Precise direct cosmic-ray (CR) measurements provide an important probe to study the energetic particle sources in our Galaxy, and the interstellar environment through which these particles propagate. Uncertainties on hadronic models, ion-nucleon cross sections in particular, are currently the limiting factor toward obtaining more accurate CR ion flux measurements with calorimetric space-based experiments. We present an energy-dependent measurement of the inelastic cross section of protons and helium-4 nuclei (alpha particles) on a Bi4Ge3O12 target, using 88 months of data collected by the DAMPE space mission. The kinetic energy range per nucleon of the measurement points ranges from 18 GeV to 9 TeV for protons, and from 5 GeV/n to 3 TeV/n for helium-4 nuclei. Our results lead to a significant improvement of the CR flux normalization. In the case of helium-4, these results correspond to the first cross section measurements on a heavy target material at energies above 10 GeV/n. Published by the American Physical Society 2025

Recent observations of the light component of the cosmic-ray spectrum have revealed unexpected features that motivate further and more precise measurements up to the highest energies. The Dark Matter Particle Explorer is a satellite-based cosmic-ray experiment that has been operational since December 2015, continuously collecting data on high-energy cosmic particles with very good statistics, energy resolution, and particle identification capabilities. In this work, the latest measurements of the energy spectrum of proton+helium in the energy range from 46 GeV to 464 TeV are presented. Among the most distinctive features of the spectrum, a spectral hardening at 600 GeV has been observed, along with a softening at 29 TeV measured with a 6.6σ significance. Moreover, the detector features and the analysis approach allowed for the extension of the spectral measurement up to the sub-PeV region. Even if with small statistical significance due to the low number of events, data suggest a new spectral hardening at about 150 TeV.

Precise direct cosmic-ray (CR) measurements provide an important probe to study the energetic particle sources in our Galaxy, and the interstellar environment through which these particles propagate. Uncertainties on hadronic models, ion-nucleon cross sections in particular, are currently the limiting factor towards obtaining more accurate CR ion flux measurements with calorimetric space-based experiments. We present an energy-dependent measurement of the inelastic cross section of protons and helium-4 nuclei (alpha particles) on a Bi_4Ge_3O_12 target, using 88 months of data collected by the DAMPE space mission. The kinetic energy range per nucleon of the measurement points ranges from 18 GeV to 9 TeV for protons, and from 5 GeV/n to 3 TeV/n for helium-4 nuclei. Our results lead to a significant improvement of the CR flux normalisation. In the case of helium-4, these results correspond to the first cross section measurements on a heavy target material at energies above 10 GeV/n.

RET-fusion was reported contribute about 2% of acquired resistance mechanisms of EGFR/ALK-TKIs. Selective RET inhibitor pralsetinib demonstrated impressive improvement of survival in patients with RET+ aNSCLC in the I/II ARROW study. However, the efficacy in patients with acquired RET-fusion after resistance to EGFR/ALK-TKIs was only reported by case, and the strategy of overcome the acquired RET-fusion has not been fully investigated.

