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Materials with structural gradients often have unique combinations of properties. Gradient-structured materials are found in nature and can be engineered. Cheng et al. made a structural gradient by introducing gradients of crystallographic twins into copper. This strategy creates bundles of dislocations in the crystal interiors, which makes the metal stronger than any of the individual components. This method offers promise for developing high-performance metals. Science , this issue p. eaau1925 A structural gradient made of nanotwins improves the strength of copper. Gradient structures exist ubiquitously in nature and are increasingly being introduced in engineering. However, understanding structural gradient–related mechanical behaviors in all gradient structures, including those in engineering materials, has been challenging. We explored the mechanical performance of a gradient nanotwinned structure with highly tunable structural gradients in pure copper. A large structural gradient allows for superior work hardening and strength that can exceed those of the strongest component of the gradient structure. We found through systematic experiments and atomistic simulations that this unusual behavior is afforded by a unique patterning of ultrahigh densities of dislocations in the grain interiors. These observations not only shed light on gradient structures, but may also indicate a promising route for improving the mechanical properties of materials through gradient design.

Background Immune checkpoint inhibitors (ICIs) are currently the first line of tumor immunotherapy for the treatment of a wide range of tumors. However, the main side effect of immune checkpoint inhibitors is that they cause immune-related adverse events (irAEs) in patients. The relationship between the occurrence of immune side effects in patients and efficacy is controversial. The objective of this study was to confirm the relationship between patients who develop thyroid dysfunction after immune checkpoint inhibitors and efficacy. Methods This study was a retrospective real-world clinical study, and a total of 50 patients with advanced tumors treated with immune checkpoint inhibitors at Anqing People's Hospital from 2020.8 to 2022.5 were retrospectively collected. Among them, 30 patients with hypothyroidism and 20 patients with normal or hyperthyroidism occurred, and the treatment effects and prognostic differences between the two groups were compared. Finding After PD1 treatment in all patients, there were 10 cases of partial remission(PR), 18 cases of stable disease(SD) and 2 cases of progressive disease(PD) in patients who developed hypothyroidism, with a disease control rate(DCR) of 93.3% and objective remission rate(ORR) of 33.3%. There were 0 complete remission (CR) patient, 3 PR patients, 11 SD patients, 6 PD patients, 70.0% DCR and 15.0% ORR in patients who did not develop hypothyroidism. The DCR and ORR of patients who developed hypothyroidism were better than those of non-hypothyroid patients, and the difference was statistically significant ( P  < 0.05). Kaplan–Meier survival analysis showed that progression-free survival (PFS) reached 9.2 months (95% CI 7.726–10.779) in patients who developed hypothyroidism and did not hypothyroidism patients have a PFS of 7.3 months (95% CI 5.604–8.505), with a statistically significant difference ( P  = 0.0341 < 0.05). Further subgroup analysis revealed that among patients who developed hypothyroidism, PFS was 3.3 months (95% CI 0.630–5.440) in patients with cholangiocarcinoma, 6.89 months (95% CI 5.604–8.505) in patients with non-small cell lung cancer, > 12 months in patients with hepatocellular carcinoma, and 11.05 months (95% CI 9.308–12.792) in patients with esophageal cancer months and PFS for patients with gastric cancer was 9.74 months (95% CI 6.979–12.502). Interpretation When patients with advanced tumors were treated with immune checkpoint inhibitors, DCR and ORR were higher in patients who developed hypothyroidism, and patients had better PFS. The benefits were greater in patients with gastric, esophageal, and hepatocellular carcinomas.

Cancer is a leading cause of death around the world. Apoptosis, one of the pathways of programmed cell death, is a promising target for cancer therapy. Traditional Tibetan medicine (TTM) has been used by Tibetan people for thousands of years, and many TTMs have been proven to be effective in the treatment of cancer. This paper summarized the medicinal plants with anticancer activity in the Tibetan traditional system of medicine by searching for Tibetan medicine monographs and drug standards and reviewing modern research literatures. Forty species were found to be effective in treating cancer. More importantly, some TTMs ( ., , L. and (Regel) Maxim.) and their active ingredients ( , cordycepin, salidroside, and gallic acid) have been reported to possess anticancer activity by targeting some apoptosis pathways in cancer, such as Bcl-2/Bax, caspases, PI3K/Akt, JAK2/STAT3, MAPK, and AMPK. These herbs and natural compounds would be potential drug candidates for the treatment of cancer.

