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Abstract Background Heart failure (HF) significantly impacts quality of life and healthcare systems worldwide. Assessing left ventricular mechanical dyssynchrony (LVMD) is crucial for understanding cardiac function and optimizing treatments like cardiac resynchronization therapy (CRT). Phase analysis using gated single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) has shown promise in predicting outcomes, yet recent comprehensive reviews are lacking. Objective To systematically assess the prognostic value of phase analysis by gated SPECT MPI in the HF population through a systematic review. Methods We conducted a systematic review by collecting studies from databases including PubMed, CINAHL, and Web of Science. Two reviewers independently performed study selection, data extraction, and risk of bias assessment. Systematic reviews were conducted using Review Manager Software 5.4 and STATA 16.0. Results A total of 2004 patients from seven studies were included in our review and analysis. The systematic review indicated that patients with predetermined clinical events had higher PSD [MD = 6.45, 95% CI (5.83, 7.07), p

Abstract Insulin-like growth factor-binding protein 5 (IGFBP5) has been shown to be useful for the diagnosis and treatment of multiple tumors and cerebrovascular diseases. However, it is unknown whether IGFBP5 is involved in myocardial repair following myocardial infarction (MI). Here we show high expression of IGFBP5 in multiple models of ischemic and hypoxic injury. IGFBP5 affected the proliferation of neonatal rat cardiomyocytes (NRCMs) and the cardiomyocyte apoptosis induced by oxygen-glucose deprivation (OGD). Subsequently, heart-specific IGFBP5 knockdown inhibited myocardial apoptosis and increased cardiomyocyte proliferation in mice with MI. During the chronic remodeling stage, heart-specific regulation of IGFBP5 ameliorated pathological cardiac remodeling and dysfunction. Mechanistically, IGFBP5 regulated cardiomyocyte survival through the insulin-like growth factor 1 (IGF1) receptor (IGF1R)/protein kinase B (PKB/AKT) pathway. In summary, our results provide mechanistic insights into the effect of IGFBP5 on cardiomyocyte during cardiac repair. IGFBP5 may represent a therapeutic target for myocardial ischemic injury.

Abstract Hutchinson–Gilfor progeria syndrome (HGPS) is caused by a mutation in Lamin A resulting in the production of a protein called progerin. The accumulation of progerin induces inflammation, cellular senescence and activation of the P53 pathway. In this study, through public dataset analysis, we identified Syntaxin Binding Protein 5 (STXBP5) as an influencing factor of progerin expression. STXBP5 overexpression accelerated the onset of senescence, while STXBP5 deletion suppressed progerin expression, delayed senility, and decreased the expression of senescence-related factors. STXBP5 and progerin have synergistic effects and a protein-protein interaction. Through bioinformatics analysis, we found that STXBP5 affects ageing-related signalling pathways such as the mitogen-activated protein kinase (MAPK) pathway, the hippo pathway and the interleukin 17 (IL17) signalling pathway in progerin-expressing cells. In addition, STXBP5 overexpression induced changes in transposable elements (TEs), such as the human endogenous retrovirus H internal coding sequence (HERVH-int) changes. Our protein coimmunoprecipitation (Co-IP) results indicated that STXBP5 bound directly to progerin. Therefore, decreasing STXBP5 expression is a potential new therapeutic strategy for treating ageing-related phenotypes in patients with HGPS.

Abstract In this study, we analyzed pooled data from two prospective population-based cohorts—the Health Retirement Study (HRS) and the English Longitudinal Study of Ageing (ELSA)—to explore the association between trajectories of depressive symptoms and the risk of cardiac events. Depressive symptoms were assessed using the 8-item CES-D scale and categorized into somatic and cognitive-affective subtypes. Trajectories were tracked for four surveys from baseline. Heart disease was identified based on self-reported physician-diagnosed conditions. Hazard ratios and 95% confidence intervals were calculated with Cox proportional risk models that adjusted for potential confounders. In total, 17,787 subjects (59.7% female, median age 63 years) were enrolled at baseline. During a 10-year follow-up, 2409 cases of heart disease were identified. Participants with fluctuating (HR = 1.13, 95% CI: 1.06–1.20), increasing (HR = 1.43, 95% CI: 1.25–1.64), and consistently high (HR = 1.64, 95% CI: 1.45–1.84) depressive symptom trajectories exhibited an increased risk of heart disease compared to those with consistently low depressive symptoms, while a decreasing (HR = 1.07, 95% CI: 0.96–1.19) depressive symptom trajectory did not significantly affect the risk of heart disease. Moreover, the association between heart disease and somatic depressive symptoms was found to be stronger than with cognitive-affective symptoms. These findings suggest a significant link between depressive symptom trajectories and heart disease, with particular emphasis on stronger associations with somatic symptoms. It is recommended that the identification and management of depressive symptoms be incorporated into heart disease prevention strategies.

Streptomycetes are well-known antibiotic producers possessing in their genomes numerous silent biosynthetic pathways that might direct the biosynthesis of novel bio-active specialized metabolites. It is thus of great interest to find ways to enhance the expression of these pathways to discover most needed novel antibiotics. In this study, we demonstrated that the over-expression of acetyltransferase SCO0988 up-regulated the production of specialized metabolites and accelerated sporulation of the weak antibiotic producer, Streptomyces lividans and that the deletion of this gene had opposite effects in the strong antibiotic producer, Streptomyces coelicolor. The comparative analysis of the acetylome of a S. lividans strain over-expressing sco0988 with that of the original strain revealed that SCO0988 acetylates a broad range of proteins of various pathways including BldKB/SCO5113, the extracellular solute-binding protein of an ABC-transporter involved in the up-take of a signal oligopeptide of the quorum sensing pathway. The up-take of this oligopeptide triggers the “bald cascade” that regulates positively specialized metabolism, aerial mycelium formation and sporulation in S. coelicolor. Interestingly, BldKB/SCO5113 was over-acetylated on four Lysine residues, including Lys425, upon SCO0988 over-expression. The bald phenotype of a bldKB mutant could be complemented by native bldKB but not by variant of bldKB in which the Lys425 was replaced by arginine, an amino acid that could not be acetylated or by glutamine, an amino acid that is expected to mimic acetylated lysine. Our study demonstrated that Lys425 was a critical residue for BldKB function but was inconclusive concerning the impact of acetylation of Lys425 on BldKB function.

BackgroundThe cGAS-STING axis-mediated type I interferon pathway is a crucial strategy for host defense against DNA virus infection. Numerous evasion strategies developed by the pseudorabies virus (PRV) counteract host antiviral immunity. To what extent PRV-encoded proteins evade the cGAS-STING signaling pathway is unknown.MethodsUsing US2 stably expressing cell lines and US2-deficient PRV model, we revealed that the PRV tegument protein US2 reduces STING protein stability and downregulates STING-mediated antiviral signaling.ResultsTo promote K48-linked ubiquitination and STING degradation, US2 interacts with the LBD structural domain of STING and recruits the E3 ligase TRIM21. TRIM21 deficiency consistently strengthens the host antiviral immune response brought on by PRV infection. Additionally, US2-deficient PRV is less harmful in mice.ConclusionsOur study implies that PRV US2 inhibits IFN signaling by a new mechanism that selectively targets STING while successfully evading the host antiviral response. As a result, the present study reveals a novel strategy by which PRV evades host defense and offers explanations for why the Bartha-K61 classical vaccine strain failed to offer effective defense against PRV variant strains in China, indicating that US2 may be a key target for developing gene-deficient PRV vaccines.

Abstract Embryonic stem cells (ESCs) exhibit unique attributes of boundless self-renewal and pluripotency, making them invaluable for fundamental investigations and clinical endeavors. Previous examinations of microgravity effects on ESC self-renewal and differentiation have predominantly maintained a descriptive nature, constrained by limited experimental opportunities and techniques. In this investigation, we present compelling evidence derived from murine and human ESCs, demonstrating that simulated microgravity (SMG)-induced stress significantly impacts self-renewal and pluripotency through a previously unidentified conserved mechanism. Specifically, SMG induces the upregulation of heat shock protein genes, subsequently enhancing the expression of core pluripotency factors and activating the Wnt and/or LIF/STAT3 signaling pathways, thereby fostering ESC self-renewal. Notably, heightened Wnt pathway activity, facilitated by Tbx3 upregulation, prompts mesoendodermal differentiation in both murine and human ESCs under SMG conditions. Recognizing potential disparities between terrestrial SMG simulations and authentic microgravity, forthcoming space flight experiments are imperative to validate the impact of reduced gravity on ESC self-renewal and differentiation mechanisms.

