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Highlights The incorporation of quantum dots (QDs) as crystallization seeds results in the growth of larger perovskite crystals with reduced defect densities and preferential orientations along the (001) and (002) planes, significantly improving the film morphology. The QD-seeded films exhibit reduced non-radiative recombination and enhanced charge transport, as confirmed by steady-state and time-resolved photoluminescence, transient photovoltage measurements, and electrochemical impedance spectroscopy. Devices fabricated with QD-treated films achieve a remarkable power conversion efficiency (PCE) of 24.75% and exhibit exceptional long-term stability under simulated sunlight exposure, retaining 80% of their PCE after 1000 h of continuous illumination.

Abstract Timber members are often strengthened with bonded FRP sheets for a better mechanical performance. For these members, eigenstress can develop in their interfaces due to swelling and shrinkage of the member, which can cause cracks and delamination. Sophisticated evaluation of these phenomenon requires understanding of the moisture gradient in the composite member as well as fracture energy of these interface layers. However, these data are currently insufficient in literature. This paper investigates delamination between wood and FRP focusing on influences of the swelling and shrinkage of the wood. Tests were conducted regarding fracture energy of the adhesive layer joining the wood and the FRP as well as moisture transfer process crossing the adhesive layers. Using the derived experimental data, numerical parametric studies were performed. The results show that significant damages could be introduced to bonding of the FRP sheets due to eigenstress introduced by hygroscopic swelling and shrinkage of the member which can be significantly affected by layout of the FRP sheet.

Abstract Serine metabolism provides important metabolic intermediates that support the rapid proliferation of tumor cells. However, the role of serine metabolism in esophageal squamous cell carcinoma (ESCC) and the underlying mechanism remains unclear. Here, we show that serine starvation predominantly inhibits ESCC cell proliferation by suppressing purine nucleotides and NADPH synthesis. Mechanistically, serine depletion led to the accumulation of aminoimidazole carboxamide ribonucleoside (AICAR), an intermediate metabolite of de novo purine synthesis, and AMP/ATP ratio. These increases activated 5'-AMP-activated kinase (AMPK), which subsequently inhibited the mTORC1 pathway by phosphorylating Raptor at Ser792. Moreover, serine depletion decreased NADPH level followed by elevated reactive oxygen species (ROS) production and DNA damage, which induced p53-p21 mediated G1 phase cell cycle arrest. Conversely, serine starvation activated transcription factor 4 (ATF4)-mediated robust expression of phosphoserine aminotransferase 1 (PSAT1) which in turn promoted compensatory endogenous serine synthesis, thus maintaining ESCC cell survival under serine-limited conditions. Accordingly, serine deprivation combined with PSAT1 inhibition significantly suppressed ESCC tumor growth both in vitro and in vivo. Taken together, our findings demonstrate that serine starvation suppresses the proliferation of ESCC cells by disturbing the synthesis of purine nucleotides and NADPH, and the combination of serine deprivation and PSAT1 inhibition significantly impairs ESCC tumor growth. Our study provides a theoretical basis for targeting serine metabolism as a potential therapeutic strategy for ESCC.

Abstract Hantaan orthohantavirus (HTNV) is responsible for severe hemorrhagic fever with renal syndrome (HFRS), which has a case fatality rate of 1% to 10%. Currently, the inactive vaccine licensed in endemic areas elicit low levels of neutralizing antibodies (NAbs). Early NAbs administration is helpful for patients recovery from HFRS. Therefore, measuring NAbs is crucial for evaluating the immune response following infection or vaccination. The golden standard for HTNV NAbs measurement is the focus reduction neutralization test (FRNT), which typically requires skilled technicians and is performed under high biosafety containment facility. Here, we established a surrogate NAbs titration method with replication-competent vesicular stomatitis virus (VSV) bearing HTNV glycoprotein (rVSV-HTNV-GP) based plaque reduction neutralization test (PRNT). Then compared and correlated this method with the authentic HTNV based FRNT, and applied it to measure the NAbs level in 47 serum samples from HFRS patients, healthy donors and inactive vaccine recipients. We observed positive correlations between two neutralization assays among HFRS patients and inactive vaccine recipients (R2 = 0.5994 and 0.3440, respectively) and confirmed the clear specificity with healthy donors without vaccinated and reproducibility with three more assays. Our results suggest that rVSV-HTNV-GP based PRNT is a reliable lower-biosafety level surrogate for HTNV NAbs evaluation, which is easy to perform with higher sensitivity. Graphical abstract

