An application study-subjective cognitive decline Questionnaire9 in detecting mild cognitive impairment (MCI).

Objective: Subjective cognitive decline (SCD) complaints as the early manifestation of mild cognitive impairment (MCI) may be harbingers of objective cognitive decline. SCD-questinnaire9 (SCD-Q9) is developed to investigate the early sign for MCI. However, few studies have reported its power for discriminating MCI from healthy controls (HCs). Therefore, this study aims to investigate the discrimination power of SCD-Q9 as a brief screening tool for early detection of SCD in MCI.Methods: 84 HCs and 205 people with MCI were recruited. Their demographic information and scores of SCD-Q9 were compared. A binary logistic regression model was used to analyze the potential affecting factors of MCI, and the Receiver Operating Characteristic analysis was applied to test the discrimination powers of those factors, including SCD-Q9.Results: (1) Single and total scores of SCD-Q9 were all lower in the MCI group than those in the HC group. (2) Ageing, lower education and higher total scores of SCD-Q9 were associated with MCI. (3) Area Under the Curves (AUC) of SCD-Q9 for discriminating MCI from HC group was 0.815 and when integrating age and education, the AUC improved slightly and reached 0.839. Additionally, the sensitivity and specificity were 68.8% and 85.7%, respectively when a cut-off value of 3 was applied. Conclusions: SCD-Q9 may be able to detect the subjective cognitive decline in MCI early, but it may be used together with other screening questionnaires to improve its sensitivity and further verification of its power is needed.

Nur77 deficiency exacerbates cardiac fibrosis after myocardial infarction by promoting endothelial-to-mesenchymal transition.

Cardiac fibrosis is a reparative process after myocardial infarction (MI), which leads to cardiac remodeling and finally heart failure. Endothelial-to-mesenchymal transition (EndMT) is induced after MI and contributes to cardiac fibrosis after MI. Orphan nuclear receptor Nur77 is a key regulator of inflammation, angiogenesis, proliferation, and apoptosis in vascular endothelial cells. Here, we investigated the role of orphan nuclear receptor Nur77 in EndMT and cardiac fibrosis after MI. Cardiac fibrosis was induced through MI by ligation of the left anterior descending coronary artery. We demonstrated that Nur77 knockout aggravated cardiac dysfunction and cardiac fibrosis 30 days after MI. Moreover, Nur77 deficiency resulted in enhanced EndMT as shown by increased expression of FSP-1, SM22α, Snail, and decreased expression of PECAM-1 and eNOS compared with wild-type mice after MI. Then, we found overexpression Nur77 in human coronary artery endothelial cells significantly inhibited interleukin 1ß and transforming growth factor ß2-induced EndMT, as shown by a reduced transition to a fibroblast-like phenotype and preserved angiogenesis potential. Mechanistically, we demonstrated that Nur77 downregulated EndMT by inhibiting the nuclear factor-κB-dependent pathway. In conclusion, Nur77 is involved in cardiac fibrosis by inhibiting EndMT and may be a promising target for therapy of cardiac fibrosis after MI.

Disease Burden Attributable to the First Wave of COVID-19 in China and the Effect of Timing on the Cost-Effectiveness of Movement Restriction Policies.

OBJECTIVES: Movement restriction policies (MRPs) are effective in preventing/delaying COVID-19 transmission but are associated with high societal cost. This study aims to estimate the health burden of the first wave of COVID-19 in China and the cost-effectiveness of early versus late implementation of MRPs to inform preparation for future waves. METHODS: The SEIR (susceptible, exposed, infectious, and recovered) modeling framework was adapted to simulate the health and cost outcomes of initiating MRPs at different times: rapid implementation (January 23, the real-world scenario), delayed by 1 week, delayed by 2 weeks, and delayed by 4 weeks. The end point was set as the day when newly confirmed cases reached zero. Two costing perspectives were adopted: healthcare and societal. Input data were obtained from official statistics and published literature. The primary outcomes were disability-adjusted life-years, cost, and net monetary benefit. Costs were reported in both Chinese renminbi (RMB) and US dollars (USD) at 2019 values. RESULTS: The first wave of COVID-19 in China resulted in 38 348 disability adjusted life-years lost (95% CI 19 417-64 130) and 2639 billion RMB losses (95% CI 1347-4688). The rapid implementation strategy dominated all other delayed strategies. This conclusion was robust to all scenarios tested. At a willingness-to-pay threshold of 70 892 RMB (the national annual GDP per capita) per disability-adjusted life-year saved, the probability for the rapid implementation to be the optimal strategy was 96%. CONCLUSIONS: Early implementation of MRPs in response to COVID-19 reduced both the health burden and societal cost and thus should be used for future waves of COVID-19.

