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A direct measurement of cosmic-ray electrons and positrons with unprecedentedly high energy resolution reveals a spectral break at about 0.9 teraelectronvolts, confirming the evidence found by previous indirect measurements. A break in the cosmic-ray spectrum The spectrum of cosmic-ray electrons and positrons that arrive at Earth potentially contains information about the sources that accelerated them, and may reveal dark-matter annihilation. The spectrum has previously been measured directly up to around 2 teraelectronvolts (TeV), and indirectly up to around 5 TeV from ground-based Cherenkov arrays, which revealed a possible break in the spectrum. The Dark Matter Particle Explorer (DAMPE) Collaboration reports a direct measurement between 25 gigaelectronvolts and 4.6 TeV, which clearly reveals a spectral break at around 0.9 TeV. High-energy cosmic-ray electrons and positrons (CREs), which lose energy quickly during their propagation, provide a probe of Galactic high-energy processes 1 , 2 , 3 , 4 , 5 , 6 , 7 and may enable the observation of phenomena such as dark-matter particle annihilation or decay 8 , 9 , 10 . The CRE spectrum has been measured directly up to approximately 2 teraelectronvolts in previous balloon- or space-borne experiments 11 , 12 , 13 , 14 , 15 , 16 , and indirectly up to approximately 5 teraelectronvolts using ground-based Cherenkov γ-ray telescope arrays 17 , 18 . Evidence for a spectral break in the teraelectronvolt energy range has been provided by indirect measurements 17 , 18 , although the results were qualified by sizeable systematic uncertainties. Here we report a direct measurement of CREs in the energy range 25 gigaelectronvolts to 4.6 teraelectronvolts by the Dark Matter Particle Explorer (DAMPE) 19 with unprecedentedly high energy resolution and low background. The largest part of the spectrum can be well fitted by a ‘smoothly broken power-law’ model rather than a single power-law model. The direct detection of a spectral break at about 0.9 teraelectronvolts confirms the evidence found by previous indirect measurements 17 , 18 , clarifies the behaviour of the CRE spectrum at energies above 1 teraelectronvolt and sheds light on the physical origin of the sub-teraelectronvolt CREs.

Central Asia is currently a semiarid‐arid region, dominated by the Westerlies. It is important to understand mechanisms of climate and precipitation changes here, as water availability in the region is crucial today and in the future. High‐resolution, absolutely‐dated oxygen isotope (δ18O) records of stalagmites from Kesang Cave characterize a dynamic precipitation history over most of the past 500,000 years. This record demonstrates, for the first time, that climate change in the region exhibits a processional rhythm with abrupt inceptions of low δ18O speleothem growth at times of high Northern Hemisphere summer insolation followed by gradual δ18O increases that track decreases of insolation. These observations and interpretations contrast with the interpretation of nearby, but higher elevation ice core records. The absolutely‐dated caveδ18O shifts can be used to correlate the regional climate variability by providing chronological marks. Combined with other paleoclimate records, the Kesang observations suggest that possible incursions of Asian summer monsoon rainfall or related moisture into the Kesang site and/or adjacent areas during the high insolation times may play an important role in changing orbital‐scale hydrology of the region. Based on our record, arid climate will prevail in this region for the next several millennia, providing that anthropogenic effects do not supersede natural processes. Key Points Speleothem records characterize 500 ka precipitation history in Central Asia Climatic patterns in the Westerlies region are dominated by a precession rhythm Asian Monsoon incursions may explain the hydrological change on precession scale

Although significant advances have recently been made in the diagnosis and treatment of cervical carcinoma, the long-term survival rate for advanced cervical cancer remains low. Therefore, an urgent need exists to both uncover the molecular mechanisms and identify potential therapeutic targets for the treatment of cervical cancer. MicroRNAs (miRNAs) have important roles in cancer progression and could be used as either potential therapeutic agents or targets. miR-506 is a component of an X chromosome-linked miRNA cluster. The biological functions of miR-506 have not been well established. In this study, we found that miR-506 expression was downregulated in approximately 80% of the cervical cancer samples examined and inversely correlated with the expression of Ki-67, a marker of cell proliferation. Gain-of-function and loss-of-function studies in human cervical cancer, Caski and SiHa cells, demonstrated that miR-506 acts as a tumor suppressor by inhibiting cervical cancer growth in vitro and in vivo . Further studies showed that miR-506 induced cell cycle arrest at the G1/S transition, and enhanced apoptosis and chemosensitivity of cervical cancer cell. We subsequently identified Gli3, a hedgehog pathway transcription factor, as a direct target of miR-506 in cervical cancer. Furthermore, Gli3 silencing recapitulated the effects of miR-506, and reintroduction of Gli3 abrogated miR-506-induced cell growth arrest and apoptosis. Taken together, we conclude that miR-506 exerts its anti-proliferative function by directly targeting Gli3. This newly identified miR-506/Gli3 axis provides further insight into the pathogenesis of cervical cancer and indicates a potential novel therapeutic agent for the treatment of cervical cancer.

