CircUGP2 Suppresses Intrahepatic Cholangiocarcinoma Progression via p53 Signaling Through Interacting With PURB to Regulate ADGRB1 Transcription and Sponging miR-3191-5p.

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer and its prognosis remains poor. Although growing numbers of studies have verified the involvement of circular RNAs (circRNAs) in various cancer types, their specific functions in ICC remain elusive. Herein, a circRNA, circUGP2 is identified by circRNA sequencing, which is downregulated in ICC tissues and correlated with patients' prognosis. Moreover, circUGP2 overexpression suppresses tumor progression in vitro and in vivo. Mechanistically, circUGP2 functions as a transcriptional co-activator of PURB over the expression of ADGRB1. It can also upregulate ADGRB1 expression by sponging miR-3191-5p. As a result, ADGRB1 prevents MDM2-mediated p53 polyubiquitination and thereby activates p53 signaling to inhibit ICC progression. Based on these findings, circUGP2 plasmid is encapsulated into a lipid nanoparticle (LNP) system, which has successfully targeted tumor site and shows superior anti-tumor effects. In summary, the present study has identified the role of circUGP2 as a tumor suppressor in ICC through regulating ADGRB1/p53 axis, and the application of LNP provides a promising translational strategy for ICC treatment.

BACE1 inhibitors from the fruits of Alpinia oxyphylla have efficacy to treat T2DM-related cognitive disorder.

The fruits of Alpinia oxyphylla (Alpiniae Oxyphyllae Fructus, AOF) are one of the "Four Famous South Medicines" in China. In this study, beta-site amyloid protein precursor cleaving enzyme 1 (BACE1) was applied to explore the active components in AOF responsible for type 2 diabetes mellitus (T2DM)-related cognitive disorder. As a result, 24 compounds including three unreported ones (1, 3, 4) were isolated from AOF. Compound 1 is an unusual carbon­carbon linked diarylheptanoid dimer, and compound 4 is the first case of 3,4-seco-eudesmane sesquiterpenoid with a 5/6-bicyclic skeleton. Four diarylheptanoids (3, 5-7), one flavonoid (9) and two sesquiterpenoids (14 and 20) showed BACE1 inhibitory activity, of which the most active 6 was revealed to be a non-competitive and anti-competitive mixed inhibitor. Docking simulation suggested that OH-4' of 6 played important roles in maintaining activity by forming hydrogen bonds with Ser36 and Ile126 residues. Compounds 3, 5, 9 and 20 displayed neuroprotective effects against amyloid ß (Aß)-induced damage in BV2 cells. Mechanism study revealed that compounds 5 and 20 downregulated the expression of BACE1 and upregulated the expression of Lamp2 to exert effects. Thus, the characteristic diarylheptanoids and sesquiterpenoids in AOF had the efficacy to alleviate T2DM-related cognitive disorder by inhibiting BACE1 activity and reversing Aß-induced neuronal damage.

Improving Generalization and Personalization in Model-Heterogeneous Federated Learning.

Conventional federated learning (FL) assumes the homogeneity of models, necessitating clients to expose their model parameters to enhance the performance of the server model. However, this assumption cannot reflect real-world scenarios. Sharing models and parameters raises security concerns for users, and solely focusing on the server-side model neglects clients' personalization requirements, potentially impeding expected performance improvements of users. On the other hand, prioritizing personalization may compromise the generalization of the server model, thereby hindering extensive knowledge migration. To address these challenges, we put forth an important problem: How can FL ensure both generalization and personalization when clients' models are heterogeneous? In this work, we introduce FedTED, which leverages a twin-branch structure and data-free knowledge distillation (DFKD) to address the challenges posed by model heterogeneity and diverse objectives in FL. The employed techniques in FedTED yield significant improvements in both personalization and generalization, while effectively coordinating the updating process of clients' heterogeneous models and successfully reconstructing a satisfactory global model. Our empirical evaluation demonstrates that FedTED outperforms many representative algorithms, particularly in scenarios where clients' models are heterogeneous, achieving a remarkable 19.37% enhancement in generalization performance and up to 9.76% improvement in personalization performance.

