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Aims/hypothesisMicrovascular endothelial hyperpermeability, mainly caused by claudin-5 deficiency, is the initial pathological change that occurs in diabetes-associated cardiovascular disease. The ketone body β-hydroxybutyrate (BHB) exerts unique beneficial effects on the cardiovascular system, but the involvement of BHB in promoting the generation of claudin-5 to attenuate cardiac microvascular hyperpermeability in diabetes is poorly understood.MethodsThe effects of BHB on cardiac microvascular endothelial hyperpermeability and claudin-5 generation were evaluated in rats with streptozotocin-induced diabetes and in high glucose (HG)-stimulated human cardiac microvascular endothelial cells (HCMECs). To explore the underlying mechanisms, we also measured β-catenin nuclear translocation, binding of β-catenin, histone deacetylase (HDAC)1, HDAC3 and p300 to the Claudin-5 (also known as CLDN5) promoter, interaction between HDAC3 and β-catenin, and histone acetylation in the Claudin-5 promoter.ResultsWe found that 10 weeks of BHB treatment promoted claudin-5 generation and antagonised cardiac microvascular endothelial hyperpermeability in rat models of diabetes. Meanwhile, BHB promoted claudin-5 generation and inhibited paracellular permeability in HG-stimulated HCMECs. Specifically, BHB (2 mmol/l) inhibited HG-induced HDAC3 from binding to the Claudin-5 promoter, although nuclear translocation or promoter binding of β-catenin did not change with BHB treatment. In addition, BHB prevented the binding and co-localisation of HDAC3 to β-catenin in HG-stimulated HCMECs. Furthermore, using mass spectrometry, acetylated H3K14 (H3K14ac) in the Claudin-5 promoter following BHB treatment was identified, regardless of whether cells were stimulated by HG or not. Although reduced levels of acetylated H3K9 in the Claudin-5 promoter were found following HG stimulation, increased H3K14ac was specifically associated with BHB treatment.Conclusions/interpretationBHB inhibited HDAC3 and caused acetylation of H3K14 in the Claudin-5 promoter, thereby promoting claudin-5 generation and antagonising diabetes-associated cardiac microvascular hyperpermeability.

Photons with zero rest mass are impossible to be stopped. However, a pulse of light can be slowed down and even halted through strong light-matter interaction in a dispersive medium in atomic systems. Exceptional point (EP), a non-Hermitian singularity point, can introduce an abrupt transition in dispersion. Here we experimentally observe room-temperature storing light near an exceptional point induced by nonlinear Brillouin scattering in a chip-scale 90-μm-radius optical microcavity, the smallest platform up to date to store light. Through nonlinear coupling, a Parity-Time (PT) symmetry can be constructed in optical-acoustical hybrid modes, where Brillouin scattering-induced absorption (BSIA) can lead to both slow light and fast light of incoming pulses. A subtle transition of slow-to-fast light reveals a critical point for storing a light pulse up to half a millisecond. This compact and room-temperature scheme of storing light paves the way for practical applications in all-optical communications and quantum information processing. Exceptional point introduces the ability to control and tune light propagation. Here the authors demonstrate a 90-μm-radius optical microcavity to store light, induced by nonlinear Brillouin scattering at room temperature.

INTRODUCTION Research on somatic and germline mutations in Chinese individuals with early‐onset Alzheimer's disease (EOAD) has been limited. METHODS We conducted whole‐genome sequencing of blood DNA from 108 patients with EOAD and 116 controls. The analysis included somatic and germline mutations across coding and non‐coding regions, mutational signature determination, pathway enrichment identification, and predictive model. RESULTS The mutational burden was significantly higher in the EOAD group compared to the control group. The prevalence of single‐base substitution signature 5, which is strongly associated with aging, was much higher in patients with EOAD than in controls. EOAD‐specific somatic mutations were identified in genes such as MIR31HG, TUBB4B, and APP. Germline mutations in DOCK3, PCSK5, and PDE4D were significantly associated with age of dementia onset. Furthermore, a predictive model comprising 15 mutations demonstrated an area under the curve of 0.78. DISCUSSION The accumulation of senescence‐related somatic mutations may increase the risk of developing EOAD. Highlights Whole genome sequencing was used to find somatic and germline mutations in Chinese individuals with early‐onset Alzheimer's disease (EOAD). Total number and burden of blood somatic mutations were significantly higher. The prevalence of single‐base substitution signature 5 was notably elevated in EOAD. EOAD‐specific somatic mutations were identified in MIR31HG, TUBB4B, and APP. DOCK3, PCSK5, and PDE4D germline mutations were associated with the age of EOAD onset.

