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Quantum simulation: no satisfaction A network is termed 'frustrated' when competing interactions between nodes prevent each bond from being satisfied. Frustration in quantum networks can lead to massively entangled ground states. The authors study this process by performing a quantum simulation of a frustrated spin system using three trapped atomic ions, whose interactions are precisely controlled using optical forces. A network is frustrated when competing interactions between nodes prevent each bond from being satisfied. Frustration in quantum networks can lead to massively entangled ground states, as occurs in exotic materials such as quantum spin liquids and spin glasses. Here, a quantum simulation of a frustrated spin system is described, in which there are three trapped atomic ions whose interactions are controlled using optical forces. A network is frustrated when competing interactions between nodes prevent each bond from being satisfied. This compromise is central to the behaviour of many complex systems, from social 1 and neural 2 networks to protein folding 3 and magnetism 4 , 5 . Frustrated networks have highly degenerate ground states, with excess entropy and disorder even at zero temperature. In the case of quantum networks, frustration can lead to massively entangled ground states, underpinning exotic materials such as quantum spin liquids and spin glasses 6 , 7 , 8 , 9 . Here we realize a quantum simulation of frustrated Ising spins in a system of three trapped atomic ions 10 , 11 , 12 , whose interactions are precisely controlled using optical forces 13 . We study the ground state of this system as it adiabatically evolves from a transverse polarized state, and observe that frustration induces extra degeneracy. We also measure the entanglement in the system, finding a link between frustration and ground-state entanglement. This experimental system can be scaled to simulate larger numbers of spins, the ground states of which (for frustrated interactions) cannot be simulated on a classical computer.

A quantum simulator is a well-controlled quantum system that can follow the evolution of a prescribed model whose behaviour may be difficult to determine. A good example is the simulation of a set of interacting spins, where phase transitions between various spin orders can underlie poorly understood concepts such as spin liquids. Here we simulate the emergence of magnetism by implementing a fully connected non-uniform ferromagnetic quantum Ising model using up to 9 trapped 171 Yb + ions. By increasing the Ising coupling strengths compared with the transverse field, the crossover from paramagnetism to ferromagnetic order sharpens as the system is scaled up, prefacing the expected quantum phase transition in the thermodynamic limit. We measure scalable order parameters appropriate for large systems, such as various moments of the magnetization. As the results are theoretically tractable, this work provides a critical benchmark for the simulation of intractable arbitrary fully connected Ising models in larger systems. A quantum simulator can follow the evolution of a prescribed model, whose behaviour may be difficult to determine. Here, the emergence of magnetism is simulated by implementing a quantum Ising model, providing a benchmark for simulations in larger systems.

HER2-targeted treatments have improved outcomes in patients with HER2-positive breast cancer in the neoadjuvant, adjuvant, and metastatic settings; however, some patients remain at risk of relapse or death for many years after treatment of early-stage disease. Therefore, new strategies are needed. We did a phase 3 trial to assess a neoadjuvant regimen for HER2-positive breast cancer that replaces traditional systemic chemotherapy with targeted treatment. We did a randomised, open-label phase 3 KRISTINE trial in 68 Translational Research In Oncology centres (hospitals and specialty cancer centres in Asia, Europe, USA, and Canada). Eligible participants were aged 18 years or older with centrally confirmed HER2-positive stage II–III operable breast cancer (>2 cm tumour size), an Eastern Cooperative Oncology Group performance status of 0–1, and a baseline left ventricular ejection fraction of at least 55% (by echocardiogram or multiple-gated acquisition scan). We randomly assigned participants (1:1) to receive either trastuzumab emtansine plus pertuzumab or docetaxel, carboplatin, and trastuzumab plus pertuzumab. We did the randomisation via an interactive response system under a permuted block randomisation scheme (block size of four), stratified by hormone receptor status, stage at diagnosis, and geographical location. Patients received six cycles (every 3 weeks) of neoadjuvant trastuzumab emtansine plus pertuzumab (trastuzumab emtansine 3·6 mg/kg; pertuzumab 840 mg loading dose, 420 mg maintenance doses) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (docetaxel 75 mg/m2; carboplatin area under the concentration–time curve 6 mg/mL × min; trastuzumab 8 mg/kg loading dose, 6 mg/kg maintenance doses) plus pertuzumab [same dosing as in the other group]). All treatments were administered intravenously. The primary objective was to compare the number of patients who achieved a pathological complete response (ypT0/is, ypN0), between groups in the intention-to-treat population (two-sided assessment), based on local evaluation of tumour samples taken at breast cancer surgery done between 14 days and 6 weeks after completion of neoadjuvant therapy. Safety was analysed in patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02131064, and follow-up of the adjuvant phase is ongoing. Between June 25, 2014, and June 15, 2015, we randomly assigned 444 patients to neoadjuvant treatment with trastuzumab emtansine plus pertuzumab (n=223) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (n=221). A pathological complete response was achieved by 99 (44·4%) of 223 patients in the trastuzumab emtansine plus pertuzumab group and 123 (55·7%) of 221 patients in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group (absolute difference −11·3 percentage points, 95% CI −20·5 to −2·0; p=0·016). During neoadjuvant treatment, compared with patients receiving docetaxel, carboplatin, and trastuzumab plus pertuzumab, fewer patients receiving trastuzumab emtansine plus pertuzumab had a grade 3–4 adverse event (29 [13%] of 223 vs 141 [64%] of 219) or a serious adverse event (11 [5%] of 223 vs 63 [29%] of 219). The most common grade 3–4 adverse events in the trastuzumab emtansine plus pertuzumab group were decreased platelet count (three [1%] of 223 patients vs 11 [5%] of 219 with docetaxel, carboplatin, and trastuzumab plus pertuzumab), fatigue (three [1%] vs seven [3%]), alanine aminotransferase increase (three [1%] vs four [2%]), and hypokalaemia (three [1%] vs five [2%]). The most common grade 3–4 adverse events in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group were neutropenia (55 [25%] of 219 vs one [<1%] of 223 with trastuzumab emtansine plus pertuzumab), diarrhoea (33 [15%] vs 2 [<1%]), and febrile neutropenia (33 [15%] vs 0). No deaths were reported during neoadjuvant treatment. Traditional neoadjuvant systemic chemotherapy plus dual HER2-targeted blockade (docetaxel, carboplatin, and trastuzumab plus pertuzumab) resulted in significantly more patients achieving a pathological complete response than HER2-targeted chemotherapy plus HER2-targeted blockade (trastuzumab emtansine plus pertuzumab); however, numerically more grade 3–4 and serious adverse events occurred in the chemotherapy plus trastuzumab and pertuzumab group. Further efforts to improve the efficacy of chemotherapy without imparting more toxicity are warranted. F Hoffmann-La Roche and Genentech.