Principle and application of self-transcribing active regulatory region sequencing in enhancer discovery research.

Self-transcribing active regulatory region sequencing (STARR-seq) is a high-throughput sequencing method capable of simultaneously discovering and validating all enhancers within the genome. In this method, candidate sequences are inserted into plasmid vectors and electroporated into cells. Acting as both enhancers and target genes, the self-transcription of these sequences will also be enhanced by themselves. By sequencing the transcriptome and comparing the results with the non-inserted control, the locations and activity of enhancers can be determined. In traditional enhancer discovery strategies, the chromatin open regions and transcription active regions were sequenced and predicted as enhancers. However, the activity of these putative enhancers could only be validated one by one without a high-throughput method. STARR-seq solved this limitation, allowing simultaneous enhancers discovery and activity validation in a high-throughput manner. Since the introduction of STARR-seq, it has been widely used to discover enhancers and validate enhancer activity in a number of organisms and cells. In this review, we present the traditional enhancer prediction methods and the basic principles, development history, specific applications of STARR-seq, and its future prospects, aiming to provide a reference for researchers in related fields conducting enhancer studies.

A Nanocapsule System Combats Aging by Inhibiting Age-Related Angiogenesis Deficiency and Glucolipid Metabolism Disorders.

Insufficient angiogenic stimulation and dysregulated glycolipid metabolism in senescent vascular endothelial cells (VECs) constitute crucial features of vascular aging. Concomitantly, the generation of excess senescence-associated secretory phenotype (SASP) and active immune-inflammatory responses propagates within injured vessels, tissues, and organs. Until now, targeted therapies that efficiently rectify phenotypic abnormalities in senescent VECs have still been lacking. Here, we constructed a Pd/hCeO2-BMS309403@platelet membrane (PCBP) nanoheterostructured capsule system loaded with fatty acid-binding protein 4 (FABP4) inhibitors and modified with platelet membranes and investigated its therapeutic role in aged mice. PCBP showed significant maintenance in aged organs and demonstrated excellent biocompatibility. Through cyclic tail vein administration, PCBP extended the lifespan and steadily ameliorated abnormal phenotypes in aged mice, including SASP production, immune and inflammatory status, and age-related metabolic disorders. In senescent ECs, PCBP mediated the activation of vascular endothelial growth factor (VEGF) signaling and glycolysis and inhibition of FABP4 by inducing the synthesis of hypoxia-inducible factor-1α, thereby reawakening neovascularization and restoring glycolipid metabolic homeostasis. In conclusion, the PCBP nanocapsule system provides a promising avenue for interventions against aging-induced dysfunction.

GelMA loaded with platelet lysate promotes skin regeneration and angiogenesis in pressure ulcers by activating STAT3.

Pressure ulcers (PU) are caused by persistent long-term pressure, which compromises the integrity of the epidermis, dermis, and subcutaneous adipose tissue layer by layer, making it difficult to heal. Platelet products such as platelet lysate (PL) can promote tissue regeneration by secreting numerous growth factors based on clinical studies on skin wound healing. However, the components of PL are difficult to retain in wounds. Gelatin methacrylate (GelMA) is a photopolymerizable hydrogel that has lately emerged as a promising material for tissue engineering and regenerative medicine. The PL liquid was extracted, flow cytometrically detected for CD41a markers, and evenly dispersed in the GelMA hydrogel to produce a surplus growth factor hydrogel system (PL@GM). The microstructure of the hydrogel system was observed under a scanning electron microscope, and its sustained release efficiency and biological safety were tested in vitro. Cell viability and migration of human dermal fibroblasts, and tube formation assays of human umbilical vein endothelial cells were applied to evaluate the ability of PL to promote wound healing and regeneration in vitro. Real-time polymerase chain reaction (PCR) and western blot analyses were performed to elucidate the skin regeneration mechanism of PL. We verified PL's therapeutic effectiveness and histological analysis on the PU model. PL promoted cell viability, migration, wound healing and angiogenesis in vitro. Real-time PCR and western blot indicated PL suppressed inflammation and promoted collagen I synthesis by activating STAT3. PL@GM hydrogel system demonstrated optimal biocompatibility and favorable effects on essential cells for wound healing. PL@GM also significantly stimulated PU healing, skin regeneration, and the formation of subcutaneous collagen and blood vessels. PL@GM could accelerate PU healing by promoting fibroblasts to migrate and secrete collagen and endothelial cells to vascularize. PL@GM promises to be an effective and convenient treatment modality for PU, like chronic wound treatment.