IntroductionPsycholinguistic studies have argued for the age of acquisition (AoA) of words as a marker of concept learning, showing that the semantic features of concepts themselves influence the age at which their labels are learned. However, empirical evidence suggests that semantic features such as imageability and linguistic phenomena such as frequency do not adequately predict AoA. The present study takes the developmental approach of embodied cognition and investigates the effects of sensorimotor experiences on the ease of acquisition of the concept acquired in bilinguals. Specifically, we investigated (1) whether the sensorimotor experience can explain AoA beyond frequency; (2) and whether these patterns are consistent across L1 Chinese and L2 English.MethodsWe conducted sensorimotor rating measures in both Chinese and English on 207 items in which Chinese-English bilingual adults were requested to evaluate the extent to which they experienced concepts by employing six perceptual senses and five effectors for actions located in various regions of the body. Meanwhile, data on AoA and frequency were collected.ResultsThe present study showed the sensorimotor experience was closely linked with AoAs in both languages. However, the correlation analysis revealed a trend of higher correlations between AoAs for the same concepts and L1 Chinese, relative to L2 English for the present Chinese-English bilinguals. Importantly, the hierarchical regression analysis demonstrated that after controlling for frequency, sensorimotor experience explained additional variance in L1 AoA. However, L2 sensorimotor experience did not explain the variance in L2 AoA. Sensorimotor experience explained more share of variance in L1 AoA but frequency accounted for more variance in L2 AoA.DiscussionThe findings suggest that concept acquisition should consider the grounding in appropriate sensorimotor experience beyond linguistic phenomena like frequency.

The induction of ferroptosis is promising for cancer therapy. However, the mechanisms enabling cancer cells to evade ferroptosis, particularly in low-cystine environments, remain elusive. Our study delves into the intricate regulatory mechanisms of Activating transcription factor 3 (ATF3) on Cystathionine β-synthase (CBS) under cystine deprivation stress, conferring resistance to ferroptosis in colorectal cancer (CRC) cells. Additionally, our findings establish a positively correlation between this signaling axis and CRC progression, suggesting its potential as a therapeutic target. Mechanistically, ATF3 positively regulates CBS to resist ferroptosis under cystine deprivation stress. In contrast, the suppression of CBS sensitizes CRC cells to ferroptosis through targeting the mitochondrial tricarboxylic acid (TCA) cycle. Notably, our study highlights that the ATF3-CBS signaling axis enhances ferroptosis-based CRC cancer therapy. Collectively, the findings reveal that the ATF3-CBS signaling axis is the primary feedback pathway in ferroptosis, and blocking this axis could be a potential therapeutic approach for colorectal cancer.

Abstract Background A data mining algorithm is proposed based on BERTopic to provide new insights into the analysis of medication rules in Traditional Chinese Medicine (TCM) prescriptions. Methods Using the BERTopic algorithm, collected TCM prescriptions for corneal diseases are converted to embeddings through a transformer based on the Bidirectional Encoder Representations from Transformers pre‐trained model. Then, Uniform Manifold Approximation and Projection is applied to perform dimensionality reduction in prescription embeddings. Subsequently, Hierarchical Density‐Based Spatial Clustering of Applications with Noise is used for clustering. Finally, class‐based term frequency–inverse document frequency is used to generate several main drug combinations from the clustered results. Results The highest frequency of drugs used included Buddleja officinalis, Bidens pilosa, Angelica sinensis, Eriocaulon buergerianum, and Raw Rehmannia glutinosa. The most frequent drug combinations were “Eriocaulon buergerianum, Raw Rehmannia glutinosa, Prunella vulgaris, Notopterygium incisum” “Lycii Fructus, Bidens pilosa, Buddleja officinalis” and “Kochiae Fructus, Cortex Dictamni.” Conclusions The proposed data mining algorithm based on BERTopic demonstrated promising outcomes in the analysis of TCM prescription medication rules. This method exhibited simplicity and efficiency, thereby offering a novel avenue for analysis.

Abstract Background Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related deaths worldwide, primarily due to its propensity for metastasis. Patients diagnosed with localized primary cancer have higher survival rates than those with metastasis. Thus, it is imperative to discover biomarkers for the early detection of NSCLC and the timely prediction of tumor metastasis to improve patient outcomes. Methods Here, we utilized an integrated approach to isolate and characterize plasma exosomes from NSCLC patients as well as healthy individuals. We then conducted proteomics analysis and parallel reaction monitoring to identify and validate the top-ranked proteins of plasma exosomes. Results Our study revealed that the proteome in exosomes from NSCLC patients with metastasis was distinctly different from that from healthy individuals. The former had larger diameters and lower concentrations of exosomes than the latter. Furthermore, among the 1220 identified exosomal proteins, we identified two distinct panels of biomarkers. The first panel of biomarkers (FGB, FGG, and VWF) showed potential for early NSCLC diagnosis and demonstrated a direct correlation with the survival duration of NSCLC patients. The second panel of biomarkers (CFHR5, C9, and MBL2) emerged as potential biomarkers for assessing NSCLC metastasis, of which CFHR5 alone was significantly associated with the overall survival of NSCLC patients. Conclusions These findings underscore the potential of plasma exosomal biomarkers for early NSCLC diagnosis and metastasis prediction. Notably, CFHR5 stands out as a promising prognostic indicator for NSCLC patients. The clinical utility of exosomal biomarkers offers the potential to enhance the management of NSCLC.

Abstract Background To summarize the efficacy of combined robot-assisted laparoscopy and ureteroscopy in treating complex ureteral strictures. Methods Eleven patients underwent combined robot-assisted laparoscopy and ureteroscopy for ureteral strictures between January 2020 and August 2022. Preoperative B-ultrasound, glomerular filtration rate measurement, and intravenous pyelography showed different degrees of hydronephrosis in the affected kidney and moderate to severe stenosis in the corresponding part of the ureter. During the operation, stricture segment resection and end-to-end anastomosis were performed using the da Vinci robot to find the stricture point under the guidance of a ureteroscopic light source in the lateral or supine lithotomy position. Results All the patients underwent robot-assisted laparoscopy and ureteroscopy combined with end-to-end ureterostenosis. There were no conversions to open surgery or intraoperative complications. Significant ureteral stricture segments were found in all patients intraoperatively; however, stricture length was not significantly different from the imaging findings. Patients were followed up for 3–27 months. Two months postoperatively, the double-J stent was removed, a ureteroscopy was performed, the ureteral mucosa at the end-to-end anastomosis grew well, and the lumen was patent in all patients. Furthermore, imaging examination showed that hydronephrosis was significantly improved in all patients, with grade I hydronephrosis in three cases and grade 0 hydronephrosis in eight cases. No recurrence of ureteral stricture was observed in patients followed up for > 1 year. Conclusion Robot-assisted laparoscopy combined with ureteroscopy is an effective method for treating complex ureteral strictures and can achieve accurate localization of the structured segment.

