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Resonant scattering (RS) of X-ray line emission in supernova remnants (SNRs) may modify the observed line profiles and fluxes and has potential impact on estimating the physical properties of the hot gas and hence on understanding the SNR physics, but has not been theoretically modeled ever. Here we present our Monte-Carlo simulation of RS effect on X-ray resonant-line emission, typified by O VII He$\alpha$ r line, from SNRs. We employ the physical conditions characterized by the Sedov-Taylor solution and some basic parameters similar to those in Cygnus Loop. We show that the impact of RS effect is most significant near the edge of the remnant. The line profiles are predicted to be asymmetric because of different temperatures and photon production efficiencies of the expanding gas at different radii. We also predict the surface brightness of the line emission would decrease in the outer projected region but is slightly enhanced in the inner. The G-ratio of the OVII He$\alpha$ triplet can be effectively elevated by RS in the outer region. We show that RS effect of the O VII He$\alpha$ r line in the southwestern boundary region of Cygnus Loop is non-negligible. The observed OVII G-ratio $\sim$1.8 of the region could be achieved with RS taken into account for properly elevated O abundance from the previous estimates. Additional simulation performed for the SNRs in ejecta-dominated phase like Cas A shows that RS in the shocked ejecta may have some apparently effects on the observational properties of oxygen resonant lines., Comment: 19 pages, 17 figures, accepted by ApJ

Galactic supernova remnants (SNRs) and their environments provide the nearest laboratories to study SN feedback. We performed molecular observations toward SNR W49B -- the most luminous Galactic SNR in the X-ray band, aiming to explore signs of multiple feedback channels of SNRs on nearby molecular clouds (MCs). We found very broad HCO+ lines with widths of dv = 48--75 km/s in the SNR southwest, providing strong evidence that W49B is perturbing MCs at a systemic velocity of $V_{LSR}=61$--65 km/s, and placing W49B at a distance of $7.9\pm 0.6$ kpc. We observed unusually high intensity ratios of HCO+ J=1-0/CO J=1-0 not only at shocked regions ($1.1\pm 0.4$ and $0.70\pm 0.16$), but also in quiescent clouds over 1 pc away from the SNR's eastern boundary (> 0.2). By comparing with the magnetohydrodynamics (MHD) shock models, we interpret that the high ratio in the broad-line regions can result from a cosmic-ray (CR) induced chemistry in shocked MCs, where the CR ionization rate is enhanced to around 10--100 times of the Galactic level. The high HCO+/CO ratio outside the SNR is probably caused by the radiation precursor, while the luminous X-ray emission of W49B can explain a few properties in this region. The above results provide observational evidence that SNR can strongly influence the molecular chemistry in and outside the shock boundary via their shocks, CRs, and radiation. We propose that the HCO+/CO ratio is a potentially useful tool to probe SNR's multi-channel influence on MCs., Comment: 19 pages, 11 figures. Submitted to ApJ. Comments welcome

Introduction: The criteria for organ distribution in Colombia establish an initial local distribution, then regional and finally national. In December 2019, 2,822 people were on the kidney transplant waiting list in Colombia, assigned mostly to the Bogotá and IPS regions with the largest waiting lists. This high concentration of patients could be generating unwanted effects on the opportunity that patients have to receive a kidney transplant. Objectives:In this paper we seek to study, based on synthetic data generated with the information available from the INS, the probability of organ allocation, identifying the most informative variables and proposing a method to calculate the probability of allocation for a given patient on the waiting list of organs.Material and methods: The adjustment of a model based on decision trees is presented, which showed a high precision and allows the prediction of the probability of obtaining an organ. Results: Time, transplant IPS and blood group were identified as the most informative variables. Likewise, there are differences in the time it takes to obtain kidney transplants between regions and between transplanting IPS due to the effect of the size of their waiting list. Conclusions: The proposed method allows us to identify the importance of the variables that define obtaining an organ. Finally, for a given patient, it is possible to estimate the probability of being classified in one of the outcome categories., Introducción: Los criterios de distribución de órganos en Colombia establecen una distribución inicial local, luego regional y por último nacional. Para diciembre de 2019 estaban en lista de espera de trasplante renal 2.822 personas en Colombia, asignadas en su mayoría a la regional Bogotá e IPS con mayores listas de espera. Esta alta concentración de pacientes podría estar generando efectos indeseados en la oportunidad que tienen los pacientes para recibir un trasplante renal. Objetivos: En el presente trabajo se busca estudiar, con base en datos sintéticos generados con la información disponible del INS la probabilidad de asignación de órganos identificando las variables más informativas y proponiendo un método para calcular la probabilidad de asignación para un paciente dado en lista de espera. Material y métodos: Se presenta el ajuste de un modelo basado en árboles de decisión que presentó una alta precisión y permite realizar la predicción de la probabilidad de obtener un órgano. Resultados: Se identificaron como variables más informativas el tiempo, la IPS trasplantadora y el grupo sanguíneo. Así mismo, se evidencian diferencias en los tiempos de obtención de trasplante renal entre regionales y entre IPS trasplantadoras debido al efecto que tiene el tamaño de su lista de espera. Conclusiones: El método propuesto permite identificar la importancia de las variables que definen la obtención de un órgano. Finalmente, para un paciente dado, es posible estimar la probabilidad de ser clasificado en alguna de las categorías de desenlace.