Nacre-like surface nanolaminates enhance fatigue resistance of pure titanium.

Fatigue failure is invariably the most crucial failure mode for metallic structural components. Most microstructural strategies for enhancing fatigue resistance are effective in suppressing either crack initiation or propagation, but often do not work for both synergistically. Here, we demonstrate that this challenge can be overcome by architecting a gradient structure featuring a surface layer of nacre-like nanolaminates followed by multi-variant twinned structure in pure titanium. The polarized accommodation of highly regulated grain boundaries in the nanolaminated layer to cyclic loading enhances the structural stability against lamellar thickening and microstructure softening, thereby delaying surface roughening and thus crack nucleation. The decohesion of the nanolaminated grains along horizonal high-angle grain boundaries gives rise to an extraordinarily high frequency (≈1.7 × 103 times per mm) of fatigue crack deflection, effectively reducing fatigue crack propagation rate (by 2 orders of magnitude lower than the homogeneous coarse-grained counterpart). These intriguing features of the surface nanolaminates, along with the various toughening mechanisms activated in the subsurface twinned structure, result in a fatigue resistance that significantly exceeds those of the homogeneous and gradient structures with equiaxed grains. Our work on architecting the surface nanolaminates in gradient structure provides a scalable and sustainable strategy for designing more fatigue-resistant alloys.

MFGE8 promotes adult hippocampal neurogenesis in rats following experimental subarachnoid hemorrhage via modifying the integrin ß3/Akt signaling pathway.

Subarachnoid hemorrhage (SAH) is one of the most severe type of cerebral strokes, which can cause multiple cellular changes in the brain leading to neuronal injury and neurological deficits. Specifically, SAH can impair adult neurogenesis in the hippocampal dentate gyrus, thus may affecting poststroke neurological and cognitive recovery. Here, we identified a non-canonical role of milk fat globule epidermal growth factor 8 (MFGE8) in rat brain after experimental SAH, involving a stimulation on adult hippocampal neurogenesis(AHN). Experimental SAH was induced in Sprague-Dawley rats via endovascular perforation, with the in vivo effect of MFGE8 evaluated via the application of recombinant human MFGE8 (rhMFGE8) along with pharmacological interventions, as determined by hemorrhagic grading, neurobehavioral test, and histological and biochemical analyses of neurogenesis related markers. Results: Levels of the endogenous hippocampal MFGE8 protein, integrin-ß3 and protein kinase B (p-Akt) were elevated in the SAH relative to control groups, while that of hippocalcin (HPCA) and cyclin D1 showed the opposite change. Intraventricular rhMGFE8 infusion reversed the decrease in doublecortin (DCX) immature neurons in the DG after SAH, along with improved the short/long term neurobehavioral scores. rhMGFE8 treatment elevated the levels of phosphatidylinositol 3-kinase (PI3K), p-Akt, mammalian target of rapamycin (mTOR), CyclinD1, HPCA and DCX in hippocampal lysates, but not that of integrin ß3 and Akt, at 24 hr after SAH. Treatment of integrin ß3 siRNA, the PI3K selective inhibitor ly294002 or Akt selective inhibitor MK2206 abolished the effects of rhMGFE8 after SAH. In conclusion, MFGE8 is upregulated in the hippocampus in adult rats with reduced granule cell genesis. rhMFGE8 administration can rescue this impaired adult neurogenesis and improve neurobehavioral recovery. Mechanistically, the effect of MFGE8 on hippocampal adult neurogenesis is mediated by the activation of integrin ß3/Akt pathway. These findings suggest that exogenous MFGE8 may be of potential therapeutic value in SAH management. Graphical abstract and proposed pathway of rhMFGE8 administration attenuate hippocampal injury by improving neurogenesis in SAH models. SAH caused hippocampal injury and neurogenesis interruption. Administered exogenous MFGE8, recombinant human MFGE8(rhMFGE8), could ameliorate hippocampal injury and improve neurological functions after SAH. Mechanistically, MFGE8 bind to the receptor integrin ß3, which activated the PI3K/Akt pathway to increase the mTOR expression, and further promote the expression of cyclin D1, HPCA and DCX. rhMFGE8 could attenuated hippocampal injury by improving neurogenesis after SAH, however, know down integrin ß3 or pharmacological inhibited PI3K/Akt by ly294002 or MK2206 reversed the neuro-protective effect of rhMFGE8.