Abstract Background The influence of sarcopenic obesity (SO) on overall survival in older adults with hypertension has not been addressed. The aim of this study was to investigate the prevalence and mortality predictive value of various body composition phenotypes, focusing mainly on SO, in older adults with hypertension. Methods We included 1105 hypertensive patients aged ≥ 60 years from the National Health and Nutrition Examination Survey 1999–2004. Sarcopenia was broadly defined based on low lean mass (LLM; as measured by dual-energy X-ray absorptiometry), and was defined using appendicular lean mass (ALM) divided by height squared (ALM/height2), weight (ALM/weight), and body mass index (BMI; ALM/BMI), respectively. Obesity was defined as BMI ≥ 30 kg/m2, body fat percentage ≥ 30/42%, or waist circumference ≥ 102/88 cm. The prevalence of LLM with obesity was estimated according to each ALM index (ALMI). Multivariable Cox regression analysis and sensitivity analysis were used to examine the association between various body composition phenotypes and all-cause mortality. Results In older adults with hypertension, the prevalence of LLM with obesity by the ALM/height2 index (9.8%) was lower relative to the ALM/weight (11.7%) and ALM/BMI indexes (19.6%). After a median follow-up of 15.4 years, 642 deaths occurred. In the fully adjusted models, LLM with obesity was significantly associated with a higher risk of all-cause mortality (hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.14–2.49, P = 0.008; HR 1.48, 95% CI 1.04–2.10, P = 0.028; HR 1.30, 95% CI 1.02–1.66, P = 0.037; respectively) compared with the normal body phenotype, with no statistical differences found in individuals with LLM or obesity alone. Sensitivity analysis confirmed the robustness of the results. Conclusions The prevalence of LLM with obesity markedly differed in older adults with hypertension according to the 3 different ALMIs, varying from 9.8%, 11.7%, to 19.6%. Patients with both LLM and obesity had a higher risk of all-cause mortality. Further large, prospective, cohort studies are warranted to validate these findings and uncover underlying mechanisms.

The use of Generally Recognized as Safe (GRAS)-grade microbial cell factories to produce recombinant protein-based nutritional products is a promising trend in developing food and health supplements. In this study, GRAS-grade Kluyveromyces marxianus was employed to express recombinant human heavy-chain ferritin (rhFTH), achieving a yield of 11 g/L in a 5 L fermenter, marking the highest yield reported for ferritin nanoparticle proteins to our knowledge. The rhFTH formed 12 nm spherical nanocages capable of ferroxidase activity, which involves converting Fe2+ to Fe3+ for storage. The rhFTH-containing yeast cell lysates promoted cytokine secretion (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and -1β (IL-1β)) and enhanced locomotion, pharyngeal pumping frequency, egg-laying capacity, and lifespan under heat and oxidative stress in the RAW264.7 mouse cell line and the C. elegans model, respectively, whereas yeast cell lysate alone had no such effects. These findings suggest that rhFTH boosts immunity, holding promise for developing ferritin-based food and nutritional products and suggesting its adjuvant potential for clinical applications of ferritin-based nanomedicine. The high-yield production of ferritin nanoparticles in K. marxianus offers a valuable source of ferritin for the development of ferritin-based products.

In the electricity spot market (ESM), thermal power plants (TPP) are quoted based on fuel costs and carbon costs, which impose carbon costs from the generation side to the load-side. The cost of load-side participation in the ESM will increase further. In addition, the traditional ESM centralized bidding model is based on the marginal clearing price, without considering the line transmission constraints, which may affect the security of the power system. To solve this challenge, firstly, an ESM centralized bidding clearing model including the generation side and the load-side is established based on the transaction mechanism of centralized bidding in the ESM. In this model, the marginal clearing prices of two possible bidding scenarios in the ESM are considered. Secondly, the marginal clearing price of the ESM is designed based on the security constraint of the power flow, which can avoid power transmission exceeding its capacity. Finally, a carbon emission cost settlement mechanism is proposed based on the carbon emission flow (CEF) method, which can reduce the carbon emission cost paid by the load-side. The effectiveness of the method is verified by simulations. Compared with a traditional load-side settlement model, the settlement cost on the load-side is reduced by 30.45 %.

Abstract The outbreak of coronavirus disease 2019 (COVID-19) posed an unprecedented challenge on public health systems. Despite the measures put in place to contain it, COVID-19 is likely to continue experiencing sporadic outbreaks for some time, and individuals will remain susceptible to recurrent infections. Chimeric antigen receptor (CAR)-T recipients are characterized by durable B-cell aplasia, hypogammaglobulinemia and loss of T-cell diversity, which lead to an increased proportion of severe/critical cases and a high mortality rate after COVID-19 infection. Thus, treatment decisions have become much more complex and require greater caution when considering CAR T-cell immunotherapy. Hence, we reviewed the current understanding of COVID-19 and reported clinical experience in the management of COVID-19 and CAR-T therapy. After a panel discussion, we proposed a rational procedure pertaining to CAR-T recipients with the aim of maximizing the benefit of CAR-T therapy in the post COVID-19 pandemic era.

Abstract Background The triglyceride glucose (TyG) index, an indicator of insulin resistance, is often associated with adverse outcomes in various cardiovascular diseases, while hypertension is associated with an increased risk of cardiovascular diseases. As the loss of muscle mass in people with hypertension is poorly understood, the current study aimed to explore the relationship between TyG index and muscle mass in hypertensive population. Methods We analyzed data from hypertensive adult participants in the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2018. The TyG index and body mass index (BMI)-adjusted skeletal muscle mass index (SMI) were calculated and the relationship between the two was evaluated using multivariable linear regression and restricted cubic spline (RCS) regression models. Results A total of 1633 participants in the dataset were included for the final analysis. In the multivariable regression analysis, the adjusted β of SMI with a 95% confidence interval (CI) for the highest TyG index quartile was − 5.27 (− 9.79 to − 0.75), compared with the lowest quartile. A negative linear relationship between TyG index and SMI was plotted by RCS regression (nonlinear P = 0.128). Stratified models of non-smoking women of different ages also demonstrated that SMI decreased as TyG index increased (all P for trend

The development of the Guangdong-Hong Kong-Macao Greater Bay Area (GBA), one of the most developed and densely populated regions in China, has posed an increasing threat to the health of the water environment in adjacent coastal oceans. However, the spatiotemporal variations of water clarity in the coastal oceans of the GBA (COGBA) have not been well-documented. Therefore, this study aims to develop a remote sensing retrieval algorithm for assessing water clarity, represented by Secchi disk depth (ZSD), based on Landsat-8 OLI imagery for the COGBA using a machine learning method. Cross-validation demonstrated that the algorithm performed exceptionally well, with an R2 value greater than 0.8. By applying the algorithm to 263 Landsat-8 OLI images, we obtained a time series of ZSD for the period of 2013–2021 over the COGBA. Results indicate that the Pearl River Estuary (PRE) exhibited the highest turbidity, followed by the Daya Bay and the Mirs Bay. Generally, ZSD increased from the northwest to the southeast of the COGBA. Seasonal, interannual, and long-term variations in ZSD were also observed with long-term increases in the PRE and the Daya Bay. The interannual variations in ZSD during fall were primarily regulated by different factors in each region. In the PRE, the negative effects of sediment discharge and wind speed played a significant role. In Mirs Bay, wind speed and sediment discharge had a negative impact on ZSD. In Daya Bay, precipitation and wind speed were the key factors influencing ZSD. The development and findings of our algorithm contribute to the protection and management of the water environment in the COGBA, facilitating effective governance measures.

Soy leghemoglobin, when bound to heme, imparts a meat-like color and flavor and can serve as a substitute for animal-derived proteins. Enhancing cellular heme synthesis improves the recombinant expression of leghemoglobin in yeast. To achieve high-level expression of leghemoglobin A (LBA) in Kluyveromyces marxianus, a food-safe yeast, large-scale heme synthesis modules were transferred into K. marxianus using yeast artificial chromosomes (KmYACs). These modules contained up to 8 native and heterologous genes to promote the supply of heme precursors and downstream synthesis. Next, eight genes inhibiting heme or LBA synthesis were individually or combinatorially deleted, with the lsc1Δssn3Δ mutant yielding the best results. Subsequently, heme synthesis modules were combined with the lsc1Δssn3Δ mutant. In the resulting strains, the module genes were all actively expressed. Among these module genes, heterologous S. cerevisiae genes in the downstream heme synthesis pathway significantly enhanced the expression of their counterparts in K. marxianus, resulting in high heme content and LBA yield. After optimizing the medium recipe by adjusting the concentrations of glucose, glycine, and FeSO4·7H2O, a heme content of 66.32 mg/L and an intracellular LBA titer of 7.27 g/L were achieved in the engineered strain in a 5 L fermentor. This represents the highest intracellular expression of leghemoglobin in microorganisms to date. The leghemoglobin produced by K. marxianus can be utilized as a safe ingredient for plant-based protein products.

