Explore the vast range of titles available.

Diabetes mellitus is a metabolic disease characterized by long-term hyperglycaemia, which leads to microangiopathy and macroangiopathy and ultimately increases the mortality of diabetic patients. Endothelial dysfunction, which has been recognized as a key factor in the pathogenesis of diabetic microangiopathy and macroangiopathy, is characterized by a reduction in NO bioavailability. Oxidative stress, which is the main pathogenic factor in diabetes, is one of the major triggers of endothelial dysfunction through the reduction in NO. In this review, we summarize the four sources of ROS in the diabetic vasculature and the underlying molecular mechanisms by which the pathogenic factors hyperglycaemia, hyperlipidaemia, adipokines and insulin resistance induce oxidative stress in endothelial cells in the context of diabetes. In addition, we discuss oxidative stress-targeted interventions, including hypoglycaemic drugs, antioxidants and lifestyle interventions, and their effects on diabetes-induced endothelial dysfunction. In summary, our review provides comprehensive insight into the roles of oxidative stress in diabetes-induced endothelial dysfunction.

A robust serological test to detect neutralizing antibodies to SARS-CoV-2 is urgently needed to determine not only the infection rate, herd immunity and predicted humoral protection, but also vaccine efficacy during clinical trials and after large-scale vaccination. The current gold standard is the conventional virus neutralization test requiring live pathogen and a biosafety level 3 laboratory. Here, we report a SARS-CoV-2 surrogate virus neutralization test that detects total immunodominant neutralizing antibodies targeting the viral spike (S) protein receptor-binding domain in an isotype- and species-independent manner. Our simple and rapid test is based on antibody-mediated blockage of the interaction between the angiotensin-converting enzyme 2 (ACE2) receptor protein and the receptor-binding domain. The test, which has been validated with two cohorts of patients with COVID-19 in two different countries, achieves 99.93% specificity and 95–100% sensitivity, and differentiates antibody responses to several human coronaviruses. The surrogate virus neutralization test does not require biosafety level 3 containment, making it broadly accessible to the wider community for both research and clinical applications. A blocking assay based on the recombinant receptor-binding domain of SARS-CoV-2 spike protein and human angiotensin-converting enzyme 2 receptor provides an alternative to conventional antibody neutralization assays requiring live virus.

Emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern pose a challenge to the effectiveness of current vaccines. A vaccine that could prevent infection caused by known and future variants of concern as well as infection with pre-emergent sarbecoviruses (i.e., those with potential to cause disease in humans in the future) would be ideal. Here we provide data showing that potent cross-clade pan-sarbecovirus neutralizing antibodies are induced in survivors of severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) infection who have been immunized with the BNT162b2 messenger RNA (mRNA) vaccine. The antibodies are high-level and broad-spectrum, capable of neutralizing not only known variants of concern but also sarbecoviruses that have been identified in bats and pangolins and that have the potential to cause human infection. These findings show the feasibility of a pan-sarbecovirus vaccine strategy. (Funded by the Singapore National Research Foundation and National Medical Research Council.) People who recovered from SARS-CoV-1 infection in 2002–2003 have neutralizing antibodies documented for up to 17 years. Vaccinating such people with the BNT162b2 SARS-CoV-2 vaccine elicited high titers of antibodies capable of neutralizing not only all SARS-CoV-2 variants of concern but also coronavirus types found in bats and pangolins. Immunity against all beta-coronaviruses may be achievable.

Abscisic acid (ABA) catabolism is one of the determinants of endogenous ABA levels affecting numerous aspects of plant growth and abiotic-stress responses. The major ABA catabolic pathway is triggered by ABA 8'-hydroxylation catalysed by ABA 8'-hydroxylase, the cytochrome P450 CYP707A family. In this study, the full-length cDNAs of AhCYP707A1 and AhCYP707A2 were cloned and characterized from peanut. Expression analyses showed that AhCYP707A1 and AhCYP707A2 were expressed ubiquitously in peanut roots, stems, and leaves with different transcript accumulation levels, including the higher expression of AhCYP707A1 in roots. The expression of AhCYP707A2 was significantly up-regulated by 20% PEG6000 or 250 mmol/L NaCl in peanut roots, stems, and leaves, whereas the up-regulation of AhCYP707A1 transcript level by PEG6000 or NaCl was observed only in roots instead of leaves and stems. Due to the osmotic and ionic stresses of high concentration of NaCl to plants simultaneously, low concentration of LiCl (30 mmol/L, at which concentration osmotic status of cells is not seriously affected, the toxicity of Li+ being higher than that of Na+) was used to examine whether the effect of NaCl might be related to osmotic or ionic stress. The results revealed visually the susceptibility to osmotic stress and the resistance to salt ions in peanut seedlings. The significant up-regulation of AhCYP707A1, AhCYP707A2 and AhNCED1 transcripts and endogenous ABA levels by PEG6000 or NaCl instead of LiCl, showed that the osmotic stress instead of ionic stress affected the expression of those genes and the biosynthesis of ABA in peanut. The functional expression of AhCYP707A1 cDNA in yeast showed that the microsomal fractions prepared from yeast cell expressing recombinant AhCYP707A1 protein exhibited the catalytic activity of ABA 8'-hydroxylase. These results demonstrate that the expressions of AhCYP707A1 and AhCYP707A2 play an important role in ABA catabolism in peanut, particularly in response to osmotic stress.

