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The high frequency of phosphoinositide 3-kinase (PI3K) pathway alterations in cancer has led to a surge in the development of PI3K inhibitors. Many of these targeted therapies are currently in clinical trials and show great promise for the treatment of PI3K-addicted tumors. These recent developments call for a re-evaluation of the oncogenic mechanisms behind PI3K pathway alterations. This pathway is unique in that every major node is frequently mutated or amplified in a wide variety of solid tumors. Receptor tyrosine kinases upstream of PI3K, the p110α catalytic subunit of PI3K, the downstream kinase, AKT, and the negative regulator, PTEN, are all frequently altered in cancer. In this review, we will examine the oncogenic properties of these genetic alterations to understand whether they are redundant or distinct and propose treatment strategies tailored for these genetic lesions.

Quantum key distribution (QKD) 1 , 2 allows two distant parties to share encryption keys with security based on physical laws. Experimentally, QKD has been implemented via optical means, achieving key rates of 1.26 megabits per second over 50 kilometres of standard optical fibre 3 and of 1.16 bits per hour over 404 kilometres of ultralow-loss fibre in a measurement-device-independent configuration 4 . Increasing the bit rate and range of QKD is a formidable, but important, challenge. A related target, which is currently considered to be unfeasible without quantum repeaters 5 – 7 , is overcoming the fundamental rate–distance limit of QKD 8 . This limit defines the maximum possible secret key rate that two parties can distil at a given distance using QKD and is quantified by the secret-key capacity of the quantum channel 9 that connects the parties. Here we introduce an alternative scheme for QKD whereby pairs of phase-randomized optical fields are first generated at two distant locations and then combined at a central measuring station. Fields imparted with the same random phase are ‘twins’ and can be used to distil a quantum key. The key rate of this twin-field QKD exhibits the same dependence on distance as does a quantum repeater, scaling with the square-root of the channel transmittance, irrespective of who (malicious or otherwise) is in control of the measuring station. However, unlike schemes that involve quantum repeaters, ours is feasible with current technology and presents manageable levels of noise even on 550 kilometres of standard optical fibre. This scheme is a promising step towards overcoming the rate–distance limit of QKD and greatly extending the range of secure quantum communications. Twin optical fields enable a form of quantum key distribution that can exceed the secret-key capacity without using quantum repeaters and that has security independent of the measuring devices.

The empirical relationship between total phosphorus and chlorophyll has guided lake management decisions for decades, but imprecision in this relationship in individual lakes limits the utility of these models. Many environmental factors that potentially affect the total phosphorus-chlorophyll relationship have been studied, but here we hypothesize that imprecision can be reduced by considering differences in the proportions of phosphorus bound to three different “compartments” in the water column: phosphorus bound in phytoplankton, phosphorus bound to suspended sediment that is not associated with phytoplankton, and dissolved phosphorus. We specify a hierarchical Bayesian network model that estimates phosphorus associated with each compartment using field measurements of chlorophyll, total suspended solids, and total phosphorus collected from reservoirs in Missouri, United States. We then demonstrate that accounting for these different compartments yields accurate predictions of total phosphorus in individual lakes. Results from this model also yield insights into the mechanisms by which lake morphometric and watershed characteristics affect observed relationships between total phosphorus and chlorophyll.

Quantum cryptography immune from detector attacks is realized by the development of a source of indistinguishable laser pulses based on optically seeded gain-switched lasers. Key rates exceeding 1 Mb s −1 are demonstrated in the finite-size regime. Security in quantum cryptography 1 , 2 is continuously challenged by inventive attacks 3 , 4 , 5 , 6 , 7 targeting the real components of a cryptographic set-up, and duly restored by new countermeasures 8 , 9 , 10 to foil them. Owing to their high sensitivity and complex design, detectors are the most frequently attacked components. It was recently shown that two-photon interference 11 from independent light sources can be used to remove any vulnerability from detectors 12 , 13 . This new form of detection-safe quantum key distribution (QKD), termed measurement-device-independent 13 (MDI), has been experimentally demonstrated 13 , 14 , 15 , 16 , 17 , 18 , 19 but with modest key rates. Here, we introduce a new pulsed laser seeding technique to obtain high-visibility interference from gain-switched lasers and thereby perform MDI-QKD with unprecedented key rates in excess of 1 megabit per second in the finite-size regime. This represents a two to six orders of magnitude improvement over existing implementations and supports the new scheme as a practical resource for secure quantum communications.

The development of quantum networks will be paramount towards practical and secure telecommunications. These networks will need to sign and distribute information between many parties with information-theoretic security, requiring both quantum digital signatures (QDS) and quantum key distribution (QKD). Here, we introduce and experimentally realise a quantum network architecture, where the nodes are fully connected using a minimum amount of physical links. The central node of the network can act either as a totally untrusted relay, connecting the end users via the recently introduced measurement-device-independent (MDI)-QKD, or as a trusted recipient directly communicating with the end users via QKD. Using this network, we perform a proof-of-principle demonstration of QDS mediated by MDI-QKD. For that, we devised an efficient protocol to distil multiple signatures from the same block of data, thus reducing the statistical fluctuations in the sample and greatly enhancing the final QDS rate in the finite-size scenario. Measurement-device-independent quantum digital signatures would allow a document to be signed and transferred with information-theoretic security. Here, the authors reach this goal using a reconfigurable quantum network where the central node can switch between trusted and untrusted operation.

