the genome, the full scope of chromatin ...dynamics during mammalian development and lineage specification remains to be determined. By mapping genome-wide chromatin interactions in human embryonic stem (ES) cells and four human ES-cell-derived lineages, we uncover extensive chromatin reorganization during lineage specification. We observe that although self-associating chromatin domains are stable during differentiation, chromatin interactions both within and between domains change in a striking manner, altering 36% of active and inactive chromosomal compartments throughout the genome. By integrating chromatin interaction maps with haplotype-resolved epigenome and transcriptome data sets, we find widespread allelic bias in gene expression correlated with allele-biased chromatin states of linked promoters and distal enhancers. Our results therefore provide a global view of chromatin dynamics and a resource for studying long-range control of gene expression in distinct human cell lineages.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Catalytic applications of waste derived materials Bennett, James A; Wilson, Karen; Lee, Adam F
Journal of materials chemistry. A, Materials for energy and sustainability,
01/2016, Letnik:
4, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Sustainability has become a watchword and guiding principle for modern society, and with it a growing appreciation that anthropogenic 'waste', in all its manifold forms, can offer a valuable source ...of energy, construction materials, chemicals and high value functional products. In the context of chemical transformations, waste materials not only provide alternative renewable feedstocks, but also a resource from which to create catalysts. Such waste-derived heterogeneous catalysts serve to improve the overall energy and atom-efficiency of existing and novel chemical processes. This review outlines key chemical transformations for which waste-derived heterogeneous catalysts have been developed, spanning biomass conversion to environmental remediation, and their benefits and disadvantages relative to conventional catalytic technologies.
Sustainability has become a watchword and guiding principle for modern society, and with it a growing appreciation that anthropogenic 'waste', in all its manifold forms, can offer a valuable source of energy, construction materials, chemicals and high value functional products.
High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, approximately half of which cannot be explained by known genes. To discover genes, we analyse germline exome ...sequencing data from 516 BRCA1/2-negative women with HGSOC, focusing on genes enriched with rare, protein-coding loss-of-function (LoF) variants. Overall, there is a significant enrichment of rare protein-coding LoF variants in the cases (p < 0.0001, chi-squared test). Only thirty-four (6.6%) have a pathogenic variant in a known or proposed predisposition gene. Few genes have LoF mutations in more than four individuals and the majority are detected in one individual only. Forty-three highly-ranked genes are identified with three or more LoF variants that are enriched by three-fold or more compared to GnomAD. These genes represent diverse functional pathways with relatively few involved in DNA repair, suggesting that much of the remaining heritability is explained by previously under-explored genes and pathways.
The synovium is a mesenchymal tissue composed mainly of fibroblasts, with a lining and sublining that surround the joints. In rheumatoid arthritis the synovial tissue undergoes marked hyperplasia, ...becomes inflamed and invasive, and destroys the joint
. It has recently been shown that a subset of fibroblasts in the sublining undergoes a major expansion in rheumatoid arthritis that is linked to disease activity
; however, the molecular mechanism by which these fibroblasts differentiate and expand is unknown. Here we identify a critical role for NOTCH3 signalling in the differentiation of perivascular and sublining fibroblasts that express CD90 (encoded by THY1). Using single-cell RNA sequencing and synovial tissue organoids, we found that NOTCH3 signalling drives both transcriptional and spatial gradients-emanating from vascular endothelial cells outwards-in fibroblasts. In active rheumatoid arthritis, NOTCH3 and Notch target genes are markedly upregulated in synovial fibroblasts. In mice, the genetic deletion of Notch3 or the blockade of NOTCH3 signalling attenuates inflammation and prevents joint damage in inflammatory arthritis. Our results indicate that synovial fibroblasts exhibit a positional identity that is regulated by endothelium-derived Notch signalling, and that this stromal crosstalk pathway underlies inflammation and pathology in inflammatory arthritis.
The Arctic has been warming faster than elsewhere, especially during the cold season. According to the leading theory, ice‐albedo feedback warms the Arctic Ocean during the summer, and the heat ...gained by the ocean is released during the winter, causing the cold‐season warming. Screen and Simmonds (2010; SS10) concluded that the theory is correct by comparing trend patterns in surface air temperature (SAT), surface turbulence heat flux (HF), and net surface infrared radiation (IR). However, in this comparison, downward IR is more appropriate to use. By analyzing the same data used in SS10 using the surface energy budget, it is shown here that over most of the Arctic the skin temperature trend, which closely resembles the SAT trend, is largely accounted for by the downward IR, not the HF, trend.
Key Points
Surface temperature should be compared with downward infrared radiation and not net infrared radiation
The Arctic surface temperature trend is driven primarily by downward infrared radiation and not surface turbulent fluxes
The downward infrared radiation trend is associated with the intraseasonal moisture intrusion trend
Plain Language Summary
The Arctic has been warming faster than elsewhere, especially during the fall and winter. According to the leading theory, ice‐albedo feedback warms the Arctic Ocean during the summer, and the heat gained by the ocean is released during the fall and winter, causing warming in these seasons. Deviating from this theory, it is shown here that over most of the Arctic, the skin temperature trend, which closely resembles the SAT trend, is largely accounted for by the downward infrared radiation, not the ocean‐to‐atmosphere heat flux, trend.
HIV-1 broadly neutralizing antibodies (bnAbs) develop in a subset of infected adults and exhibit high levels of somatic hypermutation (SHM) due to years of affinity maturation. There is no precedent ...for eliciting highly mutated antibodies by vaccination, nor is it practical to wait years for a desired response. Infants develop broad responses early, which may suggest a more direct path to generating bnAbs. Here, we isolated ten neutralizing antibodies (nAbs) contributing to plasma breadth of an infant at ∼1 year post-infection, including one with cross-clade breadth. The nAbs bind to envelope trimer from the transmitted virus, suggesting that this interaction may have initiated development of the infant nAbs. The infant cross-clade bnAb targets the N332 supersite on envelope but, unlike adult bnAbs targeting this site, lacks indels and has low SHM. The identification of this infant bnAb illustrates that HIV-1-specific neutralization breadth can develop without prolonged affinity maturation and extensive SHM.
Display omitted
•Infant HIV-1 nAbs isolated at ∼1 year post-infection contribute to plasma breadth•An infant broadly neutralizing antibody targets a known Env supersite•Infant nAbs bind early transmitted Envs but do not neutralize corresponding virus•Infant HIV-1 neutralizing antibodies have low levels of somatic hypermutation
Potent and broad neutralizing antibody responses to HIV typically take years to develop in infected adults, but new data in infected infants reveal a different pathway for their rapid development.
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