Researchers and government agencies pay too little attention to pathological gambling. This must change.
A universal flu vaccine is the only serious defence against a future flu pandemic.
After 12 months in office, Trump’s effects on science have been as bad as feared.
Chinese scientists create cloned primates that could revolutionize studies of human disease.
Research budget could rise to 3.5% of gross domestic product if agreement struck during coalition talks holds.
Science agencies poised to resume normal operations after lawmakers agree on stopgap budget measure that expires on 8 February.
Report shows increasing international competition, but suggests that United States remains a scientific powerhouse.
Few scientists have had access to a thigh bone kept in a French collection for over a decade.
New analyses undermine a popular theory about an intense asteroid storm 4 billion years ago.
Advances in genomics and imaging are reviving a fading discipline.
News & Views
A technique in which a small particle is trapped and moved by laser light has been used to produce visual representations of
objects in three dimensions, offering key advantages over currently used approaches.
Ageing is a regulated process in which hormones have pivotal roles. Crystal structures of two hormone co-receptors should be informative for drug discovery focused on age-related disorders.
Quasars are the brightest continuously emitting sources of radiation in the Universe. Measurements of the most distant quasar ever detected reveal details about the evolution and structure of the early Universe.
Large-scale tree-planting projects have taken place in regions of China prone to soil erosion. Satellite imagery reveals the effects of this work, and shows that a predicted vegetation decline didn’t occur during a period of drought.
In 1938, two studies demonstrated that liquid helium-4 flows without friction or viscosity at temperatures close to absolute zero. The finding led to major advances in our understanding of low-temperature physics.
Transient cellular contacts are essential for the generation of an immune response, but these are difficult to measure in vivo. A labelling technique now offers a way to record such interactions between cells.
Speed and gait selection in mice are controlled by glutamatergic excitatory neurons in the cuneiform nucleus and the pedunculopontine nucleus, which act in conjunction to select context-dependent locomotor behaviours.
The crystal structure of shed ectodomain of α-klotho bound to the FGFR1c ligand-binding domain and FGF23 unveils the mechanism by which klotho co-receptors promote hormonal FGF signalling.
In chromosomally unstable tumour cells, rupture of micronuclei exposes genomic DNA and activates the cGAS–STING cytosolic DNA-sensing pathway, thereby promoting metastasis.
Observations of a quasar at redshift 7.54, when the Universe was just five per cent of its current age, suggest that the Universe was significantly neutral at this epoch.
Mapping the three-dimensional trajectory of a Neptune-mass exoplanet across the disk of its cool star reveals that its orbit is nearly perpendicular to the stellar equator, implying the existence of a yet-undetected outer companion planet.
By periodically modulating the position of degenerate fermions unidirectionally in a three-dimensional optical lattice, antiferromagnetic correlations in this many-body system can be reduced, enhanced or even switched to ferromagnetic correlations.
Photophoretic optical trapping of cellulose particles and persistence of vision are used to produce real-space volumetric images that can be viewed from all angles, in geometries unachievable by holograms and light-field technologies.
Xenon isotopic anomalies found in modern plume rocks are explained as the result of iodine-to-plutonium fractionations during early, high-pressure episodes of core formation.
Interactions between different cell types are essential for multiple biological
processes, including immunity, embryonic development and neuronal signalling.
Although the dynamics of cell–cell interactions can be monitored in
vivo by intravital microscopy, this approach does not
provide any information on the receptors and ligands involved or enable the
isolation of interacting cells for downstream analysis. Here we describe a
complementary approach that uses bacterial sortase A-mediated cell labelling across
synapses of immune cells to identify receptor–ligand interactions
between cells in living mice, by generating a signal that can subsequently be
detected ex vivo by flow cytometry. We call this approach for the labelling
of ‘kiss-and-run’ interactions between immune cells
‘Labelling Immune Partnerships by SorTagging Intercellular
Contacts’ (LIPSTIC). Using LIPSTIC, we show that interactions between
dendritic cells and CD4+ T cells during T-cell priming in vivo
occur in two distinct modalities: an early, cognate stage, during which
CD40–CD40L interactions occur specifically between T cells and
antigen-loaded dendritic cells; and a later, non-cognate stage during which these
interactions no longer require prior engagement of the T-cell receptor. Therefore,
LIPSTIC enables the direct measurement of dynamic cell–cell interactions
both in vitro and in vivo. Given its flexibility for use with
different receptor–ligand pairs and a range of detectable labels, we
expect that this approach will be of use to any field of biology requiring
quantification of intercellular communication.