Protein misfolding in the endoplasmic reticulum (ER) leads to cell death through PERK-mediated phosphorylation of eIF2α, although the mechanism is not understood. ChIP-seq and mRNA-seq of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), key transcription factors downstream of p-eIF2α, demonstrated that they interact to directly induce genes encoding protein synthesis and the unfolded protein response, but not apoptosis. Forced expression of ATF4 and CHOP increased protein synthesis and caused ATP depletion, oxidative stress and cell death. The increased protein synthesis and oxidative stress were necessary signals for cell death. We show that eIF2α-phosphorylation-attenuated protein synthesis, and not Atf4 mRNA translation, promotes cell survival. These results show that transcriptional induction through ATF4 and CHOP increases protein synthesis leading to oxidative stress and cell death. The findings suggest that limiting protein synthesis will be therapeutic for diseases caused by protein misfolding in the ER. In the presence of stress stimuli, the endoplasmic reticulum either adapts the protein synthesis or triggers an apoptotic response, but the mechanisms underlying this decision are unknown. Kaufman and colleagues show that the ER stress response factors ATF4 and CHOP increase protein synthesis, which in turn induces oxidative stress and increased ATP consumption, leading to cell death during chronic ER stress.

In the quantum version of a Trojan-horse attack, photons are injected into the optical modules of a quantum key distribution system in an attempt to read information direct from the encoding devices. To stop the Trojan photons, the use of passive optical components has been suggested. However, to date, there is no quantitative bound that specifies such components in relation to the security of the system. Here, we turn the Trojan-horse attack into an information leakage problem. This allows us to quantify the system security and relate it to the specification of the optical elements. The analysis is supported by the experimental characterization, within the operation regime, of reflectivity and transmission of the optical components most relevant to security.

Oncogenic mutations in the small GTPase KRAS are frequently found in human cancers, and, currently, there are no effective targeted therapies for these tumors. Using a combinatorial siRNA approach, we analyzed a panel of KRAS mutant colorectal and pancreatic cancer cell lines for their dependency on 28 gene nodes that represent canonical RAS effector pathways and selected stress response pathways. We found that RAF node knockdown best differentiated KRAS mutant and KRAS WT cancer cells, suggesting RAF kinases are key oncoeffectors for KRAS addiction. By analyzing all 376 pairwise combination of these gene nodes, we found that cotargeting the RAF, RAC, and autophagy pathways can improve the capture of KRAS dependency better than targeting RAF alone. In particular, codepletion of the oncoeffector kinases BRAF and CRAF, together with the autophagy E1 ligase ATG7, gives the best therapeutic window between KRAS mutant cells and normal, untransformed cells. Distinct patterns of RAS effector dependency were observed across KRAS mutant cell lines, indicative of heterogeneous utilization of effector and stress response pathways in supporting KRAS addiction. Our findings revealed previously unappreciated complexity in the signaling network downstream of the KRAS oncogene and suggest rational target combinations for more effective therapeutic intervention.

Antiferromagnets have been generating intense interest in the spintronics community, owing to their intrinsic appealing properties like zero stray field and ultrafast spin dynamics. While the control of antiferromagnetic (AFM) orders has been realized by various means, applicably appreciated functionalities on the readout side of AFM-based devices are urgently desired. Here, we report the remarkably enhanced anisotropic magnetoresistance (AMR) as giant as ~160% in a simple resistor structure made of AFM Sr 2 IrO 4 without auxiliary reference layer. The underlying mechanism for the giant AMR is an indispensable combination of atomic scale giant-MR-like effect and magnetocrystalline anisotropy energy, which was not accessed earlier. Furthermore, we demonstrate the bistable nonvolatile memory states that can be switched in-situ without the inconvenient heat-assisted procedure, and robustly preserved even at zero magnetic field, due to the modified interlayer coupling by 1% Ga-doping in Sr 2 IrO 4 . These findings represent a straightforward step toward the AFM spintronic devices. The determination of the antiferromagnetic (AFM) orders by the anisotropic magnetoresistance (AMR) is one of the key components to the AFM-spintronics. Here the authors report enhanced AMR ~160% in Sr 2 IrO 4 due to the combination of atomic scale giant-MR-like effect and magnetocrystalline anisotropy energy.

To understand the impact of firework-burning (FW) particles on air quality and human health during the winter haze period, 39 elements, 10 water-soluble ions and 8 fractions of carbonaceous species in atmospheric PM2.5 in Nanjing were investigated during the 2014 Chinese Spring Festival (SF). Serious regional haze pollution persisted throughout the entire sampling period, with PM2.5 averaging at 113 ± 69 μg m−3 and visibility at 4.8 ± 3.2 km. The holiday effect led to almost all the chemical species decreasing during the SF, except for Al, K, Ba and Sr which were related to FW. The source contributions of coal combustion, vehicle emission and road dust decreased dramatically, whereas FW contributed to about half of the PM2.5 during the SF period. The intensive emission of FW particles on New Year's Eve accounted for 60.1% of the PM2.5. Fireworks also obviously modified the chemical compositions of PM2.5, with 39.3% contributed by increased organic matter, followed by steadily increased loadings of secondary inorganic ions. The aging processes of the FW particles lasted for about 4 days reflected by the variations of Ba, Sr, NH4+, NO3−, SO42− and K+, characterized by heterogeneous reactions of SO2 and NOx on crustal materials directly from FW, the replacement of Cl− by NO3− and SO42−, coating of NO3− and SO42− on soot, formation of secondary organic aerosols and metal-catalyzed formation of NO3− and SO42− at higher relative humidity. During aging, the main contributors to the extinction coefficient shifted from elemental carbon and organic matter to ammonium sulfate. The particles raised higher cancer risk of 1.62 × 10−6 by heavy metals (especially for Cd and As). This study provided detailed composition data and first comprehensive analysis of the aging processes of FW particles during the serious haze pollution period and their potential impact on human health.