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Buyang Huanwu Decoction (BHD), a classic traditional Chinese medicine (TCM) formula, has been used for recovering neurological dysfunctions and treating post-stroke disability in China for 200 years. In the present study, we investigated the effects of BHD on inhibiting neuronal apoptosis, promoting proliferation and differentiation of neural stem cells (NSCs) and neurite formation and enhancing learning and memory functional recovery in an experimental rat ischemic stroke model. BHD significantly reduced infarct volume and decreased cell apoptosis in the ischemic brain. BHD enhanced neuronal cell viability in vitro. BHD dose-dependently promoted the proliferation of NSCs in ischemic rat brains in vivo. Moreover, BHD promoted neuronal and astrocyte differentiation in primary cultured NSCs in vitro. Water maze test revealed that BHD promoted the recovery of learning function but not memory functions in the transient ischemic rats. We then investigated the changes of the cellular signaling molecules by using two-dimension (2D) gel electrophoresis and focused on the PI3K/Akt/Bad and Jak2/Stat3/cyclin D1signaling pathway to uncover its underlying mechanisms for its neuroprotective and neurogenetic effects. BHD significantly upregulated the expression of p-PI3K, p-Akt, and p-Bad as well as the expression of p-Jak, p-Stat3, and cyclin D1 in vitro and in vivo. In addition, BHD upregulated Hes1 and downregulated cav-1 in vitro and in vivo. Taken together, these results suggest that BHD has neuroprotective effects and neurogenesis-promoting effects via activating PI3K/Akt/Bad and Jak2/Stat3/Cyclin D1 signaling pathways.

Photon upconversion of near-infrared (NIR) irradiation into ultraviolet-C (UVC) emission offers many exciting opportunities for drug release in deep tissues, photodynamic therapy, solid-state lasing, energy storage, and photocatalysis. However, NIR-to-UVC upconversion remains a daunting challenge due to low quantum efficiency. Here, we report an unusual six-photon upconversion process in Gd 3+ /Tm 3+ -codoped nanoparticles following a heterogeneous core-multishell architecture. This design efficiently suppresses energy consumption induced by interior energy traps, maximizes cascade sensitizations of the NIR excitation, and promotes upconverted UVC emission from high-lying excited states. We realized the intense six-photon-upconverted UV emissions at 253 nm under 808 nm excitation. This work provides insight into mechanistic understanding of the upconversion process within the heterogeneous architecture, while offering exciting opportunities for developing nanoscale UVC emitters that can be remotely controlled through deep tissues upon NIR illumination. Photon upconversion with near-infrared excitation and ultraviolet emission has many applications, but suffers from low quantum efficiency. Here, the authors report a six-photon upconversion process in nanoparticles with heterogeneous core-multishell structure, that regulate the energy transfer pathway.

Most human diseases are systems diseases, and systems biomarkers are better fitted for diagnostic, prognostic, and treatment monitoring purposes. To search for systems biomarker candidates, lactate dehydrogenase (LDH), a housekeeping protein expressed in all living cells, was investigated. To this end, we analyzed the serum LDH activities from 172,933 patients with 48 clinically defined diseases and 9528 healthy individuals. Based on the median values, we found that 46 out of 48 diseases, leading by acute myocardial infarction, had significantly increased ( p  < 0.001), whereas gout and cerebral ischemia had significantly decreased ( p  < 0.001) serum LDH activities compared to the healthy control. Remarkably, hepatic encephalopathy and lung fibrosis had the highest AUCs (0.89, 0.80), sensitivities (0.73, 0.56), and specificities (0.90, 0.91) among 48 human diseases. Statistical analysis revealed that over-downregulation of serum LDH activities was associated with blood-related cancers and diseases. LDH activities were potential systems biomarker candidates (AUCs > 0.8) for hepatic encephalopathy and lung fibrosis.

Hydrogels are promising soft materials as tissue engineering scaffolds, stretchable sensors, and soft robotics. Yet, it remains challenging to develop synthetic hydrogels with mechanical stability and durability similar to those of the connective tissues. Many of the necessary mechanical properties, such as high strength, high toughness, rapid recovery, and high fatigue resistance, generally cannot be established together using conventional polymer networks. Here we present a type of hydrogels comprising hierarchical structures of picot fibres made of copper-bound self-assembling peptide strands with zipped flexible hidden length. The redundant hidden lengths allow the fibres to be extended to dissipate mechanical load without reducing network connectivity, making the hydrogels robust against damage. The hydrogels possess high strength, good toughness, high fatigue threshold, and rapid recovery, comparable to or even outperforming those of articular cartilage. Our study highlights the unique possibility of tailoring hydrogel network structures at the molecular level to improve their mechanical performance. Although hydrogels are increasingly used in a number of applications, it is still challenging to design materials with suitable mechanical stability and durability. Here, the authors report hydrogels with hierarchical structures with hidden length, allowing dissipation of mechanical load.

Under the background of urban connectivity, whether there are similarities and differences in the impacts of local industrial agglomeration and inter-city industrial agglomeration borrowing performance on carbon emission intensity(CI), and how cities can fully utilize the external force-borrowing performance to reduce local CI, these issues are of great significance for the cost saving and efficiency enhancement in the process of carbon emission (CE) reduction. Based on panel data of 280 prefecture-level cities in China from 2003 to 2020, the panel dual fixed-effect model, instrumental variable method, and adjustment effect model were used to analyze the impacts of the manufacturing agglomeration (MA), producer service agglomeration (PA), and the collaborative agglomeration (CA) on the CI from the perspective of individual cities and the urban system. The results showed that the influence of MA on CI presents a significant inverted U-shaped relationship, PA significantly reduces CI, and the CA of the two industries increases CI. Further analysis showed that the borrowing MA performance improves CI, especially in newer industrial-based cities, non-resource-based cities, and medium and big cities; the borrowing PA performance reduces CI, especially in old industrial-based cities, non-resource-based cities, and large cities; and the borrowing CA performance has no significant effect on CI. In addition, the development of the Internet strengthens the influence of borrowing performance in MA and PA on CI.