Background: Spliceosome machinery mutations are common early mutations in myeloid malignancies, however effective targeted therapies against them are still lacking in clinical settings. Aims: Exploring safe and efficient methods to target hematopoietic cells carrying SRSF2 mutations might be a powerful tool not just for leukemia prevention and treatment, but also to understand the mechanisms behind SRSF2 mutations. Methods: We generated five SRSF2 Mut (P95H) isogenic cell lines with CRISPR/CAS9 system and performed high throughput drug screen with 3988 compounds in a single dose. After we narrowed down our targets, dose response assay was performed on four different ROCK inhibitors (ROCKi). The leading ROCKi compound was validated in vivo with SRSF2 Mut AML xenograft models. Next, we aimed at understanding why ROCKi target SRSF2 Mut cells and used proteomics, gene expression and imaging of the cytoskeletal system to study the effect of ROCKi on Mut and WT cells. Results: In the current study, we used an in vitro high-throughput drug screen among four different isogenic cell lines and identified ROCK inhibitors (ROCKi) as selective inhibitors of SRSF2 Mut in MOLM14 and AML2 cells. To study the efficacy of RKI-1447 on human samples, we conducted six AML patient-derived xenograft (PDX) experiments, with SRSF2 Mut samples. In four out of the six primary AML samples, RKI-1447 significantly reduced engraftment compared to the untreated group and inhibited the engraftment of both leukemic blasts and pre leukemic-HSPCs (preL-HSPCS). RKI-1447 was not toxic to mice nor human cells. ROCKi induced mitotic catastrophe (G2M arrest and multipolar spindles) through their apparent effects on microtubules and nuclear organization, and leading to cell death. Confocal imaging and transmission electron microscopy (TEM) data revealed that SRSF2 mutations induce deep nuclear indentation and segmentation, which is reminiscent of the nuclear shape of Pelger–Huët anomaly (PHA). The nuclear volume and area were significantly higher in SRSF2 Mut compared with WT MOLM14 cells regardless of ROCKi. To investigate why SRSF2 Mut cause the structural changes, we looked into the cytoplasmic intrusions that segment the nuclei, and the structures that connect the lobes of the nuclei by TEM. This examination revealed enrichment of microtubule bundles inside the nuclear indentations. More importantly, these microtubules were located at the tip of the cytoplasmic intrusions suggesting that they take an active role in the nuclear segmentation process. After exposure to RKI-1447, the cytoskeletal and nuclear morphological abnormalities of SRSF2 Mut are augmented to a level which are incompatible with cell survival. Image:Summary/Conclusion: We believe it is the first report describing in high resolution the changes in the nucleus after SRSF2 mutations are introduced. The mechanisms we identified are most probably relevant to other SMMs and to the dysplastic phenotype observed in MDS and AML. Accordingly, our findings have wide implications as ROCKi might be even more useful than describe here. Altogether, we provide data from many directions that ROCKi should be tested in clinical trials.

Spliceosome machinery mutations are common early mutations in myeloid malignancies, however effective targeted therapies against them are still lacking. In the current study, we used an in vitro high-throughput drug screen among four different isogenic cell lines and identified ROCK inhibitors (ROCKi) as selective inhibitors of SRSF2 mutants. ROCKi targeted SRSF2 Mut primary human samples in a xenografts model and were not toxic to mice nor human cells. ROCKi induced mitotic catastrophe through their apparent effects on microtubules and nuclear organization. Transmission electron microscopy revealed that SRSF2 mutations induce deep nuclear indentation and segmentation, driven by microtubule-rich cytoplasmic intrusions, which were exacerbated by ROCKi. The severe nuclear deformation driven by the combination of SRSF2 Mut and ROCKi prevent cells from completing mitosis. These findings shed light on new ways to target SRSF2 and on the role of the microtubule system in SRSF2 Mut cells.

More than a century after the performance of the oil drop experiment, the possible existence of fractionally charged particles FCP still remains unsettled. The search for FCPs is crucial for some extensions of the Standard Model in particle physics. Most of the previously conducted searches for FCPs in cosmic rays were based on experiments underground or at high altitudes. However, there have been few searches for FCPs in cosmic rays carried out in orbit other than AMS-01 flown by a space shuttle and BESS by a balloon at the top of the atmosphere. In this study, we conduct an FCP search in space based on on-orbit data obtained using the DArk Matter Particle Explorer (DAMPE) satellite over a period of five years. Unlike underground experiments, which require an FCP energy of the order of hundreds of GeV, our FCP search starts at only a few GeV. An upper limit of $6.2\times 10^{-10}~~\mathrm{cm^{-2}sr^{-1} s^{-1}}$ is obtained for the flux. Our results demonstrate that DAMPE exhibits higher sensitivity than experiments of similar types by three orders of magnitude that more stringently restricts the conditions for the existence of FCP in primary cosmic rays.

