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Uncertain time series analysis has been developed for studying the imprecise observations. In this paper, we propose a nonlinear model called uncertain max-autoregressive (UMAR) model. The unknown parameters in model are estimated by the least squares estimation. Then the residual analysis is presented. In many cases, there are some outliers in the time series due to short-term change in the underlying process. The UMAR model offers an alternative for detecting outliers in the imprecise observations. Based on the previous theoretical results, the UMAR model is used to forecast the future. Finally, an example suggests that the new proposed time series model works well compared to the uncertain autoregressive (UAR) model.

The ligand exchange technique is a common method for postsynthesis isoreticular structures of metal–organic frameworks (MOFs). Here, an interesting framework transformation after linker exchange wa...

Proprotein convertase subtilisin/Kexin type 9 (PCSK9) is a secretory serine protease that plays multiple biological functions in the regulation of physiological and pathological processes. PCSK9 inhibitors decrease the circulating LDL-cholesterol level with well-known preventive and therapeutic effects on atherosclerosis (AS). Still, increasing evidence shows that the direct impact of PCSK9 on the vascular wall also plays an important role in atherosclerotic progression. Compared with other vascular cells, a large proportion of PCSK9 is originated from vascular smooth muscle cells (VSMC). Therefore, defining the effect of VSMC-derived PCSK9 on response changes, such as phenotypic switch, apoptosis, autophagy, inflammation, foam cell formation, and calcification of VSMC, helps us better understand the “pleiotropic” effects of VSMC on the atherosclerotic process. In addition, our understanding of the mechanisms of PCSK9 controlling VSMC functions in vivo is far from enough. This review aims to holistically evaluate and analyze the current state of our knowledge regarding PCSK9 actions affecting VSMC functions and its mechanism in atherosclerotic lesion development. A mechanistic understanding of PCSK9 effects on VSMC will further underpin the success of a new therapeutic strategy targeting AS.

Alcohol abuse reduces hepatic vitamin A (retinoids), reductions that are associated with progression of alcohol liver disease (ALD). Restoring hepatic retinoids through diet is contraindicated in ALD due to the negative effects of alcohol on retinoid metabolism. There are currently no drugs that can both mitigate alcohol-driven hepatic retinoid losses and progression of ALD. Using a mouse model of alcohol intake, we examined if an agonist for the retinoic acid (RA) receptor β2 (RARβ2), AC261066 (AC261) could prevent alcohol-driven hepatic retinoid losses and protect against ALD. Our results show that mice co-treated with AC261 and alcohol displayed mitigation of ALD, including reduced macro, and microvesicular steatosis, and liver damage. Alcohol intake led to increases in hepatic centrilobular levels of ALDH1A1, a rate-limiting enzyme in RA synthesis, and co-localization of ALDH1A1 with the alcohol-metabolizing enzyme CYP2E1, and 4-HNE, a marker of oxidative stress; expression of these targets was abrogated in mice co-treated with AC261 and alcohol. By RNA sequencing technology, we found that AC261 treatments opposed alcohol modulation of 68 transcripts involved in canonical retinoid metabolism. Alcohol modulation of these transcripts, including CES1D, CES1G, RBP1, RDH10, and CYP26A1, collectively favor hepatic retinoid hydrolysis and catabolism. However, despite this, co-administration of AC261 with alcohol did not mitigate alcohol-mediated depletions of hepatic retinoids, but did reduce alcohol-driven increases in serum retinol. Our data show that AC261 protected mice against ALD, even though AC261 did not prevent alcohol-mediated reductions in hepatic retinoids. These data warrant further studies of the anti-ALD properties of AC261.

Oral squamous cell carcinoma (oral SCC) is an aggressive disease and despite intensive treatments, 5-year survival rates for patients have remained low in the last 20 years. Enhancer of zeste homolog 2 (EZH2), part of polycomb repressive complex 2 (PRC2), is highly expressed in human oral SCC samples and cell lines and has been associated with greater epithelia-to-mesenchymal transition (EMT), invasion and metastasis. Here, we developed a tamoxifen-regulated, transgenic mouse line (KcEZH2) in which EZH2 is selectively knocked out (KO) in some tongue epithelial basal stem cells (SCs) in adult mice. EZH2 KO SCs do not show the H3K27me3 mark, as assessed by double-label immunofluorescence. We used this mouse line to assess EZH2 actions during oral tumorigenesis with our immunocompetent 4-nitroquinoline 1-oxide model of oral SCC. We report that higher percentages of mice with invasive SCCs and high-grade neoplastic lesions are observed in mice containing EZH2 KO SCs (KcEZH2-2TΔ and KcEZH2-5TΔ mice). Moreover, EZH2 expression does not correlate with the expression of markers of invasive SCCs. Finally, EZH2 KO cells that are E-cadherin+ are present at invasion fronts infiltrating underlying muscle tissue. Our findings indicate that the knockout of EZH2 in basal SCs of tongue epithelia results in more aggressive carcinomas, and this should be considered when targeting EZH2 as a therapeutic strategy.