Electrophysiological parameters and anatomical evaluation of left bundle branch pacing in an in vivo canine model.

INTRODUCTION: Left bundle branch pacing (LBBP), a form of conduction system pacing in addition to His bundle pacing (HBP), can potentially maintain left ventricular electrical synchrony with better sensing and a low and stable capture threshold. METHODS: We performed both HBP and LBBP using a canine model (n = 3; male; weight 30-40 kg). The electrocardiogram (ECG), intracardiac electrogram characteristics, and pacing parameters were compared between HBP and LBBP. The hearts were isolated and stained by Lugol's iodine (5%) to assess the relative locations of the leads in relation to the conduction system. RESULTS: The average potential to ventricle interval was longer with HBP compared to LBBP (26.67 ± 3.06 ms vs 12.67 ± 1.15 ms; P = .002). There were also notable differences in the pacing parameters between HBP and LBBP: R-wave amplitude (2.67 ± 0.42 mV vs 11.33 ± 3.06 mV; P = .008), pacing impedance (423.3 ± 40.4 vs 660.0 ± 45.8; P = .003), and threshold (2.30 ± 0.66 V/0.4ms vs 0.67 ± 0.15 V/0.4 ms; P = .014). The paced morphology of ECG was similar to the intrinsic with HBP while a right bundle branch block pattern was noted with LBBP. The anatomical evaluation revealed the location of the leads and the average lead depth was significantly more with LBBP as compared to HBP (12.33 ± 1.53 mm vs1.83 ± 0.29 mm; P < .0001). Furthermore, with LBBP, the tip of the lead helix was noted to be around the LBB. CONCLUSION: This in vivo canine model study confirms the significant differences between HBP and LBBP. Furthermore, this model provides a precise anatomic evaluation of the location and the depth of the leads in relation to the conduction system.

Smart All-in-One Thermometer-Heater Nanoprobe Based on Postsynthetical Functionalization of a Eu(III)-Metal-Organic Framework.

Real-time temperature feedback in tissue based on photothermal therapy is an urgent problem to be solved in cancer treatment. Herein, a smart all-in-one nanoprobe THA@Eu-NMOF@Fe/TA was designed and assembled by postsynthetical functionalization of an Eu(III)-based nanoscale metal-organic framework (Eu-NMOF) with a two-photon-absorbing ß-diketonate ligand 4,4,4-trifluoro-1-(9-hexylcarbazol-3-yl)-1,3-butanedione (HTHA) and Fe(III)/tannic acid assembly (Fe/TA). Such a functionalized material can simultaneously achieve the temperature-sensing and optical heating under a single beam of near-infrared (NIR) light. Under 808 nm laser excitation, real-time feedback of temperature by monitoring thermoresponsive fluorescence emission ratio ( I616/ I590) and fluorescence lifetime of Eu(III) ions were realized. Meantime, Fe/TA served as the photothermal agent and antibacterial agent to implement photothermal therapy (PTT) and antibacteria simultaneously. The functions of the nanoprobe were proved with ex vivo experiments, and the antibacterial activity against Gram-positive and Gram-negative bacteria of the probe was also elaborately evaluated. Our work paves a new avenue for engineering a new cancer treatment probe which can achieve real-time temperature sensing feedback during PTT and antibacterial process.