Recent years have witnessed a hot wave of deep neural networks in various domains; however, it is not yet well understood theoretically. A theoretical characterization of deep neural networks should point out their approximation ability and complexity, i.e., showing which architecture and size are sufficient to handle the concerned tasks. This work takes one step on this direction by theoretically studying the approximation and complexity of deep neural networks to invariant functions. We first prove that the invariant functions can be universally approximated by deep neural networks. Then we show that a broad range of invariant functions can be asymptotically approximated by various types of neural network models that includes the complex-valued neural networks, convolutional neural networks, and Bayesian neural networks using a polynomial number of parameters or optimization iterations. We also provide a feasible application that connects the parameter estimation and forecasting of high-resolution signals with our theoretical conclusions. The empirical results obtained on simulation experiments demonstrate the effectiveness of our method.

Recent years have emerged a surge of interest in SNNs owing to their remarkable potential to handle time-dependent and event-driven data. The performance of SNNs hinges not only on selecting an apposite architecture and fine-tuning connection weights, similar to conventional ANNs, but also on the meticulous configuration of intrinsic structures within spiking computations. However, there has been a dearth of comprehensive studies examining the impact of intrinsic structures. Consequently, developers often find it challenging to apply a standardized configuration of SNNs across diverse datasets or tasks. This work delves deep into the intrinsic structures of SNNs. Initially, we unveil two pivotal components of intrinsic structures: the integration operation and firing-reset mechanism, by elucidating their influence on the expressivity of SNNs. Furthermore, we draw two key conclusions: the membrane time hyper-parameter is intimately linked to the eigenvalues of the integration operation, dictating the functional topology of spiking dynamics, and various hyper-parameters of the firing-reset mechanism govern the overall firing capacity of an SNN, mitigating the injection ratio or sampling density of input data. These findings elucidate why the efficacy of SNNs hinges heavily on the configuration of intrinsic structures and lead to a recommendation that enhancing the adaptability of these structures contributes to improving the overall performance and applicability of SNNs. Inspired by this recognition, we propose two feasible approaches to enhance SNN learning. These involve leveraging self-connection architectures and employing stochastic spiking neurons to augment the adaptability of the integration operation and firing-reset mechanism, respectively. We verify the effectiveness of the proposed methods from perspectives of theory and practice.

Galactic supernova remnants (SNRs) and their environments provide the nearest laboratories to study SN feedback. We performed molecular observations toward SNR W49B, the most luminous Galactic SNR in the X-ray band, aiming to explore signs of multiple feedback channels of SNRs on nearby molecular clouds (MCs). We found very broad HCO+ lines with widths of dv = 48--75 km/s in the SNR southwest, providing strong evidence that W49B is perturbing MCs at a systemic velocity of $V_{LSR}=61$--65 km/s, and placing W49B at a distance of $7.9\pm 0.6$ kpc. We observed unusually high-intensity ratios of HCO+ J=1-0/CO J=1-0 not only at shocked regions ($1.1\pm 0.4$ and $0.70\pm 0.16$), but also in quiescent clouds over 1 pc away from the SNR's eastern boundary (> 0.2). By comparing with the magnetohydrodynamics shock models, we interpret that the high ratio in the broad-line regions can result from a cosmic-ray (CR) induced chemistry in shocked MCs, where the CR ionization rate is enhanced to around 10--100 times of the Galactic level. The high HCO+/CO ratio outside the SNR is probably caused by the radiation precursor, while the luminous X-ray emission of W49B can explain a few properties in this region. The above results provide observational evidence that SNRs can strongly influence the molecular chemistry in and outside the shock boundary via their shocks, CRs, and radiation. We propose that the HCO+/CO ratio is a potentially useful tool to probe an SNR's multichannel influence on MCs., Comment: 19 pages, 11 figures, ApJ in press