Aims Glioma is a highly invasive brain tumor, which makes prognosis challenging and renders patients resistant to various treatments. Induction of cell death is promising in cancer therapy. Ferroptosis, a recently discovered regulated cell death, can be induced for killing glioma cells. However, the prognostic prediction of ferroptosis‐related genes (FRGs) in glioma remains elusive. Methods The mRNA expression profiles and gene variation and corresponding clinical data of glioma patients and NON‐TUMOR control were downloaded from public databases. Risk score based on a FRGs signature was constructed in REMBRANDT cohort and validated in other datasets including CGGA‐693, CGGA‐325, and TCGA. Results Our results demonstrated that the majority of FRGs was differentially expressed among GBM, LGG, and NON‐TUMOR groups (96.6%). Furthermore, the glioma patients with low‐risk score exhibited a more satisfactory clinical outcome. The better prognosis was also validated in the glioma patients with low‐risk score no matter to which grade they were affiliated. Functional analysis revealed that the high‐risk score group was positively correlated with the enrichment scores for immune checkpoint blockade‐related positive signatures, indicating the critical role of glioma immunotherapy via risk score. Conclusion A novel FRGs‐related risk score can predict prognosis and immunotherapy in glioma patients. A random survival forest model was constructed to obtain the risk score based on 59 ferroptosis genes in glioma patients in REMBRANDT cohort and it was validated in other datasets including CGGA‐325, CGGA‐693, and TCGA cohorts. Finally, a novel ferroptosis‐related risk score can predict prognosis and immunotherapy in glioma patients.

Background N6-methyladenosine (m6A) is the most abundant reversible methylation modification of eukaryotic mRNA, and it plays vital roles in tumourigenesis. This study aimed to explore the role of the m6A demethylase ALKBH5 in pancreatic cancer (PC). Methods The expression of ALKBH5 and its clinicopathological impact were evaluated in PC cohorts. The effects of ALKBH5 on the biological characteristics of PC cells were investigated on the basis of gain-of-function and loss-of-function analyses. Subcutaneous and orthotopic models further uncovered the role of ALKBH5 in tumour growth. mRNA and m6A sequencing and assays of m6A methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) were performed to identify the targeted effect of ALKBH5 on PER1. P53-binding sites in the ALKBH5 promoter were investigated by ChIP and luciferase assays to reveal the interplay between ALKBH5 and PER1-activated ATM-CHK2-P53/CDC25C signalling. Results ALKBH5 loss characterized the occurrence and poor clinicopathological manifestations in patients with PC. Overexpression of ALKBH5 reduced tumoural proliferative, migrative, invasive activities in vitro and ameliorated tumour growth in vivo, whereas ALKBH5 knockdown facilitated PC progression. Mechanistically, ALKBH5 posttranscriptionally activated PER1 by m6A demethylation in an m6A-YTHDF2-dependent manner. PER1 upregulation led to the reactivation of ATM-CHK2-P53/CDC25C signalling, which inhibited cell growth. P53-induced activation of ALKBH5 transcription acted as a feedback loop regulating the m6A modifications in PC. Conclusion ALKBH5 serves as a PC suppressor by regulating the posttranscriptional activation of PER1 through m6A abolishment, which may highlight a demethylation-based approach for PC diagnosis and therapy.

Topological domain structures have drawn great attention as they have potential applications in future electronic devices. As an important concept linking the quantum and classical magnetism, a magnetic Bloch point, predicted in 1960s but not observed directly so far, is a singular point around which magnetization vectors orient to nearly all directions. Here we show polar Bloch points in tensile-strained ultrathin ferroelectric PbTiO 3 films, which are alternatively visualized by phase-field simulations and aberration-corrected scanning transmission electron microscopic imaging. The phase-field simulations indicate local steady-state negative capacitance around the Bloch points. The observation of polar Bloch points and their emergent properties consequently implies novel applications in future integrated circuits and low power electronic devices. Authors predict polar Bloch points with negative capacitance in tensile-strained ultrathin ferroelectric PbTiO 3 film by phase-field simulations, observing their polarization structures by scanning transmission electron microscopic imaging.

