The unique immunomodulatory properties of mesenchymal stem cells (MSCs) make them an invaluable cell type for the repair of tissue/ organ damage caused by chronic inflammation or autoimmune ...disorders. Although they hold great promise in the treatment of immune disorders such as graft versus host disease (GvHD) and allergic disorders, there remain many challenges to overcome before their widespread clinical application. An understanding of the biological properties of MSCs will clarify the mechanisms of MSC-based transplantation for immunomodulation. In this review, we summarize the preclinical and clinical studies of MSCs from different adult tissues, discuss the current hurdles to their use and propose the future development of pluripotent stem cell-derived MSCs as an approach to immunomodulation therapy.
Early detection of cancer offers the opportunity to identify candidates when curative treatments are achievable. The THUNDER study (THe UNintrusive Detection of EaRly-stage cancers, NCT04820868) ...aimed to evaluate the performance of enhanced linear-splinter amplification sequencing, a previously described cell-free DNA (cfDNA) methylation-based technology, in the early detection and localization of six types of cancers in the colorectum, esophagus, liver, lung, ovary, and pancreas.
A customized panel of 161 984 CpG sites was constructed and validated by public and in-house (cancer: n = 249; non-cancer: n = 288) methylome data, respectively. The cfDNA samples from 1693 participants (cancer: n = 735; non-cancer: n = 958) were retrospectively collected to train and validate two multi-cancer detection blood test (MCDBT-1/2) models for different clinical scenarios. The models were validated on a prospective and independent cohort of age-matched 1010 participants (cancer: n = 505; non-cancer: n = 505). Simulation using the cancer incidence in China was applied to infer stage shift and survival benefits to demonstrate the potential utility of the models in the real world.
MCDBT-1 yielded a sensitivity of 69.1% (64.8%-73.3%), a specificity of 98.9% (97.6%-99.7%), and tissue origin accuracy of 83.2% (78.7%-87.1%) in the independent validation set. For early-stage (I-III) patients, the sensitivity of MCDBT-1 was 59.8% (54.4%-65.0%). In the real-world simulation, MCDBT-1 achieved a sensitivity of 70.6% in detecting the six cancers, thus decreasing late-stage incidence by 38.7%-46.4%, and increasing 5-year survival rate by 33.1%-40.4%, respectively. In parallel, MCDBT-2 was generated at a slightly low specificity of 95.1% (92.8%-96.9%) but a higher sensitivity of 75.1% (71.9%-79.8%) than MCDBT-1 for populations at relatively high risk of cancers, and also had ideal performance.
In this large-scale clinical validation study, MCDBT-1/2 models showed high sensitivity, specificity, and accuracy of predicted origin in detecting six types of cancers.
•MCDBT-1 had a sensitivity of 69.1% and a specificity of 98.9% in detecting six cancers.•In the real world, MCDBT-1 decreased late-stage incidence by 38.7%-46.4% and increased 5-year survival rate by 33.1%-40.4%.•In parallel, MCDBT-2 was set at a lower specificity but a higher sensitivity than MCDBT-1 and had an ideal performance.
Abstract Previous experiments showed that ginsenoside Rb1 (GRb1) reduced infarct and neuronal deficit in rats followed by transient cerebral ischemia. The mechanism of this neuroprotective function ...is unclear. Here, we tested whether the effect of GRb1 can be achieved through preventing ischemic neuronal death, modulating apoptotic-related genes and affecting glial-derived neurotrophic factor (GDNF) expression in rats subjected to occlusion of the middle cerebral artery. When GRb1(40 mg/kg, i.p.) was administered immediately after reperfusion, the apoptotic cells in the GRb1 group were decreased significantly from 12 to 72 h of reperfusion compared to the ischemia group by TdT-mediated dUTP–biotin nick-end labeling. Immunostaining and Western blotting analysis showed that the expression of GDNF from 3 to 120 h of the GRb1 group was significantly increased compared to the ischemia group, and GDNF expression peaked at 48 h after reperfusion. The enhanced GDNF mRNA in the GRb1 group was not detected by RT-PCR and in situ hybridization compared to the ischemia group, but GDNF mRNA at 48 h after reperfusion was strongly increased in both the ischemia and GRb1 group when compared to other time points. The number of bcl-2-positive cells was significantly increased from 12 to 120 h of reperfusion compared to the ischemia group. However, the number of bax-positive cells in the GRb1 group was significantly declined compared to the ischemia group. In the GRb1 group, the number of neuronal apoptosis inhibitory protein-positive cells from 12 to 120 h after reperfusion was evidently higher than that in the ischemia group. Therefore, ginsenoside Rb1 prevents ischemic neuronal death induced by transient cerebral ischemia, and this mechanism of which is related to increase the expression of the antiapoptotic genes and modulate the expression of GDNF.