The outbreak of the novel coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused great harm to all countries worldwide. This disease can be prevented by vaccination and managed using various treatment methods, including injections, oral medications, or aerosol therapies. However, the selection of suitable compounds for the research and development of anti-SARS-CoV-2 drugs is a daunting task because of the vast databases of available compounds. The traditional process of drug research and development is time-consuming, labour-intensive, and costly. The application of chemometrics can significantly expedite drug R&D. This is particularly necessary and important for drug development against pandemic public emergency diseases, such as COVID-19. Through various chemometric techniques, such as quantitative structure-activity relationship (QSAR) modelling, molecular docking, and molecular dynamics (MD) simulations, compounds with inhibitory activity against SARS-CoV-2 can be quickly screened, allowing researchers to focus on the few prioritised candidates. In addition, the ADMET properties of the screened candidate compounds should be further explored to promote the successful discovery of anti-SARS-CoV-2 drugs. In this case, considerable time and economic costs can be saved while minimising the need for extensive animal experiments, in line with the 3R principles. This paper focuses on recent advances in chemometric modelling studies of COVID-19-related inhibitors, highlights current limitations, and outlines potential future directions for development.

Abstract Background Online health communities (OHCs) provide platforms for patients to seek advice from physicians and receive professional suggestions online. It can improve the efficiency of patients’ diagnosis of simple diseases and alleviate hospital congestion. However, few empirical studies have comprehensively explored the factors influencing patients’ intention to use OHCs through objective data. This study aims to fill this gap by identifying key factors that influence patients’ acceptance of OHCs and proposing effective ways to promote the applications of OHCs in China. Methods Based on the Unified Theory of Acceptance and Usage of Technology (UTAUT), extended with additional constructs identified with patients’ information demands in OHCs, this study developed a research model and proposed nine hypotheses. An online survey involving 783 valid responses was conducted in China to collect data to validate the proposed model. Confirmatory factor analysis and partial least squares (PLS) path model were conducted for instrument validation and hypothesis testing. Results Price value, eHealth literacy, and performance expectancy are the most prominent constructs in the study context. Interestingly, relation quality was also found to have a significant positive relationship with behavioral intention. Conclusions Based on these findings, OHC operators need to create a user-friendly platform, improve information quality, set reasonable prices, and establish consummate security systems. Physicians and related organizations can raise awareness and assist patients in developing the skills to appropriately comprehend and utilize information in OHCs. This study contributes to both technology adoption theory and practice.

Abstract Telomeres, at the ends of chromosomes, protect chromosomes from fusion and preserve genomic stability. However, the molecular mechanisms underlying telomere attrition-induced genome instability remain to be understood. We systematically analyzed the expression of retrotransposons and performed genomic sequencing of different cell and tissue types with telomeres of varying lengths due to telomerase deficiency. We found that critically short telomeres altered retrotransposon activity to promote genomic instability in mouse embryonic stem cells, as evidenced by elevated numbers of single nucleotide variants, indels and copy number variations (CNVs). Transpositions of retrotransposons such as LINE1 resulting from the short telomeres can also be found in these genomes with elevated number of mutations and CNVs. Retrotransposon activation is linked to increased chromatin accessibility, and reduced heterochromatin abundance correlates with short telomeres. Re-elongation of telomeres upon recovery of telomerase partly represses retrotransposons and heterochromatin accumulation. Together, our findings suggest a potential mechanism by which telomeres maintain genomic stability by suppressing chromatin accessibility and retrotransposon activity.

Background and Aims: The pathophysiology of achalasia, which involves central nuclei abnormalities, remains unknown. We investigated the resting-state functional MRI (rs-fMRI) features of patients with achalasia. Methods: We applied resting-state functional MRI (rs-fMRI) to investigate the brain features in patients with achalasia (n = 27), compared to healthy controls (n = 29). Focusing on three regions of interest (ROIs): the dorsal motor nucleus of the vagus (DMV), the nucleus ambiguus (NA), and the nucleus of the solitary tract (NTS), we analyzed variations in resting-state functional connectivity (rs-FC), fractional amplitude of low-frequency fluctuations (fALFF), and regional homogeneity (ReHo). Results: Achalasia patients demonstrated stronger functional connectivity between the NA and the right precentral gyrus, left postcentral gyrus, and left insula. No significant changes were found in the DMV or NTS. The fMRI analysis showed higher rs-FC values for NA-DMV and NA-NTS connections in achalasia patients. Achalasia patients exhibited decreased fALFF values in the NA, DMV, and NTS regions, as well as increased ReHo values in the NA and DMV regions. A positive correlation was observed between fALFF values in all six ROIs and the width of the barium meal. The NTS fALFF value and NA ReHo value displayed a positive correlation with integrated relaxation pressure (IRP), while the ReHo value in the right precentral gyrus showed an inverse correlation with the height of the barium meal. Conclusions: Abnormal rs-FC and regional brain activity was found in patients with achalasia. Our study provides new insights into the pathophysiology of achalasia and highlights the potential of rs-fMRI in improving the diagnosis and treatment of this condition.

AbstractLung tumor is the first malignant tumor with the highest mortality, but only no more than one-third of patients can be treated by surgical resection. Microwave ablation (MWA) has become a new adjuvant therapeutic mean for lung tumors because of its low trauma, short treatment time, large ablation volume and wide application range. However, the treatment parameters of MWA, such as input power and ablation time, still depend on the doctors’ experience, which leads to the ineffectiveness of MWA. Therefore, the accurate modeling of temperature distribution of lung tumor MWA has become a significant technical problem to be solved. Recent research was devoted to personalized characterization of lung tumor parameters, finite element analysis of temperature distribution in MWA and accurate ablation effect evaluation. In this paper, a review of the recently obtained results and data will be presented and discussed.

Abstract Identifying environmental drivers of demographic variation is key to predicting community‐level impacts in response to global change. Climate conditions can synchronize population trends and can occur both spatially for populations of the same species, and across multiple species within the same local community. The aim of this study was to investigate patterns of temporal variation in survival for freshwater fish communities in two geographically close but isolated sites and to understand the amount of variation accounted for by abiotic covariates including metrics of water temperature and stream flow. Using mark‐recapture data, we estimated bi‐monthly apparent survival in a Bayesian Cormack‐Jolly‐Seber framework. The model included random effects to quantify temporal variance to understand species synchrony with the rest of the fish community and between sites. Study species included bluehead chub (Nocomis leptocephalus), creek chub (Semotilus atromaculatus), and striped jumprock (Moxostoma rupiscartes) in the southeastern USA. Results showed that survival varied over time and periods of low survival were associated with higher mean water temperature. However, temporal patterns of survival differed among species and between sites, where survival was synchronous among species within a site but asynchronous between sites for the same species despite their spatial proximity. Study streams differed in summer thermal regimes, which resulted in contrasting summer survival patterns, suggesting sensitivity of these fishes to warming. We found that interspecific synchrony was greater than spatial synchrony, where regional drivers such as temperature may interact with local habitat leading to differences in survival patterns at fine spatial scales. Finally, these findings show that changes in the timing and magnitude of environmental conditions can be critical in limiting vital rates and that some populations may be more resilient to climate variation than others.

Extrachromosomal circular DNAs (eccDNAs) are widely observed in eukaryotes. Previous studies have demonstrated that eccDNAs are essential to cancer progression, and found that they can not only express in normal cells to regulate RNA, but also function differently in different tissues. It is of major interest to conduct computational or experiments assay to elucidate the mechanisms of eccDNA function, uncover key eccDNAs associated with diseases, and even develop related algorithms for liquid biopsy. Naturally, a comprehensive eccDNAs data resource is urgently needed to provide annotation and analysis more in-depth research. In this study, we constructed the eccBase (http://www.eccbase.net) in literature curation and database retrieval, which was the first database mainly collecting eccDNAs from Homo sapiens (n = 754,391) and Mus musculus (n = 481,381). Homo sapiens eccDNAs were taken from 50 kinds of cancer tissue and/or cell line, and 5 kinds of healthy tissues. The Mus musculus eccDNAs were sourced from 13 kinds of healthy tissue and/or cell line. We thoroughly annotated all eccDNA molecules in terms of basic information, genomic composition, regulatory elements, epigenetic modifications, and raw data. EccBase provided users with the ability to browse, search, download for targets of interest, as well as similarity alignment by the integrated BLAST. Further, comparative analysis suggested the cancer eccDNA is composed of nucleosomes and is prominently derived from the gene-dense regions. We also initially revealed that eccDNAs are strongly tissue-specific. In short, we have started a robust database for eccDNA resource utilization, which may facilitate studying the role of eccDNA in cancer development and therapy, cell function maintenance, and tissue differentiation.