Microglia are the primary immune cells in the central nervous system and undergo significant morphological and transcriptional changes after traumatic brain injury (TBI). However, their exact contribution to the pathogenesis of TBI is still debated and remains to be elucidated. In the present study, thy-1 GFP mice received a colony-stimulating factor 1 receptor inhibitor (PLX3397) for 21 consecutive days, then were subjected to moderate fluid percussion injury (FPI). Brain samples were collected at 1 day and 3 days after FPI for flow cytometry analysis, immunofluorescence, dendrite spine quantification, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and Western blot. We found that PLX3397 treatment significantly attenuated the percentages of resident microglia and infiltrated immune cells. Depletion of microglia promoted neurite outgrowth, preserved dendritic spines and reduced total brain cell and neuronal apoptosis after FPI, which was accompanied by decreased the protein levels of endoplasmic reticulum stress marker proteins, C/EBP-homologous protein and inositol-requiring kinase 1α. Taken together, these findings suggest that microglial depletion may exert beneficial effects in the acute stage of FPI.

Background Circular RNA (circRNA) is a novel class of noncoding RNAs with functions in various pathophysiological activities. However, the expression profiles and functions of circRNAs in colorectal cancer (CRC) remain largely unknown. Methods High-throughput RNA sequencing (RNA-seq) was performed to assess circRNA expression profiles in 4 paired CRC tissues, and significantly dysregulated circRNAs were validated by quantitative real-time polymerase chain reaction (qRT-PCR). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to predict the potential functions of dysregulated circRNAs. Target miRNAs of circRNAs were predicted using miRanda software, and were further analyzed combining DIANA-miRPath v.3 platform (Reverse Search module) with KEGG pathways of COLORECTAL CANCER and MicroRNAs in cancer (Entry: map05210 and map05206). CircRNA-miRNA interaction networks were constructed using Cytoscape software. Expression levels of a significantly down-regulated circRNA, circDDX17 (hsa_circ_0002211), was detected by qRT-PCR in 60 paired CRC tissues. CircDDX17 was knockdown by siRNA, and the biological functions of circDDX17 were examined in CRC cell lines. Results Totally 448 differentially expressed circRNAs were identified, including 394 up-regulated and 54 down-regulated circRNAs. qRT-PCR validation confirmed the reliability of the RNA-Seq data. GO and KEGG analyses revealed that these dysregulated circRNAs were potentially implicated in CRC pathogenesis. Analyses by combining miRanda and miRPath softwares with KEGG pathways suggested that the miRNAs targeted by the top 10 dysregulated circRNAs were associated with the KEGG pathways of COLORECTAL CANCER and MicroRNAs in cancer, indicating that circRNA-miRNA interactions might play important functional roles in the initiation and progression of CRC. The results of qRT-PCR for circDDX17 in 60 paired CRC tissues showed that circDDX17 was significantly down-regulated in CRC tissues and associated with unfavorable clinicopathological parameters. In vitro experiments showed that silencing of circDDX17 promoted CRC cell proliferation, migration, invasion, and inhibited apoptosis. Conclusions In conclusion, we have identified numerous circRNAs that are dysregulated in CRC tissues compared with adjacent normal mucosa tissues. Bioinformatic analyses suggested that these dysregulated circRNAs might play important functional roles in CRC tumorigenesis. CircDDX17 functions as a tumor suppressor and could serve as a potential biomarker and a therapeutic target for CRC.

The continuing increase in atmospheric CO2 concentration caused by anthropogenic CO2 emissions significantly contributes to climate change driven by global warming. Satellite measurements of long-term CO2 data with global coverage improve our understanding of global carbon cycles. However, the sensitivity of the space-borne measurements to anthropogenic emissions on a regional scale is less explored because of data sparsity in space and time caused by impacts from geophysical factors such as aerosols and clouds. Here, we used global land mapping column averaged dry-air mole fractions of CO2 (XCO2) data (Mapping-XCO2), generated from a spatio-temporal geostatistical method using GOSAT and OCO-2 observations from April 2009 to December 2020, to investigate the responses of XCO2 to anthropogenic emissions at both global and regional scales. Our results show that the long-term trend of global XCO2 growth rate from Mapping-XCO2, which is consistent with that from ground observations, shows interannual variations caused by the El Niño Southern Oscillation (ENSO). The spatial distributions of XCO2 anomalies, derived from removing background from the Mapping-XCO2 data, reveal XCO2 enhancements of about 1.5–3.5 ppm due to anthropogenic emissions and seasonal biomass burning in the wintertime. Furthermore, a clustering analysis applied to seasonal XCO2 clearly reveals the spatial patterns of atmospheric transport and terrestrial biosphere CO2 fluxes, which help better understand and analyze regional XCO2 changes that are associated with atmospheric transport. To quantify regional anomalies of CO2 emissions, we selected three representative urban agglomerations as our study areas, including the Beijing-Tian-Hebei region (BTH), the Yangtze River Delta urban agglomerations (YRD), and the high-density urban areas in the eastern USA (EUSA). The results show that the XCO2 anomalies in winter well capture the several-ppm enhancement due to anthropogenic CO2 emissions. For BTH, YRD, and EUSA, regional positive anomalies of 2.47 ± 0.37 ppm, 2.20 ± 0.36 ppm, and 1.38 ± 0.33 ppm, respectively, can be detected during winter months from 2009 to 2020. These anomalies are slightly higher than model simulations from CarbonTracker-CO2. In addition, we compared the variations in regional XCO2 anomalies and NO2 columns during the lockdown of the COVID-19 pandemic from January to March 2020. Interestingly, the results demonstrate that the variations of XCO2 anomalies have a positive correlation with the decline of NO2 columns during this period. These correlations, moreover, are associated with the features of emitting sources. These results suggest that we can use simultaneously observed NO2, because of its high detectivity and co-emission with CO2, to assist the analysis and verification of CO2 emissions in future studies.