Lithium supply shortages have prompted the search for alternatives to widespread grid system applications. Potassium-ion batteries (PIBs) have emerged to promising candidates for this purpose. Nonetheless, the large radius of K (1.38 Å) impedes the march of satisfactory cathode materials. Here, we used solid-phase synthesis to prepare a layered K MnO ·0.25H O (KMO) cathode, comprising alternately connected MnO octahedra with a large interlayer spacing (0.64 nm) to accommodate the migration and transport of K ions. The cathode material achieved initial specific capacities of 102.3 and 88.1 mA h g at current densities of 60 mA g and 1 A g , respectively. The storage mechanism of K ions in PIBs was demonstrated ex situ using X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and Raman spectroscopy measurements. Overall, our proposed KMO was confirmed as an auspicious cathode material for potential use in PIBs.

Three striking and impactful extreme cold weather events successively occurred across East Asia and North America during the mid-winter of 2020/21. These events open a new window to detect possible underlying physical processes. The analysis here indicates that the occurrences of the three events resulted from integrated effects of a concurrence of anomalous thermal conditions in three oceans and interactive Arctic-lower latitude atmospheric circulation processes, which were linked and influenced by one major sudden stratospheric warming (SSW). The North Atlantic warm blob initiated an increased poleward transient eddy heat flux, reducing the Barents-Kara seas sea ice over a warmed ocean and disrupting the stratospheric polar vortex (SPV) to induce the major SSW. The Rossby wave trains excited by the North Atlantic warm blob and the tropical Pacific La Nina interacted with the Arctic tropospheric circulation anomalies or the tropospheric polar vortex to provide dynamic settings, steering cold polar air outbreaks. The long memory of the retreated sea ice with the underlying warm ocean and the amplified tropospheric blocking highs from the midlatitudes to the Arctic intermittently fueled the increased transient eddy heat flux to sustain the SSW over a long time period. The displaced or split SPV centers associated with the SSW played crucial roles in substantially intensifying the tropospheric circulation anomalies and moving the jet stream to the far south to cause cold air outbreaks to a rarely observed extreme state. The results have significant implications for increasing prediction skill and improving policy decision making to enhance resilience in “One Health, One Future”.

Vegetarian and prudent diets are associated with several health benefits but their role in stroke epidemiology is not as clear. This study aimed to evaluate stroke risk with vegetarian, low-animal, and high-animal diets.Studies reporting stroke risk with high versus low use of vegetarian or low/high-animal diets were identified by conducting literature search in Ebsco, Ovid, PubMed, Science Direct, and Web of Science databases. Relative risks (RRs) of stroke between high and low use of vegetarian, low-animal, and high-animal were pooled to achieve overall estimates. Relationship between stroke risk and increasing quantiles of dietary patterns was sought by performing metaregression analyses.17 studies (932545 individuals; follow-up 11.7 years [95% confidence interval (CI): 9.5, 13.9]) were included. Compared to low use, high use of vegetarian and low-animal diets was associated with lower risk of hemorrhagic stroke (RR: 0.71 [95% CI: 0.47, 0.96] and 0.82 [95% CI: 0.64, 0.99]), ischemic stroke (RR: 0.78 [95% CI: 0.66, 0.91] and 0.70 [95% CI: 0.45, 0.95]) and total stroke (RR: 0.84 [95% CI: 0.71, 0.96] and 0.72 [95% CI: 0.61, 0.83]) respectively. Dose-response analyses further supported these findings. High use of high-animal diet was associated with relatively higher risk of stroke [RR: 1.12 [95%CI: 0.94, 1.29]. In vegetarians, relative to high use of vegetables, high use of fruits posed lower risk of stroke.Stroke risk is lower with more use of a vegetarian or low-animal diet but relatively higher with more use of a high-animal diet.

