Understanding the multiwavelength observation of Geminga's TeV halo: the role of anisotropic diffusion of particles

In this letter we propose that the X-ray and the TeV observations in the vicinity of Geminga can be understood in the framework of anisotropic diffusion of injected electrons/positrons. This interpretation only requires the turbulence in the vicinity of Geminga to be sub-Alfv\'enic with the local mean magnetic field direction approximately aligned with our line of sight towards Geminga, without invoking extreme conditions for the environment, such as an extremely small diffusion coefficient and a weak magnetic field of strength $<1\mu$G as suggested in previous literature.Comment: 7 pages, 4 figures, including Supplemental Material, PRL accepte

On Reinforcement Learning for Full-length Game of StarCraft

StarCraft II poses a grand challenge for reinforcement learning. The main difficulties of it include huge state and action space and a long-time horizon. In this paper, we investigate a hierarchical reinforcement learning approach for StarCraft II. The hierarchy involves two levels of abstraction. One is the macro-action automatically extracted from expert's trajectories, which reduces the action space in an order of magnitude yet remains effective. The other is a two-layer hierarchical architecture which is modular and easy to scale, enabling a curriculum transferring from simpler tasks to more complex tasks. The reinforcement training algorithm for this architecture is also investigated. On a 64x64 map and using restrictive units, we achieve a winning rate of more than 99\% against the difficulty level-1 built-in AI. Through the curriculum transfer learning algorithm and a mixture of combat model, we can achieve over 93\% winning rate of Protoss against the most difficult non-cheating built-in AI (level-7) of Terran, training within two days using a single machine with only 48 CPU cores and 8 K40 GPUs. It also shows strong generalization performance, when tested against never seen opponents including cheating levels built-in AI and all levels of Zerg and Protoss built-in AI. We hope this study could shed some light on the future research of large-scale reinforcement learning.Comment: Appeared in AAAI 201

Protein tyrosine phosphatases as potential therapeutic targets

Protein tyrosine phosphorylation is a key regulatory process in virtually all aspects of cellular functions. Dysregulation of protein tyrosine phosphorylation is a major cause of human diseases, such as cancers, diabetes, autoimmune disorders, and neurological diseases. Indeed, protein tyrosine phosphorylation-mediated signaling events offer ample therapeutic targets, and drug discovery efforts to date have brought over two dozen kinase inhibitors to the clinic. Accordingly, protein tyrosine phosphatases (PTPs) are considered next-generation drug targets. For instance, PTP1B is a well-known targets of type 2 diabetes and obesity, and recent studies indicate that it is also a promising target for breast cancer. SHP2 is a bona-fide oncoprotein, mutations of which cause juvenile myelomonocytic leukemia, acute myeloid leukemia, and solid tumors. In addition, LYP is strongly associated with type 1 diabetes and many other autoimmune diseases. This review summarizes recent findings on several highly recognized PTP family drug targets, including PTP1B, Src homology phosphotyrosyl phosphatase 2(SHP2), lymphoid-specific tyrosine phosphatase (LYP), CD45, Fas associated phosphatase-1 (FAP-1), striatal enriched tyrosine phosphatases (STEP), mitogen-activated protein kinase/dual-specificity phosphatase 1 (MKP-1), phosphatases of regenerating liver-1 (PRL), low molecular weight PTPs (LMWPTP), and CDC25. Given that there are over 100 family members, we hope this review will serve as a road map for innovative drug discovery targeting PTPs

Synchrotron Self-Compton Emission from External Shocks as the Origin of the Sub-TeV Emission in GRB 180720B and GRB 190114C