Efficacy of antihypertensive treatment for target organ protection in patients with masked hypertension (ANTI-MASK): a multicentre, double-blind, placebo-controlled trial.

Background: Masked hypertension is associated with target organ damage (TOD) and adverse health outcomes, but whether antihypertensive treatment improves TOD in patients with masked hypertension is unproven. Methods: In this multicentre, randomised, double-blind, placebo-controlled trial at 15 Chinese hospitals, untreated outpatients aged 30-70 years with an office blood pressure (BP) of <140/<90 mm Hg and 24-h, daytime or nighttime ambulatory BP of ≥130/≥80, ≥135/≥85, or ≥120/≥70 mm Hg were enrolled. Patients had ≥1 sign of TOD: electrocardiographic left ventricular hypertrophy (LVH), brachial-ankle pulse wave velocity (baPWV) ≥1400 cm/s, or urinary albumin-to-creatinine ratio (ACR) ≥3.5 mg/mmol in women and ≥2.5 mg/mmol in men. Exclusion criteria included secondary hypertension, diabetic nephropathy, serum creatinine ≥176.8 µmol/L, and cardiovascular disease within 6 months of screening. After stratification for centre, sex and the presence of nighttime hypertension, eligible patients were randomly assigned (1:1) to receive antihypertensive treatment or placebo. Patients and investigators were masked to group assignment. Active treatment consisted of allisartan starting at 80 mg/day, to be increased to 160 mg/day at month 2, and to be combined with amlodipine 2.5 mg/day at month 4, if the ambulatory BP remained uncontrolled. Matching placebos were used likewise in the control group. The primary endpoint was the improvement of TOD, defined as normalisation of baPWV, ACR or LVH or a ≥20% reduction in baPWV or ACR over the 48-week follow-up. The intention-to-treat analysis included all randomised patients, the per-protocol analysis patients who fully adhered to the protocol, and the safety analysis all patients who received at least one dose of the study medication. This study is registered with ClinicalTrials.gov, NCT02893358. Findings: Between February 14, 2017, and October 31, 2020, 320 patients (43.1% women; mean age ± SD 53.7 ± 9.7 years) were enrolled. Baseline office and 24-h BP averaged 130 ± 6.0/81 ± 5.9 mm Hg and 136 ± 8.6/84 ± 6.1 mm Hg, and the prevalence of elevated baPWV, ACR and LVH were 97.5%, 12.5%, and 7.8%, respectively. The 24-h BP decreased on average (±SE) by 10.1 ± 0.9/6.4 ± 0.5 mm Hg in 153 patients on active treatment and by 1.3 ± 0.9/1.0 ± 0.5 mm Hg in 167 patients on placebo. Improvement of TOD occurred in 79 patients randomised to active treatment and in 49 patients on placebo: 51.6% (95% CI 43.7%, 59.5%) versus 29.3% (22.1, 36.5%; p < 0.0001). Per-protocol and subgroup analyses were confirmatory. Adverse events were generally mild and occurred in 38 (25.3%) and 43 (26.4%) patients randomised to active treatment and placebo, respectively (p = 0.83). Interpretation: Our results suggest that antihypertensive treatment improves TOD in patients with masked hypertension, highlighting the need of treatment. However, the long-term benefit in preventing cardiovascular complications still needs to be established. Funding: Salubris China.