The AJCC TNM staging system (8th edition) contains a ypTNM stage classification for patients with EC receiving neoadjuvant therapy prior to surgery. However, the ypTNM staging system may be unable to represent tumor changes occurring during the treatment. This study was to develop a prognostic model for esophageal carcinoma (EC) describing both the pretreatment pathological state of the tumor and its change after neoadjuvant chemoradiotherapy (nCRT) plus surgery. 187 patients with esophageal carcinoma treated with nCRT plus surgery were identified from two medical centers. The Primary Tumor Burden Score (PTBS) was calculated by multiplying the percentage of residual primary cancer cells and the pretreatment pathological T stage (prepT-stage). Univariate and multivariate Cox regression was used to determine the relationships between clinicopathological parameters and prognosis. The discriminatory power of the model was evaluated using the area under the curve (AUC) and goodness-of-fit Akaike information criterion (ΔAIC). The revised TNM stage was compared with the ypTNM stage using the AIC and the C-index. The PTBS model (AUC:0.727) outperformed to the residual tumor ratio (AUC:0.588) and the pretreatment T stage (AUC:0.6) in OS prediction (P The PTBS model showed superior prognostic discriminatory ability than cT-stage or ypT-satge and may thus be useful for describing the influence of the primary tumor burden on survival in patients who had received neoadjuvant CRT before surgery. A revised TNM stage based on PTBS showed superior prognostic capability to the 8th AJCC ypTNM stage.

Oxidative stress-induced damage to and dysfunction of retinal pigment epithelium (RPE) cells are important pathogenetic factors of age-related macular degeneration (AMD); however, the underlying molecular mechanism is not fully understood. Long noncoding RNAs (lncRNAs) have important roles in various biological processes. In this study, using an oxidative damage model in RPE cells, we identified a novel oxidation-related lncRNA named CYLD-AS1. We further revealed that the expression of CYLD-AS1 was increased in RPEs during oxidative stress. Depletion of CYLD-AS1 promoted cell proliferation and mitochondrial function and protected RPE cells against hydrogen peroxide (H

A long-term fertilization experiment with a system of rice-wheat rotation was conducted in Chengdu Plain. Three fertilization treatments including conventional fertilization (T1), pig manure substituting for 50% nitrogen fertilizer (T2), and T2 plus straw (T3) were set up to study the characteristics of microbial carbon source utilization of soil and dissolved organic matter (DOM). The results showed that T3 improved the soil microbial carbon source metabolism in comparison with those of the T1 and T2 treatments; the average color change rate (AWCD) increased by 16% and 48%, respectively. Meanwhile, T3 improved the soil DOM microbial carbon source metabolism, and the AWCD value was 0.43. The highest Shannon, Simpson, and McIntosh indexes of soil and DOM were all found in the T3 treatment, and the Shannon, Simpson, and McIntosh indexes of DOM were 2.73, 0.91, and 3.75, respectively. The results of principal component analysis and enrichment analysis showed that the main carbon sources used by microorganisms of soil and DOM were different under different fertilization treatments. For DOM, the main carbon source used by microorganisms in the T1 and T2 treatments was sugar, whereas T3 increased the utilization of amino acids, carboxylic acids, polymers, and amines. The changes in soil pH and texture were the main factors that caused the difference in soil DOM microbial carbon source metabolism. In conclusion, the application of organic fertilizer (pig manure plus straw) significantly increased the microbial community diversity and carbon source metabolic capacity of soil and DOM and promoted the diversification of microbial carbon source preference.

Icariin (ICA) is a small molecule drug capable of promoting cartilage repair and ameliorating inflammation. Loading ICA into a biomaterial scaffold for cartilage tissue engineering will thus potentially enhance the biological functionality of the engineered scaffold. In this study, short fibers processed from electrospun poly(l-lactide

Aiming at the common problems of the high working resistance, low soil disturbance, and high rates of missed extraction in the operation of carrot combine harvesters, a high-efficiency drag-reducing bionic soil-loosening shovel was designed in this study. The physical parameters of the soil and carrots were measured, and the bionic drag-reducing shovel was designed using the badger claw toe as a bionic prototype. The shovel wing structures were designed. Based on the EDEM discrete element simulation technology, a multi-element simulation model of the shovel–soil–carrot contact was established to determine the effects of the operating speed and sliding angle of the shovel handle on the resistance. The effects of the blade inclination angle and blade opening angle on the resistance, carrot extraction force, and soil disturbance rate were also studied. The results show that the resistance increases with an increase in operating speed. With a blade angle (α) and blade inclination angle (β) of 120.27° and 47.37°, respectively, the performance of the high-efficiency drag-reducing soil-loosening shovel is the best, with the resistance and carrot extraction force being 1908.76 N and 55.37 N, respectively. The virtual simulation experiment shows that this efficient drag-reducing shovel can effectively solve the problems of the low soil disturbance, high resistance, and high missing carrot rates of carrot combine harvester shovels, while also improving the harvesting quality and efficiency of carrot combine harvesters and meeting the agronomic requirements of carrot harvesting.