Hazrat Bilal,1 Tayyab Ur Rehman,2 Muhammad Asif Khan,2 Fareeha Hameed,2 Zhang Gao Jian,1 Jianxiong Han,1 Xingyuan Yang1 1Faculty of Health Sciences, Institute of Physical Sciences and Information Technology, Anhui University, Hefei, People’s Republic of China; 2Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, PakistanCorrespondence: Xingyuan YangFaculty of Health Sciences, Institute of Physical Science and Information Technology, Anhui University, No, 111 Jiulong Road, Hefei, Anhui, 230601, People’s Republic of ChinaEmail xingyuan@ahu.edu.cnPurpose: The multiple-drug resistant Escherichia coli are among the deadliest pathogens causing life-threatening infections. This study was planned to determine the molecular epidemiology of mcr-1, blaKPC-2, and blaNDM-1 harboring clinically isolated E. coli from Pakistan.Methods: In total, 545 strains of E. coli from clinical samples were collected from June 2018 to September 2019. All the isolates were screened for colistin-resistance, extended-spectrum-β-lactamases (ESBL), and carbapenemases through the micro-dilution method, Double-Disk-Synergy-Test (DDST), and Modified-Hodge-Test (MHT). The detection, sequence-typing, conjugal transfer, S1-PFGE, plasmid-replicon-typing, and southern-blotting for mcr, ESBL, and carbapenemase-encoding genes were performed.Findings: A total of four (0.73%) colistin-resistant strains carrying alongside mcr-1 and blaCTX-M-15 genes, three of these strains also had the blaTEM-1 gene. The presence of ESBL genes was detected in 139 (25.5%) isolates harboring blaCTXM-15 (74.82%), blaTEM (34.53%), blaSHV (28.06%) and blaOXA-1 (28.78%). In 129 carbapenemase-producers, 35.83% possessed blaNDM-1, 26.67% blaKPC-2, 8.3% blaOXA-48, 25% blaVIM-1, and 20.83% blaIMP-1 genes. The sequence typing revealed that mcr-1 harboring isolates belonged to ST405, ST117, and ST156. Fifty percent of blaKPC-2 and 48.83% of blaNDM-1 were found on ST131 and ST1196, respectiv

Immune checkpoint inhibitors (ICIs) produce durable responses in some melanoma patients, but many patients derive no clinical benefit, and the molecular underpinnings of such resistance remain elusive. Here, we leveraged single-cell RNA sequencing (scRNA-seq) from 33 melanoma tumors and computational analyses to interrogate malignant cell states that promote immune evasion. We identified a resistance program expressed by malignant cells that is associated with T cell exclusion and immune evasion. The program is expressed prior to immunotherapy, characterizes cold niches in situ, and predicts clinical responses to anti-PD-1 therapy in an independent cohort of 112 melanoma patients. CDK4/6-inhibition represses this program in individual malignant cells, induces senescence, and reduces melanoma tumor outgrowth in mouse models in vivo when given in combination with immunotherapy. Our study provides a high-resolution landscape of ICI-resistant cell states, identifies clinically predictive signatures, and suggests new therapeutic strategies to overcome immunotherapy resistance. Single-cell sequencing of checkpoint-inhibitor-resistant melanomas identifies predictive signatures to guide therapeutic approaches to overcome immunotherapy resistance., National Cancer Institute (U.S.) (Grant K08-CA222663)

We describe an improved nonequilibrium ionization (NEI) method that we have developed as an optional module for the FLASH magnetohydrodynamic simulation code. The method employs an eigenvalue approach rather than the earlier iterative ordinary differential equation approach to solve the stiff differential equations involved in NEI calculations. The new code also allows the atomic data to be easily updated from the AtomDB database. We compare both the updated atomic data and the methods separately. The new atomic data are shown to make a significant difference in some circumstances, although the general trends remain the same. Additionally, the new method also allows simultaneous calculation of the nonequilibrium radiative cooling, which is not included in the original method. The eigenvalue method improves the calculation efficiency overall with no loss of accuracy. We explore some common ways to present the NEI state with a sample simulation and find that using the average ionic charge difference from the equilibrium tends to be the clearest method., Comment: 15 pages, 8 figures

The mixed morphology class of supernova remnants (MMSNRs) comprises a substantial fraction of observed remnants and yet there is as yet no consensus on their origin. A clue to their nature is the presence of regions that show X-ray evidence of recombining plasmas. Recent calculations of remnant evolution in a cloudy interstellar medium (ISM) that included thermal conduction but not non-equilibrium ionization (NEI) showed promise in explaining observed surface brightness distributions but could not determine if recombining plasmas were present. In this paper, we present numerical hydrodynamical models of MMSNRs in 2D and 3D including explicit calculation of NEI effects. Both the spatial ionization distribution and temperature-density diagrams show that recombination occurs inside the simulated MMSNR, and that both adiabatic expansion and thermal conduction cause recombination, albeit in different regions. Features created by the adiabatic expansion stand out in the spatial and temperature-density diagrams, but thermal conduction also plays a role. Thus thermal conduction and adiabatic expansion both contribute significantly to the cooling of high-temperature gas. Realistic observational data are simulated with both spatial and spectral input from various regions. We also discuss the possibility of analyzing the sources of recombination and dominant hydrodynamical processes in observations using temperature-density diagrams and spatial maps., Comment: 36 pages, 25 figures

Although research into multimodal interfaces has been around for a long time, we believe that some basic issues have not been studied yet, e.g. the choice of modalities and their combinations is usually made without any quantitative evaluation. This study seeks to identify the best combinations of modalities through usability testing. How do users choose different interaction modes when they work on a particular application? Two experimental evaluations were conducted to compare interaction modes on a CAD system and a map system respectively. For the CAD system, the results show that, in terms of total manipulation time (drawing and modification time) and subjective preferences, the "pen + speech + mouse" combination was the best of the seven interaction modes tested. On the map system, the results show that the "pen + speech" combination mode is the best of fourteen interaction modes tested. The experiments also provide information on how users adapt to each interaction mode and the ease with which they are able to use these modes.