Chromosome-level genome assembly and annotation of the Rhabdophis nuchalis (Hubei keelback).

Rhabdophis nuchalis, a snake widely distributed in China, possesses a unique trait: glands beneath the skin on its neck and back, known as nucho-dorsal glands. These features make it a valuable subject for studying genetic diversity and the evolution of complex traits. In this study, we obtained a high-quality chromosome-level reference genome of R. nuchalis using MGI short-read sequencing, PacBio Revio long-read sequencing, and Hi-C sequencing techniques. The final assembly comprised 1.92 Gb of the R. nuchalis genome, anchored to 20 chromosomes (including 9 macrochromosomes and 11 microchromosomes), with a contig N50 of 104.79 Mb, a scaffold N50 of 204.96 Mb, and a BUSCO completeness of 97.50%. Additionally, we annotated a total of 1.09 Gb of repetitive sequences (which constitute 56.51% of the entire genome) and identified 22,057 protein-coding genes. This high-quality reference genome of R. nuchalis furnishes essential genomic data for comprehending the genetic diversity and evolutionary history of the species, as well as for facilitating species conservation efforts and comparative genomics studies.

Nuclear HMGB1 is critical for CD8 T cell IFN-γ production and anti-tumor immunity.

HMGB1 (high-mobility group box-1) has been extensively studied as a damage-associated molecular pattern, with secreted cytokine function. However, its regulation on T cells, especially the function in the nucleus, has not been elucidated. Here, we use conditional knockout (HMGB1-f/f; CD2-cre) mice and find that HMGB1 potentiates the proliferation and interferon gamma (IFN-γ) expression of CD8 T cells rather than CD4 T cells. Notably, nuclear, but not secreted, HMGB1 supports the expression of IFN-γ in CD8 T cells via directly regulating the activity of Eomes, the transcription factor for IFN-γ. Functional study shows that HMGB1 promotes the anti-tumor ability of CD8 T cells in vitro and in vivo. Finally, tumor environmental interleukin-7 promotes HMGB1 and IFN-γ production via fatty acid oxidation in CD8 T cells. Overall, we identify the role of nuclear HMGB1 in CD8 T cell differentiation and demonstrate that it plays an important role in the anti-tumor programs of CD8 T cells.

Nano-Enhanced Graphite/Phase Change Material/Graphene Composite for Sustainable and Efficient Passive Thermal Management.

Passive battery thermal management systems (BTMSs) are critical for mitigation of battery thermal runaway (TR). Phase change materials (PCMs) have shown promise for mitigating transient thermal challenges. Fluid leakage and low effective thermal conductivity limit PCM adoption. Furthermore, the thermal capacitance of PCMs diminishes as their latent load is exhausted, creating an unsustainable cooling effect that is transitory. Here, an expanded graphite/PCM/graphene composite that solves these challenges is proposed. The expanded graphite/PCM phase change composite eliminates leakage and increases effective thermal conductivity while the graphene coating enables radiative cooling for PCM regeneration. The composite demonstrates excellent thermal performance in a real BTMS and shows a 26% decrease in temperature when compared to conventional BTMS materials. The composite exhibits thermal control performance comparable with active cooling, resulting in reduced cost and increased simplicity. In addition to BTMSs, this material is anticipated to have application in a plethora of engineered systems requiring stringent thermal management.

Palmatine Ameliorates Motor Deficits and Dopaminergic Neuron Loss by Regulating NLRP3 Inflammasome through Mitophagy in Parkinson's Disease Model Mice.