Lithium supply shortages have prompted the search for alternatives to widespread grid system applications. Potassium-ion batteries (PIBs) have emerged to promising candidates for this purpose. Nonetheless, the large radius of K+ (1.38 Å) impedes the march of satisfactory cathode materials. Here, we used solid-phase synthesis to prepare a layered K0.37MnO2·0.25H2O (KMO) cathode, comprising alternately connected MnO6 octahedra with a large interlayer spacing (0.71 nm) to accommodate the migration and transport of K+ ions. The cathode material achieved initial specific capacities of 102.3 and 88.1 mA h g−1 at current densities of 60 mA g−1 and 1 A g−1, respectively. The storage mechanism of K+ ions in PIBs was demonstrated ex situ using x-ray diffraction, x-ray photoelectron spectroscopy, and Raman spectroscopy measurements. Overall, our proposed KMO was confirmed as an auspicious cathode material for potential use in PIBs.

Primary cutaneous lymphomas are rare non-Hodgkin lymphomas consisting of heterogeneous disease entities. Photodynamic therapy (PDT) utilizing photosensitizers irradiated with a specific wavelength of light in the presence of oxygen exerts promising anti-tumor effects on non-melanoma skin cancer, yet its application in primary cutaneous lymphomas remains less recognized. Despite many in vitro data showing PDT could effectively kill lymphoma cells, clinical evidence of PDT against primary cutaneous lymphomas is limited. Recently, a phase 3 “FLASH” randomized clinical trial demonstrated the efficacy of topical hypericin PDT for early-stage cutaneous T-cell lymphoma. An update on recent advances of photodynamic therapy in primary cutaneous lymphomas is provided.

Engineering scaffolds with structurally and biochemically biomimicking cues is essential for the success of tissue-engineered cartilage. Chitosan (CS)-based scaffolds have been widely used for cartilage regeneration due to its chemostructural similarity to the glycosaminoglycans (GAGs) found in the extracellular matrix of cartilage. However, the weak mechanical properties and inadequate chondroinduction capacity of CS give rise to compromised efficacy of cartilage regeneration. In this study, we incorporated short fiber segments, processed from electrospun aligned poly(lactic-co-glycolic acid) (PLGA) fiber arrays, into a citric acid-modified chitosan (CC) hydrogel scaffold for mechanical strengthening and structural biomimicking and meanwhile introduced cartilage-decellularized matrix (CDM) for biochemical signaling to promote the chondroinduction activity. We found that the incorporation of PLGA short fibers and CDM remarkably strengthened the mechanical properties of the CC hydrogel (+349% in compressive strength and +153% in Young's modulus), which also exhibited a large pore size, appropriate porosity, and fast water absorption ability. Biologically, the engineered CDM-Fib/CC scaffold significantly promoted the adhesion and proliferation of chondrocytes and supported the formation of matured cartilage tissue with a cartilagelike structure and deposition of abundant cartilage ECM-specific GAGs and type II collagen (+42% in GAGs content and +295% in type II collagen content). The enhanced mechanical competency and chondroinduction capacity with the engineered CDM-Fib/CC scaffold eventually fulfilled successful in situ osteochondral regeneration in a rabbit model. This study thereby demonstrated a great potential of the engineered highly biomimetic chitosan-based scaffold in cartilage tissue repair and regeneration.

Uncertain time series analysis is a methodology that deals with expert’s experimental time series data. Previous studies mainly focus on linear models such as an uncertain autoregressive (UAR) mode...