We describe an improved nonequilibrium ionization (NEI) method that we have developed as an optional module for the FLASH magnetohydrodynamic simulation code. The method employs an eigenvalue approach rather than the earlier iterative ordinary differential equation approach to solve the stiff differential equations involved in NEI calculations. The new code also allows the atomic data to be easily updated from the AtomDB database. We compare both the updated atomic data and the methods separately. The new atomic data are shown to make a significant difference in some circumstances, although the general trends remain the same. Additionally, the new method also allows simultaneous calculation of the nonequilibrium radiative cooling, which is not included in the original method. The eigenvalue method improves the calculation efficiency overall with no loss of accuracy. We explore some common ways to present the NEI state with a sample simulation and find that using the average ionic charge difference from the equilibrium tends to be the clearest method., Comment: 15 pages, 8 figures

The mixed morphology class of supernova remnants (MMSNRs) comprises a substantial fraction of observed remnants and yet there is as yet no consensus on their origin. A clue to their nature is the presence of regions that show X-ray evidence of recombining plasmas. Recent calculations of remnant evolution in a cloudy interstellar medium (ISM) that included thermal conduction but not non-equilibrium ionization (NEI) showed promise in explaining observed surface brightness distributions but could not determine if recombining plasmas were present. In this paper, we present numerical hydrodynamical models of MMSNRs in 2D and 3D including explicit calculation of NEI effects. Both the spatial ionization distribution and temperature-density diagrams show that recombination occurs inside the simulated MMSNR, and that both adiabatic expansion and thermal conduction cause recombination, albeit in different regions. Features created by the adiabatic expansion stand out in the spatial and temperature-density diagrams, but thermal conduction also plays a role. Thus thermal conduction and adiabatic expansion both contribute significantly to the cooling of high-temperature gas. Realistic observational data are simulated with both spatial and spectral input from various regions. We also discuss the possibility of analyzing the sources of recombination and dominant hydrodynamical processes in observations using temperature-density diagrams and spatial maps., Comment: 36 pages, 25 figures

Diffuse soft X-ray line emission is commonly used to trace the thermal and chemical properties of the hot interstellar medium, as well as its content, in nearby galaxies. Although resonant line scattering complicates the interpretation of the emission, it also offers an opportunity to measure the kinematics of the medium. We have implemented a direct Monte Carlo simulation scheme that enables us to account for resonant scattering effect in the medium, in principle, with arbitrary spatial, thermal, chemical, and kinematic distributions. Here we apply this scheme via dimensionless calculation to an isothermal, chemically uniform, and spherically symmetric medium with a radial density distribution characterized by a $\beta$-model. This application simultaneously account for both optical depth-dependent spatial distortion and intensity change of the resonant line emission due to the scattering, consistent with previous calculations. We further apply the modeling scheme to the OVII and OVIII emission line complex observed in the XMM-Newton RGS spectrum of the M31 bulge. This modeling, though with various limitations due to its simplicity, shows that the resonant scattering could indeed account for much of the spatial distortion of the emission, as well as the relative strengths of the lines, especially the large forbidden to resonant line ratio of the OVII He$\alpha$ triplet. We estimate the isotropic turbulence Mach number of the medium in M31 as $\sim0.17$ for the first time and the line-emitting gas temperature as $\sim2.3\times10^6$ K. We conclude that the resonant scattering may in general play an important role in shaping the soft X-ray spectra of diffuse hot gas in normal galaxies., Comment: emulateapj, 14 pages including 13 figures, accepted by ApJ

Small GTPases of the Ras superfamily are master regulators of intracellular trafficking and constitute essential signaling components in all eukaryotes. Aberrant small GTPase signaling is associated with a wide spectrum of human diseases, including cancer. Here, we developed a high-throughput, multiple reaction monitoring-based workflow, coupled with stable isotope labeling by amino acids in cell culture, for targeted quantification of approximately 100 small GTPases in cultured human cells. Using this method, we investigated the differential expression of small GTPases in three pairs of primary and metastatic melanoma cell lines. Bioinformatic analyses of The Cancer Genome Atlas data and other publicly available data as well as cell-based assays revealed previously unrecognized roles of RAB38 in promoting melanoma metastasis. Diminished promoter methylation and the subsequent augmented binding of transcription factor MITF contributed to elevated expression of RAB38 gene in metastatic versus primary melanoma cells. Moreover, RAB38 promoted invasion of cultured melanoma cells by modulating the expression and activities of matrix metalloproteinases-2 and -9. Together, these data establish a novel targeted proteomic method for interrogating the small GTPase proteome in human cells and identify epigenetic reactivation of RAB38 as a contributing factor to metastatic transformation in melanoma.Significance: A novel quantitative proteomic method leads to the discovery of RAB38 as a new driver of metastasis in melanoma. Cancer Res; 78(18); 5431-45. ©2018 AACR.