The gastrointestinal microbiota develop alongside the host and play a vital role in the health of cecal fermenters such as chinchillas. However, little is known about the microbiota architecture in healthy chinchillas. Illumine-based 16S rRNA gene amplicon sequencing was used to investigate the microbiota present in six different gastrointestinal tract regions of three healthy adult chinchillas. The findings revealed significantly more abundant microbiota in the large intestine compared with the proximal segments. In addition, the cecum exhibited better evenness compared to the colon. The core microbiota are Firmicutes, Bacteroidota, Actinobacteriota, and Proteobacteria at the phylum level. The signature microbiota of each segment were identified. The cecum had 10 signature microbiota, which had the widest coverage and overlapped with that of the cecum. The stomach had five signature microbiota, exhibiting the second widest coverage and overlapping with the duodenum. No signature microbiota were detected in the jejunum and ileum. While similarities exist with the microbiota of other cecal fermenters, chinchillas exhibit distinct microbiota closely related to their unique digestive mechanisms. This study is a preliminary study of the gastrointestinal microbiota architecture and distribution in healthy chinchillas. Further study is needed in order to better understand the effect of gastrointestinal microbiota on the health of the chinchilla.

Per- and polyfluoroalkyl substances (PFASs) are emerging contaminants of concern that can enter the human body through a variety of pathways and thereby cause harmful effects. Exposure of pregnant women to PFASs could even affect both the mother and the child. Human serum albumin (HSA) is considered to be the primary transport protein for a variety of substances in body fluids. It can be bound to different contaminants and might result in possible effects on human health. Yet, few studies are available on the binding affinity of legacy PFASs and their novel alternatives to HSA. In this study, the binding mechanisms of HSA to both legacy PFASs and their novel alternatives were investigated using fluorescence spectroscopy, together with further molecular docking. The results show that all the target PFASs were statically quenched against HSA with binding ratios of 1:1. The binding constants of long-chain PFASs and novel alternatives of perfluoroalkanesulfonic acids (PFSAs) were greater than 102, whereas those of short-chain PFASs alternatives and novel alternatives of perfluorocarboxylic acids (PFCAs) were less than 102. In general, the binding affinities of PFCAs on HSA were less than that of PFSAs, while the binding affinities of short-chain PFASs alternatives on HSA were smaller than those of long-chain PFASs and their novel alternatives. Therefore, bindings to HSA could be considered as an important influencing factor for the bioaccumulation of legacy and novel PFASs in the human body.

Summary: The purpose of this study is to explore the prognostic values of ventricle epicardial fat volume (EFV) calculated by cardiac magnetic resonance in patients with chronic heart failure (CHF).A total of 516 patients with CHF (left ventricular ejection fraction ≤ 50%) were recruited, and 136 (26.4%) of whom experienced major adverse cardiovascular events (MACE) within median follow-up of 24 months. The target marker—EFV was found to be associated with MACE in both univariate and multivariable analysis adjusted for various clinical variables (p

Abstract Background Histone cell cycle regulator (HIRA) complex is an important histone chaperone that mediates the deposition of the H3.3 histone variant onto chromatin independently from DNA synthesis. However, it is still unknown whether it participates in the expression control of retrotransposons and cell fate determination. Methods We screened the role of HIRA complex members in repressing the expression of retrotransposons by shRNA depletion in embryonic stem cells (ESCs) followed by RT-qPCR. RNA-seq was used to study the expression profiles after depletion of individual HIRA member. RT-qPCR and western blot were used to determine overexpression of HIRA complex members. Chromatin immunoprecipitation (ChIP)-qPCR was used to find the binding of H3.3, HIRA members to chromatin. Co-immunoprecipitation was used to identify the interaction between Hira mutant and Ubn2. ChIP-qPCR was used to identify H3.3 deposition change and western blot of chromatin extract was used to validate the epigenetic change. Bioinformatics analysis was applied for the analysis of available ChIP-seq data. Results We revealed that Hira, Ubn2, and Ubn1 were the main repressors of 2-cell marker retrotransposon MERVL among HIRA complex members. Surprisingly, Ubn2 and Hira targeted different groups of retrotransposons and retrotransposon-derived long noncoding RNAs (lncRNAs), despite that they partially shared target genes. Furthermore, Ubn2 prevented ESCs to gain a 2-cell like state or activate trophectodermal genes upon differentiation. Mechanistically, Ubn2 and Hira suppressed retrotransposons by regulating the deposition of histone H3.3. Decreased H3.3 deposition, that was associated with the loss of Ubn2 or Hira, caused the reduction of H3K9me2 and H3K9me3, which are known repressive marks of retrotransposons. Conclusions Overall, our findings shed light on the distinct roles of HIRA complex members in controlling retrotransposons and cell fate conversion in ESCs.

Finding novel and effective suppression of hepatic glucagon response antidiabetic compounds is urgently required for the development of new drugs against diabetes. Fungi are well known for their ability to produce new bioactive secondary metabolites. In this study, four new prenylated indole-terpenoids (1-4), named encindolenes I-L, as well as a known analogue (5), were isolated from the fungus Penicillium sp. HFF16from the rhizosphere soil of Cynanchum bungei Decne. The structures of the compounds were elucidated by spectroscopic data and ECD analysis. In the antidiabetic activity assay, compounds 1-5 could inhibit glucagon-induced hepatic glucose output with EC50 values of 67.23, 102.1, 49.46, 25.20, and 35.96 μM, respectively, and decrease the intracellular cAMP contents in primary hepatocytes.

BackgroundOnline health communities (OHCs) can alleviate the uneven distribution and use of medical resources and severe hospital congestion. Patients may seek health information through OHCs before or after visiting physicians, which may affect their cognition, health literacy, decision-making preferences, and health-related behaviors such as compliance. Social factors (social support, social presence, and responsiveness) are closely related to patients’ health information–seeking behavior and are significantly considered in OHCs. ObjectiveThis study aimed to explore the effects of patients’ health information–seeking behavior (way and effectiveness) on compliance with physicians from the perspectives of patients’ perceived social support, social presence, and responsiveness. MethodsThis study established a research model from the perspective of social information processing by using the social exchange theory. An anonymous questionnaire survey was conducted with several Chinese OHCs to collect data. Partial least squares and structural equation modeling were adopted to test the hypotheses and develop the model. ResultsThis study received 403 responses, of which 332 were valid, giving a validity rate of 82.4% (332/403). Among the sample, 78.6% (261/332) of the individuals were aged between 20 and 40 years, 59.3% (197/332) were woman, 69.9% (232/332) lived in urban areas, and 50% (166/332) had at least a bachelor’s degree. The reliability, convergent validity, and discriminant validity were acceptable. Both the way and effectiveness of patients seeking health information through OHCs have a positive impact on their compliance through the mediation of their perceived social support, social presence, and responsiveness from OHCs and other users, and patient compliance can be improved by guiding patient health information–seeking behavior in OHCs from a social perspective. ConclusionsThis study proposes a research model to corroborate that patient health information–seeking behavior (way and effectiveness) in OHCs exerts positive effects on patient compliance with the treatment and physician’s advice and provides suggestions for patients, physicians, and OHC service providers in China to help guide patients’ health-related behaviors through OHCs to improve patient compliance, patient satisfaction, treatment efficiency, and health outcomes.