Background/Aims: The metabolic features of cancer cells have long been acknowledged to be altered and to provide new therapeutic opportunities. The expression of glycolytic enzyme enolase 2 (ENO2) was found to be closely associated with the clinical features of acute lymphoblastic leukemia (ALL) patients, but its functions remain unclear in ALL. Methods: We evaluated the association between ENO2 mRNA expression in bone marrow mononuclear cells (BM-MNCs) and the efficacy of chemotherapy, and further explored the function of ENO2 in ALL. The molecular mechanisms of ENO2 expression and its effects on cell growth, glycolysis and glucocorticoid resistance were explored by Cell Counting Kit-8, glucose-consumption assay, Quantitative RT-PCR, Western blotting and in vivo tumorigenesis in NOD/SCID mice. Results: The results showed that ENO2 mRNA expression in BM-MNCs was significantly decreased when patients completed induction chemotherapy and reached complete remission (CR). ENO2 mRNA expression was increased when patients suffered relapse. Functional studies demonstrated that ENO2 promoted cell growth, glycolysis, and glucocorticoid resistance, all of which were effectively inhibited when ENO2 was silenced with shRNAs. Further studies revealed that ENO2 up-regulated various glycolysis-related genes and enhanced Akt activity with subsequent glycogen synthase kinase3β (GSK-3β) phosphorylation, inducing cell proliferation and glycolysis. The combination of silencing ENO2 and 2-deoxyglucose (2-DG) synergistically inhibited leukemia cell survival. Conclusions: These results indicate that ENO2 may be a biological marker for monitoring chemotherapeutic efficacy and relapse in ALL. ENO2 may provide a potential therapeutic strategy for ALL.

Mammalian two-pore-channels (TPC1, 2; TPCN1, TPCN2) are ubiquitously- expressed, PI(3,5)P2-activated, Na+-selective channels in the endosomes and lysosomes that regulate luminal pH homeostasis, membrane trafficking, and Ebola viral infection. Whereas the channel activity of TPC1 is strongly dependent on membrane voltage, TPC2 lacks such voltage dependence despite the presence of the presumed ‘S4 voltage-sensing’ domains. By performing high-throughput screening followed by lysosomal electrophysiology, here we identified a class of tricyclic anti-depressants (TCAs) as small-molecule agonists of TPC channels. TCAs activate both TPC1 and TPC2 in a voltage-dependent manner, referred to as Lysosomal Na+ channel Voltage-dependent Activators (LyNa-VAs). We also identified another compound which, like PI(3,5)P2, activates TPC2 independent of voltage, suggesting the existence of agonist-specific gating mechanisms. Our identification of small-molecule TPC agonists should facilitate the studies of the cell biological roles of TPCs and can also readily explain the reported effects of TCAs in the modulation of autophagy and lysosomal functions.

Rock penetration is the most important function of tunnel boring machines (TBMs). Based on a detailed review of TBM rock penetration research, this study introduces a rarely reported full-scale experimental cutterhead system that combines the advantages of in situ penetration tests and laboratory rock-breaking tests. The main focus of this study is to investigate TBM penetration performance using this experimental cutterhead system. Nine groups of penetration tests were conducted on an integral concrete specimen with cutterhead rotational speed and net penetration varying from 1.9 to 5.9 r/min and 2.5 to 8.8 mm/r, respectively. The cutting force and chipping performance of each cutter were monitored, examined, and analyzed considering boreability and mechanical efficiency. The results indicate that the cutter normal force is unaffected by the cutter installment radius and cutterhead rotational speed. However, the muck weight and specific excavation rate increase in perfectly fitted exponential functions with increasing cutter position number, indicating that the cutting efficiency increases with cutter position number. Muck sieving results show that face cutters produce larger and more elongated chips than center cutters, as the extent of cutter side sliding declines with increasing cutter installation radius. The boreability index decreases in a perfectly fitted power function with increasing net penetration, indicating that the critical threshold for cutterhead net penetration is approximately 5 mms/rev. The proposed models predicting the cutter normal force and boreability index were compared with 13 sets of in situ penetration test data. This study can guide TBM excavations encountering rocks with equivalent strength and intactness.HighlightsA rarely-reported experimental cutterhead system is introduced to study TBM rock-breaking performances.The cutter normal force is unaffected by the cutter installation radius and cutterhead rotational speed.The disc cutter rock-breaking efficiency increases with the cutter position number.The critical threshold of the penetration rate is approximately 5 mm/rev for the studied sample.

The mediation of maternal-embryonic cross-talk via nutrition and metabolism impacts greatly on offspring health. However, the underlying key interfaces remain elusive. Here, we determined that maternal high-fat diet during pregnancy in mice impaired preservation of the ovarian primordial follicle pool in female offspring, which was concomitant with mitochondrial dysfunction of germ cells. Furthermore, this occurred through a reduction in maternal gut microbiota-related vitamin B1 while the defects were restored via vitamin B1 supplementation. Intriguingly, vitamin B1 promoted acetyl-CoA metabolism in offspring ovaries, contributing to histone acetylation and chromatin accessibility at the promoters of cell cycle-related genes, enhancement of mitochondrial function, and improvement of granulosa cell proliferation. In humans, vitamin B1 is downregulated in the serum of women with gestational diabetes mellitus. In this work, these findings uncover the role of the non-gamete transmission of maternal high-fat diet in influencing offspring oogenic fate. Vitamin B1 could be a promising therapeutic approach for protecting offspring health. The authors show that maternal high-fat diet influences offspring’s ovarian reserve through maternal-embryonic cross-talk in mice and that maternal vitamin B1 supplementation could rescue ovarian primordial follicle reserve in mouse offspring.

