GPro: generative AI-empowered toolkit for promoter design.

MOTIVATION: Promoters with desirable properties are crucial in biotechnological applications. Generative AI (GenAI) has demonstrated potential in creating novel synthetic promoters with significantly enhanced functionality. However, these methods' reliance on various programming frameworks and specific task-oriented contexts limits their flexibilities. Overcoming these limitations is essential for researchers to fully leverage the power of GenAI to design promoters for their tasks. RESULTS: Here, we introduce GPro (Generative AI-empowered toolkit for promoter design), a user-friendly toolkit that integrates a collection of cutting-edge GenAI-empowered approaches for promoter design. This toolkit provides a standardized pipeline covering essential promoter design processes, including training, optimization, and evaluation. Several detailed demos are provided to reproduce state-of-the-art promoter design pipelines. GPro's user-friendly interface makes it accessible to a wide range of users including non-AI experts. It also offers a variety of optional algorithms for each design process, and gives users the flexibility to compare methods and create customized pipelines. AVAILABILITY AND IMPLEMENTATION: GPro is released as an open-source software under the MIT license. The source code for GPro is available on GitHub for Linux, macOS, and Windows: https://github.com/WangLabTHU/GPro, and is available for download via Zenodo repository at https://zenodo.org/doi/10.5281/zenodo.10681733.

Protein expression patterns and metal metabolites in a protogynous hermaphrodite fish, the ricefield eel (Monopterus albus).

BACKGROUND: The ricefield eel Monopterus albus undergoes a natural sex change from female to male during its life cycle, and previous studies have shown the potential mechanisms of this transition at the transcriptional and protein levels. However, the changes in protein levels have not been fully explored, especially in the intersexual stage. RESULTS: In the present study, the protein expression patterns in the gonadal tissues from five different periods, the ovary (OV), early intersexual stage gonad (IE), middle intersexual stage gonad (IM), late intersexual stage gonad (IL), and testis (TE), were determined by untargeted proteomics sequencing. A total of 5125 proteins and 394 differentially expressed proteins (DEPs) were detected in the gonadal tissues. Of the 394 DEPs, there were 136 between the OV and IE groups, 20 between the IM and IE groups, 179 between the IL and IM groups, and 59 between the TE and IL groups. Three candidate proteins, insulin-like growth factor 2 mRNA-binding protein 3 isoform X1 (Igf2bp3), triosephosphate isomerase (Tpi), and Cu-Zn superoxide dismutase isoform X1 [(Cu-Zn) Sod1], were validated by western blotting to verify the reliability of the data. Furthermore, metal metabolite-related proteins were enriched in the IL vs. IM groups and TE vs. IL groups, which had close relationships with sex change, including Cu2+-, Ca2+-, Zn2+- and Fe2+/Fe3+-related proteins. Analysis of the combined transcriptome data revealed consistent protein/mRNA expression trends for two metal metabolite-related proteins/genes [LOC109953912 and calcium Binding Protein 39 Like (cab39l)]. Notably, we detected significantly higher levels of Cu2+ during the sex change process, suggesting that Cu2+ is a male-related metal metabolite that may have an important function in male reproductive development. CONCLUSIONS: In summary, we analyzed the protein profiles of ricefield eel gonadal tissues in five sexual stages (OV, IE, IM, IL, and TE) and verified the plausibility of the data. After preforming the functional enrichment of metal metabolite-related DEPs, we detected the contents of the metal metabolites Zn2+, Cu2+, Ca2+, and Fe2+/Fe3+ at these five stages and screened for (Cu-Zn) Sod1 and Mmp-9 as possible key proteins in the sex reversal process.

Population structure and adaptability analysis of Schizothorax o'connori based on whole-genome resequencing.