The limited availability of cathode materials with high specific capacity and significant cycling stability for aqueous K-ion batteries (AKIBs) hinder their further development owing to the large radius of K

Electrospun-aligned fibers in ultrathin fineness have previously demonstrated a limited capacity in driving stem cells to differentiate into tendon-like cells. In view of the tendon's mechanoactive nature, endowing such aligned fibrous structure with mechanoactivity to exert

Apurinic endonuclease 1 (APE1) has been suggested as an oncogene of lung tumours and our bioinformatics analysis identified the association between Erlotinib resistance and interleukin-6 (IL-6). Thus, we performed this work to delineate the mechanistic actions of APE1/IL-6 signalling in Erlotinib resistance of non-small cell lung cancer (NSCLC).We selected human NSCLC cell lines HCC827 and PC9 to establish Erlotinib-resistant HCC827R and PC9R cells. Cancer stem cells (CSCs) were isolated from Erlotinib-sensitive HCC827P and PC9P cells (PCSCs) and from HCC827R and PC9R cells (RCSCs). Further, extracellular vesicles (EVs) were separated from PCSCs (PCSC-EVs) and RCSCs (RCSC-EVs) and co-cultured with RCSCs with or without short hairpin RNA (shRNA)-targeting APE1 (APE1 shRNA) transduction. In addition, functional assays were conducted to determine the effect of APE1 shRNA on malignant phenotypes of cancer cells in vitro and in vivo and the activation of IL-6/STAT3 signalling.It was found that NSCLC cells could internalize both RCSC-EVs and PCSC-EVs. RCSC-EVs augmented the resistance of NSCLC cells to Erlotinib. The overexpression of APE1 occurred in NSCLC tissues, and IL-6 was enriched in serum samples of patients with NSCLC. APE1 shRNA was demonstrated to restrict the Erlotinib resistance of NSCLC cells by inactivating the IL-6/STAT3 signalling. Additionally, shAPE1-loaded RCSC-EVs suppressed the Erlotinib resistance of NSCLC via the IL-6/STAT3 axis both in vitro and in vivo, as reflected by impeded malignant phenotypes and xenograft tumour formation.Collectively, these data indicate that APE1 confers Erlotinib resistance by activating the IL-6/STAT3 signalling, suggesting targeting APE1 as a possible therapeutic target in Erlotinib-resistant NSCLC.

The phytohormone auxin and its directional transport through tissues play a fundamental role in development of higher plants. This polar auxin transport predominantly relies on PIN-FORMED (PIN) auxin exporters. Hence, PIN polarization is crucial for development, but its evolution during the rise of morphological complexity in land plants remains unclear. Here, we performed a cross-species investigation by observing the trafficking and localization of endogenous and xenologous PINs in two bryophytes,Physcomitrium patensandMarchantia polymorpha, and in the flowering plantArabidopsis thaliana. We confirmed that the GFP fusion did not compromise the auxin export function of all examined PINs by using radioactive auxin export assay and by observing the phenotypic changes in transgenic bryophytes. Endogenous PINs polarize to filamentous apices, while xenologous Arabidopsis PINs distribute symmetrically on the membrane in both bryophytes. In Arabidopsis root epidermis, bryophytic PINs show no defined polarity. Pharmacological interference revealed a strong cytoskeleton dependence of bryophytic but not Arabidopsis PIN polarization. The divergence of PIN polarization and trafficking is also observed within the bryophyte clade and between tissues in individual species. These results collectively reveal a divergence of PIN trafficking and polarity mechanisms throughout land plant evolution and a co-evolution of PIN sequence-based and cell-based polarity mechanisms.

Cardiac angiosarcomas are highly aggressive, extremely rare malignancies with a poor prognosis. We report the case of a 39-year-old woman presenting with a right atrial angiosarcoma with perforation of the right atrium. There is almost always a diagnostic lag for cardiac angiosarcoma, leading to a poor prognosis. Cardiovascular sarcoma is one of the most invasive malignant tumors. Radical resection surgery as the core of comprehensive treatment presently is the best treatment plan.

Osteoarthritis (OA) is the most prevalent type of degenerative joint disease, and its pathological progression is highly associated with oxidative stress. Natural antioxidants can attenuate oxidative stress and chondrocyte injury, suggesting that antioxidants have potential applications in the management of OA. Ellagic acid (EA), a natural polyphenol derived from fruits or nuts, exerts antioxidant and anti-inflammatory effects in diseases related to oxidative stress. Herein, we investigated the effects of EA on interleukin-1β (IL-1β)-induced oxidative stress and degeneration in C28/I2 human chondrocytes. EA efficiently suppressed IL-1β-induced oxidative stress and ameliorated oxidative stress-induced dysfunction of chondrocytes, as indicated by the promotion of cartilage matrix secretion. Moreover, EA remarkably suppressed cell apoptosis and senescence, and reduced the expression of proinflammatory factors and metalloproteinases, suggesting that EA could alleviate chondrocyte injury under oxidative stress. Mechanistically, EA upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) as well as its downstream targets NADPH quinone oxidoreductase 1 and heme oxygenase-1. ML385, a specific Keap1/Nrf2 pathway inhibitor, blocked the antioxidant and chondroprotective effects of EA. Our findings demonstrated that EA could attenuate oxidative stress and exert protective effects on chondrocytes by upregulating the Keap1/Nrf2 signaling pathway.