Background/Aims: Transmembrane 4 L six family member 1 (TM4SF1) is highly expressed and contributes to the progression of various malignancies. However, how it modulates hepatocellular carcinoma (HCC) progression and senescence remains to be elucidated. Methods: TM4SF1 expression in HCC samples was evaluated using immunohistochemistry and flow cytometry. Cellular senescence was assessed through SA-β-gal activity assays and Western blot analysis. TM4SF1-related protein interactions were investigated using immunoprecipitation-mass spectrometry, co-immunoprecipitation, bimolecular fluorescence complementation, and immunofluorescence. Tumor-infiltrating immune cells were analyzed by flow cytometry. The HCC mouse model was established via hydrodynamic tail vein injection. Results: TM4SF1 was highly expressed in human HCC samples and murine models. Knockdown of TM4SF1 suppressed HCC proliferation both in vitro and in vivo, inducing non-secretory senescence through upregulation of p16 and p21. TM4SF1 enhanced the interaction between AKT1 and PDPK1, thereby promoting AKT phosphorylation, which subsequently downregulated p16 and p21. Meanwhile, TM4SF1-mediated AKT phosphorylation enhanced PD-L1 expression while reducing major histocompatibility complex class I level on tumor cells, leading to impaired cytotoxic function of CD8+ T cells and an increased proportion of exhausted CD8+ T cells. In clinical HCC samples, elevated TM4SF1 expression was associated with resistance to anti-PD-1 immunotherapy. Targeting TM4SF1 via adeno-associated virus induced tumor senescence, reduced tumor burden and synergistically enhanced the efficacy of anti-PD-1 therapy. Conclusions: Our results revealed that TM4SF1 regulated tumor cell senescence and immune evasion through the AKT pathway, highlighting its potential as a therapeutic target in HCC, particularly in combination with first-line immunotherapy. (Clin Mol Hepatol 2025;31:489-508)

The rice orthologue of maize domestication gene Teosinte branched 1 ( Tb1 ) affects tillering. But, unlike maize Tb1 gene, it was not selected during domestication. Here, we report that an OsTb1 duplicate gene ( OsTb2 ) has been artificially selected during upland rice adaptation and that natural variation in OsTb2 is associated with tiller number. Interestingly, transgenic rice overexpressing this gene shows increased rather than decreased tillering, suggesting that OsTb2 gains a regulatory effect opposite to that of OsTb1 following duplication. Functional analyses suggest that the OsTb2 protein positively regulates tillering by interacting with the homologous OsTb1 protein and counteracts the inhibitory effect of OsTb1 on tillering. We further characterize two functional variations within OsTb2 that regulate protein function and gene expression, respectively. These results not only present an example of neo-functionalization that generates an opposite function following duplication but also suggest that the Tb1 homologue has been selected in upland rice. A transposon insertion in the regulatory region of maize Tb1 gene leads to increased apical dominance and a reduction of tillering. Here, the authors showed that a duplicated rice Tb1 orthologue, OsTb2 , has gained a regulatory effect on tillering opposite that of OsTb1 during artificial selection only in upland japonica rice.

The presence of a static tilt between the inner core and mantle is an ongoing discussion encompassing the geodynamic state of the inner core. Here, we confirm an approximate 8.5 yr signal in polar motion is the inner core wobble (ICW), and find that the ICW is also contained in the length-of-day variations of the Earth’s rotation. Based on the determined amplitudes of the ICW and its good phase consistency in both polar motion and the length-of-day variations, we infer that there must be a static tilt angle θ between the inner core and the mantle of about 0.17 ± 0.03°, most likely towards ~90°W relative to the mantle, which is two orders of magnitude lower than the 10° assumed in certain geodynamic research. This tilt is consistent with the assumption that the average density in the northwestern hemisphere of the inner core should be greater than that in the other regions. Further, the observed ICW period (8.5 ± 0.2 yr) suggests a 0.52 ± 0.05 g/cm 3 density jump at the inner core boundary. A static tilt of some 0.17° between the rotation axes of the solid inner core and the mantle is inferred from the observed approximate 8.5 year periodic inner core wobble in both polar motion and length-of-day variations of the Earth’s rotation.

Multi-label classification has aroused extensive attention in various fields. With the emergence of high-dimensional label space, academia has devoted to performing label embedding in recent years. Whereas current embedding approaches do not take feature space correlation sufficiently into consideration or require an encoding function while learning embedded space. Besides, few of them can be spread to track the missing labels. In this paper, we propose a Label Embedding method via Dependence Maximization (LEDM), which obtains the latent space on which the label and feature information can be embedded simultaneously. To end this, the low-rank factorization model on the label matrix is applied to exploit label correlations instead of the encoding process. The dependence between feature space and label space is increased by the Hilbert–Schmidt independence criterion to facilitate the predictability. The proposed LEDM can be easily extended the missing labels in learning embedded space at the same time. Comprehensive experimental results on data sets validate the effectiveness of our approach over the state-of-art methods on both complete-label and missing-label cases.