NLRP3 inflammasomes-mediated proinflammatory response and mitochondrial dysfunction play a critical role in the etiology and pathogenesis of Parkinson's disease. Negative regulation of NLRP3 inflammasome activation through mitophagy may be an important strategy to control NLRP3 inflammasome-mediated proinflammatory responses. Palmatine (PAL), an isoquinoline alkaloid found in various of plants, has potent pharmacological effects such as anti-inflammatory and anti-oxidation. However, the specific role of PAL in the pathology of Parkinson's disease remains unclear. In this study, we found that treatment with PAL improved motor deficits and reduced the loss of dopaminergic neurons in MPTP mice. Further results showed that PAL promoted mitophagy and inhibited the proinflammatory response mediated by NLRP3 inflammasomes. In addition, chloroquine (CQ, mitophagy inhibitor) attenuated the ameliorative effects of PAL on the motor deficits and dopaminergic neuron damage, as well as the inhibitory effect of PAL on NLRP3 inflammasome. Collectively, these results provide strong evidence that PAL ameliorates motor deficits and dopaminergic neuron death in Parkinson's disease, and the mechanism may be related to its inhibition of NLRP3 inflammasome activation via promoting mitophagy.

Synthesis of highly sensitive and multi-response Eu-MOF, fluorescence sensing properties and anti-counterfeiting applications.

A new Europium metal-organic framework (Eu-MOF), namely [Eu(dpa) (H2O)]·0.5(bpy)·4H2O}n (H4dpa = 5-(3,4-dicarboxyphenoxy) isophenic acid, bpy = protonated 4,4'-bipyridine) was synthesized and structurally characterized by elemental analyses, infrared spectroscopy, and X-ray single-crystal diffraction analyses. Eu-MOF shows a three-dimensional network structure based on EuIII ions and (dpa)4- ligands via µ4: η1, η2, η2, η2 coordination mode. Fluorescence analysis shows that Eu-MOF has excellent fluorescence sensing characteristics, which can efficiently and sensitively detect various pollutants in water: the limit of detection (LOD) of ratiometric fluorescence detection of ANI in water was 42.9 nM, which was better than the single-peak detection limit. In addition, the peak detection limits of Eu-MOF for Flu, ORN and NB were 120 nM, 27 nM and 94 nM, respectively. In addition, XPS, LUMO orbital energy level, fluorescence lifetime, ultraviolet absorption and other principles are used to explore the mechanism of fluorescence quenching. Surprisingly, Eu-MOF not only has excellent anti- counterfeiting ability and stability, can be used as anti-counterfeiting material in life, but also has good selectivity to Flu. Eu-MOF has obvious fluorescence quenching effect on Flu on paper under ultraviolet light, which can be used for rapid in situ imaging test paper of pesticide residues.

Comprehensive insights into the organoleptic characteristics attributes of "HuangYuXiang": Integration of volatilomics, sensomics, macrogenomics, lipidomics, and metabolomics.

HuangYuXiang (HYX) is a colorful and flavorful traditional cuisine in China, which development of organoleptic attributes is a complex process. Flavor sensory attributes was explored through volatilomics, sensomics, macrogenomics, lipidomics, and metabolomics in seven HYXs. Group B demonstrated the highest sensory scores. A total of 41 volatiles were detected, of which 7 were identified as key volatiles. Caulobacteraceae sp., Psychrobacter faecalis, Ralstonia pickettii, Carnobacterium divergens, and Psychrobacter cibarius were representative bacteria in HYXs. A total of 679 lipids (251 differential lipids) and 329 (113 differential metabolites) metabolites were identified. The differential compounds were the main contributors to flavor differences. L-homocitrulline, arg-ser, 4-aminobenzoic acid, arg-gly, sucrose, pyridoxine, D-cyclohexylglycine, PC 21:4/22:6, PC O-15:0/22:5, PC O-20:2/20:5, and FA 18:2 were heavily accumulated under the microbial action, which in turn promoted the formation of aroma and taste substances. The results of this study provide a theoretical basis for the standardized processing of high-quality HYX.