BACKGROUND: Schizothorax o'connori is an endemic fish distributed in the upper and lower reaches of the Yarlung Zangbo River in China. It has experienced a fourth round of whole gene replication events and is a good model for exploring the genetic differentiation and environmental adaptability of fish in the Qinghai-Tibet Plateau. The uplift of the Qinghai-Tibet Plateau has led to changes in the river system, thereby affecting gene exchange and population differentiation between fish populations. With the release of fish whole genome data, whole genome resequencing has been widely used in genetic evolutionary analysis and screening of selected genes in fish, which can better elucidate the genetic basis and molecular environmental adaptation mechanisms of fish. Therefore, our purpose of this study was to understand the population structure and adaptive characteristics of S. o'connori using the whole-genome resequencing method. RESULTS: The results showed that 23,602,746 SNPs were identified from seven populations, mostly distributed on chromosomes 2 and 23. There was no significant genetic differentiation between the populations, and the genetic diversity was relatively low. However, the Zangga population could be separated from the Bomi, Linzhi, and Milin populations in the cluster analysis. Based on historical dynamics analysis of the population, the size of the ancestral population of S. o'connori was affected by the late accelerated uplift of the Qinghai Tibet Plateau and the Fourth Glacial Age. The selected sites were mostly enriched in pathways related to DNA repair and energy metabolism. CONCLUSION: Overall, the whole-genome resequencing analysis provides valuable insights into the population structure and adaptive characteristics of S. o'connori. There was no obvious genetic differentiation at the genome level between the S. o'connori populations upstream and downstream of the Yarlung Zangbo River. The current distribution pattern and genetic diversity are influenced by the late accelerated uplift of the Qinghai Tibet Plateau and the Fourth Ice Age. The selected sites of S. o'connori are enriched in the energy metabolism and DNA repair pathways to adapt to the low temperature and strong ultraviolet radiation environment at high altitude.

PCK2 induces gefitinib resistance by suppresses ferroptosis in non-small cell lung cancer.

OBJECTIVES: This study aimed to explore the involvement of phosphoenolpyruvate carboxykinase 2 (PCK2) in gefitinib-resistant non-small cell lung cancer (NSCLC) cells and assess its feasibility as a therapeutic target against gefitinib resistance. METHODS: Gefitinib-resistant cell lines, PC9GR and HCC827GR, were generated through progressive exposure of parental cells to escalating concentrations of gefitinib. Transcriptomic analysis encompassed the treatment of PC9 and PC9GR cells with gefitinib or vehicle, followed by RNA extraction, sequencing, and subsequent bioinformatic analysis. Cell viability was determined via CCK-8 assay, while clonogenic assays assessed colony formation. Apoptosis was detected utilizing the Annexin V-FITC/7AAD kit. Iron ion concentrations were quantified using FerroOrange. mRNA analysis was conducted through quantitative RT-PCR. Western blotting was employed for protein analysis. H&E and immunohistochemical staining were performed on tumor tissue sections. RESULTS: The results revealed that depletion or inhibition of PCK2 significantly enhanced gefitinib's efficacy in inducing cell growth arrest, apoptosis, and ferroptosis in resistant NSCLC. Moreover, PCK2 knockdown led to the downregulation of key ferroptosis-related proteins, GPX4 and SLC7A11, while upregulating ASCL4. Conversely, overexpression of PCK2 in gefitinib-sensitive cells rendered resistance to gefitinib. In vivo experiments using a gefitinib-resistant xenograft model demonstrated that PCK2 silencing not only reduced tumor growth but also considerably increased the anti-tumor effect of gefitinib. CONCLUSIONS: In conclusion, our study presents compelling evidence indicating that PCK2 plays a pivotal role in gefitinib resistance in NSCLC. The modulation of ferroptosis-related proteins and the involvement of Akt activation further elucidate the mechanisms underlying this resistance. Consequently, PCK2 emerges as a promising therapeutic target for overcoming gefitinib resistance in NSCLC, offering a new avenue for the development of more effective treatment strategies.