Abstract Aggressive prostate cancer (PCa) variants associated with androgen receptor signaling inhibitor (ARSI) resistance and metastasis remain poorly understood. Here, we identify the axon guidance semaphorin receptor PlexinD1 as a crucial driver of cancer aggressiveness in metastatic castration-resistant prostate cancer (CRPC). High PlexinD1 expression in human PCa is correlated with adverse clinical outcomes. PlexinD1 critically maintains CRPC aggressive behaviors in vitro and in vivo, and confers stemness and cellular plasticity to promote multilineage differentiation including a neuroendocrine-like phenotype for ARSI resistance. Mechanistically, PlexinD1 is upregulated upon relief of AR-mediated transcriptional repression of PlexinD1 under ARSI treatment, and subsdquently transactivates ErbB3 and cMet via direct interaction, which triggers the ERK/AKT pathways to induce noncanonical Gli1-dictated Hedgehog signaling, facilitating the growth and plasticity of PCa cells. Blockade of PlexinD1 by the protein inhibitor D1SP restricted CRPC growth in multiple preclinical models. Collectively, these findings characterize PlexinD1’s contribution to PCa progression and offer a potential PlexinD1-targeted therapy for advanced PCa.

Abstract DNA methylation modifications are an important mechanism affecting the process of atherosclerosis (AS). Previous studies have shown that Galectin-8 (GAL8) DNA methylation level is associated with sudden death of coronary heart disease or acute events of coronary heart disease. However, the mechanism of GAL8 DNA methylation and gene expression in AS has not been elucidated, prompting us to carry out further research on it. ApoE-/- mice were used to establish an atherosclerosis model, and DNA methylation inhibitor DO05 and MAPK/mTOR inhibitor UO126 were used for intervention. Pyrosequencing was used to detect changes in GAL8 DNA methylation levels of the mouse aorta between groups. ROC curve analysis was performed to assess the relationship between GAL8 DNA methylation and atherosclerosis. Aortic staining with hematoxylin and eosin (H&E) was used to observe the aortic intima, plaque area, and characteristics of secondary lesions within the plaque. Oil Red O staining was used to detect lipid deposition in mouse arterial plaques or macrophages. Movat staining was used to detect the number of foam cells in the plaque. Immunohistochemistry (IHC) and Western blot were used to quantify the localization and expression levels of DNA methyltransferase1 (DNMT1), GAL8, MAPK/mTOR pathway proteins, Light Chain3 (LC3), Beclin1, Sequestosome1 (p62), Tumor Necrosis Factor-α (TNF-α), and other proteins. Immunofluorescence (IF) was used to detect the fluorescence intensity of GAL8, LC3, Monocyte chemoattractant protein-1(MCP-1), and other proteins. Detection of autophagosomes in macrophages by transmission electron microscopy was also performed. The foam cell model was induced with human monocytes (THP-1) and co-cultured with foam cells using siRNAs targeting GAL8, DO05, and UO126. The level of DNMT1 was detected by Western blot; Oil red O staining was used to detect lipid deposition in foam cells in each group, and the localization and expression levels of GAL8, MAPK/mTOR pathway proteins, LC3, Beclin1, p62, and TNF-α were quantitatively determined by Western blot. Immunofluorescence (IF) was used to detect the fluorescence intensity of GAL8, MAPK/mTOR pathway protein, LC3, p62, TNF-α, and other proteins. The GAL-8 promoter region harbors six CpG sites susceptible to DNA methylation. Following DNMT1 inhibition, the DC05 group displayed a significant decrease in methylation across all six CpG sites compared to the C57 and AS groups. Conversely, the UO126 group exhibited increased methylation at the first three CpG loci relative to the AS group. ROC curve analysis revealed GAL8 DNA methylation as an independent risk factor for atherosclerosis: GAL8, along with inflammation-related proteins MCP-1, MMP9, and TNF-α, were upregulated in the mouse lesion group, while expression of autophagy-related proteins LC3 and Beclin1 was downregulated. Additionally, phosphorylated MAPK/mTOR pathway proteins were detected in the mouse model of atherosclerosis. After inhibiting the methylation level of GAL-8 DNA, the expression of GAL-8 was up-regulated, macrophage autophagy was inhibited, inflammation was increased, and atherosclerotic lesions in mice were aggravated. After direct inhibition of the activity of the MAPK/mTOR pathway, macrophage autophagy was further weakened, the inflammatory response was further aggravated, and the atherosclerotic lesions of mice were further aggravated. After the specific knockdown of GAL-8 using siRNA GAL-8 using foam cells, the above phenomenon was reversed, macrophage autophagy was promoted, the inflammatory response was reduced, and the degree of atherosclerosis was alleviated. The degree of GAL8 DNA methylation is related to the progression of atherosclerosis, and its hypomethylation can aggravate atherosclerotic lesions. The mechanism may be through the regulation of MAPK/mTOR pathway to slow down the autophagy of macrophages, and then aggravate the inflammation in plaques. Targeting GAL8 DNA methylation may be a new target for the diagnosis and treatment of atherosclerosis.