The measurement of the energy spectrum of cosmic ray helium nuclei from 70 GeV to 80 TeV using 4.5 years of data recorded by the Dark Matter Particle Explorer (DAMPE) is reported in this work. A hardening of the spectrum is observed at an energy of about 1.3 TeV, similar to previous observations. In addition, a spectral softening at about 34 TeV is revealed for the first time with large statistics and well controlled systematic uncertainties, with an overall significance of 4.3σ. The DAMPE spectral measurements of both cosmic protons and helium nuclei suggest a particle charge dependent softening energy, although with current uncertainties a dependence on the number of nucleons cannot be ruled out.

Abstract Background Cardiovascular diseases (CVD) is the leading cause of death in China. Secondary prevention medications can improve the prognosis of CVD, yet little is known about the current use, variation and associated factors of these therapies in China. Purpose The aim of this study was to describe the current use of secondary prevention medications among patients with established CVD in the community setting in China, assess variations across population subgroups, and identify the individual characteristics associated with these therapies. Methods We studied 2.6 million participants aged 35–75 years from all 31 provinces in the China Patient-Centered Evaluative Assessment of Cardiac Events (PEACE) Million Persons Project, a government-funded public health program conducted from 2014 to 2018. Participants self-reported their history of ischemic heart disease (IHD) or ischemic stroke (IS) and medication use in an interview. Among participants with IHD and/or IS, we assessed the reported use of secondary prevention medications (anti-platelet drugs and statins) in the overall population and in 1,530,408 population subgroups, defined by all possible combinations of 16 factors (age, sex, urbanity, geographic region, ethnicity, occupation, annual household income, education, marital status, medical insurance, current smoker, current drinker, history of hypertension, history of diabetes, body mass index and years since diagnosis). Multivariable mixed models with a logit link function and community-specific random intercepts were fitted to assess the associations of demographic, socioeconomic and health behavior factors with the reported use of secondary prevention mediations. Results Among 2,613,035 screened participants, 2.9% (74,830) had history of IHD and/or IS (1.2% for IHD, 2.4% for IS). Overall, the reported use rate either anti-platelet drugs or statins was 21.9% (18.3% anti-platelet drugs, 11.0% statins, and 7.4% both). Among the 1,530,408 population subgroups, the use of secondary prevention medications varied substantially (3.4% to 52.0%). Multivariable analyses found that that younger people, women, those living in rural areas, current smokers, current drinkers, people without hypertension or diabetes, and those with established CVD for more than 2 years were less likely to take anti-platelet drugs or statins (Figure). Forest plot of multivariable mixed model Conclusions The current use of secondary prevention drugs is suboptimal and varies substantially across population subgroups in China. Our study identifies target populations for interventions to improve secondary prevention of CVD. Acknowledgement/Funding This study was supported by the Ministry of Finance of China and National Health Commission of China

The precise measurement of the spectrum of protons, the most abundant component of the cosmic radiation, is necessary to understand the source and acceleration of cosmic rays in the Milky Way. This work reports the measurement of the cosmic ray proton fluxes with kinetic energies from 40 GeV to 100 TeV, with 2 1/2 years of data recorded by the DArk Matter Particle Explorer (DAMPE). This is the first time that an experiment directly measures the cosmic ray protons up to ~100 TeV with high statistics. The measured spectrum confirms the spectral hardening at ~300 GeV found by previous experiments and reveals a softening at ~13.6 TeV, with the spectral index changing from ~2.60 to ~2.85. Our result suggests the existence of a new spectral feature of cosmic rays at energies lower than the so-called knee and sheds new light on the origin of Galactic cosmic rays.