The RAG endonuclease initiates Igh locus V(D)J recombination in progenitor (pro)-B cells 1 . Upon binding a recombination centre-based J H , RAG scans upstream chromatin via loop extrusion, potentially mediated by cohesin, to locate Ds and assemble a DJ H -based recombination centre 2 . CTCF looping factor-bound elements (CBEs) within IGCR1 upstream of Ds impede RAG scanning 3 – 5 ; however, their inactivation allows scanning to proximal V H s, where additional CBEs activate rearrangement and impede scanning any further upstream 5 . Distal V H utilization is thought to involve diffusional access to the recombination centre following large-scale Igh locus contraction 6 – 8 . Here we test the potential of linear RAG scanning to mediate distal V H usage in G1-arrested v-Abl pro-B cell lines 9 , which undergo robust D-to-J H but little V H -to-DJ H rearrangements, presumably owing to lack of locus contraction 2 , 5 . Through an auxin-inducible approach 10 , we degraded the cohesin component RAD21 10 – 12 or CTCF 12 , 13 in these G1-arrested lines. Degradation of RAD21 eliminated all V(D)J recombination and interactions associated with RAG scanning, except for reecombination centre-located DQ52-to-J H joining, in which synapsis occurs by diffusion 2 . Remarkably, while degradation of CTCF suppressed most CBE-based chromatin interactions, it promoted robust recombination centre interactions with, and robust V H -to-DJ H joining of, distal V H s, with patterns similar to those of ‘locus-contracted’ primary pro-B cells. Thus, downmodulation of CTCF-bound scanning-impediment activity promotes cohesin-driven RAG scanning across the 2.7-Mb Igh locus. Using an auxin-inducible approach, the authors show that downmodulation of CTCF activity promotes cohesin-driven RAG endonuclease scanning, and thus V(D)J recombination, across the Igh locus.

The functional consequences of somatic non-coding mutations in ovarian cancer (OC) are unknown. To identify regulatory elements (RE) and genes perturbed by acquired non-coding variants, here we establish epigenomic and transcriptomic landscapes of primary OCs using H3K27ac ChIP-seq and RNA-seq, and then integrate these with whole genome sequencing data from 232 OCs. We identify 25 frequently mutated regulatory elements, including an enhancer at 6p22.1 which associates with differential expression of ZSCAN16 (P = 6.6 × 10-4) and ZSCAN12 (P = 0.02). CRISPR/Cas9 knockout of this enhancer induces downregulation of both genes. Globally, there is an enrichment of single nucleotide variants in active binding sites for TEAD4 (P = 6 × 10-11) and its binding partner PAX8 (P = 2×10-10), a known lineage-specific transcription factor in OC. In addition, the collection of cis REs associated with PAX8 comprise the most frequently mutated set of enhancers in OC (P = 0.003). These data indicate that non-coding somatic mutations disrupt the PAX8 transcriptional network during OC development. The role of non-coding somatic mutations in ovarian cancer is unclear. Here, the authors integrate genomic and epigenomic data from patient samples to show that these mutations frequently converge on the PAX8 transcriptional network.

