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The crystal structures of the human adiponectin receptors AdipoR1 and AdipoR2 are solved at 2.9 and 2.4 Å resolution, respectively; the structural and functional information may aid the development and optimization of adiponectin receptor agonists for the treatment of obesity-related diseases.
This study identifies a crucial role for fatty acid oxidation (FAO) in endothelial cells during angiogenesis, and reveals that fatty-acid-derived carbons are used for the de novo synthesis of nucleotides, and hence FAO stimulates vessel sprouting by increasing endothelial cell proliferation.
The physical size of the commonly used Cas9 from Streptococcus pyogenes poses challenges for CRISPR-Cas genome editing systems that use the adeno-associated virus as a delivery vehicle; here, smaller Cas9 orthologues are characterized, and Cas9 from Staphylococcus aureus allowed targeting of the cholesterol regulatory gene Pcsk9 in the mouse liver.
Analysis of a global data set of local biodiversity comparisons reveals an average 13.6% reduction in species richness and 10.7% reduction in abundance as a result of past human land use, and projections based on these data under a business-as-usual land-use scenario predict further substantial loss this century, unless strong mitigation efforts are undertaken to reverse the effects.
Two X-ray crystal structures are presented of the human P2Y1 G-protein-coupled receptor, which is an important target for anti-thrombotic drugs; the structures unexpectedly reveal two ligand-binding sites.
Ca2+ spikes are generated on different dendritic branches in the primary motor cortex of mice performing different motor learning tasks, causing long-lasting potentiation of postsynaptic dendritic spines; inactivation of a population of interneurons disrupts the spatial separation of Ca2+ spikes and persistent dendritic spine potentiation, suggesting that the generation of Ca2+ spikes on different dendritic branches is crucial for storing information in individual neurons.
In severe autism, deleterious variants at conserved residues are enriched in patients arising from female-enriched multiplex families, enhancing the detection of key autism genes in modest numbers of cases.
p53 suppresses expression of SLC7A11, a key component of the cystine/glutamate amino acid transport machinery, leading to inhibition of cystine uptake and promoting ferroptosis, an iron-dependent form of cell death.
A new MAP4K4–moesin–talin–β1-integrin pathway regulating endothelial cell motility was discovered through chemical and siRNA screens; loss of Map4k4 or inhibition of MAP4K4 kinase activity altered the sprout morphology of endothelial cells during angiogenesis by blocking moesin phosphorylation, which regulates the disassembly of focal adhesions, demonstrating that this pathway is involved in both normal and pathological angiogenesis.
Extensive genetic analysis of over 2,000 individuals from different locations in Britain reveals striking fine-scale patterns of population structure; comparisons with similar genetic data from the European continent reveal the legacy of earlier population migrations and information about the ancestry of current populations in specific geographic regions.
dG•dT and rG•rU ‘wobble’ mispairs in DNA and RNA transiently form base pairs with Watson–Crick geometry via tautomerization and ionization with probabilities that correlate with misincorporation probabilities during replication and translation.
The crystal structure of the heterohexameric origin recognition complex (ORC), essential for coordinating DNA replication onset in eukaryotes, is resolved at 3.5 Å resolution.
It has long been a goal to reconstitute eukaryotic DNA replication; here a purified in vitro system from budding yeast containing 16 factors, themselves composed of 42 polypeptides, fulfils the staged process of origin-dependent initiation, including its regulation by kinases.
This study demonstrates the activation of a STAT3-independent healing pathway in response to mucosal injury which involves the co-receptor for IL-6 cytokines gp130 and downstream effectors Src, Yes, YAP and Notch.
A whole-genome sequencing analysis of 100 pancreatic ductal adenocarcinomas has discovered known and newly identified genetic drivers of pancreatic cancer; these genetic alterations can be classified into four subtypes, which raises the possibility of improved targeting of clinical treatments.
Random DNA barcodes were used to simultaneously track hundreds of thousands of lineages in large cell populations, revealing deterministic dynamics early in their evolution.
During movement preparation, motor cortical neuronal subpopulations that project to downstream motor areas are more selective for the direction of upcoming movement than those that project to other cortical targets, especially immediately before movement, emphasizing the need to interpret complex neuronal responses measured during behaviour in the context of hierarchically organized cortical circuits.
The biochemical activity of Notum as a carboxylesterase that removes an essential lipid moiety from Wnt proteins is uncovered; the interaction of Notum with glypicans is required to ensure localization at the cell surface, and Notum may provide a new target for therapeutic development in diseases with defective Wnt signalling.