IntroductionThis research explored the clinical application of grade ≥ 3 infection predictive models for the newly diagnosed multiple myeloma (NDMM) population.MethodsIt evaluated 306 patients with NDMM based on three different predictive models. The relationship between the grade ≥ 3 infection rates in NDMM and the scores was analyzed retrospectively. The cumulative incidence of early grade ≥ 3 infection was estimated using the Kaplan–Meier method and log-rank test to assess the statistical significance of the difference. To compare the predictive performance in the prediction of infection, the Receiver Operating Characteristic Curve (ROC) curve was used to show the area under the curve (AUC), and DeLong’s test was used to analyze the difference in AUC.ResultsThe incidence of grade ≥ 3 infection within the first 4 months of NDMM was 40.20%. Concerning the FIRST score (predictors: ECOG, β2-microglobulin, hemoglobin, and lactate dehydrogenase), GEM-PETHEMA score (predictors: albumin, male sex, ECOG, and non-IgA type MM), and Infection Risk model of Multiple Myeloma (IRMM) score (predictors: ECOG, serum β2-microglobulin, globulin, and hemoglobin), the probability of early grade ≥ 3 infection in the different groups showed statistically significant differences (low-risk vs. high-risk: 25.81% vs. 50.00%, p

Abstract Background Naïve and primed pluripotent stem cells (PSCs) represent two different pluripotent states. Primed PSCs following in vitro culture exhibit lower developmental potency as evidenced by failure in germline chimera assays, unlike mouse naïve PSCs. However, the molecular mechanisms underlying the lower developmental competency of primed PSCs remain elusive. Results We examine the regulation of telomere maintenance, retrotransposon activity, and genomic stability of primed PSCs and compare them with naïve PSCs. Surprisingly, primed PSCs only minimally maintain telomeres and show fragile telomeres, associated with declined DNA recombination and repair activity, in contrast to naïve PSCs that robustly elongate telomeres. Also, we identify LINE1 family integrant L1Md_T as naïve-specific retrotransposon and ERVK family integrant IAPEz to define primed PSCs, and their transcription is differentially regulated by heterochromatic histones and Dnmt3b. Notably, genomic instability of primed PSCs is increased, in association with aberrant retrotransposon activity. Conclusions Our data suggest that fragile telomere, retrotransposon-associated genomic instability, and declined DNA recombination repair, together with reduced function of cell cycle and mitochondria, increased apoptosis, and differentiation properties may link to compromised developmental potency of primed PSCs, noticeably distinguishable from naïve PSCs.

Background: There are strong association between remnant cholesterol (RC)/non-high density lipoprotein cholesterol (NHDL-C) and increase cardiovascular (CV) risk. The aim of present study was to investigate the association between target lipid parameters (RC and NHDL-C) and the risk of CV mortality in general population. Methods: Data set from an open database—National Health and Nutrition Examination Surveys (NHANES) 2003–2014 were extracted (n = 14992). Kaplan-Meier, multivariable COX regression, and restricted cubic spline (RCS) parameters. Results: Compared to the lowest quartile, RC (adjusted hazard ratio [HR] = 1.63 95%CI 1.05–2.52, P for trend = 0.037) and triglycerides (TG: Model 3: HR = 1.69 95%CI 1.10–2.60, P for trend = 0.049) in the highest quartile were independently associated with the increased cardiovascular mortality, while NHDL-C and apolipoprotein B (ApoB) in adjusted models did not show association (P for trend >0.05). In addition, RCS regression demonstrated that RC (P for nonlinearity = 0.011) and TG (P for nonlinearity = 0.010) levels had a similar J-shape association with CV mortality. Threshold effect analysis showed that when RC ≤ 29.3 mg/dL, the level of RC and CV mortality risk were positively correlated. Conclusions: Our findings suggest high RC levels are associated with an increased risk of CV mortality, which support that the integration of TG-rich lipoproteins parameters in risk assessment might optimize the identification and management of selected population.

Abstract Background Reintroducing predators is a promising conservation tool to help remedy human-caused ecosystem changes. However, the growth and spread of a reintroduced population is a spatiotemporal process that is driven by a suite of factors, such as habitat change, human activity, and prey availability. Sea otters (Enhydra lutris) are apex predators of nearshore marine ecosystems that had declined nearly to extinction across much of their range by the early 20th century. In Southeast Alaska, which is comprised of a diverse matrix of nearshore habitat and managed areas, reintroduction of 413 individuals in the late 1960s initiated the growth and spread of a population that now exceeds 25,000. Methods Periodic aerial surveys in the region provide a time series of spatially-explicit data to investigate factors influencing this successful and ongoing recovery. We integrated an ecological diffusion model that accounted for spatially-variable motility and density-dependent population growth, as well as multiple population epicenters, into a Bayesian hierarchical framework to help understand the factors influencing the success of this recovery. Results Our results indicated that sea otters exhibited higher residence time as well as greater equilibrium abundance in Glacier Bay, a protected area, and in areas where there is limited or no commercial fishing. Asymptotic spread rates suggested sea otters colonized Southeast Alaska at rates of 1–8 km/yr with lower rates occurring in areas correlated with higher residence time, which primarily included areas near shore and closed to commercial fishing. Further, we found that the intrinsic growth rate of sea otters may be higher than previous estimates suggested. Conclusions This study shows how predator recolonization can occur from multiple population epicenters. Additionally, our results suggest spatial heterogeneity in the physical environment as well as human activity and management can influence recolonization processes, both in terms of movement (or motility) and density dependence.

Abstract Background Liver and renal function evaluated by the model for end-stage liver disease (MELD) score, the MELD excluding the international normalized ratio (MELD_XI) score and the MELD including sodium (MELD_sodium) score have been considered predictors of adverse events for patients with acute heart failure (AHF). However, the prognostic value of the MELD including albumin (MELD_albumin) score in patients with AHF has not been assessed. Methods A total of 466 patients with AHF were prospectively evaluated. We compared the accuracy of the 4 MELD score formulas using the time-dependent receiver operating characteristic (ROC) curve and corresponding areas under the curve (AUC). Results During a median follow-up period of 34 months, 196 deaths occurred. In the fully adjusted Cox regression model, standardized hazard ratios with 95% confidence interval expressing the risk of all-cause mortality were 1.22 (1.06–1.40), 1.20 (1.04–1.39), 1.23 (1.06–1.42) and 1.21 (1.05–1.41) for MELD, MELD_XI, MELD_sodium and MELD_albumin scores, respectively. The MELD_albumin score showed the best prognostic accuracy (AUC = 0.658) for the prediction of long-term all-cause mortality, followed by the MELD_sodium score (AUC = 0.590), the MELD score (AUC = 0.580), and the MELD_XI score (AUC = 0.544); the MELD_albumin score performs significantly more accurate than MELD and MELD_XI score for predicting the risk of all-cause mortality. Considering reclassification, MELD_albumin score increased the net reclassification improvement over and beyond MELD (13.1%, P = 0.003), MELD_XI (14.8%, P = 0.002), and MELD_sodium (11.9%, P = 0.006) scores for all-cause mortality. Conclusions The MELD_albumin score increases risk stratification of all-cause mortality over and beyond the MELD score and the other modified MELD scores in patients with acute heart failure.

With the boom of digital landscape architecture, the evaluation of landscape efficacy has evolved from pictorial description to model analysis. Many scholars have explored the mathematical model behind traditional geometric laws. Structural equation modelling (SEM) provides a scientific measurement tool for landscape performance, thanks to its simple path, simultaneous equations, and in-depth variable measurement. Inspired by the theories of the SEM, this paper establishes a theoretical model for landscape efficacy based on five unobservable factors, namely, spatial density, vegetation coverage, recreational travel, scenic integration, and topological depth. Next, typical new Chinese style (NCS) commercial streets were selected as samples, and the initial data on the five factors were extracted and normalized by depthmapX, Grasshopper, and SPSS. With the aid of SPSS Amos, the path between each unobserved element and landscape efficacy was simulated, quantified, and fitted by our model. The fitting results were verified and analysed through multiple regression. A total of 200 typical NCS commercial streets were selected as samples to verify the established model. The results show that topological depth (path coefficient: 0.98) has the greatest impact on landscape efficacy, followed in turn by spatial density (0.86), vegetation coverage (0.65), scenic integration (0.59), and recreational travel (0.50). The empirical analysis proves that the SEM can effectively evaluate the landscape efficacy of the NCS commercial streets. The research results provide a good reference for the quantification of the coupling relationship between unobserved factors in built environment.