The non-locality of quantum correlations is a fundamental feature of quantum theory. The Bell inequality serves as a benchmark for distinguishing between predictions made by quantum theory and local hidden variable theory (LHVT). Recent advancements in photon-entanglement experiments have addressed potential loopholes and have observed significant violations of variants of Bell inequality. However, examples of Bell inequalities violation in high energy physics are scarce. In this study, we utilize (10.087  ± 0.044) × 10 9   J / ψ events collected with the BES-III detector at the BEPCII collider, performing non-local correlation tests using the entangled hyperon pairs. The massive-entangled Λ Λ ¯ systems are formed and decay through strong and weak interactions, respectively. Through measurements of the angular distribution of p p ¯ in J / ψ  →  γ η c and subsequent η c → Λ ( p π − ) Λ ¯ ( p ¯ π + ) cascade decays, a significant violation of LHVT predictions is observed. The exclusion of LHVT is found to be statistically significant at a level exceeding 5.2 σ in the testing of three Bell-like inequalities. While Bell inequalities have been violated several times—mostly in photonic systems—their violations within particle physics experiments are less explored. Here, the BESIII Collaboration showcases Bell-violating nonlocal correlations between entangled hyperon pairs.

In recent years, online retailers (also called e-tailers) have started allowing manufacturers direct access to their customers while charging a fee for providing this access, a format commonly referred to as agency selling. In this paper, we use a stylized theoretical model to answer a key question that e-tailers are facing: When should they use an agency selling format instead of using the more conventional reselling format? We find that agency selling is more efficient than reselling and leads to lower retail prices; however, the e-tailers end up giving control over retail prices to the manufacturer. Therefore, the reaction by the manufacturer, who makes electronic channel pricing decisions based on their impact on demand in the traditional channel (brick-and-mortar retailing), is an important factor for e-tailers to consider. We find that when sales in the electronic channel lead to a negative effect on demand in the traditional channel, e-tailers prefer agency selling, whereas when sales in the electronic channel lead to substantial stimulation of demand in the traditional channel, e-tailers prefer reselling. This preference is mediated by competition between e-tailers—as competition between them increases, e-tailers prefer to use agency selling. We also find that when e-tailers benefit from positive externalities from the sales of the focal product (such as additional profits from sales of associated products), retail prices may be lower under reselling than under agency selling, and the e-tailers prefer reselling under some conditions for which they would prefer agency selling without the positive externalities. This paper was accepted by Chris Forman, information systems.

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in malignant tumors and has important roles in multiple aspects of cancer aggressiveness. Thus targeting STAT3 promises to be an attractive strategy for treatment of advanced metastatic tumors. Although many STAT3 inhibitors targeting the SH2 domain have been reported, few have moved into clinical trials. Targeting the DNA-binding domain (DBD) of STAT3, however, has been avoided due to its ‘undruggable‘ nature and potentially limited selectivity. In a previous study, we reported an improved in silico approach targeting the DBD of STAT3 that resulted in a small-molecule STAT3 inhibitor (inS3-54). Further studies, however, showed that inS3-54 has off-target effect although it is selective to STAT3 over STAT1. In this study, we describe an extensive structure and activity-guided hit optimization and mechanistic characterization effort, which led to identification of an improved lead compound (inS3-54A18) with increased specificity and pharmacological properties. InS3-54A18 not only binds directly to the DBD and inhibits the DNA-binding activity of STAT3 both in vitro and in situ but also effectively inhibits the constitutive and interleukin-6-stimulated expression of STAT3 downstream target genes. InS3-54A18 is completely soluble in an oral formulation and effectively inhibits lung xenograft tumor growth and metastasis with little adverse effect on animals. Thus inS3-54A18 may serve as a potential candidate for further development as anticancer therapeutics targeting the DBD of human STAT3 and DBD of transcription factors may not be ‘undruggable‘ as previously thought.