CD204-positive M2-like tumor-associated macrophages increase migration of gastric cancer cells by upregulating miR-210 to reduce NTN4 expression.

BACKGROUND: Tumor-associated macrophages (TAMs) are the predominant immune cells in the tumor microenvironment and portend poor prognosis. However, the molecular mechanisms underlying the tumor promotion of TAMs have not been fully elucidated. METHODS: Coculture of gastric cancer cells with U937 cells was performed to investigate the impact of TAMs on cancer cell behavior. MicroRNA (miRNA) microarray and bioinformatics were applied to identify the involved miRNAs and the functional target genes. The regulation of the miRNA on its target gene was studied using anti-miRNA and miRNA mimic. RESULTS: Coculture with CD204+ M2-like TAMs increased proliferation, migration, and epithelial-mesenchymal transition of gastric cancer cells. MiR-210 was the most upregulated miRNA in cancer cells identified by miRNA microarray after coculture. In gastric cancer tissues, miR-210 expression was positively correlated with CD204+ M2-like TAM infiltration. Inactivation of miR-210 by antimir attenuated CD204+ M2-like TAMs-induced cancer cell migration. Using pharmacological inhibitors and neutralizing antibodies, CD204+ M2-like TAMs-secreted TNFα was found to upregulate miR-210 through NF-κB/HIF-1α signaling. Bioinformatics analysis showed netrin-4 (NTN4) as a potential target of miR-210 to suppress gastric cancer cell migration. We also found an inverse expression between miR-210 and NTN4 in cancer cells after coculture or in tumor xenografts. Anti-miR-210 increased NTN4 expression, while miR-210 mimics downregulated NTN4 in cancer cells. Reporter luciferase assays showed that MiR-210 mimics suppressed NTN4 3' untranslated region-driven luciferase activity in cancer cells, but this effect was blocked after mutating miR-210 binding site. CONCLUSIONS: CD204+ M2-like TAMs can utilize the TNF-α/NF-κB/HIF-1α/miR-210/NTN4 pathway to facilitate gastric cancer progression.

Transcription factors RhbZIP17 and RhWRKY30 enhance resistance to Botrytis cinerea by increasing lignin content in rose petals.

The petals of ornamental plants such as roses (Rosa spp.) are the most economically important organs. This delicate, short-lived plant tissue is highly susceptible to pathogens, in large part because the walls of petal cells are typically thinner and more flexible compared with leaf cells, allowing the petals to fold and bend without breaking. The cell wall is a dynamic structure that rapidly alters its composition in response to pathogen infection, thereby reinforcing its stability and boosting plant resistance against diseases. However, little is known about how dynamic changes in the cell wall contribute to resistance to Botrytis cinerea in rose petals. Here, we show that the B. cinerea-induced transcription factor RhbZIP17 is required for the defense response of rose petals. RhbZIP17 is associated with phenylpropanoid biosynthesis and binds to the promoter of the lignin biosynthesis gene RhCAD1, activating its expression. Lignin content showed a significant increase under gray mold infection compared with the control. RhCAD1 functions in the metabolic regulation of lignin production and, consequently, disease resistance, as revealed by transient silencing and overexpression in rose petals. The WRKY transcription factor RhWRKY30 is also required to activate RhCAD1 expression and enhance resistance against B. cinerea. We propose that RhbZIP17 and RhWRKY30 increase lignin biosynthesis, improve the resistance of rose petals to B. cinerea, and regulate RhCAD1 expression.

Flexible multifunctional titania nanotube array platform for biological interfacing.