The optimal scheduling of integrated energy system (IES) can improve energy efficiency and economic operation. However, the existing scheduling methods cannot accurately handle the dynamic changes of supply and demand sides in the electricity-gas-heat IES thanks to their power uncertainties. To tackle this problem, an optimal dispatch framework based on the asynchronous advantage actor-critic (A3C) method of IES is proposed. Firstly, we describe the dispatch problem of IES with multiple uncertainties as Markov decision process (MDP) according to the corresponding mathematical models and constraints. Then, the dispatch framework based on A3C is developed to optimize the control decision for supply and demand sides by asynchronous learning of agents and to reduce the relevance of parameters update of neural networks by the multi-agent utilization of the central processing unit (CPU) multi-threading function. Finally, our proposed methods are verified by the simulations. Compared with the previous optimization algorithms, the training time of the proposed methods is shortened by 37% and 30%, and the daily average operating cost is reduced by 3%, 5.2% and 8.7%.

ObjectiveUsing a newly released National Health and Nutrition Examination Survey (NHANES) data of serum Klotho, this study aimed to explore the relationship between Klotho and specific cardiovascular diseases (CVD), as well as the mediation effect of renal function, among middle-aged and older individuals within the general population.MethodsThis nationally representative cross-sectional study analyzed data from the 2007–2016 NHANES. A total of 13,765 participants, who aged 40 years or older, from the general population were examined. Klotho were divided into four groups based on median and interquartile range. The associations among Klotho (exposure), congestive heart failure (CHF; outcome), and renal function markers [estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), uric acid (UA), and urine albumin-to-creatinine ratio (UACR); mediators] were investigated using mediation analysis.ResultsIn comparison to the lowest quartile, Klotho in the highest quartile was independently associated with the prevalence of CHF (OR 0.59; 95% CI 0.46–0.77, p for trend = 0.001), but not with other individual CVDs. Klotho had a significant direct effect on the prevalence of CHF (all p < 0.001), while eGFR, BUN, UA, and UACR partly mediated the indirect effect of Klotho on the prevalence of CHF (all p < 0.05), explaining 19.51, 6.98, 13.93, and 0.71% of the association between Klotho and CHF, respectively. Additionally, restricted cubic spline regression demonstrated a linear association and negative correlation between Klotho level and CHF.ConclusionThese findings suggest that Klotho is closely linked to CHF and renal function may be a key mediator of this association.

The flySAM/CRISPRa system has recently emerged as a powerful tool for gain-of-function studies in Drosophila melanogaster. This system includes Gal4/UAS-driven dCas9 activators and U6 promoter-controlled sgRNA. Having established dCas9 activators superior to other combinations, to further enhance the efficiency of the targeting activators we systematically optimized the parameters of the sgRNA. Interestingly, the most efficient sgRNAs were found to accumulate in the region from -150bp to -450bp upstream of the transcription start site (TSS), and the activation efficiency showed a strong positive correlation with the GC content of the sgRNA targeting sequence. In addition, the target region is dominant to the GC content, as sgRNAs targeting areas beyond -600bp from the TSS lose efficiency even when containing 75% GC. Surprisingly, when comparing the activities of sgRNAs targeting to either DNA strand, sgRNAs targeting to the non-template strand outperform those complementary to the template strand, both in cells and in vivo. In summary, we define criteria for sgRNA design which will greatly facilitate the application of CRISPRa in gain-of-function studies.

BackgroundOn January 2, 2020, the US Food and Drug Administration (FDA) released the electronic cigarette (e-cigarette) flavor enforcement policy to prohibit the sale of all flavored cartridge–based e-cigarettes, except for menthol and tobacco flavors. ObjectiveThis research aimed to examine the public perception of this FDA flavor enforcement policy and its impact on the public perception of e-cigarettes on Twitter. MethodsA total of 2,341,660 e-cigarette–related tweets and 190,490 FDA flavor enforcement policy–related tweets in the United States were collected from Twitter before (between June 13 and August 22, 2019) and after (between January 2 and March 30, 2020) the announcement of the FDA flavor enforcement policy. Sentiment analysis was conducted to detect the changes in the public perceptions of the policy and e-cigarettes on Twitter. Topic modeling was used for finding frequently discussed topics about e-cigarettes. ResultsThe proportion of negative sentiment tweets about e-cigarettes significantly increased after the announcement of the FDA flavor enforcement policy compared with before the announcement of the policy. In contrast, the overall sentiment toward the FDA flavor enforcement policy became less negative. The FDA flavor enforcement policy was the most popular topic associated with e-cigarettes after the announcement of the FDA flavor enforcement policy. Twitter users who discussed about e-cigarettes started to talk about other alternative ways of getting e-cigarettes after the FDA flavor enforcement policy. ConclusionsTwitter users’ perceptions of e-cigarettes became more negative after the announcement of the FDA flavor enforcement policy.

BackgroundFlavored electronic cigarettes (e-cigarettes) have become popular in recent years, especially among youth and young adults. To address the epidemic of e-cigarettes, New York State approved a ban on sales of most flavored vaping products other than tobacco and menthol flavors on September 17, 2019. ObjectiveThis study aims to examine the attitude of Twitter users to the policy on flavored e-cigarettes in New York State and the impact of this policy on public perceptions of e-cigarettes. This study also compares the attitudes and topics between New York Twitter users and Twitter users from other states who were not directly affected by this policy. MethodsTweets related to e-cigarettes and the New York State policy on flavored e-cigarettes were collected using the Twitter streaming application programming interface from June 2019 to December 2019. Tweets from New York State and those from other states that did not have a flavored e-cigarette policy were extracted. Sentiment analysis was applied to analyze the proportion of negative and positive tweets about e-cigarettes or the flavor policy. Topic modeling was applied to e-cigarette–related data sets and New York flavor policy–related data sets to identify the most frequent topics before and after the announcement of the New York State policy. ResultsWe found that the average number of tweets related to e-cigarettes and the New York State policy on flavored e-cigarettes increased in both New York State and other states after the flavor policy announcement. Sentiment analysis revealed that after the announcement of the New York State flavor policy, in both New York State and other states, the proportion of negative tweets on e-cigarettes increased from 34.07% (4531/13,299) to 44.58% (18,451/41,390) and from 32.48% (14,320/44,090) to 44.40% (64,262/144,734), respectively, while positive tweets decreased significantly from 39.03% (5191/13,299) to 32.86% (13,601/41,390) and from 42.78% (18,863/44,090) to 33.93% (49,105/144,734), respectively. The majority of tweets related to the New York State flavor policy were negative both before and after the announcement of this policy in both New York (87/98, 89% and 3810/4565, 83.46%, respectively) and other states (200/255, 78.4% and 12,695/15,569, 81.54%, respectively), while New York State had a higher proportion of negative tweets than other states. Topic modeling results demonstrated that teenage vaping and health problems were the most discussed topics associated with e-cigarettes. ConclusionsPublic attitudes toward e-cigarettes became more negative on Twitter after New York State announced the policy on flavored e-cigarettes. Twitter users in other states that did not have such a policy on flavored e-cigarettes paid close attention to the New York State flavor policy. This study provides some valuable information about the potential impact of the flavored e-cigarettes policy in New York State on public attitudes toward flavored e-cigarettes.

Background: Antioxidant micronutrients represent an important therapeutic option for the treatment of oxidative stress-associated cardiovascular diseases (CVDs). However, few studies have evaluated the relationship between the levels of multiple dietary antioxidants and CVDs.Objective: The study therefore aimed to evaluate associations between dietary antioxidants and total and specific CVDs among a nationally representative sample of adults in the US.Design: In total, 39,757 adults (>20 years) were included in this cross-sectional study from the 2005–2018 National Health and Nutrition Examination Survey. We analyzed dietary recall of 11 antioxidant micronutrients in this population. Multivariate logistic and weighted quantile sum (WQS) regression were both applied to examine the relationships between these antioxidants, alone and in combination, with the prevalence of all CVDs and specific CVDs. The linearity of these correlations was also explored using restricted cubic spline (RCS) regression.Results: Multivariate logistic models showed that, compared with the lowest quartile, the levels of 11 antioxidants in the highest quartile were independently associated with decreased total CVD (all P < 0.05). The WQS index showed that, when considered together, the 11 micronutrients were negatively correlated with total CVD (P < 0.001) and five specific CVDs (all P < 0.05), and selenium had the strongest association (weight = 0.219) with total CVD. Moreover, the RCS model demonstrated that iron, zinc and copper were all negatively and non-linearly correlated with total CVD, while the eight other micronutrients had non-significant, linear, negative relationships with total CVD (P for non-linearity >0.05). A piecewise binary logistic regression analysis showed that the inflection points in the relationships between CVD and iron, zinc and copper were 7.71, 6.61, and 0.74 mg/day, respectively.Conclusions: Our findings suggested that high levels of combined dietary antioxidant micronutrients are associated with decreased prevalence of CVDs, and that selenium has the greatest contribution to this association.