Serum N-Terminal Pro-B-Type Natriuretic Peptide Level is Negatively Associated with Vascular Reactivity Index by Digital Thermal Monitoring in Patients with Hypertension.

Background: B-type natriuretic peptide (BNP) coordinates endothelial homeostasis and remodeling, with endothelial dysfunction associated with cardiovascular mortality in the general population without heart failure. The objective of this study was to investigate the correlation between serum N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) levels and endothelial dysfunction among patients diagnosed with hypertension. Methods: This cross-sectional, single-center study included 90 patients with hypertension. An electrochemiluminescence immunoassay measured NT-pro-BNP levels, and a digital thermal monitoring device calculated a vascular reactivity index (VRI) as a measurement for endothelial function. In this study, VRI < 1.0 denoted poor vascular reactivity, 1.0 ≤ VRI < 2.0 indicated intermediate vascular reactivity, and a VRI ≥ 2.0 suggested good vascular reactivity. Results: Out of all the hypertensive patients, eight (8.9%) displayed poor vascular reactivity (VRI < 1.0), while 39 (43.3%) exhibited intermediate vascular reactivity (1.0 ≤ VRI < 2.0), leaving the remaining 43 patients demonstrating good vascular reactivity. Older age (p = 0.012) and elevated serum NT-pro-BNP levels (p < 0.001) were found to be associated with poorer vascular reactivity. Older age (r = -0.221, p = 0.036) and log-transformed serum levels of NT-pro-BNP (log-NT-pro-BNP, r = -0.505, p < 0.001) exhibited a negative correlation with VRI values in patients with hypertension. Following a multivariate linear regression test, serum log-NT-pro-BNP level ( ß = -0.505, adjusted R 2 change = 0.246, p < 0.001) emerged as being significantly and independently associated with VRI values among hypertensive patients. Conclusions: In patients with hypertension, there was a negative association observed between serum log-NT-pro-BNP levels and endothelial dysfunction determined by VRI values.

The neurotransmitter calcitonin gene-related peptide shapes an immunosuppressive microenvironment in medullary thyroid cancer.

Neurotransmitters are key modulators in neuro-immune circuits and have been linked to tumor progression. Medullary thyroid cancer (MTC), an aggressive neuroendocrine tumor, expresses neurotransmitter calcitonin gene-related peptide (CGRP), is insensitive to chemo- and radiotherapies, and the effectiveness of immunotherapies remains unknown. Thus, a comprehensive analysis of the tumor microenvironment would facilitate effective therapies and provide evidence on CGRP's function outside the nervous system. Here, we compare the single-cell landscape of MTC and papillary thyroid cancer (PTC) and find that expression of CGRP in MTC is associated with dendritic cell (DC) abnormal development characterized by activation of cAMP related pathways and high levels of Kruppel Like Factor 2 (KLF2), correlated with an impaired activity of tumor infiltrating T cells. A CGRP receptor antagonist could offset CGRP detrimental impact on DC development in vitro. Our study provides insights of the MTC immunosuppressive microenvironment, and proposes CGRP receptor as a potential therapeutic target.

May Measurement Month 2021: an analysis of blood pressure screening results from China.