After a preliminary study, it was found that modern research on the cold and hot properties of CHMs is often hampered by significant subjectivity, lack of standardization, and incomplete data, limiting the scientific robustness and practical applicability of the findings. [...]in order to avoid the bias caused by the internal data set validation, we also constructed an external validation dataset based on data mining [Supplementary Table 1, http://links.lww.com/CM9/C411], and selected 10 representative CHMs with hot and cold properties [Supplementary Table 2, http://links.lww.com/CM9/C411] and their active ingredients to be used to validate the stability and accuracy of the model. After constructing the cold and hot properties identification model based on the four AI algorithms and deriving the accuracy of each AI algorithm model, the results showed that the model constructed by SVM algorithm had an accuracy value of 89.5%, while the accuracy values of the models were 93.3%, 90.2%, and 86.7%, respectively, for those constructed by RF, DNN, and XGBOOST algorithms [Supplementary Figure 1A and B, http://links.lww.com/CM9/C411]. [...]the quality of current CHM data is inconsistent, with many datasets containing incomplete or erroneous information. [...]strict data standards and quality control mechanisms must be established to improve the accuracy of identifying the cold and hot properties of CHMs.

As a new type of power device, the X-type rotary engine (XRE) is regarded as a major revolution of the internal combustion engine with its special structure and high-efficiency hybrid cycle (HEHC). A 3D CFD model of an XRE with hydrogen–gasoline fuel is firstly built in this paper. The gasoline is premixed with air in the intake of the XRE. The hydrogen is directly injected (DI) into the cylinder with four different injection positions. The effects of the hydrogen injection position on the combustion process, engine thermodynamic performance, and unburned carbon emissions and NOx emissions are investigated. The results show that, due to the interaction between the in-cylinder main flow field and the injected hydrogen gas flow, different hydrogen concentration zones are formed at different injection positions. Furthermore, a larger hydrogen distribution area and being closer to the ignition position led to a faster in-cylinder combustion rate and a higher in-cylinder temperature and pressure. When the injection position is from the front to the back of the combustion chamber such as in position 2, the hydrogen has the widest distribution area and is closest to the ignition position, resulting in its fastest combustion speed. Meanwhile, the peak in-cylinder pressure is 3.73 MPa and the peak temperature is a maximum of 1835.16 K. Especially, the highest indicated thermal efficiency of 26.56% is found in position 2, which is 10.08% higher than that of position 4 (from right to left of the combustion chamber), which was 24.13%. At the same time, due to the best overall combustion effect, position 2 presents the lowest final unburned carbon emission of 0.36 mg, while it produces the highest NOx emission of 9.15 μg. Thus, this study provides important theoretical guidelines for the hydrogen injection strategy of the XRE using hydrogen–gasoline fuel.

Background Gray leaf spot (GLS), which is caused by the necrotrophic fungi Cercospora zeae-maydis and Cercospora zeina , is one of the most impactful diseases in maize worldwide. The aim of the present study is to identify the resistance genes and understand the molecular mechanisms for GLS resistance. Results Two cultivars, ‘Yayu889’ and ‘Zhenghong532,’ which are distinguished as resistant and susceptible cultivars, respectively, were challenged with the GLS disease and a RNA-seq experiment was conducted on infected plants at 81, 89, 91, and 93 days post planting (dap). Compared with the beginning stage at 81 dap, 4666, 1733, and 1166 differentially expressed genes (DEGs) were identified at 89, 91, and 93 dap, respectively, in ‘Yayu889,’ while relatively fewer, i.e., 4713, 881, and 722 DEGs, were identified in ‘Zhenghong532.’ Multiple pathways involved in the response of maize to GLS, including ‘response to salicylic acid,’ ‘protein phosphorylation,’ ‘oxidation-reduction process,’ and ‘carotenoid biosynthetic process,’ were enriched by combining differential expression analysis and Weighted Gene Co-expression Network Analysis (WGCNA). The expression of 12 candidate resistance proteins in these pathways were quantified by the multiple reaction monitoring (MRM) method. This approach identified two candidate resistance proteins, a calmodulin-like protein and a leucine-rich repeat receptor-like protein kinase with SNPs that were located in QTL regions for GLS resistance. Metabolic analysis showed that, compared with ‘Zhenghong532,’ the amount of salicylic acid (SA) and total carotenoids in ‘Yayu889’ increased, while peroxidase activity decreased during the early infection stages, suggesting that increased levels of SA, carotenoids, and reactive oxygen species (ROS) may enhance the defense response of ‘Yayu889’ to GLS. Conclusion By combining transcriptome and proteome analyses with comparisons of resistance QTL regions, calmodulin-like protein and leucine-rich repeat receptor-like protein kinase were identified as candidate GLS resistance proteins. Moreover, we found that the metabolic pathways for ROS, SA, and carotenoids are especially active in the resistant cultivar. These findings could lead to a better understanding of the GLS resistance mechanisms and facilitate the breeding of GLS-resistant maize cultivars.