Canonical fibroblast growth factors (FGFs) activate FGF receptors (FGFRs) through paracrine or autocrine mechanisms in a process that requires cooperation with heparan sulfate proteoglycans, which function as co-receptors for FGFR activation. By contrast, endocrine FGFs (FGF19, FGF21 and FGF23) are circulating hormones that regulate critical metabolic processes in a variety of tissues. FGF19 regulates bile acid synthesis and lipogenesis, whereas FGF21 stimulates insulin sensitivity, energy expenditure and weight loss. Endocrine FGFs signal through FGFRs in a manner that requires klothos, which are cell-surface proteins that possess tandem glycosidase domains. Here we describe the crystal structures of free and ligand-bound β-klotho extracellular regions that reveal the molecular mechanism that underlies the specificity of FGF21 towards β-klotho and demonstrate how the FGFR is activated in a klotho-dependent manner. β-Klotho serves as a primary ‘zip code’-like receptor that acts as a targeting signal for FGF21, and FGFR functions as a catalytic subunit that mediates intracellular signalling. Our structures also show how the sugar-cutting enzyme glycosidase has evolved to become a specific receptor for hormones that regulate metabolic processes, including the lowering of blood sugar levels. Finally, we describe an agonistic variant of FGF21 with enhanced biological activity and present structural insights into the potential development of therapeutic agents for diseases linked to endocrine FGFs.
The production of haematopoietic stem cells is repressed during early mammalian embryogenesis by an epigenetic mechanism that involves the action of the Polycomb protein EZH1.
Relapsed acute lymphoblastic leukaemia (ALL) is associated with resistance to chemotherapy and poor prognosis. Gain-of-function mutations in the 5′-nucleotidase, cytosolic II (NT5C2) gene induce resistance to 6-mercaptopurine and are selectively present in relapsed ALL. Yet, the mechanisms involved in NT5C2 mutation-driven clonal evolution during the initiation of leukaemia, disease progression and relapse remain unknown. Here we use a conditional-and-inducible leukaemia model to demonstrate that expression of NT5C2(R367Q), a highly prevalent relapsed-ALL NT5C2 mutation, induces resistance to chemotherapy with 6-mercaptopurine at the cost of impaired leukaemia cell growth and leukaemia-initiating cell activity. The loss-of-fitness phenotype of NT5C2+/R367Q mutant cells is associated with excess export of purines to the extracellular space and depletion of the intracellular purine-nucleotide pool. Consequently, blocking guanosine synthesis by inhibition of inosine-5′-monophosphate dehydrogenase (IMPDH) induced increased cytotoxicity against NT5C2-mutant leukaemia lymphoblasts. These results identify the fitness cost of NT5C2 mutation and resistance to chemotherapy as key evolutionary drivers that shape clonal evolution in relapsed ALL and support a role for IMPDH inhibition in the treatment of ALL.
The transcription factor Myc is essential for the regulation of haematopoietic stem
cells and progenitors and has a critical function in haematopoietic
malignancies. Here we show that an evolutionarily conserved
region located 1.7 megabases downstream of the Myc gene that has previously
been labelled as a ‘super-enhancer’ is
essential for the regulation of Myc expression levels in both normal
haematopoietic and leukaemic stem cell hierarchies in mice and humans. Deletion of
this region in mice leads to a complete loss of Myc expression in
haematopoietic stem cells and progenitors. This caused an accumulation of
differentiation-arrested multipotent progenitors and loss of myeloid and B cells,
mimicking the phenotype caused by Mx1-Cre-mediated conditional deletion of
the Myc gene in haematopoietic stem cells. This
super-enhancer comprises multiple enhancer modules with selective activity that
recruits a compendium of transcription factors, including GFI1b, RUNX1 and MYB.
Analysis of mice carrying deletions of individual enhancer modules suggests that
specific Myc expression levels throughout most of the haematopoietic
hierarchy are controlled by the combinatorial and additive activity of individual
enhancer modules, which collectively function as a ‘blood enhancer
cluster’ (BENC). We show that BENC is also essential for the maintenance
of MLL–AF9-driven leukaemia in mice. Furthermore, a BENC module, which
controls Myc expression in mouse haematopoietic stem cells and progenitors,
shows increased chromatin accessibility in human acute myeloid leukaemia stem cells
compared to blasts. This difference correlates with MYC expression and
patient outcome. We propose that clusters of enhancers, such as BENC, form highly
combinatorial systems that allow precise control of gene expression across normal
cellular hierarchies and which also can be hijacked in malignancies.
Cryo-electron microscopy reveals the structure of the Kaposi’s sarcoma-associated herpesvirus capsid, and experiments with polypeptides that mimic the smallest capsid protein demonstrate the potential for structure-derived insights to help to develop antiviral agents.
The X-ray structure of the integral membrane protein isoprenylcysteine carboxyl methyltransferase suggests mechanisms by which it recognizes both water-soluble and membrane-bound reactants to catalyze the methylation of RAS and other CAAX proteins at the membrane-cytosol interface.