Loss of synapse and functional connectivity in brain circuits is associated with aging and neurodegeneration, however, few molecular mechanisms are known to intrinsically promote synaptogenesis or enhance synapse function. We have previously shown that MET receptor tyrosine kinase in the developing cortical circuits promotes dendritic growth and dendritic spine morphogenesis. To investigate whether enhancing MET in adult cortex has synapse regenerating potential, we created a knockin mouse line, in which the human MET gene expression and signaling can be turned on in adult (10–12 months) cortical neurons through doxycycline-containing chow. We found that similar to the developing brain, turning on MET signaling in the adult cortex activates small GTPases and increases spine density in prefrontal projection neurons. These findings are further corroborated by increased synaptic activity and transient generation of immature silent synapses. Prolonged MET signaling resulted in an increased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N-methyl-D-aspartate (AMPA/NMDA) receptor current ratio, indicative of enhanced synaptic function and connectivity. Our data reveal that enhancing MET signaling could be an interventional approach to promote synaptogenesis and preserve functional connectivity in the adult brain. These findings may have implications for regenerative therapy in aging and neurodegeneration conditions.

Abstract Background Evidence has revealed that oestrogen deprivation-induced osteolysis is microbiota-dependent and can be treated by probiotics. However, the underlying mechanism require further investigation. This study aims to provide additional evidence supporting the use of probiotics as an adjuvant treatment and to explore the pathophysiology of oestrogen-deprived osteolysis. Methods Forty-five SD rats were randomly divided into five groups (n = 9). Rats from four groups were ovariectomised and treated with NS, calcium, probiotics, or calcium + probiotics, while one group underwent a sham operation and was treated with NS. The osteometabolic effects were evaluated, and the mechanistic role of the probiotic supplement was explored. Results Intragastric administration of Bifidobacterium animalis subsp. lactis LPL-RH (LPL-RH) markedly suppressed osteoclastic activation and bone calcium loss by downregulating TRAP enzymatic activity, the OPG/RANKL ratio, and the downstream signalling pathway RANKL/TRAF6/NF-κB/NFATc1/TRAP in ovariectomised SD rats. LPL-RH also reduced CD4+IL-17 A+ TH17 cells in the bone marrow, the pro-osteoclastogenic cytokine IL-17 A, pro-inflammatory molecules (LPS), and its binding protein (LBP) in the blood. LPL-RH restored intestinal ZO-1, occludin, claudin 2, claudin 12, and claudin 15, which improved ileal histopathology, reduced ileal oxidative stress, and attenuated the LPS-responsive TLR4/MyD88/NF-κB pathway. Furthermore, 16 S rRNA sequencing revealed that LPL-RH altered the faecal microbiome by reducing the relative abundance of S24-7 at the family level and promoting Prevotella and Bacteroides at the genus level. Conclusion Collectively, LPL-RH suppressed osteoclastogenesis and osteolysis by modulating type 17 immunity and gut microbiome.