Terbium Functionalized Micelle Nanoprobe for Ratiometric Fluorescence Detection of Anthrax Spore Biomarker.

Rapid, sensitive, and selective quantitative detection of pyridine dicarboxylic acid (DPA) as biomarker of anthrax spores is in great demand since anthrax spores are highly lethal to human beings and animals and also potential biological warfare agents. Herein, we prepared a ratiometric fluorescence lanthanide functionalized micelle nanoprobe by "one-pot" self-assembly, with an amphiphilic ligand containing ß-diketone derivative which can "immobilize" terbium ions through the coordination interaction and a fluorophore as fluorescence reference (FR). The detection strategy was ascribed to Tb3+ ions in lanthanide functionalized micelle, which can be sensitized to emit the intrinsic luminescence upon addition of DPA due to the presence of energy transfer when DPA chromophore coordinated with Tb3+ ion. The fluorescence intensity of FR remained essentially constant, leading to ratiometric fluorescence response toward DPA. The results demonstrate that the terbium functionalized micelle was able to sensitively detect DPA with a linear relation in the range of 0 µM to 7.0 µM in aqueous solution, which also showed remarkable selectivity to DPA over other aromatic ligands. Our work paves a new way in the design of ratiometric fluorescence lanthanide functionalized micelle nanoprobes which can be promising for selective and sensitive detection of bacterial spores or biomolecules.

Mechanical stresses induce paracrine ß-2 microglobulin from cardiomyocytes to activate cardiac fibroblasts through epidermal growth factor receptor.

By employing a proteomic analysis on supernatant of mechanically stretched cardiomyocytes, we found that stretch induced a significantly high level of ß-2 microglobulin (ß2M), a non-glycosylated protein, which is related to inflammatory diseases but rarely known in cardiovascular diseases. The present data showed that serum ß2M level was increased in patients with hypertension and further increased in patients with chronic heart failure (HF) as compared with control group, and the high level of serum ß2M level correlated to cardiac dysfunction in these patients. In pressure overload mice model by transverse aortic constriction (TAC), ß2M levels in serum and heart tissue increased progressively in a time-dependent manner. Exogenous ß2M showed pro-fibrotic effects in cultured cardiac fibroblasts but few effects in cardiomyocytes. Adeno-associated virus 9 (AAV9)-mediated knockdown of ß2M significantly reduced cardiac ß2M level and inhibited myocardial fibrosis and cardiac dysfunction but not cardiac hypertrophy at 4 weeks after TAC. In vitro, mechanical stretch induced the rapid secretion of ß2M mainly from cardiomyocytes by activation of extracellular-regulated protein kinase (ERK). Conditional medium (CM) from mechanically stretched cardiomyocytes activated cultured cardiac fibroblasts, and the effect was partly abolished by CM from ß2M-knockdown cardiomyocytes. In vivo, knockdown of ß2M inhibited the increase in phosphorylation of epidermal growth factor receptor (EGFR) induced by TAC. In cultured cardiac fibroblasts, inhibition of EGFR significantly attenuated the ß2M-induced the activation of EGFR and pro-fibrotic responses. The present study suggests that ß2M is a paracrine pro-fibrotic mediator and associated with cardiac dysfunction in response to pressure overload.

Functionalized Eu(III)-Based Nanoscale Metal-Organic Framework To Achieve Near-IR-Triggered and -Targeted Two-Photon Absorption Photodynamic Therapy.

The postsynthetic-modified nanoscale metal-organic framework (NMOF) probes selected as potential drug delivery platforms and photodynamic therapy agents to fulfill the effective and safe treatment of neoplastic diseases have attracted increasing attention recently. Herein, a Eu(III)-based NMOF probe elaborately postsynthetically modified with a ß-diketonate two-photon-absorbing (TPA) ligand is rationally designed and further functionalized by assembling the photosensitizer molecule (methylene blue, MB) in the pores and a cyclic peptide targeting motif on the surface of the NMOF, which could achieve highly efficient near-infrared (NIR)-triggered and -targeted photodynamic therapy (PDT). On the basis of the luminescence resonance energy transfer process between the NMOF donor and the photosensitizer MB acceptor, the probe can achieve a high tissue-penetrable TPA-PDT effect. Thus, the NMOFs in this study play the role of not only the nanocontainer for the photosensitizer but also the energy-transfer donor. Studies in vitro show enhanced cellular uptake and satisfactory PDT effectiveness toward cancer cells compared to the free photosensitizer MB. It is highly expected that this study contributes to the development of smart luminescent diagnostic and therapeutic probes.