Recently, very high-energy photons above 100 GeV were reported to be detected from GRB 190114C and GRB 180720B at, respectively, 100–1000 s and 10 hr after the burst. We model the available broadband data of both GRBs with the synchrotron plus synchrotron self-Compton (SSC) emission of the afterglow shocks. We find that the sub-TeV emission of GRB 180720B can be interpreted as the SSC emission from afterglow shocks expanding in a constant-density circumburst medium. The SSC emission of GRB 190114C dominates over the synchrotron component from GeV energies at ~100 s, which can explain the possible hard spectrum of the GeV emission at this time. The extrapolated flux of this SSC component to sub-TeV energies can explain the high-significance detection of GRB 190114C by the MAGIC telescope. The parameter values (such as the circumburst density and shock microphysical parameters) in the modeling are not unusual for both gamma-ray bursts, implying that the detection of sub-TeV photons from these two bursts should be attributed to their large burst energies and low redshifts

Molecular Basis of Gain-of-Function LEOPARD Syndrome-Associated SHP2 Mutations

The Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP2) is a critical signal transducer downstream of growth factors that promotes the activation of the RAS-ERK1/2 cascade. In its basal state, SHP2 exists in an autoinhibited closed conformation because of an intramolecular interaction between its N-SH2 and protein tyrosine phosphatase (PTP) domains. Binding to pTyr ligands present on growth factor receptors and adaptor proteins with its N-SH2 domain localizes SHP2 to its substrates and frees the active site from allosteric inhibition. Germline mutations in SHP2 are known to cause both Noonan syndrome (NS) and LEOPARD syndrome (LS), two clinically similar autosomal dominant developmental disorders. NS-associated SHP2 mutants display elevated phosphatase activity, while LS-associated SHP2 mutants exhibit reduced catalytic activity. A conundrum in how clinically similar diseases result from mutations to SHP2 that have opposite effects on this enzyme’s catalytic functionality exists. Here we report a comprehensive investigation of the kinetic, structural, dynamic, and biochemical signaling properties of the wild type as well as all reported LS-associated SHP2 mutants. The results reveal that LS-causing mutations not only affect SHP2 phosphatase activity but also induce a weakening of the intramolecular interaction between the N-SH2 and PTP domains, leading to mutants that are more readily activated by competing pTyr ligands. Our data also indicate that the residual phosphatase activity associated with the LS SHP2 mutant is required for enhanced ERK1/2 activation. Consequently, catalytically impaired SHP2 mutants could display gain-of-function properties because of their ability to localize to the vicinity of substrates for longer periods of time, thereby affording the opportunity for prolonged substrate turnover and sustained RAS-ERK1/2 activation

SHP2 phosphatase as a novel therapeutic target for melanoma treatment

Melanoma ranks among the most aggressive and deadly human cancers. Although a number of targeted therapies are available, they are effective only in a subset of patients and the emergence of drug resistance often reduces durable responses. Thus there is an urgent need to identify new therapeutic targets and develop more potent pharmacological agents for melanoma treatment. Herein we report that SHP2 levels are frequently elevated in melanoma, and high SHP2 expression is significantly associated with more metastatic phenotype and poorer prognosis. We show that SHP2 promotes melanoma cell viability, motility, and anchorage-independent growth, through activation of both ERK1/2 and AKT signaling pathways. We demonstrate that SHP2 inhibitor 11a-1 effectively blocks SHP2-mediated ERK1/2 and AKT activation and attenuates melanoma cell viability, migration and colony formation. Most importantly, SHP2 inhibitor 11a-1 suppresses xenografted melanoma tumor growth, as a result of reduced tumor cell proliferation and enhanced tumor cell apoptosis. Taken together, our data reveal SHP2 as a novel target for melanoma and suggest SHP2 inhibitors as potential novel therapeutic agents for melanoma treatment

A Thiazole Orange Derivative Targeting the Bacterial Protein FtsZ Shows Potent Antibacterial Activity.