Abstract Immune checkpoint inhibitors (ICIs) have dramatically transformed the treatment landscape for various malignancies, achieving notable clinical outcomes across a wide range of indications. Despite these advances, resistance to immune checkpoint blockade (ICB) remains a critical clinical challenge, characterized by variable response rates and non-durable benefits. However, growing research into the complex intrinsic and extrinsic characteristics of tumors has advanced our understanding of the mechanisms behind ICI resistance, potentially improving treatment outcomes. Additionally, robust predictive biomarkers are crucial for optimizing patient selection and maximizing the efficacy of ICBs. Recent studies have emphasized that multiple rational combination strategies can overcome immune checkpoint resistance and enhance susceptibility to ICIs. These findings not only deepen our understanding of tumor biology but also reveal the unique mechanisms of action of sensitizing agents, extending clinical benefits in cancer immunotherapy. In this review, we will explore the underlying biology of ICIs, discuss the significance of the tumor immune microenvironment (TIME) and clinical predictive biomarkers, analyze the current mechanisms of resistance, and outline alternative combination strategies to enhance the effectiveness of ICIs, including personalized strategies for sensitizing tumors to ICIs.

Abstract Background Sodium–glucose cotransporter-2 inhibitors (SGLT2i) have been proven to prevent decline in kidney function and failure. Whether SGLT2i affect the risk of contrast-associated acute kidney injury (CA-AKI) remains uncertain. Methods Use of SGLT2i was assessed in consecutive diabetics undergoing coronary angiography (CA) or percutaneous coronary intervention (PCI) from January 2020 to May 2023 at a tertiary hospital in Chongqing, China. Propensity-matched analysis was used to adjust for baseline variables. CA-AKI was defined by the Acute Kidney Injury Network (AKIN) as creatinine increase ≥ 0.3 mg/dl (26.4 μmol/l), or a percentage increase in the serum creatinine level of ≥ 50%. Results A total of 604 new users of SGLT2i, and 298 chronic users of SGLT2i were matched with non-users. New use of SGLT2i was not associated with an increased incidence of AKIN-defined CA-AKI (OR 1.60; 95% CI 0.97–2.63; p = 0.065), in-hospital new-onset dialysis (OR 0.50; 95% CI 0.09–2.73; p = 0.422), or death (OR 0.55; 95% CI 0.18–1.66; p = 0.289). However, it was associated with a minor (> 25%) creatinine elevation (OR 1.55; 95% CI 1.04–2.30; p = 0.030), a 0.3 mg/dl increase in creatinine (OR 1.66; 95% CI 1.01–2.75; p = 0.048), and CMSC-defined CA-AKI (OR 1.51; 95% CI 1.02–2.24; p = 0.039). By 90 days, there was no evidence creatinine elevation differed between the two groups (p = 0.590). Chronic use of SGLT2i was not associated with AKIN-defined CA-AKI (OR, 0.92; 95% CI 0.41–2.05; p = 0.838). Conclusions New use of SGLT2i during CA or PCI was not associated with an AKIN-defined CA-AKI, and it did not translate into new-onset dialysis or death during hospital stay. Chronic usage of SGLT2i did not affect creatinine. Further randomized clinical trials are warranted to confirm this finding.