Abstract: The current work presents a novel flexible multifunctional platform for biological interface applications. The use of titania nanotube arrays (TNAs) as a multifunctional material is explored for soft-tissue interface applications. In vitro biocompatibility of TNAs to brain-derived cells was first examined by culturing microglia cells-the resident immune cells of the central nervous system on the surface of TNAs. The release profile of an anti-inflammatory drug, dexamethasone from TNAs-on-polyimide substrates, was then evaluated under different bending modes. Flexible TNAs-on-polyimide sustained a linear release of anti-inflammatory dexamethasone up to ~11 days under different bending conditions. Finally, microfabrication processes for patterning and transferring TNA microsegments were developed to facilitate structural stability during device flexing and to expand the set of compatible polymer substrates. The techniques developed in this study can be applied to integrate TNAs or other similar nanoporous inorganic films onto various polymer substrates. Impact statement: Titania nanotube arrays (TNAs) are highly tunable and biocompatible structures that lend themselves to multifunctional implementation in implanted devices. A particularly important aspect of titania nanotubes is their ability to serve as nano-reservoirs for drugs or other therapeutic agents that slowly release after implantation. To date, TNAs have been used to promote integration with rigid, dense tissues for dental and orthopedic applications. This work aims to expand the implant applications that can benefit from TNAs by integrating them onto soft polymer substrates, thereby promoting compatibility with soft tissues. The successful direct growth and integration of TNAs on polymer substrates mark a critical step toward developing mechanically compliant implantable systems with drug delivery from nanostructured inorganic functional materials. Diffusion-driven release kinetics and the high drug-loading efficiency of TNAs offer tremendous potential for sustained drug delivery for scientific investigations, to treat injury and disease, and to promote device integration with biological tissues. This work opens new opportunities for developing novel and more effective implanted devices that can significantly improve patient outcomes and quality of life. Supplementary information: The online version contains supplementary material available at 10.1557/s43577-023-00628-y.

Effects of different sizes of ambient particulate matter and household fuel use on physical function: National cohort study in China.

BACKGROUND: Impact of outdoor and household air pollution on physical function remains unelucidated. This study examined the influence of various ambient particulate sizes (PM1, PM2.5, and PM10) and household fuel usage on physical function. METHODS: Data from the China Health and Retirement Longitudinal Study (CHARLS) spanning 2011 and 2015 were utilized. The physical functional score was computed by summing scores from four tests: grip strength, gait speed, chair stand test, and balance. Multivariate linear and linear mixed-effects models were used to explore the separate and combined effects of PM1, PM2.5, PM10 and household fuel use on physical function in the cross-sectional and longitudinal analyses, respectively, and to further observe the effects of fuel cleanup on physical function in the context of air pollution exposure. RESULTS: Both cross-sectional and longitudinal analyses revealed negative correlations between PM1 (ß = -0.044; 95% CI: -0.084, -0.004), PM2.5 (ß = -0.024; 95% CI: -0.046, -0.001), PM10 (ß = -0.041; 95% CI: -0.054, -0.029), and physical function, with a more pronounced impact observed for fine particulate matter (PM1). Cleaner fuel use was associated with enhanced physical function compared to solid fuels (ß = 0.143; 95% CI: 0.070, 0.216). The presence of air pollutants and use of solid fuels had a negative impact on physical function, while cleaner fuel usage mitigated the adverse effects of air pollutants, particularly in areas with high exposure. CONCLUSION: This study underscores the singular and combined detrimental effects of air pollutants and solid fuel usage on physical function. Addressing fine particulate matter, specifically PM1, and prioritizing efforts to improve household fuel cleanliness in regions with elevated air pollution levels are crucial for preventing physical disability.

Rapid Geometric Evaluation of Transportation Infrastructure Based on a Proposed Low-Cost Portable Mobile Laser Scanning System.

Efficient geometric evaluation of roads and tunnels is crucial to traffic management, especially in post-disaster situations. This paper reports on a study of the geometric feature detection method based on multi-sensor mobile laser scanning (MLS) system data. A portable, low-cost system that can be mounted on vehicles and utilizes integrated laser scanning devices was developed. Coordinate systems and timestamps from numerous devices were merged to create 3D point clouds of objects being measured. Feature points reflecting the geometric information of measuring objects were retrieved based on changes in the point cloud's shape, which contributed to measuring the road width, vertical clearance, and tunnel cross section. Self-developed software was used to conduct the measuring procedure, and a real-time online visualized platform was designed to reconstruct 3D models of the measured objects, forming a 3D digital map carrying the obtained geometric information. Finally, a case study was carried out. The measurement results of several representative nodes are discussed here, verifying the robustness of the proposed system. In addition, the main sources of interference are also discussed.