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Anion exchange membranes (AEMs) are a crucial constituent for alkaline fuel cells. As the core component of fuel cells, the low performance AEMs restrict the development and ...application of the fuel cells. Herein, the trade-off between the OH– conductivity and dimensional stability was solved by constructing AEMs with adequate OH– conductivity and satisfactory alkali resistance using Tröger’s base (TB) poly (crown ether)s (PCEs) as the main chain, the embedded quaternary ammonium (QA) and Na+-functionalized crown ether units as the cationic group. Crown ether is an electron donator, and can capture Na+ to form Na+-functionalized crown ether units to conveniently transfer OH– and significantly promote the alkaline stability of the AEMs. The influence of the Na+-functionalized crown ether units on the performance of AEMs was studied in detail. The PCEs based AEMs show an obvious hydrophobic-hydrophilic microphase separation. These features make them ideal platforms for the OH– conduction applications. As expected, the as-prepared PCEs-QA-100% (100% is the degree of cross-linking) AEM with an ionic exchange capacity (IEC) of 2.07 meq g−1 has a high OH– conductivity of 159 mS cm−1 at 80 °C. Furthermore, the membrane electrode assemblies fabricated using the PCEs-QA-100% AEM possess a maximum power density of 291 mW cm−2 under the current density of 500 mA cm−2.
The amalgamation of South (SCB) and North China Blocks (NCB) along the Qinling‐Dabie orogenic belt involved several stages of high pressure (HP)‐ultra high pressure (UHP) metamorphism. The new ...discovery of UHP metamorphic rocks in the North Qinling (NQ) terrane can provide valuable information on this process. However, no precise age for the UHP metamorphism in the NQ terrane has been documented yet, and thus hinders deciphering of the evolution of the whole Qinling‐Dabie‐Sulu orogenic belt. This article reports an integrated study of U–Pb age, trace element, mineral inclusion and Hf isotope composition of zircon from an eclogite, a quartz vein and a schist in the NQ terrane. The zircon cores in the eclogite are characterized by oscillatory zoning or weak zoning, high Th/U and 176Lu/177Hf ratios, pronounced Eu anomalies and steep heavy rare earth element (HREE) patterns. The zircon cores yield an age of 796 ± 13 Ma, which is taken as the protolith formation age of the eclogite, and implies that the NQ terrane may belong to the SCB before it collided with the NCB. The ɛHf(t) values vary from −11.3 to 3.2 and corresponding two‐stage Hf model ages are 2402 to 1495 Ma, suggesting the protolith was derived from an enriched mantle. In contrast, the metamorphic zircon rims show no zoning or weak zoning, very low Th/U and 176Lu/177Hf ratios, insignificant Eu anomalies and flat HREE patterns. They contain inclusions of garnet, omphacite and phengite, suggesting that the metamorphic zircon formed under eclogite facies metamorphic conditions, and their weighted mean 206Pb/238U age of 485.9 ± 3.8 Ma was interpreted to date the timing of the eclogite facies metamorphism. Zircon in the quartz vein is characterized by perfect euhedral habit, some oscillatory zoning, low Th/U ratios and variable HREE contents. It yields a weighted mean U–Pb age of 480.5 ± 2.5 Ma, which registers the age of fluid activity during exhumation. Zircon in the schist is mostly detrital and U–Pb age peaks at c. 1950 to 1850, 1800 to 1600, 1560 to 1460 and 1400 to 1260 Ma with an oldest grain of 2517 Ma, also suggesting that the NQ terrane may have an affinity to the SCB. Accordingly, the amalgamation between the SCB and the NCB is a multistage process that spans c. 300 Myr, which includes: the formation of the Erlangping intra‐oceanic arc zone onto the NCB before c. 490 Ma, the c. 485 Ma crustal subduction and UHP metamorphism of the NQ terrane, the c. 430 Ma arc‐continent collision and granulite facies metamorphism, the 420 to 400 Ma extension and rifting in relation to the opening of the Palaeo‐Tethyan ocean, the c. 310 Ma HP eclogite facies metamorphism of oceanic crust and associated continental basement, and the final 250 to 220 Ma continental subduction and HP–UHP metamorphism.