Measurement while drilling (MWD) for high temperature well has always been a worldwide problem. So far, no effective active cooling method has been applied to MWD. In this paper, a new active cooling method based on insulated pipe is proposed. Three calculation models: theoretical model, numerical model - segmentation and numerical model - overall are established. In the theoretical model, a one-dimensional heat transfer control model is established, taking the fluid inside the insulated tube as the research object and considering the thermal resistance of the insulated tube and the heat entering the fluid through the tube wall. By iterating the boundary conditions of numerical model-segmentation, the heat transfer problem of insulated pipes with a length to diameter ratio exceeding 1000 is solved. By copying, translating, and stitching finite length meshes, the overall grid model of numerical model - overall is achieved. The calculation results of the three models mutually verify their reliability. The research results indicate that external cold fluid technology can be used for active cooling underground when the cold fluid is water. The mass flow rate of cold fluid and the heating time are the key factors affecting the temperature of cold fluid reaching the bottom hole. The cooling effect can be significantly improved by reducing the injection temperature of cold fluid and increasing cold fluid flow rate.

Evolutionary Agroecology theory predicts that the relationship between population yield and individual fitness among genotypes of a crop species is unimodal, and experimental evidence supports this. We test the theory further by investigating the role of resource availability on this relationship by comparing growth and reproductive output of three old and three modern cultivars of wheat (Triticum aestivum) in mixture and monocultures grown at three resource levels. The relationship between population grain yield and individual fitness (mean individual grain yield in mixture) of genotypes was resource dependent in a way that is consistent with the theory: when resource levels are low and limit individual growth directly, individual and population yield are positively correlated. When resource levels are high and the growth of individual plants is limited by competition for these resources, the relationship between individual fitness and population yield becomes negative. There was evidence for the unimodal relationship at the intermediate resource level. Old cultivars had higher fitness than newer cultivars at all three resource levels. Old cultivars had higher yields at low resource levels, but the newer cultivars yielded more when resource levels were high. Evaluating individual fitness and population yield in different environments may help wheat breeders to develop locally adapted, cooperative cultivars to increase production across large wheat-producing areas.

Abstract Background The study, undertaken in Fengxian District, Shanghai, seeks to investigate the correlation between the sanitary conditions of high school classrooms and the changes in students' uncorrected visual acuity and refractive status, given their predominantly classroom-centric lifestyle and the considerable academic pressures they encounter. Methods Utilizing a cluster random sampling approach, we randomly selected 48 classrooms for monitoring from 8 high schools within the jurisdiction, taking into account factors such as classroom orientation and floor level. A cohort comprising 1087 students was enrolled and followed for a year, with their refractive data being collected. A generalized additive model was employed to examine the associations between classroom environmental factors and students' visual acuity as well as refractive status. Results Significant increases were observed in the spherical equivalent, cylinder, and corneal astigmatism for both the right and left eyes from 2022 to 2023 (P 0.05). The compliance rate for blackboard size (height) was 100%, with an average of (1.16 ± 0.06) m and a minimum of 1.06 m. None of the classrooms met the standards for the distance between the multimedia display and the front seat, with an average of (177.26 ± 17.78) m. Classroom per capita area, blackboard size (height), and the distance between the multimedia display and the front seat influenced changes in uncorrected visual acuity. Additionally, classroom per capita area affected changes in the spherical equivalent. The window-to-ground area ratio and blackboard reflectance ratio impacted changes in astigmatism values at 90°-180° (J180) and 45°-135° (J45). Blackboard size (width) and the window-to-ground area ratio influenced changes in students' corneal astigmatism. The classroom with the least impact on refractive status had a per capita area of 1.6 m2, a blackboard size (width) of approximately 4.2 m, and a window-to-floor area ratio of around 0.27. Conclusions Schools should adhere to national standards to enhance the classroom visual environment and further improve the compliance rate.