Diffuse soft X-ray line emission is commonly used to trace the thermal and chemical properties of the hot interstellar medium, as well as its content, in nearby galaxies. Although resonant line scattering complicates the interpretation of the emission, it also offers an opportunity to measure the kinematics of the medium. We have implemented a direct Monte Carlo simulation scheme that enables us to account for resonant scattering effect in the medium, in principle, with arbitrary spatial, thermal, chemical, and kinematic distributions. Here we apply this scheme via dimensionless calculation to an isothermal, chemically uniform, and spherically symmetric medium with a radial density distribution characterized by a $\beta$-model. This application simultaneously account for both optical depth-dependent spatial distortion and intensity change of the resonant line emission due to the scattering, consistent with previous calculations. We further apply the modeling scheme to the OVII and OVIII emission line complex observed in the XMM-Newton RGS spectrum of the M31 bulge. This modeling, though with various limitations due to its simplicity, shows that the resonant scattering could indeed account for much of the spatial distortion of the emission, as well as the relative strengths of the lines, especially the large forbidden to resonant line ratio of the OVII He$\alpha$ triplet. We estimate the isotropic turbulence Mach number of the medium in M31 as $\sim0.17$ for the first time and the line-emitting gas temperature as $\sim2.3\times10^6$ K. We conclude that the resonant scattering may in general play an important role in shaping the soft X-ray spectra of diffuse hot gas in normal galaxies., Comment: emulateapj, 14 pages including 13 figures, accepted by ApJ

Kes 79 (G33.6+0.1) is an aspherical thermal composite supernova remnant (SNR) observed across the electromagnetic spectrum and showing an unusual highly-structured morphology, in addition to harboring a central compact object (CCO). Using the CO J=1-0, J=2-1, and J=3-2 data, we provide the first direct evidence and new morphological evidence to support the physical interaction between the SNR and the molecular cloud at $V_LSR\sim 105$ km s$^{-1}$. We revisit the 380 ks XMM-Newton observations and perform a dedicated spatially resolved X-ray spectroscopic study with careful background subtraction. The overall X-ray-emitting gas is characterized by an under-ionized ($\tau_c \sim 6\times 10^{11}$ cm^${-3}$) cool ($kT_c \approx 0.20$ keV) plasma with solar abundances, plus an under-ionized ($\tau_h\sim 8\times 10^{10}$ cm$^{-3}$) hot ($kT_h\approx 0.80$ keV) plasma with elevated Ne, Mg, Si, S and Ar abundances. Kes 79 appears to have a double-hemisphere morphology viewed along the symmetric axis. Projection effect can explain the multiple shell structures and the thermal composite morphology. The X-ray filaments, spatially correlated with the 24 um IR filaments, are suggested to be due to the SNR shock interaction with dense gas, while the halo forms from SNR breaking out into a tenuous medium. The high-velocity, hot ($kT_h\sim 1.4$--1.6 keV) ejecta patch with high metal abundances, together with the non-uniform metal distribution across the SNR, indicating an asymmetric SN explosion of Kes 79. We refine the Sedov age to 4.4--6.7 kyr and the mean shock velocity to 730 km s$^{-1}$. Our multi-wavelength study suggests a progenitor mass of $\sim 15$--20 solar masses for the core-collapse explosion that formed Kes 79 and its CCO, PSR J1852+0040., Comment: 17 pages, 12 figures, 3 tables, published in ApJ

Kes 79 (G33.6+0.1) is an aspherical thermal composite supernova remnant (SNR) observed across the electromagnetic spectrum and showing an unusual highly-structured morphology, in addition to harboring a central compact object (CCO). Using the CO J=1-0, J=2-1, and J=3-2 data, we provide the first direct evidence and new morphological evidence to support the physical interaction between the SNR and the molecular cloud at $V_LSR\sim 105$ km s$^{-1}$. We revisit the 380 ks XMM-Newton observations and perform a dedicated spatially resolved X-ray spectroscopic study with careful background subtraction. The overall X-ray-emitting gas is characterized by an under-ionized ($\tau_c \sim 6\times 10^{11}$ cm^${-3}$) cool ($kT_c \approx 0.20$ keV) plasma with solar abundances, plus an under-ionized ($\tau_h\sim 8\times 10^{10}$ cm$^{-3}$) hot ($kT_h\approx 0.80$ keV) plasma with elevated Ne, Mg, Si, S and Ar abundances. Kes 79 appears to have a double-hemisphere morphology viewed along the symmetric axis. Projection effect can explain the multiple shell structures and the thermal composite morphology. The X-ray filaments, spatially correlated with the 24 um IR filaments, are suggested to be due to the SNR shock interaction with dense gas, while the halo forms from SNR breaking out into a tenuous medium. The high-velocity, hot ($kT_h\sim 1.4$--1.6 keV) ejecta patch with high metal abundances, together with the non-uniform metal distribution across the SNR, indicating an asymmetric SN explosion of Kes 79. We refine the Sedov age to 4.4--6.7 kyr and the mean shock velocity to 730 km s$^{-1}$. Our multi-wavelength study suggests a progenitor mass of $\sim 15$--20 solar masses for the core-collapse explosion that formed Kes 79 and its CCO, PSR J1852+0040., Comment: 17 pages, 12 figures, 3 tables, published in ApJ