This manuscript describes our experience in early identifying MDR-TB cases in high-risk populations by setting up a single-referral molecular diagnosis laboratory in Taiwan. Taiwan Centers for Disease Control designated a single-referral laboratory to provide the GenoType MTBDR plus test for screening high-risk MDR-TB populations nationwide in 2012–2015. A total of 5,838 sputum specimens from 3,308 patients were tested within 3 days turnaround time. Compared with the conventional culture and drug susceptibility testing, the overall performance of the GenoType MTBDR plus test for detecting TB infection showed accuracy of 70.7%, sensitivity of 85.9%, specificity of 65.7%, positive predictive value of 45.5%, and negative predictive value of 93.3%. And the accuracy of detecting rifampin (RIF) resistance, isoniazid (INH) resistance, and MDR-TB (resistant to at least RIF and INH) were 96.5%, 95.2%, and 97.7%, respectively. MDR-TB contacts presented a higher rate of mutated codons 513–519, GenoType MTBDR plus banding pattern: rpoB WT3(−), and rpoB WT4(−) than the treatment failure group. The MDR-TB contact group also had a higher rate of inhA C15T mutation, banding pattern: inh A WT1(−), and inhA MUT1(+) than the recurrent group. Resistance profiles of MDR-TB isolates also varied geographically. The referral molecular diagnosis system contributed to rapid detection and initiation of appropriate therapy.

There is growing interest in the formation of secondary organic aerosol (SOA) through condensed aqueous-phase reactions. In this study, we use a global model (IMPACT) to investigate the potential formation of SOA in the aqueous phase. We compare results from several multiphase process schemes with detailed aqueous-phase reactions to schemes that use a first-order gas-to-particle formation rate based on uptake coefficients. The predicted net global SOA production rate in cloud water ranges from 13.1 Tg yr−1 to 46.8 Tg yr−1 while that in aerosol water ranges from −0.4 Tg yr−1 to 12.6 Tg yr−1. The predicted global burden of SOA formed in the aqueous phase ranges from 0.09 Tg to 0.51 Tg. A sensitivity test to investigate two representations of cloud water content from two global models shows that increasing cloud water by an average factor of 2.7 can increase the net SOA production rate in cloud water by a factor of 4 at low altitudes (below approximately 900 hPa). We also investigated the importance of including dissolved Fe chemistry in cloud water aqueous reactions. Adding these reactions increases the formation rate of aqueous-phase OH by a factor of 2.6 and decreases the amount of global aqueous SOA formed by 31%. None of the mechanisms discussed here is able to provide a best fit for all observations. Rather, the use of an uptake coefficient method for aerosol water and a multi-phase scheme for cloud water provides the best fit in the Northern Hemisphere and the use of multiphase process scheme for aerosol and cloud water provides the best fit in the tropics. The model with Fe chemistry underpredicts oxalate measurements in all regions. Finally, the comparison of oxygen-to-carbon (O / C) ratios estimated in the model with those estimated from measurements shows that the modeled SOA has a slightly higher O / C ratio than the observed SOA for all cases.

Fragile X syndrome (FXS) is the most common inherited form of autism and intellectual disability and is caused by the silencing of a single gene, fragile X mental retardation 1 (Fmr1). The Fmr1 KO mouse displays phenotypes similar to symptoms in the human condition—including hyperactivity, repetitive behaviors, and seizures—as well as analogous abnormalities in the density of dendritic spines. Here we take a hypothesis-driven, mechanism-based approach to the search for an effective therapy for FXS. We hypothesize that a treatment that rescues the dendritic spine defect in Fmr1 KO mice may also ameliorate autism-like behavioral symptoms. Thus, we targeted a protein that regulates spines through modulation of actin cytoskeleton dynamics: p21-activated kinase (PAK). Our results demonstrate that a potent small molecule inhibitor of group I PAKs reverses dendritic spine phenotypes in Fmr1 KO mice. Moreover, this PAK inhibitor—which we call FRAX486—also rescues seizures and behavioral abnormalities such as hyperactivity and repetitive movements, thereby supporting the hypothesis that a drug treatment that reverses the spine abnormalities can also treat neurological and behavioral symptoms. Finally, a single administration of FRAX486 is sufficient to rescue all of these phenotypes in adult Fmr1 KO mice, demonstrating the potential for rapid, postdiagnostic therapy in adults with FXS.

Free-electron lasers have been successfully operated with ultrahigh brightness and excellent transverse coherence at X-ray wavelengths 1 , 2 , 3 , 4 . One of the next goals for further improvements is full coherence 5 , 6 . An obvious approach is to seed the free-electron laser interaction using a conventional source that has good temporal coherence 7 , 8 , 9 , 10 , 11 , 12 . Here, we show the first lasing of a free-electron laser with an echo-enabled harmonic generation scheme 11 , which shows great promise for producing coherent lasing at short wavelengths, even in the X-ray regime. The experiment was conducted at a test facility 13 , 14 that combines a 135.4 MeV electron accelerator with an amplifier consisting of a series of undulator magnets. Lasing was achieved at the third harmonic of the seed with a gain of ∼100,000 over spontaneous radiation. The measurements show typical exponential growth and excellent spectral characteristics, as well as good intensity stability. Lasing in X-ray free-electron lasers is typically achieved by self-amplification of spontaneous emission, which is known to have non-ideal temporal coherence and suffer from beam fluctuations. Here researchers report lasing based on echo-enabled harmonic generation at the Shanghai Deep Ultraviolet free-electron laser facility.