Abstract This paper focuses on sensitivity analysis in the design of Attack helicopter combat indicators, and combines the advantages of machine learning to propose a combat effectiveness oriented ...sensitivity analysis method for Attack helicopter combat indicators. Firstly, the steps of sensitivity analysis of Attack helicopter combat indicators based on machine learning are introduced. Secondly, through operational scenarios, constructing indicator systems, collecting relevant data, evaluating effectiveness, and using machine learning algorithms for modelling and training, the sensitivity assessment of the damage probability of Attack helicopter to ground armoured weapons can be achieved. This paper is able to provide reference for the sensitivity analysis of weapon equipment system effectiveness, and provide more scientific and reasonable support for the research and application of helicopters in combat systems.
The timing and route of the earliest dispersal from Africa to Eastern Asia are contentious topics in the study of early human evolution because Asian hominin fossil sites with precise age constraints ...are very limited. Here we report new high-resolution magnetostratigraphic results that place stringent age controls on excavated hominin incisors and stone tools from the Yuanmou Basin, southwest China. The hominin-bearing layer resides in a reverse polarity magnetozone just above the upper boundary of the Olduvai subchron, yielding an estimated age of 1.7
Ma. The finding represents the age of the earliest documented presence of
Homo, with affinities to
Homo erectus, in mainland East Asia. This age estimate is roughly the same as for
H. erectus in island Southeast Asia and immediately prior to the oldest archaeological evidence in northeast Asia. Mammalian fauna and pollen obtained directly from the hominin site indicate that the Yuanmou hominins lived in a varied habitat of open vegetation with patches of bushland and forest on an alluvial fan close to a lake or swamp. The age and location are consistent with a rapid southern migration route of initial hominin populations into Eastern Asia.
Quercetin (3,3′,4′,5,7-pentahydroxyflavone, Qu) is a promising cancer chemo-preventive agent for various cancers because it inhibits disease progression and promotes apoptotic cell death. In our ...previous study, we demonstrated that Qu could evoke ER stress to enhance drug cytotoxicity in ovarian cancer (OC). However, Qu-induced ER stress in OC is still poorly understood. Here, we demonstrated that Qu evoked ER stress to involve in mitochondria apoptosis pathway via the p-STAT3/Bcl-2 axis in OC cell lines and in primary OC cells. Unexpectedly, inhibition of ER stress did not reverse Qu-induced cell death. Further functional studies revealed that Qu-induced ER stress could activate protective autophagy concomitantly by activating the p-STAT3/Bcl-2 axis in this process. Moreover, the autophagy scavenger 3-MA was shown to enhance Qu’s anticancer effects in an ovarian cancer mice xenograft model. These findings revealed a novel role of ER stress as a “double edge sword” participating in Qu-induced apoptosis of OC and might provide a new angle to consider in clinical studies of biological modifiers that may circumvent drug resistance in patients by targeting protective autophagy pathways.
Deterministic creation of multiple ferroelectric states with intermediate values of polarization remains challenging due to the inherent bi-stability of ferroelectric switching. Here we show the ...ability to select any desired intermediate polarization value via control of the switching pathway in (111)-oriented PbZr
Ti
O
films. Such switching phenomena are driven by kinetic control of the volume fraction of two geometrically different domain structures which are generated by two distinct switching pathways: one direct, bipolar-like switching and another multi-step switching process with the formation of a thermodynamically-stable intermediate twinning structure. Such control of switching pathways is enabled by the competition between elastic and electrostatic energies which favors different types of ferroelastic switching that can occur. Overall, our work demonstrates an alternative approach that transcends the inherent bi-stability of ferroelectrics to create non-volatile, deterministic, and repeatedly obtainable multi-state polarization without compromising other important properties, and holds promise for non-volatile multi-state functional applications.
Abstract
Helicopters are characterized by complex missions, high risk, high cost, high reliability and long lead times. In order to adapt to the more complex operational requirements in the future, ...the thesis addresses the problems of long iterative cycles, low efficiency and model duality in the traditional helicopter operation requirements analysis process, the theory of model-based systems engineering (MBSE) is introduced into operation requirements analysis for helicopter. A modelling analysis and design method for helicopter operation requirements analysis is proposed based on MBSE. The overall framework for helicopter operation requirements analysis based on the model is designed. On this basis, a modelling design method and key implementation process of requirements analysis is established, which provides theoretical and technical support for the positive design of helicopter operation requirements demonstration.
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