Background The adverse reactions (ADRs) of targeted therapy were closely associated with treatment response, clinical outcome, quality of life (QoL) of patients with cancer. However, few studies presented the correlation between ADRs of targeted therapy and treatment effects among cancer patients. This study was to explore the characteristics of ADRs with targeted therapy and the prognosis of cancer patients based on the clinical data. Methods A retrospective secondary data analysis was conducted within an ADR data set including 2703 patients with targeted therapy from three Henan medical centers of China between January 2018 and December 2019. The significance was evaluated with chi-square test between groups with or without ADRs. Univariate and multivariate logistic regression with backward stepwise method were applied to assess the difference of pathological characteristics in patients with cancer. Using the univariate Cox regression method, the actuarial probability of overall survival was performed to compare the clinical outcomes between these two groups. Results A total of 485 patients were enrolled in this study. Of all patients, 61.0% (n = 296) occurred ADRs including skin damage, fatigue, mucosal damage, hypertension and gastrointestinal discomfort as the top 5 complications during the target therapy. And 62.1% of ADRs were mild to moderate, more than half of the ADRs occurred within one month, 68.6% ADRs lasted more than one month. Older patients (P = 0.022) and patients with lower education level (P = 0.036), more than 2 comorbidities (P = 0.021), longer medication time (P = 0.022), drug combination (P = 0.033) and intravenous administration (P = 0.019) were more likely to have ADRs. Those with ADRs were more likely to stop taking (P = 0.000), change (P = 0.000), adjust (P = 0.000), or not take the medicine on time (P = 0.000). The number of patients with recurrence (P = 0.000) and metastasis (P = 0.006) were statistically significant difference between ADRs and non-ADRs group. And the patients were significantly poor prognosis in ADRs groups compared with non-ADRs group. Conclusion The high incidence of ADRs would affect the treatment and prognosis of patients with cancer. We should pay more attention to these ADRs and develop effective management strategies.

Within a short period of time, COVID-19 grew into a world-wide pandemic. Transmission by pre-symptomatic and asymptomatic viral carriers rendered intervention and containment of the disease extremely challenging. Based on reported infection case studies, we construct an epidemiological model that focuses on transmission around the symptom onset. The model is calibrated against incubation period and pairwise transmission statistics during the initial outbreaks of the pandemic outside Wuhan with minimal non-pharmaceutical interventions. Mathematical treatment of the model yields explicit expressions for the size of latent and pre-symptomatic subpopulations during the exponential growth phase, with the local epidemic growth rate as input. We then explore reduction of the basic reproduction number R0 through specific transmission control measures such as contact tracing, testing, social distancing, wearing masks and sheltering in place. When these measures are implemented in combination, their effects on R0 multiply. We also compare our model behaviour to the first wave of the COVID-19 spreading in various affected regions and highlight generic and less generic features of the pandemic development., Transmission by pre-symptomatic and asymptomatic viral carriers makes intervention and containment of the COVID-19 extremely challenging. Here, the authors construct an epidemiological model that focuses on transmission around the symptom onset, exploring specific transmission control measures.

Coronary heart disease (CHD) is closely related to hypercholesterolemia, and lowering serum cholesterol is currently the most important strategy in reducing CHD. In humans, the serum cholesterol level is determined mainly by three metabolic pathways, namely, dietary cholesterol intake, cholesterol synthesis, and cholesterol degradation in vivo. An intervention that targets the key molecules in the three pathways is an important strategy in lowering serum lipids. Statins inhibit 3-hydroxyl-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) to reduce low-density lipoprotein (LDL) by about 20% to 45%. However, up to 15% of patients cannot tolerate the potential side effects of high statin dosages, and several patients also still do not reach their optimal LDL goals after being treated with statins. Ezetimibe inhibits cholesterol absorption by targeting the Niemann–Pick C1-like 1 protein (NPC1L1), which is related to cholesterol absorption in the intestines. Ezetimibe lowers LDL by about 18% when used alone and by an additional 25% when combined with statin therapy. The proprotein convertase subtilisin/kexin type 9 (PCSK9) increases hepatic LDLR degradation, thereby reducing the liver’s ability to remove LDL, which can lead to hypercholesterolemia. Evolocumab, which is a PCSK9 monoclonal antibody, can reduce LDL from baseline by 53% to 56%. The three drugs exert lipid-lowering effects by regulating the three key pathways in lipid metabolism. Combining any with the two other drugs on the basis of statin treatment has improved the lipid-lowering effect. Whether the combination of the three musketeers will reduce the side effects of monotherapy and achieve the lipid-lowering effect should be studied further in the future.