We reported findings from participants screened during the May Measurement Month 2021 in China, which aimed to raise awareness of raised blood pressure (BP), and to investigate the risk factors of BP. The study participants were adults (≥18 years), ideally in whom BP had not been measured in the previous year. Blood pressure was measured three times consecutively with 1 min intervals in the sitting position, using a validated upper-arm cuff automated BP monitor (Omron HEM-7081IT), and transmitted to a central cloud database via a smartphone app. The measurement was performed in 218 844 participants in 183 sites across 31 China provinces. The mean (standard deviation) age was 47.0 (15.7) years, and 51.8% (n = 113 466) were women. The mean systolic/diastolic BP was 120.2/77.5 mmHg. Among 57 178 (26.1%) participants with hypertension, the awareness, treatment, and control rates of hypertension were 30.4% (n = 17 354), 28.7% (n = 16 369), and 17.1% (n = 9743), respectively. After adjustment for age, sex, and use of antihypertensive medication, both systolic and diastolic BP were significantly (P ≤ 0.01) higher in current smokers (n = 22 344, +0.4/+0.7 mmHg) and with moderate (n = 4780, +1.4/+4.2 mmHg) or daily alcohol intake (n = 2427, +1.3/+2.5 mmHg). Blood pressure was lower in those reporting regular exercise (n = 32 328, -2.2/-1.4 mmHg). In addition, individuals with previous COVID-19 vaccination had lower systolic and diastolic BP (n = 88 945, -1.8/-1.5 mmHg, P ≤ 0.001). In conclusion, our study showed that long-term large-scale screening for hypertension is feasible, and there is a strong association between BP and major lifestyle factors.

Characteristics of Gaseous Elemental Mercury in a Suburban Area of Shanghai, China.

To clarify gaseous elemental mercury (GEM) in suburban megacities in the Yangtze River Delta region, China, we observed GEM concentrations from December 2019 to November 2020 in Wujing town, a suburban area of Shanghai. The annual mean GEM concentration was 1.44 ± 0.88 ng m-3. Compared with the historical monitoring data of GEM in Shanghai over the past 10 years, the concentration of GEM showed a decreasing trend. The monthly mean concentrations of GEM showed clear seasonal variation, with higher values in the spring and winter. In spring and winter, typical Hg pollution events were observed, which could be mostly associated with increased local anthropogenic activity and temperature inversion. The results of the correlation analysis of the daily mean GEM concentrations with the AQI and backward trajectory calculations indicate that mercury pollution at monitoring sites can be affected by local, regional and interregional influences.

PRMT6 facilitates EZH2 protein stability by inhibiting TRAF6-mediated ubiquitination degradation to promote glioblastoma cell invasion and migration.

Invasion and migration are the key hallmarks of cancer, and aggressive growth is a major factor contributing to treatment failure and poor prognosis in glioblastoma. Protein arginine methyltransferase 6 (PRMT6), as an epigenetic regulator, has been confirmed to promote the malignant proliferation of glioblastoma cells in previous studies. However, the effects of PRMT6 on glioblastoma cell invasion and migration and its underlying mechanisms remain elusive. Here, we report that PRMT6 functions as a driver element for tumor cell invasion and migration in glioblastoma. Bioinformatics analysis and glioma sample detection results demonstrated that PRMT6 is highly expressed in mesenchymal subtype or invasive gliomas, and is significantly negatively correlated with their prognosis. Inhibition of PRMT6 (using PRMT6 shRNA or inhibitor EPZ020411) reduces glioblastoma cell invasion and migration in vitro, whereas overexpression of PRMT6 produces opposite effects. Then, we identified that PRMT6 maintains the protein stability of EZH2 by inhibiting the degradation of EZH2 protein, thereby mediating the invasion and migration of glioblastoma cells. Further mechanistic investigations found that PRMT6 inhibits the transcription of TRAF6 by activating the histone methylation mark (H3R2me2a), and reducing the interaction between TRAF6 and EZH2 to enhance the protein stability of EZH2 in glioblastoma cells. Xenograft tumor assay and HE staining results showed that the expression of PRMT6 could promote the invasion of glioblastoma cells in vivo, the immunohistochemical staining results of mouse brain tissue tumor sections also confirmed the regulatory relationship between PRMT6, TRAF6, and EZH2. Our findings illustrate that PRMT6 suppresses TRAF6 transcription via H3R2me2a to enhance the protein stability of EZH2 to facilitate glioblastoma cell invasion and migration. Blocking the PRMT6-TRAF6-EZH2 axis is a promising strategy for inhibiting glioblastoma cell invasion and migration.