Formation of Supernarrow Borophene Nanoribbons.

Borophenes have sparked considerable interest owing to their fascinating physical characteristics and diverse polymorphism. However, borophene nanoribbons (BNRs) with widths less than 2 nm have not been achieved. Herein, we report the experimental realization of supernarrow BNRs. Combining scanning tunneling microscopy imaging with density functional theory modeling and ab initio molecular dynamics simulations, we demonstrate that, under the applied growth conditions, boron atoms can penetrate the outermost layer of Au(111) and form BNRs composed of a pair of zigzag (2,2) boron rows. The BNRs have a width self-contained to ∼1 nm and dipoles at the edges to keep them separated. They are embedded in the outermost Au layer and shielded on top by the evacuated Au atoms, free of the need for post-passivation. Scanning tunneling spectroscopy reveals distinct edge states, primarily attributed to the localized spin at the BNRs' zigzag edges. This work adds a new member to the boron material family and introduces a new physical feature to borophenes.

DISMIR: Deep learning-based noninvasive cancer detection by integrating DNA sequence and methylation information of individual cell-free DNA reads.

Detecting cancer signals in cell-free DNA (cfDNA) high-throughput sequencing data is emerging as a novel noninvasive cancer detection method. Due to the high cost of sequencing, it is crucial to make robust and precise predictions with low-depth cfDNA sequencing data. Here we propose a novel approach named DISMIR, which can provide ultrasensitive and robust cancer detection by integrating DNA sequence and methylation information in plasma cfDNA whole-genome bisulfite sequencing (WGBS) data. DISMIR introduces a new feature termed as 'switching region' to define cancer-specific differentially methylated regions, which can enrich the cancer-related signal at read-resolution. DISMIR applies a deep learning model to predict the source of every single read based on its DNA sequence and methylation state and then predicts the risk that the plasma donor is suffering from cancer. DISMIR exhibited high accuracy and robustness on hepatocellular carcinoma detection by plasma cfDNA WGBS data even at ultralow sequencing depths. Further analysis showed that DISMIR tends to be insensitive to alterations of single CpG sites' methylation states, which suggests DISMIR could resist to technical noise of WGBS. All these results showed DISMIR with the potential to be a precise and robust method for low-cost early cancer detection.

Inference of relative permeability curves in reservoir rocks with ensemble Kalman method.

Multiphase flows through reservoir rocks are a universal and complex phenomenon. Relative permeability is one of the primary determinants in reservoir performance calculations. Accurate estimation of the relative permeability is crucial for reservoir management and future production. In this paper, we propose inferring relative permeability curves from sparse saturation data with an ensemble Kalman method. We represent these curves through a series of positive increments of relative permeability at specified saturation values, which guarantees monotonicity within, and boundedness between 0 and 1. The proposed method is validated by the inference performances in two synthetic benchmarks designed by SPE and a field-scale model developed by Equinor that includes certain real field features. The results indicate that the relative permeability curves can be accurately estimated within the saturation intervals having available observations and appropriately extrapolated to the remaining saturations by virtue of the embedded constraints. The predicted well responses are comparable to the ground truths, even though they are not included as the observation. The study demonstrates the feasibility of using ensemble Kalman method to infer relative permeability curves from saturation data, which can aid in the predictions of multiphase flow and reservoir production.

Natural anti-inflammatory products for osteoarthritis: From molecular mechanism to drug delivery systems and clinical trials.