Nonmagnetic Rashba systems with broken inversion symmetry are expected to exhibit nonreciprocal charge transport, a new paradigm of unidirectional magnetoresistance in the absence of ferromagnetic layer. So far, most work on nonreciprocal transport has been solely limited to cryogenic temperatures, which is a major obstacle for exploiting the room-temperature two-terminal devices based on such a nonreciprocal response. Here, we report a nonreciprocal charge transport behavior up to room temperature in semiconductor α-GeTe with coexisting the surface and bulk Rashba states. The combination of the band structure measurements and theoretical calculations strongly suggest that the nonreciprocal response is ascribed to the giant bulk Rashba spin splitting rather than the surface Rashba states. Remarkably, we find that the magnitude of the nonreciprocal response shows an unexpected non-monotonical dependence on temperature. The extended theoretical model based on the second-order spin–orbit coupled magnetotransport enables us to establish the correlation between the nonlinear magnetoresistance and the spin textures in the Rashba system. Our findings offer significant fundamental insight into the physics underlying the nonreciprocity and may pave a route for future rectification devices. Most work on nonreciprocal transport is limited to cryogenic temperatures due to the low Rashba spin splitting energy. Here, the authors report a nonreciprocal charge transport behavior up to room temperature in semiconductor α-GeTe with coexisting the surface and bulk Rashba states.

Although the classical PID（proportional-integral-derivative） controller is most widely and successfully used in engineering systems which are typically nonlinear with various uncertainties, almost all the existing investigations on PID controller focus on linear systems. The aim of this paper is to present a theory on PID controller for nonlinear uncertain systems, by giving a simple and analytic design method for the PID parameters together with a mathematic proof for the global stability and asymptotic regulation of the closed-loop control systems. To be specific, we will construct a 3-dimensional manifold within which the three PID parameters can be chosen arbitrarily to globally stabilize a wide class of second order nonlinear uncertain dynamical systems, as long as some knowledge on the upper bound of the derivatives of the nonlinear uncertain function is available.We will also try to make the feedback gains as small as possible by investigating the necessity of the manifold from which the PID parameters are chosen, and to establish some necessary and sufficient conditions for global stabilization of several special classes of nonlinear uncertain systems.

A contribution of DNA methylation to defense against invading nucleic acids and maintenance of genome integrity is uncontested; however, our understanding of the extent of involvement of this epigenetic mark in genome-wide gene regulation and plant developmental control is incomplete. Here, we knock out all five known DNA methyltransferases in Arabidopsis , generating DNA methylation-free plants. This quintuple mutant exhibits a suite of developmental defects, unequivocally demonstrating that DNA methylation is essential for multiple aspects of plant development. We show that CG methylation and non-CG methylation are required for a plethora of biological processes, including pavement cell shape, endoreduplication, cell death, flowering, trichome morphology, vasculature and meristem development, and root cell fate determination. Moreover, we find that DNA methylation has a strong dose-dependent effect on gene expression and repression of transposable elements. Taken together, our results demonstrate that DNA methylation is dispensable for Arabidopsis survival but essential for the proper regulation of multiple biological processes. Our understanding of the extent of involvement of DNA methylation in genome-wide gene regulation and plant developmental control is incomplete. Here, the authors knock out all five known DNA methyltransferases and show the developmental and gene expression changes in the DNA methylation-free Arabidopsis plants.