The prevalence of multidrug resistance among clinically significant bacteria calls for the urgent development of new antibiotics with novel mechanisms of action. In this study, a new small molecule exhibiting excellent inhibition of bacterial cell division with potent antibacterial activity was discovered through cell-based screening. The compound exhibits a broad spectrum of bactericidal activity, including the methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus and NDM-1 Escherichia coli. The in vitro and in vivo results suggested that this compound disrupts the dynamic assembly of FtsZ protein and Z-ring formation through stimulating FtsZ polymerization. Moreover, this compound exhibits no activity on mammalian tubulin polymerization and shows low cytotoxicity on mammalian cells. Taken together, these findings could provide a new chemotype for development of antibacterials with FtsZ as the target

Modeling the broadband emission of Fermi/LAT GRB 090902B

GRB 090902B, detected by Fermi Large Array Telescope (Fermi/LAT), shows extend high-energy emission (>100 MeV) up to 10^3 s after the burst, which decays with time in a power-law as t^{-1.5}. It has been also observed by several follow-up low-energy instruments, including an early optical detection around 5000 s after the burst. The optical emission at early time decays faster than t^{-1.6}, which has been suspected to originate from the reverse shock. We here explore the models that can possibly explain the the broadband afterglow emission of GRB 090902B. We find that the reverse shock model for the early optical emission would overpredict the radio afterglow flux that is inconsistent with observations. A partially radiative blast wave model, which though is able to produce a sufficiently steep decay slope, can not explain the broadband data of GRB 090902B. The two-component jet model, which consists of a narrow and bright jet component in the core and a surrounding wider and less energetic jet component, is shown to be able to explain the broadband afterglow data, including the LAT high-energy data after ~50 s and low-energy (radio, optical and X-ray) afterglow data. The early-time high-energy emission detected by LAT before ~50 s is likely due to internal origin as that of the sub-MeV emission. The highest energy (33 GeV) photon of GRB090902B detected at 80 s can be marginally accommodated within the forward shock emission under the optimistic condition that electrons are accelerated by the Bohm diffusive shock.Comment: Accepted for publication in ApJ (minor changes, references updated), 11 pages (emulateapj style), 4 figure

Therapeutic Potential of Targeting the Oncogenic SHP2 Phosphatase

, The Src homology 2 domain containing protein tyrosine phosphatase-2 (SHP2) is an oncogenic phosphatase associated with various kinds of leukemia and solid tumors. Thus, there is substantial interest in developing SHP2 inhibitors as potential anticancer and antileukemia agents. Using a structure-guided and fragment-based library approach, we identified a novel hydroxyindole carboxylic acid-based SHP2 inhibitor 11a-1, with an IC50 value of 200 nM and greater than 5-fold selectivity against 20 mammalian PTPs. Structural and modeling studies reveal that the hydroxyindole carboxylic acid anchors the inhibitor to the SHP2 active site, while interactions of the oxalamide linker and the phenylthiophene tail with residues in the β5–β6 loop contribute to 11a-1’s binding potency and selectivity. Evidence suggests that 11a-1 specifically attenuates the SHP2-dependent signaling inside the cell. Moreover, 11a-1 blocks growth factor mediated Erk1/2 and Akt activation and exhibits excellent antiproliferative activity in lung cancer and breast cancer as well as leukemia cell lines

Constraining the jet composition of GRB 221009A with the prompt TeV emission limit

Recent LHAASO observations of the prompt emission phase of the brightest-of-all-time GRB 221009A imposes a stringent limit on the flux ratio between the TeV and MeV emissions, $F_{\rm TeV}/F_{\rm MeV}\le 2\times10^{-5}$, during the period $220 \operatorname{-}230\, {\rm s}$ after the trigger. bf This period covers the peak of the main MeV burst and is just before the TeV afterglow emerges. Within the framework of internal shocks, we study the internal $\gamma\gamma$ absorption in GRB 221009A by generating a set of synthetic bursts in a simulation that reproduces the observed feature of GRB 221009A. We find that the $\gamma\gamma$ absorption does not lead to an exponential cutoff, but rather a power-law spectrum, consistent with previous works. We further find that the attenuation due to $\gamma\gamma$ absorption alone cannot explain the flux limit ratio of GRB 221009A, suggesting a low ratio between synchrotron self-Compton (SSC) and synchrotron emission outputs. This requires the magnetic field energy density to be much larger than the synchrotron photon energy density so that the SSC flux is greatly suppressed. This indicates that the jet composition of GRB 221009A is likely Poynting-flux-dominated.Comment: 11 pages, 5 figures, comments are welcom