It is time for scientists and politicians alike to constructively engage with core issues — from climate change and energy independence to social inequality.
Establishing a Martian outpost is likely to bring many of the same societal problems we face on Earth.
The first person to invoke the ‘man on the street’ has been identified, but sometimes maths is just too difficult to make simple.
Climate-change and immigration policies raise alarm, but much of the incoming US president's agenda is simply unknown.
Most surveys did not predict Donald Trump’s victory over Hillary Clinton.
Davide Vannoni is barred from offering a controversial stem-cell therapy in Italy but may be continuing his work abroad.
At a conference in San Francisco, a group drafted proposals to add more planets, instruments and other science icons to the keyboard.
Country's progress on public health and science prompts funding shift to more-troubled nations.
Journal experiments and surveys suggest scientists are coming round to the idea of publishing review reports.
The waters of the Southern Ocean have absorbed much of the excess heat and carbon generated by humanity.
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Random lasers use disordered structures to produce light, which is usually emitted in many directions. A random laser that can produce a collimated beam offers a wide range of applications, from imaging to security scanning.
Hsp70 chaperone molecules help other proteins to fold, and were thought to bind mainly to unfolded proteins. Single-molecule experiments now suggest that Hsp70s can also stabilize almost fully folded proteins. See Letter p.448
Models indicate that there are strong gradients in element concentrations and in the pH of fluids at the slab–mantle interface — a major discontinuity deep within Earth. This transforms our view of global geochemical transport. See Letter p.420
Sleep in mammals consists of non-rapid-eye-movement and rapid-eye-movement sleep. A large genetic screen reveals that these two sleep states are altered in mice by mutations dubbed Sleepy and Dreamless. See Article p.378
Polymeric semiconductors have been prepared whose molecular properties make them stretchable and healable — a milestone in the development of sophisticated organic electronic surfaces that mimic human skin. See Letter p.411
Anaerobic microbes have been found to break down the hydrocarbon butane by a pathway with some similarities to anaerobic methane breakdown. Harnessing the butane pathway might enable biofuel generation. See Article p.396
A review into the complex effects of Δ9-tetrahydrocannabinol on the dopamine system, examining data from animal and human studies and discussing the necessary future direction of research.
Two mutations affecting the sleep–wakefulness balance in mice are detected, showing that the SIK3 protein kinase is essential for determining daily wake time, and the NALCN cation channel regulates the duration of rapid eye movement sleep.
These preclinical studies outline a CRISPR-based methodology for correcting β-globin gene mutations in haematopoietic stem cells to advance the development of next-generation therapies for β-haemoglobinopathies.
Human tumours with mutations in LKB1 and Kras have a specific hypermetabolic state associated with increased DNA methylation, pointing to potential metabolic and epigenetic vulnerabilities of specific tumours.
Anaerobic archaea enriched in thermophilic microbial consortia completely degrade butane by modifying mechanisms which were hitherto thought to be specific to methane metabolism.
A model of the Moon’s tidal evolution, starting from the fast-spinning, high-obliquity Earth that would be expected after a giant impact, reveals that solar perturbations on the Moon’s orbit naturally produce the current lunar inclination and Earth’s low obliquity.
A cryogenic thermal imaging technique that uses a superconducting quantum interference device fabricated on the tip of a sharp pipette can be used to image the thermal signature of extremely low power nanometre-scale dissipation processes.
Introducing non-covalent crosslinking moieties to polymer semiconductors produces a stretchable and healable material suitable for wearable electronics.
Rapid vertical transport of small aerosol particles from the free troposphere to the atmospheric boundary layer occurs during precipitation and maintains the population of aerosol particles over Amazonia.
A thermodynamic model of fluid pH and its variability in Earth’s mantle and subducting crust highlights chemical feedbacks that connect deep Earth to surface processes.
Variation in plant nutrient levels suppresses insect herbivore populations and the homogenous nutrient content of modern agricultural crops could be contributing to insect pest outbreaks.
Calcium signalling in astrocytes, driven through the octopamine/tyramine receptor and the TRP channel Water witch, is essential for neuromodulation and sensory responses in Drosophila larvae.
Transcription of a long non-coding RNA, known as upperhand (Uph) located upstream of the HAND2 transcription factor is required to maintain transcription of the Hand2 gene by RNA polymerase, and blockade of Uph expression leads to heart defects and embryonic lethality in mice.
Macrophages play critical, but opposite, roles in acute and chronic inflammation and cancer. In response to pathogens or injury, inflammatory macrophages express cytokines that stimulate cytotoxic T cells, whereas macrophages in neoplastic and parasitic diseases express anti-inflammatory cytokines that induce immune suppression and may promote resistance to T cell checkpoint inhibitors. Here we show that macrophage PI 3-kinase γ controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3Kγ signalling through Akt and mTor inhibits NFκB activation while stimulating C/EBPβ activation, thereby inducing a transcriptional program that promotes immune suppression during inflammation and tumour growth. By contrast, selective inactivation of macrophage PI3Kγ stimulates and prolongs NFκB activation and inhibits C/EBPβ activation, thus promoting an immunostimulatory transcriptional program that restores CD8+ T cell activation and cytotoxicity. PI3Kγ synergizes with checkpoint inhibitor therapy to promote tumour regression and increased survival in mouse models of cancer. In addition, PI3Kγ-directed, anti-inflammatory gene expression can predict survival probability in cancer patients. Our work thus demonstrates that therapeutic targeting of intracellular signalling pathways that regulate the switch between macrophage polarization states can control immune suppression in cancer and other disorders.
Recent clinical trials using immunotherapy have demonstrated its potential to control cancer by disinhibiting the immune system. Immune checkpoint blocking (ICB) antibodies against cytotoxic-T-lymphocyte-associated protein 4 or programmed cell death protein 1/programmed death-ligand 1 have displayed durable clinical responses in various cancers. Although these new immunotherapies have had a notable effect on cancer treatment, multiple mechanisms of immune resistance exist in tumours. Among the key mechanisms, myeloid cells have a major role in limiting effective tumour immunity. Growing evidence suggests that high infiltration of immune-suppressive myeloid cells correlates with poor prognosis and ICB resistance. These observations suggest a need for a precision medicine approach in which the design of the immunotherapeutic combination is modified on the basis of the tumour immune landscape to overcome such resistance mechanisms. Here we employ a pre-clinical mouse model system and show that resistance to ICB is directly mediated by the suppressive activity of infiltrating myeloid cells in various tumours. Furthermore, selective pharmacologic targeting of the gamma isoform of phosphoinositide 3-kinase (PI3Kγ), highly expressed in myeloid cells, restores sensitivity to ICB. We demonstrate that targeting PI3Kγ with a selective inhibitor, currently being evaluated in a phase 1 clinical trial (NCT02637531), can reshape the tumour immune microenvironment and promote cytotoxic-T-cell-mediated tumour regression without targeting cancer cells directly. Our results introduce opportunities for new combination strategies using a selective small molecule PI3Kγ inhibitor, such as IPI-549, to overcome resistance to ICB in patients with high levels of suppressive myeloid cell infiltration in tumours.
Hsp70 binds unfolded protein segments in its groove, but can also bind and stabilize folded protein structures, owing to its moveable lid, with ATP hydrolysis and co-chaperones allowing control of these contrasting effects.
Various cis-regulatory functions of genomic loci that produce long non-coding RNAs are revealed, including instances where their promoters have enhancer-like activity and the lncRNA transcripts themselves are not required for activity.