Osteoarthritis (OA) is a degenerative joint disease that affects millions globally. The present nonsteroidal anti-inflammatory drug treatments have different side effects, leading researchers to focus on natural anti-inflammatory products (NAIPs). To review the effectiveness and mechanisms of NAIPs in the cellular microenvironment, examining their impact on OA cell phenotype and organelles levels. Additionally, we summarize relevant research on drug delivery systems and clinical randomized controlled trials (RCTs), to promote clinical studies and explore natural product delivery options. English-language articles were searched on PubMed using the search terms "natural products," "OA," and so forth. We categorized search results based on PubChem and excluded "natural products" which are mix of ingredients or compounds without the structure message. Then further review was separately conducted for molecular mechanisms, drug delivery systems, and RCTs later. At present, it cannot be considered that NAIPs can thoroughly prevent or cure OA. Further high-quality studies on the anti-inflammatory mechanism and drug delivery systems of NAIPs are needed, to determine the appropriate drug types and regimens for clinical application, and to explore the combined effects of different NAIPs to prevent and treat OA.

Edge-Cloud Collaborative Defense against Backdoor Attacks in Federated Learning.

Federated learning has a distributed collaborative training mode, widely used in IoT scenarios of edge computing intelligent services. However, federated learning is vulnerable to malicious attacks, mainly backdoor attacks. Once an edge node implements a backdoor attack, the embedded backdoor mode will rapidly expand to all relevant edge nodes, which poses a considerable challenge to security-sensitive edge computing intelligent services. In the traditional edge collaborative backdoor defense method, only the cloud server is trusted by default. However, edge computing intelligent services have limited bandwidth and unstable network connections, which make it impossible for edge devices to retrain their models or update the global model. Therefore, it is crucial to detect whether the data of edge nodes are polluted in time. This paper proposes a layered defense framework for edge-computing intelligent services. At the edge, we combine the gradient rising strategy and attention self-distillation mechanism to maximize the correlation between edge device data and edge object categories and train a clean model as much as possible. On the server side, we first implement a two-layer backdoor detection mechanism to eliminate backdoor updates and use the attention self-distillation mechanism to restore the model performance. Our results show that the two-stage defense mode is more suitable for the security protection of edge computing intelligent services. It can not only weaken the effectiveness of the backdoor at the edge end but also conduct this defense at the server end, making the model more secure. The precision of our model on the main task is almost the same as that of the clean model.

Minimizing thermal damage using self-cooling jaws for radiofrequency intestinal tissue fusion.

INTRODUCTION: Radiofrequency (RF)-induced tissue fusion shows great potential in sealing intestinal tissue without foreign materials. To improve the performance of RF-induced tissue fusion, a novel self-cooling jaw has been designed to minimize thermal damage during the fusion. MATERIAL AND METHODS: The prototype of self-cooling jaws was developed and manufactured. A total number of 60 mucosa-to-mucosa fusions were conducted using ex-vivo porcine intestinal segments with the proposed design and conventional bipolar jaws. The effects of intestinal fusion were evaluated based on temperature curves, burst pressure, thermal damage, and histological appearances. RESULTS: The self-cooling jaws showed significant decrease in temperature during the fusion process. An optimal burst pressure (5.7 ± 0.5 kPa) and thermal damage range (0.9 ± 0.1 mm) were observed when the applied RF power was 100 W. The thermal damage range of the prototype has almost decreased 36% in comparison with the conventional bipolar jaws (1.4 ± 0.1 mm). The histological observation revealed that a decrease of thermal damage was achieved through the application of self-cooling jaws. CONCLUSIONS: The self-cooling jaws were proved to be effective for reducing the thermal damage during RF-induced tissue fusion, which could potentially promote the clinical application of tissue fusion techniques in the future.

Smart Materials Based on Synthetic Host Molecules: The Role of Host-Guest Chemistry in the Fabrication and Application.