The DArk Matter Particle Explorer (DAMPE), a satellite-based cosmic ray and gamma-ray detector, was launched on December 17, 2015, and began its on-orbit operation on December 24, 2015. In this work we document the on-orbit calibration procedures used by DAMPE and report the calibration results of the Plastic Scintillator strip Detector (PSD), the Silicon-Tungsten tracKer-converter (STK), the BGO imaging calorimeter (BGO), and the Neutron Detector (NUD). The results are obtained using Galactic cosmic rays, bright known GeV gamma-ray sources, and charge injection into the front-end electronics of each sub-detector. The determination of the boundary of the South Atlantic Anomaly (SAA), the measurement of the live time, and the alignments of the detectors are also introduced. The calibration results demonstrate the stability of the detectors in almost two years of the on-orbit operation.

Objective: To investigate the effect of decellularized osteochondral extracellular matrix (ECM) scaffold for osteochondral defect regeneration. Design: We compared the histological features and microstructure of degenerated cartilage to normal articular cartilage. We also generated and evaluated osteochondral ECM scaffolds through decellularization technology. Then scaffolds were implanted to osteochondral defect in rabbit model. After 12 weeks surgery, regeneration tissues were analyzed by histology, immunohistochemistry evaluation. And possible mechanisms of angiogenesis and cell migration were explored. Results: We demonstrated decreased cell numbers, formation of fibrous cartilage, lost microstructure and worse permeability in degenerated cartilage compared to normal cartilage. We also generated an osteochondral ECM scaffold with a hierarchical structure that exhibited low immunogenicity, high bioactivity, and well biocompatibility. We found that the ECM scaffold promoted tissue regeneration in osteochondral defects, which was dependent on the scaffold constituents and stratified threedimensional microstructure as well as on its ability to inhibit angiogenesis and stimulate cell migration. Conclusions: Our findings demonstrated that the biphasic hierarchical ECM scaffold represents a novel and effective biomaterial that can be used in the treatment of osteochondral defect. (c) 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

A new environmentally friendly flocculant was synthesized by cationic modified poly(γ-glutamic acid) (γ-PGA). The flocculant was prepared via chemical reaction between γ-PGA and 3-chloro-2-hydroxypropyl trimethyl ammonium chloride (CHPTMA). γ-PGA, as a new type of microbial flocculant with water-soluble, biodegradable, non-toxic and edible characteristics in water treatment has broad application prospects. The cationic degree of cationic modified γ-PGA was characterized by conductivity meter. Infrared spectrometry (FTIR) and 1H NMR were explored to determine chemical structure of the composite flocculant. The influence of etherification agent, reaction temperature, reaction time, as well as the molar ratio of etherifying agent and NaOH on flocculation performance were investigated. The results showed that the turbidity of the seawater distinctly decreased from 95 NTU to 10 NTU with 2 mg/L modified γ- PGA.

Background: Previous studies have demonstrated that patients with inflammatory bowel disease (IBD) have increased vulnerability for psychological symptoms. However, the further investigation of the psychological symptoms and impaired daily function in Chinese patients with Crohn's disease (CD) is not well described. Our aim is to estimate the psychological symptoms and daily function of the patients with CD comparing with health controls and the risk factors for psychological symptoms of the Chinese patients with CD. Methods: A cross-sectional study was undertaken including 169 patients with CD and 174 healthy controls. The Research Electronic Data Capture (REDCap) were adopted to perform web-based surveys. Sociodemographic variables including age, gender, employment state, marriage state, education, place of residence and fertility, clinical variables including surgery history, stoma, course of disease, therapy and disease activity estimated by the Harvey-Bradshaw Index (HBI), psychological symptoms measured by the Depression Anxiety Stress Scales (DASS-21), daily function measured by the Work and Social Adjustment Scale (WSAS) were estimated in both patients with CD and healthy controls. Chi-square test was performed to identify differences of psychological symptoms and daily function between the patients with CD and the controls. Logistic regression was performed to identify the risk factors associated with psychological symptoms in patients with CD. Results: The median age of the patients with CD and the controls was 30.75±10.79 and 30.99±8.48 years old, respectively. The patients with CD experienced elevated depression symptoms (10/169, 14.8%), anxiety symptoms (40/169, 23.6%) and impaired daily function (92/169, 54.5%) than the controls (10/174, 1.4%; 14/174, 8.0%; 14/174, 8.0%, respectively). The patients with active CD experienced elevated anxiety symptoms (25/72, 34.7%) and impaired daily function (49/72, 68.1%) than the patients in remission (15/97, 15.5%; 38/97, 39.2%). Urban life (OR=2.631, 95% CI: 1.176 to 5.885) is the independent risk factor for psychological symptoms. Conclusions: The Chinese Patients with CD experience elevated psychological symptoms and impaired daily function, particular the Patients in activity diseases state. Urban life is the independent risk factor for psychological symptoms. So the Chinese Patients with CD need psychological assessment and support.