Hyperglycaemia-induced endothelial dysfunction is a key factor in the pathogenesis of diabetic microangiopathy and macroangiopathy. STING, which is a newly discovered regulator of innate immunity, has also been reported to play an important role in various metabolic diseases. However, the role of STING in diabetes-induced endothelial cell dysfunction is unknown. In this study, we established a diabetic macroangiopathy mouse model by streptozotocin (STZ) injection combined with high-fat diet (HFD) feeding and a glucotoxicity cell model in high glucose (HG)-treated rat aortic endothelial cells (RAECs). We found that STING expression was specifically increased in the endothelial cells of diabetic arteries, as well as in HG-treated RAECs. Moreover, genetic deletion of STING significantly ameliorated diabetes-induced endothelial cell dysfunction and apoptosis in vivo. Likewise, STING inhibition by C-176 reversed HG-induced migration dysfunction and apoptosis in RAECs, whereas STING activation by DMXAA resulted in migration dysfunction and apoptosis. Mechanistically, hyperglycaemia-induced oxidative stress promoted endothelial mitochondrial dysfunction and mtDNA release, which subsequently activated the cGAS-STING system and the cGAS-STING-dependent IRF3/NF-kB pathway, ultimately resulting in inflammation and apoptosis. In conclusion, our study identified a novel role of STING in diabetes-induced aortic endothelial cell injury and suggested that STING inhibition was a potential new therapeutic strategy for the treatment of diabetic macroangiopathy. 3DZkNh_P7BQbJb1WXuwa3R Video Abstract

State-of-art quantum key distribution (QKD) systems are performed with several GHz pulse rates, meanwhile privacy amplification (PA) with large scale inputs has to be performed to generate the final secure keys with quantified security. In this paper, we propose a fast Fourier transform (FFT) enhanced high-speed and large-scale (HiLS) PA scheme on commercial CPU platform without increasing dedicated computational devices. The long input weak secure key is divided into many blocks and the random seed for constructing Toeplitz matrix is shuffled to multiple sub-sequences respectively, then PA procedures are parallel implemented for all sub-key blocks with correlated sub-sequences, afterwards, the outcomes are merged as the final secure key. When the input scale is 128 Mb, our proposed HiLS PA scheme reaches 71.16 Mbps, 54.08 Mbps and 39.15 Mbps with the compression ratio equals to 0.125, 0.25 and 0.375 respectively, resulting achievable secure key generation rates close to the asymptotic limit. HiLS PA scheme can be applied to 10 GHz QKD systems with even larger input scales and the evaluated throughput is around 32.49 Mbps with the compression ratio equals to 0.125 and the input scale of 1 Gb, which is ten times larger than the previous works for QKD systems. Furthermore, with the limited computational resources, the achieved throughput of HiLS PA scheme is 0.44 Mbps with the compression ratio equals to 0.125, when the input scale equals up to 128 Gb. In theory, the PA of the randomness extraction in quantum random number generation (QRNG) is same as the PA procedure in QKD, and our work can also be efficiently performed in high-speed QRNG.

The dorsolateral prefrontal cortex (DLPFC) plays a crucial role in cognitive-motor integration through its top-down regulation of the primary motor cortex (M1). However, the functional lateralization of the left and right DLPFC and the differences between intra-hemispheric and inter-hemispheric regulation of M1, particularly in populations with brain injury, remain controversial and insufficiently studied. This study aimed to systematically achieve the following four objectives using a dual-site paired-pulse transcranial magnetic stimulation (TMS) technique: (1) to evaluate the integrated regulatory effects of bilateral DLPFC on M1; (2) to compare the differences in regulatory effects between ipsilateral and contralateral DLPFC; (3) to analyze the impact of functional lateralization of the left and right DLPFC on their regulation of M1; (4) to investigate the effects of brain injury on the DLPFC-M1 regulatory pathway by comparing healthy participants and stroke patients. A total of 30 right-handed participants were enrolled, including 20 stroke patients in the recovery phase (divided into left and right lesion groups) and 10 healthy volunteers. These three participant groups were tested under conditions that varied the targeted motor cortex (M1) side, yielding four key experimental conditions for analysis. Accordingly, a paired-pulse TMS paradigm was employed. Following a conditioning stimulus (CS) applied to the left or right DLPFC, a test stimulus (TS) was delivered to the ipsilateral or contralateral M1 after an inter-stimulus interval of 20 ms. The amplitude of the motor evoked potential (MEP) was recorded. In experiments targeting the left M1, both the healthy group (Experiment 1) and the patient group (Experiment 3) exhibited significant regulatory effects (  = 12.2,  = 0.002;  = 9.6,  = 0.008). Post-hoc analysis revealed that, compared to baseline, both ipsilateral DLPFC (  = 0.011;  = 0.022) and contralateral DLPFC (  = 0.005;  = 0.022) significantly enhanced M1 excitability, with no significant difference between the two (  = 1.000). However, in experiments targeting the right M1 across all groups (Experiments 2 and 4), no significant regulatory effect of DLPFC was observed (  = 0.2,  = 0.905). This study confirms that, at rest, the bilateral DLPFC exerts a stable and non-specific facilitatory regulation on the left M1. This effect persists in the affected M1 of stroke patients, suggesting plasticity in the relevant pathways after injury. The negative findings for the right M1 reveal a lateralization characteristic in DLPFC-M1 regulation. These results provide an important basis for elucidating the physiological mechanisms of cognitive-motor circuits and for developing targeted neurorehabilitation strategies.