We reevaluate the hadronic vacuum polarisation contributions to the muon magnetic anomaly and to the running of the electromagnetic coupling constant at the Z -boson mass. We include newest e + e - → hadrons cross-section data together with a phenomenological fit of the threshold region in the evaluation of the dispersion integrals. The precision in the individual datasets cannot be fully exploited due to discrepancies that lead to additional systematic uncertainty in particular between BABAR and KLOE data in the dominant π + π - channel. For the muon ( g - 2 ) / 2 , we find for the lowest-order hadronic contribution ( 694.0 ± 4.0 ) · 10 - 10 . The full Standard Model prediction differs by 3.3 σ from the experimental value. The five-quark hadronic contribution to α ( m Z 2 ) is evaluated to be ( 276.0 ± 1.0 ) · 10 - 4 .

Combustion is a complex chemical system which involves thousands of chemical reactions and generates hundreds of molecular species and radicals during the process. In this work, a neural network-based molecular dynamics (MD) simulation is carried out to simulate the benchmark combustion of methane. During MD simulation, detailed reaction processes leading to the creation of specific molecular species including various intermediate radicals and the products are intimately revealed and characterized. Overall, a total of 798 different chemical reactions were recorded and some new chemical reaction pathways were discovered. We believe that the present work heralds the dawn of a new era in which neural network-based reactive MD simulation can be practically applied to simulating important complex reaction systems at ab initio level, which provides atomic-level understanding of chemical reaction processes as well as discovery of new reaction pathways at an unprecedented level of detail beyond what laboratory experiments could accomplish. Gaining insights into combustion processes is challenging due to the complex reactions involved. The present work proposes a neural network potential model trained to ab initio data that enables to simulate the combustion of methane by predicting reactants, products and reaction intermediates.

Various factors and cellular components in the tumor microenvironment are key drivers associated with drug resistance in many cancers. Here, we analyzed the factors and molecular mechanisms involved in chemoresistance in patients with esophageal squamous cell carcinoma (ESCC). We found that interleukin 6 (IL6) derived mainly from cancer-associated fibroblasts played the most important role in chemoresistance by upregulating C-X-C motif chemokine receptor 7 (CXCR7) expression through signal transducer and activator of transcription 3/nuclear factor-κB pathway. CXCR7 knockdown resulted in the inhibition of IL6-induced proliferation and chemoresistance. In addition, CXCR7 silencing significantly decreased gene expression associated with stemness, chemoresistance and epithelial–mesenchymal transition and suppressed the proliferation ability of ESCC cells in three-dimensional culture systems and angiogenesis assay. In clinical samples, ESCC patients with high expression of CXCR7 and IL6 presented a significantly worse overall survival and progression-free survival upon receiving cisplatin after operation. These results suggest that the IL6–CXCR7 axis may provide a promising target for the treatment of ESCC.

Retrotransposons are one type of mobile genetic element that abundantly reside in the genomes of nearly all animals. Their uncontrolled activation is linked to sterility, cancer and other pathologies, thereby being largely considered detrimental. Here we report that, within a specific time window of development, retrotransposon activation can license the host’s immune system for future antiviral responses. We found that the mdg4 (also known as Gypsy ) retrotransposon selectively becomes active during metamorphosis at the Drosophila pupal stage. At this stage, mdg4 activation educates the host’s innate immune system by inducing the systemic antiviral function of the nuclear factor-κB protein Relish in a dSTING-dependent manner. Consequently, adult flies with mdg4 , Relish or dSTING silenced at the pupal stage are unable to clear exogenous viruses and succumb to viral infection. Altogether, our data reveal that hosts can establish a protective antiviral response that endows a long-term benefit in pathogen warfare due to the developmental activation of mobile genetic elements. Expression of mdg4 retrotransposons during Drosophila metamorphosis activates the antiviral NF-κB factor Relish. Silencing of mdg4 or Relish at the pupal stage leads to an inability to clear exogenous viruses in adulthood.