Background: As a traditional method for the assessment of colon dynamics, radio-opaque markers (ROMs) are limited in clinical use because of their ionizing radiation. We compared the accuracy and applicability of gadolinium-based capsules with ROMs in the measurement of colon dynamics in healthy controls and slow transit constipation (STC) patients.Methods: Seven patients with STC and nine healthy controls under a normal diet orally consumed ROMs and gadolinium-based capsules simultaneously. All subjects underwent X-ray and magnetic resonance imaging (MRI). Healthy control images were acquired at 12, 24, and 48 h, and STC patient images were acquired at 24, 48, and 72 h. The scores based on the position of the labeling capsules and ROMs in the colon and the colon transit times (CTTs) in the two groups were compared.Key Results: The CTTs obtained via the ROMs were 34.7 +/- 17.4 and 67.3 +/- 6.5 h in the healthy controls and STC patients, respectively (P <.05). The CTTs obtained via MRI were 30.9 +/- 15.9 and 74.1 +/- 7.2 h in the healthy controls and STC patients, respectively (P <.05). The CTTs of the STC patients were significantly longer than the healthy controls. The correlation (r(s)) between the scores based on the position of the labeling capsule and ROMs in the healthy group and the STC patients was .880 (P <.05) and .889 (P <.05), respectively.Conclusions and Inferences: As a MRI contrast label, gadolinium-based capsules exhibit results comparable to ROMs in colon motility measurements.

The DArk Matter Particle Explorer (DAMPE), one of the four scientific space science missions within the framework of the Strategic Pioneer Program on Space Science of the Chinese Academy of Sciences, is a general purpose high energy cosmic-ray and gamma-ray observatory, which was successfully launched on December 17th, 2015 from the Jiuquan Satellite Launch Center. The DAMPE scientific objectives include the study of galactic cosmic rays up to ∼ 10 TeV and hundreds of TeV for electrons/gammas and nuclei respectively, and the search for dark matter signatures in their spectra. In this paper we illustrate the layout of the DAMPE instrument, and discuss the results of beam tests and calibrations performed on ground. Finally we present the expected performance in space and give an overview of the mission key scientific goals.

PANGU (the PAir-productioN Gamma-ray Unit) is a gamma-ray telescope with a wide field of view optimized for spectro-imaging, timing and polarization studies. It will map the gamma-ray sky from 10 MeV to a few GeV with unprecedented spatial resolution. This window on the Universe is unique to detect photons produced directly by relativistic particles, via the decay of neutral pions, or the annihilation or decay light from anti-matter and the putative light dark matter candidates. A wealth of questions can be probed among the most important themes of modern physics and astrophysics. The PANGU instrument is a pair-conversion gamma-ray telescope based on an innovative design of a silicon strip tracker. It is light, compact and accurate. It consists of 100 layers of silicon micro-strip detectors of 80 x 80 cm(2) in area, stacked to height of about 90 cm, and covered by an anticoincidence detectors. PANGU relies on multiple scattering effects for energy measurement, reaching an energy resolution between 30-50% for 10 MeV - 1GeV. The novel tracker will allow the first polarization measurement and provide the best angular resolution ever obtained in the soft gamma ray and GeV band.