BackgroundeHealth literacy is significantly associated with patients’ online information behavior, physician-patient relationship, patient adherence, and health outcomes. As an important product of the internet, online health communities (OHCs) can help redistribute idle medical resources, increase medical resource utilization, and improve patient adherence. However, studies on eHealth literacy in OHCs are limited. Therefore, this study examined patients’ eHealth literacy regarding health information–seeking behavior and physician-patient communication in OHCs. ObjectiveThis study aimed to investigate the association between eHealth literacy in OHCs and patient adherence by employing social cognitive theory. MethodsThis was an empirical study, in which a research model consisting of 1 independent variable (patients’ eHealth literacy), 3 mediators (physician-patient communication in OHCs, patient health information–seeking behavior in OHCs, and patients’ perceived quality of health information in OHCs), 1 dependent variable (patient adherence), and 4 control variables (age, gender, living area, and education level) was established to examine the associations. Multi-item scales were used to measure variables. An anonymous online survey involving 560 participants was conducted through Chinese OHCs in July 2018 to collect data. Partial least squares and structural equation modeling were adopted to analyze data and test hypotheses. ResultsThe survey response rate was 79.6% (446/560). The reliability, convergent validity, and discriminant validity were acceptable. Age, gender, living area, and education level were positively associated with patient adherence, and gender was positively associated with physician-patient communication and patients’ perceived quality of internet health information in OHCs. Patients’ eHealth literacy was positively associated with patient adherence through the mediations of physician-patient communication, internet health information–seeking behavior, and perceived quality of internet health information in OHCs. ConclusionsResults indicate that physician-patient communication, internet health information–seeking behavior, and the perceived quality of internet health information are significantly associated with improving patient adherence via a guiding of eHealth literacy in OHCs. These findings suggest that physicians can understand and guide their patients’ eHealth literacy to improve treatment efficiency; OHCs’ operators should this strengthen the management of information quality, develop user-friendly features, and minimize the gap between the actual and perceived information quality.

Abstract Background Triggering receptor expressed on myeloid cells-1 (TREM-1) is inducible on monocyte/macrophages and neutrophils and amplifies the inflammatory response. The aim of this study was to determine whether rheumatoid arthritis synovial fibroblasts (RASF) promote the expression of TREM-1 in monocytes and its potential regulatory mechanism. Methods Synovial fluid and paired peripheral blood from rheumatoid arthritis (RA) patients were analyzed using flow cytometry. Expression of TREM-1 in monocytes was detected after co-culture with RASF, with or without pre-treatment with toll-like receptor (TLR) ligands. Whether RASF-regulated TREM-1 level in monocytes require direct cell contact or soluble factors was evaluated by transwell experiment. COX-2 expression and PGE2 secretion in RASF were determined by quantitative PCR (qPCR) and ELISA. RASF, with and without TLR ligand stimulation, were treated with COX-2 inhibitors, COX-2 siRNA (siCOX-2) or EP1–4 antagonists, and the resulting TREM-1 level in CD14+ monocytes was measured using flow cytometry. Results TREM-1 was highly expressed in CD14+ cells from peripheral blood and especially synovial fluid from RA patients. The expression of TREM-1 in monocytes was increased by co-culture with RASF. TLR-ligand-activated RASF further elevated TREM-1 level. Transwell assay indicated that soluble factors played a key role in RASF-promoted expression of TREM-1 in monocytes. RASF, with or without stimulation by TLR ligands, increased secretion of PGE2 in a cyclooxygenase (COX)-2-dependent manner. PGE2 enhanced the increase in TREM-1 level in monocytes. Finally, studies using COX-2 inhibitors, COX-2 siRNA (siCOX-2) and EP1–4 antagonists, showed that RASF promotion of TREM-1 expression in monocytes was mediated by COX-2/PGE2/EP2,4 signaling. Conclusions Our data is the first report to reveal the critical role of RASF in upregulating TREM-1 expression in monocytes, which indicates that TREM-1 might be a novel target for RA therapy.

Abstract Background In general, medical regimens and treatments are more likely to be effective if patients follow their physicians’ advice. However, limited studies have focused on the relationship between regulatory focus and patient adherence. This study explores the antecedents of patient adherence employing regulatory focus theory. Methods This study established a research model consisting of two independent variables, two mediators, one dependent variable, two moderators, three control variables, and six hypotheses. An online survey involving 336 valid responses was conducted to collect data in China. We used structural equation modelling and confirmatory factor analysis to test the hypotheses and to develop the research model. Results The reliability and validity of the measures were accepted. In terms of control variables, age had a positive effect on conservative treatment-related health information seeking behaviour, and patients with different resident statuses held different attitudes towards seeking conservative treatment-related health information. However, educational level did not have any effect on the variables of the research model. The hypothesis testing results corroborate that promotion focus had a positive impact on patients’ emerging treatment-related health information seeking behaviour; prevention focus had a positive impact on patients’ conservative treatment-related health information seeking behaviour, which had a positive impact on patient adherence. In addition, media campaigns had a positive impact on the relationship between promotion focus and emerging treatment-related health information seeking behaviour, and website reputation had a positive impact on the relationship between prevention focus and conservative treatment-related health information seeking behaviour. Conclusions Individuals can be encouraged to seek health information and share health-related knowledge through mass media, such as the Internet, when the quality of information, especially information from online sources, is guaranteed. In addition, physicians need to improve their professionalism and expand their knowledge of conservative healthcare. As a further application of our work, an Internet information recommendation system can be designed to recommend different types of health information for users according to their regulatory focus.

The aim of present study was to investigate the association of acrylamide (AA) hemoglobin biomarkers and serum lipids level in a general population. Data set of our study were extracted from an open database - National Health and Nutrition Examination Surveys (NHANES) 2013–2016. In total 2899 participants were enrolled. The associations between AA hemoglobin parameters [hemoglobin adducts of AA (HbAA) and glycidamide (HbGA), total of HbAA and HbGA (HbAA+HbGA), and ratio of HbGA to HbAA (HbGA/HbAA)] and lipid levels [total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C)] were analyzed. Generalized linear models and restricted cubic spline plots were conducted to address the relationship between lipid levels and acrylamide markers. Comparing the lowest quantiles, HbGA and HbGA/HbAA both remained a significant trend regardless of lipid types. Analyses using a generalized linear model with restricted cubic spline and validated with regression models, all 4 AA parameters demonstrated a linear association and positive correlation with TG. Furthermore, there were also opposite nonlinear association between HbGA/HbAA and LDL-C (positive correlation), and HbGA/HbAA and HDL-C (negative correlation). Further analysis with threshold effect analysis or regression analysis showed HbGA and HbGA/HbAA remained significant association with all TC, TG, LDL-C, and HDL-C. The hemoglobin adducts AA parameters as long-term exposure biomarkers are associated with the atherosclerotic lipid changes in a population of US adults.

Pluripotency and self-renewal of embryonic stem cells (ESCs) are marked by core transcription regulators such as Oct4, Sox2, and Nanog. Another important marker of pluripotency is the long noncoding RNA (lncRNA). Here, we ind that a novel long noncoding RNA (lncRNA) Lx8-SINE B2 is a marker of pluripotency. LncRNA Lx8-SINE B2 is enriched in ESCs and downregulated during ESC differentiation. By rapid amplification of cDNA ends, we identified the full-length sequence of lncRNA Lx8-SINE B2. We further showed that transposable elements at upstream of lncRNA Lx8-SINE B2 could drive the expression of lncRNA Lx8-SINE B2. Furthermore, ESC-specific expression of lncRNA Lx8-SINE B2 was driven by Oct4 and Sox2. In summary, we identified a novel marker lncRNA of ESCs, which is driven by core pluripotency regulators.