Neurodegenerative disorders are one of the leading causes of death among the elderly. Therapeutic approaches with a single target have proven unsuccessful in treating these diseases. Structural combination of multi-functional compounds may lead to a molecule with multiple properties. In this study, we designed and synthesized T-006, a novel analog derived from two multi-functional neuroprotective chemicals, tetramethylpyrazine and J147. The methoxyphenyl group of J147 was replaced by tetramethylpyrazine. Bioactivity evaluation showed that T-006 at very low concentrations had multifunctional neuroprotective effects including rescuing iodoacetic acid-induced neuronal loss, preventing oxidative stress-induced neurotoxicity and reducing glutamate-induced excitotoxicity in vitro. Most importantly, T-006 significantly ameliorated memory impairments in APP/PS1 transgenic mice. These multiple functions of a single molecule suggest that T-006 is a promising novel neuroprotective agent for treating various neurodegenerative disorders, including and in particular Alzheimer's disease.

The physical nature of thermal composite supernova remnants (SNRs) remains controversial. We have revisited the archival XMM-Newton and Chandra data of the thermal composite SNR Kesteven 41 (Kes 41 or G337.8-0.1) and performed a millimeter observation toward this source in the $^{12}$CO, $^{13}$CO, and C$^{18}$O lines. The X-ray emission, mainly concentrated toward the southwestern part of the SNR, is characterized by distinct S and Ar He-like lines in the spectra. The X-ray spectra can be fitted with an absorbed nonequilibrium ionization collisional plasma model at a temperature of 1.3-2.6 keV and an ionization timescale of 0.1-1.2$\times$10$^{12}$ cm$^{-3}$ s. The metal species S and Ar are overabundant, with 1.2-2.7 and 1.3-3.8 solar abundances, respectively, which strongly indicate the presence of a substantial ejecta component in the X-ray-emitting plasma of this SNR. Kes 41 is found to be associated with a giant molecular cloud (MC) at a systemic local standard of rest velocity of -50 km s$^{-1}$ and confined in a cavity delineated by a northern molecular shell, a western concave MC that features a discernible shell, and an HI cloud seen toward the southeast of the SNR. The birth of the SNR in a preexisting molecular cavity implies a mass of $\gtrsim$18 M$_{\odot}$ for the progenitor if it was not in a binary system. Thermal conduction and cloudlet evaporation seem to be feasible mechanisms to interpret the X-ray thermal composite morphology, and the scenario of gas reheating by the shock reflected from the cavity wall is quantitatively consistent with the observations. An updated list of thermal composite SNRs is also presented in this paper., Comment: 27 pages, 11 figures, published in ApJ

Hadron emission from supernova remnant (SNR)-molecular cloud (MC) association systems has been widely regarded as a probe of the shock-accelerated cosmic-ray protons. Here, we report on the detection of a {\gamma}-ray emission source, with a significance of 24{\sigma} in 0.2-300 GeV, projected to lie to the northwest of the thermal composite SNR Kesteven 41, using 5.6 years of Fermi-Large Area Telescope (LAT) observation data. No significant long-term variability in the energy range 0.2--300 GeV is detected around this source. The 3{\sigma} error circle, 0.09 degree; in radius, covers the 1720MHz OH maser and is essentially consistent with the location of the V_{LSR} ~-50 km/s MC with which the SNR interacts. The source emission has an exponential cutoff power-law spectrum with a photon index of 1.9+/-0.1 and a cutoff energy of 4.0+/-0.9 GeV, and the corresponding 0.2-300 GeV luminosity is ~1.3*10^36 erg/s at a distance of 12 kpc. There is no radio pulsar in the 3{\sigma} circle responsible for the high {\gamma}-ray luminosity. While the inverse Compton scattering scenario would lead to a difficulty in the electron energy budget, the source emission can naturally be explained by the hadronic interaction between the relativistic protons accelerated by the shock of SNR Kesteven 41 and the adjacent northwestern MC. In this paper, we present a list of Galactic thermal composite SNRs detected at GeV {\gamma}-ray energies by Fermi-LAT is presented.