Two new quassinoids (1 and 2) were isolated from the twigs of Harrisonia perforata (Blanco) Merr. Perforalactone E (2) possesses an uncommon hexacyclic 1α,12α:5α,13α-dicyclo-9βH-picrasane skeleton. Its structure was determined based on spectroscopic data and X-ray crystallography. Compounds 1 and 2 could significantly induce lysosomal biogenesis through transcriptional activation of lysosomal genes.

Poly(l-lactide) (PLLA) as one of the most well-known biodegradable polyesters has been studied extensively for bone tissue engineering. If being properly programmed, scaffolds from PLLA can also be...

Extrusible biomaterials have recently attracted increasing attention due to the desirable injectability and printability to allow minimally invasive administration and precise construction of tissue mimics. Specifically, self-healing colloidal gels are a novel class of candidate materials as injectables or printable inks considering their fascinating viscoelastic behavior and high degree of freedom on tailoring their compositional and mechanical properties. Herein, we developed a novel class of adaptable and osteogenic composite colloidal gels via electrostatic assembly of gelatin nanoparticles and nanoclay particles. These composite gels exhibited excellent injectability and printability, and remarkable mechanical properties reflected by the maximal elastic modulus reaching ∼150 kPa combined with high self-healing efficiency, outperforming most previously reported self-healing hydrogels. Moreover, the cytocompatibility and the osteogenic capacity of the colloidal gels were demonstrated by inductive culture of MC3T3 cells seeded on the three-dimensional (3D)-printed colloidal scaffolds. Besides, the biocompatibility and biodegradability of the colloidal gels was proved in vivo by subcutaneous implantation of the 3D-printed scaffolds. Furthermore, we investigated the therapeutic capacity of the colloidal gels, either in form of injectable gels or 3D-printed bone substitutes, using rat sinus bone augmentation model or critical-sized cranial defect model. The results confirmed that the composite gels were able to adapt to the local complexity including irregular or customized defect shapes and continuous on-site mechanical stimuli, but also to realize osteointegrity with the surrounding bone tissues and eventually be replaced by newly formed bones.

Side effects from chemotherapy may disturb healthy eating. There are many food taboos among Chinese patients with cancer treated with chemotherapy; they may be conservative in food intake and seek help from traditional Chinese medicine to adjust to healthy eating. Differences in eating cultures may lead Chinese patients with cancer to generate different knowledge, attitudes, and behaviors toward healthy eating. This systematic review explored the knowledge, attitudes, and behaviors toward healthy eating and summarized influencing factors among Chinese patients with cancer treated with chemotherapy. Two English and three Chinese databases were searched since 2007. The eligibility criteria were quantitative descriptive studies, participants who were adult Chinese patients with cancer who received chemotherapy, and primary outcomes that included knowledge, attitudes, or behaviors toward healthy eating. A total of 12 studies were identified. The 11-item tool from the Agency for Healthcare Research and Quality was used to assess quality. All studies were of moderate quality. Narrative qualitative analysis was considered to summarize the findings, and the results were reported by scores or percentages. Four studies measured knowledge, and the information about what to eat and how much to eat was contradictory and confused patients, with little known about Chinese food therapy. Ten studies involved attitudes, and patients were aware of the importance and willingness for eating guidance before, during, and after chemotherapy. Strategies to relieve vomiting and nausea, engage in healthy food choices, and seek food therapy were the main behaviors. The influencing factors were found only in behaviors, including demographic and psychological factors. Knowledge, attitudes, and behaviors toward healthy eating are not satisfactory and need to be improved. More high-quality studies should regard health behavior as a distal outcome and explore the influences of knowledge and attitudes on behaviors.