Aldehyde dehydrogenase 2 deficiency blunts compensatory cardiac hypertrophy through modulating Akt phosphorylation early after transverse aorta constriction in mice.

AIMS: This study was designed to examine the impact of mitochondrial aldehyde dehydrogenase 2 (ALDH2) on transverse aorta constriction (TAC)-induced cardiac hypertrophy and related molecular mechanisms using an ALDH2 knockout (ALDH2-/-) murine model. METHODS: Male wild-type and ALDH2-/- mice were subjected to TAC or sham operation (n=6-8 for each group). After two weeks, cardiac function was assessed by echocardiography and hemodynamic measurements. Myocardial phosphorylated and total PI3K, the catalytic subunit of PI3Ks (p110α and p110γ), Akt, and total PTEN levels were detected by Western blotting. Cardiomyocytes were stretched for 6h in vitro in the presence or absence of Alda-1 (a small-molecule activator of ALDH2) prior to assessment of phosphorylated PI3K, Akt and total PTEN expressions by Western blot. RESULTS: Heart to body weight ratio and left ventricular posterior wall thickness as well as the cross-sectional area of cardiomyocyte were significantly lower in ALDH2-/- mice than in wild-type mice following TAC. Western blot analysis showed p110γ was upregulated post TAC in both wild-type mice and ALDH2-/- mice, phosphorylation of Akt was disrupted, PTEN expression was upregulated in ALDH2-/- mice post TAC while phosphorylated PI3K, p110α and p110γ expression was similar between ALDH2-/- and wild-type mice post TAC. In vitro, phosphorylation of Akt was significantly accentuated and PTEN expression was reduced while PI3K phosphorylation remained unchanged in stretched cardiomyocytes pretreated by Alda-1 compared to stretched cardiomyocytes treated by saline. CONCLUSIONS: Our results show that ALDH2 deficiency attenuates compensatory cardiac hypertrophy through regulating Akt but not PI3K phosphorylation early after TAC in mice.

Urotensin II inhibited the proliferation of cardiac side population cells in mice during pressure overload by JNK-LRP6 signalling.

Cardiac side population cells (CSPs) are promising cell resource for the regeneration in diseased heart as intrinsic cardiac stem cells. However, the relative low ratio of CSPs in the heart limited the ability of CSPs to repair heart and improve cardiac function effectively under pathophysiological condition. Which factors limiting the proliferation of CSPs in diseased heart are unclear. Here, we show that urotensin II (UII) regulates the proliferation of CSPs by c-Jun N-terminal kinase (JNK) and low density lipoprotein receptor-related protein 6 (LRP6) signalling during pressure overload. Pressure overload greatly upregulated UII level in plasma, UII receptor (UT) antagonist, urantide, promoted CSPs proliferation and improved cardiac dysfunction during chronic pressure overload. In cultured CSPs subjected to mechanical stretch (MS), UII significantly inhibited the proliferation by UT. Nanofluidic proteomic immunoassay showed that it is the JNK activation, but not the extracellular signal-regulated kinase signalling, that involved in the UII-inhibited- proliferation of CSPs during pressure overload. Further analysis in vitro indicated UII-induced-phospho-JNK regulates phosphorylation of LRP6 in cultured CSPs after MS, which is important in the inhibitory effect of UII on the CSPs during pressure overload. In conclusion, UII inhibited the proliferation of CSPs by JNK/LRP6 signalling during pressure overload. Pharmacological inhibition of UII promotes CSPs proliferation in mice, offering a possible therapeutic approach for cardiac failure induced by pressure overload.