Neurodegenerative disorders are one of the leading causes of death among the elderly. Therapeutic approaches with a single target have proven unsuccessful in treating these diseases. Structural combination of multi-functional compounds may lead to a molecule with multiple properties. In this study, we designed and synthesized T-006, a novel analog derived from two multi-functional neuroprotective chemicals, tetramethylpyrazine and J147. The methoxyphenyl group of J147 was replaced by tetramethylpyrazine. Bioactivity evaluation showed that T-006 at very low concentrations had multifunctional neuroprotective effects including rescuing iodoacetic acid-induced neuronal loss, preventing oxidative stress-induced neurotoxicity and reducing glutamate-induced excitotoxicity in vitro. Most importantly, T-006 significantly ameliorated memory impairments in APP/PS1 transgenic mice. These multiple functions of a single molecule suggest that T-006 is a promising novel neuroprotective agent for treating various neurodegenerative disorders, including and in particular Alzheimer's disease.

To evaluate the underreporting rate of death -cause data in Shandong province during 2012 to 2013 by capture -mark -recapture method and to provide the base for health strategy. Methods All counties were divided into 5 stratifications according the death rates of 2012, and 14 counties were selected, then 3 towns or streets were selected in each country, 10 villages or neighborhood committees were selected in each town （street）. The death data collected from security bureau and civil affairs bureau were compared with the reporting death data from the National Cause of Death Surveillance, and the underreporting rate was calculated. Results In present study, 6 929 death cases were collected, it was found that 1 556 cases were underreported. The death cases estimated by CMR method were 6 227 cases （95%CI: 7 593-7 651）, and the average underreporting rate was 23.15%. There were significantly differences between different stratifications （P<0.01）. The underreporting rate in 0-4 years old group was 56.93%, the male underreporting rate was 22.31% and the female underreporting rate was 24.09%. There was no significant difference between male and female groups （P>0.05）. Conclusion There is an obvious underreport in the cause of death surveillance of Shandong province, and the underreporting rates are different among the 5 stratifications. The underreporting rate is higher in 0-4 years old group, and the investigation of the death cause surveillance for young residents is not perfect in some countries. The investigation quality of the death cause surveillance should be improved, increasing the integrity of the report data and adjusting the mortalities in different stratifications for obtaining a accurate mortality in Shandong province.

Hadron emission from supernova remnant (SNR)-molecular cloud (MC) association systems has been widely regarded as a probe of the shock-accelerated cosmic-ray protons. Here, we report on the detection of a {\gamma}-ray emission source, with a significance of 24{\sigma} in 0.2-300 GeV, projected to lie to the northwest of the thermal composite SNR Kesteven 41, using 5.6 years of Fermi-Large Area Telescope (LAT) observation data. No significant long-term variability in the energy range 0.2--300 GeV is detected around this source. The 3{\sigma} error circle, 0.09 degree; in radius, covers the 1720MHz OH maser and is essentially consistent with the location of the V_{LSR} ~-50 km/s MC with which the SNR interacts. The source emission has an exponential cutoff power-law spectrum with a photon index of 1.9+/-0.1 and a cutoff energy of 4.0+/-0.9 GeV, and the corresponding 0.2-300 GeV luminosity is ~1.3*10^36 erg/s at a distance of 12 kpc. There is no radio pulsar in the 3{\sigma} circle responsible for the high {\gamma}-ray luminosity. While the inverse Compton scattering scenario would lead to a difficulty in the electron energy budget, the source emission can naturally be explained by the hadronic interaction between the relativistic protons accelerated by the shock of SNR Kesteven 41 and the adjacent northwestern MC. In this paper, we present a list of Galactic thermal composite SNRs detected at GeV {\gamma}-ray energies by Fermi-LAT is presented.

The physical nature of thermal composite supernova remnants (SNRs) remains controversial. We have revisited the archival XMM-Newton and Chandra data of the thermal composite SNR Kesteven 41 (Kes 41 or G337.8-0.1) and performed a millimeter observation toward this source in the $^{12}$CO, $^{13}$CO, and C$^{18}$O lines. The X-ray emission, mainly concentrated toward the southwestern part of the SNR, is characterized by distinct S and Ar He-like lines in the spectra. The X-ray spectra can be fitted with an absorbed nonequilibrium ionization collisional plasma model at a temperature of 1.3-2.6 keV and an ionization timescale of 0.1-1.2$\times$10$^{12}$ cm$^{-3}$ s. The metal species S and Ar are overabundant, with 1.2-2.7 and 1.3-3.8 solar abundances, respectively, which strongly indicate the presence of a substantial ejecta component in the X-ray-emitting plasma of this SNR. Kes 41 is found to be associated with a giant molecular cloud (MC) at a systemic local standard of rest velocity of -50 km s$^{-1}$ and confined in a cavity delineated by a northern molecular shell, a western concave MC that features a discernible shell, and an HI cloud seen toward the southeast of the SNR. The birth of the SNR in a preexisting molecular cavity implies a mass of $\gtrsim$18 M$_{\odot}$ for the progenitor if it was not in a binary system. Thermal conduction and cloudlet evaporation seem to be feasible mechanisms to interpret the X-ray thermal composite morphology, and the scenario of gas reheating by the shock reflected from the cavity wall is quantitatively consistent with the observations. An updated list of thermal composite SNRs is also presented in this paper., Comment: 27 pages, 11 figures, published in ApJ