Atherosclerosis is a chronic inflammatory vascular disease. Atherosclerotic cardiovascular disease is the main cause of death in both developed and developing countries. Many pathophysiological factors, including abnormal cholesterol metabolism, vascular inflammatory response, endothelial dysfunction and vascular smooth muscle cell proliferation and apoptosis, contribute to the development of atherosclerosis and the molecular mechanisms underlying the development of atherosclerosis are not fully understood. Ubiquitination is a multistep post-translational protein modification that participates in many important cellular processes. Emerging evidence suggests that ubiquitination plays important roles in the pathogenesis of atherosclerosis in many ways, including regulation of vascular inflammation, endothelial cell and vascular smooth muscle cell function, lipid metabolism and atherosclerotic plaque stability. This review summarizes important contributions of various E3 ligases to the development of atherosclerosis. Targeting ubiquitin E3 ligases may provide a novel strategy for the prevention of the progression of atherosclerosis.

BACKGROUND The number of dissected lymph nodes (LNs) in rectal cancer after neoadjuvant therapy has a controversial effect on the prognosis. AIM To investigate the prognostic impact of the number of LN dissected in rectal cancer patients after neoadjuvant therapy. METHODS We performed a systematic review and searched PubMed, Embase (Ovid), MEDLINE (Ovid), Web of Science, and Cochrane Library from January 1, 2000 until January 1, 2020. Two reviewers examined all the publications independently and extracted the relevant data. Articles were eligible for inclusion if they compared the number of LNs in rectal cancer specimens resected after neoadjuvant treatment (LNs ≥ 12 vs LNs < 12). The primary endpoints were the overall survival (OS) and disease-free survival (DFS). RESULTS Nine articles were included in the meta-analyses. Statistical analysis revealed a statistically significant difference in OS [hazard ratio (HR) = 0.76, 95% confidence interval (CI): 0.66-0.88, I2 = 12.2%, P = 0.336], DFS (HR = 0.76, 95%CI: 0.63-0.92, I2 = 68.4%, P = 0.013), and distant recurrence (DR) (HR = 0.63, 95%CI: 0.48-0.93, I2 = 30.5%, P = 0.237) between the LNs ≥ 12 and LNs < 12 groups, but local recurrence (HR = 0.67, 95%CI: 0.38-1.16, I2 = 0%, P = 0.348) showed no statistical difference. Moreover, subgroup analysis of LN negative patients revealed a statistically significant difference in DFS (HR = 0.67, 95%CI: 0.52-0.88, I2 = 0%, P = 0.565) between the LNs ≥ 12 and LNs < 12 groups. CONCLUSION Although neoadjuvant therapy reduces LN production in rectal cancer, our data indicate that dissecting at least 12 LNs after neoadjuvant therapy may improve the patients’ OS, DFS, and DR.

Harpertrioate A (1), an A,B,D-seco-limonoid with a rearranged ring B incorporating exocyclic C-30, was isolated from the EtOAc extract of Harrisonia perforata twigs. Its structure, including absolute configurations, was determined on the basis of spectroscopic data and X-ray crystallography. This compound exhibited biological activities against Alzheimer's disease by reducing Aβ42 and Aβ40 production and shifting APP processing toward nonamyloidogenic pathway. The effect of 1 on the Aβ production was comparable to that of gemfibrozil.

Retinoblastoma (RB) is a common intraocular malignancy in children. Due to the poor prognosis of RB, it is crucial to search for efficient diagnostic and therapeutic strategies. Studies have shown that methyltransferase-like 3 (METTL3), a major RNA N (6)-adenosine methyltransferase, is closely related to the initiation and development of cancers. Nevertheless, whether METTL3 is associated with RB remains unexplored. Therefore, we investigated the function and mechanisms of METTL3 in the regulation of RB progression. We manipulated METTL3 expression in RB cells. Then, cell proliferation, apoptosis, migration and invasion were analysed. We also analysed the expression of PI3K/AKT/mTOR pathway members. Finally, we incorporated subcutaneous xenograft mouse models into our studies. The results showed that METTL3 is highly expressed in RB patients and RB cells. We found that METTL3 knockdown decreases cell proliferation, migration and invasion of RB cells, while METTL3 overexpression promotes RB progression in vitro and in vivo. Moreover, two downstream members of the PI3K/AKT/mTOR pathway, P70S6K and 4EBP1, were affected by METTL3. Our study revealed that METTL3 promotes the progression of RB through PI3K/AKT/mTOR pathways in vitro and in vivo. Targeting the METTL3/PI3K/AKT/mTOR signalling axis could be a promising therapeutic strategy for the treatment of RB.