Neurodegenerative disorders are one of the leading causes of death among the elderly. Therapeutic approaches with a single target have proven unsuccessful in treating these diseases. Structural combination of multi-functional compounds may lead to a molecule with multiple properties. In this study, we designed and synthesized T-006, a novel analog derived from two multi-functional neuroprotective chemicals, tetramethylpyrazine and J147. The methoxyphenyl group of J147 was replaced by tetramethylpyrazine. Bioactivity evaluation showed that T-006 at very low concentrations had multifunctional neuroprotective effects including rescuing iodoacetic acid-induced neuronal loss, preventing oxidative stress-induced neurotoxicity and reducing glutamate-induced excitotoxicity in vitro. Most importantly, T-006 significantly ameliorated memory impairments in APP/PS1 transgenic mice. These multiple functions of a single molecule suggest that T-006 is a promising novel neuroprotective agent for treating various neurodegenerative disorders, including and in particular Alzheimer's disease.

Oncogene-induced senescence (OIS) is a well-documented phenomenon both in vitro and in vivo as a tumor-suppression mechanism. It functions as a barrier to tumor initiation and progression. However, tumor cells develop a sophisticated yet not well-understood mechanism to overcome and subsequently repress cellular senescence to facilitate its progression. Here we report our findings on oncogene-induced senescence and therapy-induced senescence in human melanoma cells. Mutated BRAF or NRAS oncogenes can induce senescence in some but not all melanoma cells, whereas some small molecules are more potent triggers of premature senescence in melanoma cells than others. We established an integrated FACS approach to quantify the heterogeneous response of melanoma cells to therapies. Importantly, we identified two distinct forms of therapy-induced senescence, which were dependent on the type of therapy. By implementing a systems biology approach, we identified core senescence components that were sufficient and necessary for the induction of therapy-induced senescence in melanoma cells. Furthermore, we showed that oncogene-induced senescence in normal cells resembled therapy-induced senescence in cancer cells based on gene expression profiles. Our work unraveled an intimate link between autophagy and senescence in melanoma cells undergoing therapy-induced senescence. We proved that combination therapy might not necessarily lead to synergy but antagonism, depending on which pathways were targeted. Thus we present the rationale for utilizing pro-senescence therapy as a novel therapeutic strategy for patients with advanced melanoma, and suggest that pro-senescence therapy should be combined with other targeted therapies or immunotherapies to maximize cell death.

Although research into multimodal interfaces has been around for a long time, we believe that some basic issues have not been studied yet, e.g. the choice of modalities and their combinations is usually made without any quantitative evaluation. This study seeks to identify the best combinations of modalities through usability testing. How do users choose different interaction modes when they work on a particular application? Two experimental evaluations were conducted to compare interaction modes on a CAD system and a map system respectively. For the CAD system, the results show that, in terms of total manipulation time (drawing and modification time) and subjective preferences, the "pen + speech + mouse" combination was the best of the seven interaction modes tested. On the map system, the results show that the "pen + speech" combination mode is the best of fourteen interaction modes tested. The experiments also provide information on how users adapt to each interaction mode and the ease with which they are able to use these modes., journal article

As more information becomes available on the World Wide Web, it has become an acute problem to provide effective search tools for information access. Previous generations of search engines are mainly keyword-based and cannot satisfy many informational needs of their users. Search based on simple keywords returns many irrelevant documents that can easily swamp the user. In this paper, we describe the system architecture of a next-generation search engine that we have built with a goal to provide accurate search result on frequently asked concepts. Our key differentiating factors from other search engines are natural language user interface, accurate search results, and interactive user interface and multimedia content retrieval. We describe the architecture, design goals and experience in developing the search engine

As more information becomes available on the World Wide Web, it has become an acute problem to provide effective search tools for information access. Previous generations of search engines are mainly keyword-based and cannot satisfy many informational needs of their users. Search based on simple keywords returns many irrelevant documents that can easily swamp the user. In this paper, we describe the system architecture of a next-generation search engine that we have built with a goal to provide accurate search result on frequently asked concepts. Our key differentiating factors from other search engines are natural language user interface, accurate search results, and interactive user interface and multimedia content retrieval. We describe the architecture, design goals and experience in developing the search engine

As more information becomes available on the World Wide Web, it has become an acute problem to provide effective search tools for information access. Previous generations of search engines are mainly keyword-based and cannot satisfy many informational needs of their users. Search based on simple keywords returns many irrelevant documents that can easily swamp the user. In this paper, we describe the system architecture of a next-generation search engine that we have built with a goal to provide accurate search result on frequently asked concepts. Our key differentiating factors from other search engines are natural language user interface, accurate search results, and interactive user interface and multimedia content retrieval. We describe the architecture, design goals and experience in developing the search engine