Stimuli-responsive or smart materials have recently shown a significant impact on the frontier of material science and engineering. The exponential development of synthetic host molecules (SHMs) over the last decades and their corresponding host-guest chemistry, have empowered researchers with new opportunities to design and construct tailored or guest-specific smart materials. In this Minireview, we present the recent advancements in synthetic host based smart materials, ranging from the fabrication strategies to the state-of-art applications including adsorption, separation, luminescence, self-healing and actuation. The role that the host-guest chemistry plays in these systems is highlighted throughout to give a better prospective of the available possibilities for emerging materials of future economies.

Long-Term Trends in Risk Factor Management in Respondents with Chronic Kidney Disease in the USA.

INTRODUCTION: Unhealthy lifestyle factors are known to increase the risk of chronic kidney disease (CKD) and its complications. The long-term trends in these factors are unclear. METHODS: The aim of the study was to assess temporal trends in the prevalence of risk factors in adults with CKD in the USA and identify sociodemographic subgroups at most risk. Subanalysis of data was carried out from a stratified, complex, multistage probability-based cross-sectional and nationally representative survey. We examined participants from National Health and Nutritional Examination Survey (NHANES) respondents aged ≥20 years with CKD from 1999 to 2018. CKD was defined as estimated glomerular filtration rate of 15-59 mL/min/1.73 m2. Evaluated risk factors included uncontrolled blood pressure, blood glucose, blood lipids, excessive sodium intake, excessive protein intake, poor diet, obesity, smoking, depression, physical inactivity, and sedentary behavior. Sociodemographic variables included age, sex, race/ethnicity, marital status, education level, family income, and employment status. RESULTS: Blood pressure control among respondents with CKD (n = 4,342) was poor but significantly improved from the 1999-2000 (82% uncontrolled) to 2017-2018 surveys (66%; p for linear trend = 0.02). Prevalence of uncontrolled blood glucose (15-22%; p < 0.01), excessive sodium intake (72-78%; p = 0.04), and obesity (32-51%; p < 0.01) significantly increased over this time. The proportion of respondents with uncontrolled blood lipids, depression, smoking, excessive protein intake, poor diet, physical inactivity, or sedentary behavior showed no significant change over the 10-year period. Older people were more likely to have high blood pressure, high blood glucose, and high blood lipids but healthier lifestyle habits than younger people. And respondents of males, non-Hispanic blacks, Hispanics, low income, low education, widowed/divorced/separated, and employed had worse risk factor control compared to reference groups. DISCUSSION/CONCLUSION: Although the control of several risk factors in US NHANES respondents with CKD improved from 1999 to 2018, further reductions remain of value.

Autophagy inhibition facilitates wound closure partially dependent on the YAP/IL-33 signaling in a mouse model of skin wound healing.

Autophagy is a self-phagocytic and highly evolutionarily conserved intracellular lysosomal catabolic system, which plays a vital role in a variety of trauma models, including skin wound healing (SWH). However, the roles and potential mechanisms of autophagy in SWH are still controversial. We firstly investigated the role of autophagy in SWH-induced wound closure rate, inflammatory response, and histopathology, utilizing an inhibitor of autophagy 3-methyladenine (3-MA) and its agonist rapamycin (RAP). As expected, we found 3-MA treatment remarkably increased the wound closure rate, combated inflammation response, and mitigated histopathological changes, while RAP delivery aggravated SWH-induced pathological damage. To further exploit the underlying mechanism of autophagy regulating inflammation, the specific inhibitors of yes-associated protein (YAP), Verteporfin, and Anti-IL-33 were applied. Herein, treating with 3-MA markedly suppressed the expression of tumor necrosis factor-α (TNF-α), IL-1ß, and IL-6, promoted that of IL-10, IL-33, and ST2, while RAP administration reverted SWH-induced the up-regulation of these inflammatory cytokines mentioned above. Importantly, Verteporfin administration not only down-regulated the expression levels of YAP, TNF-α, and IL-6 but also up-regulated that of IL-33 and IL-10. Unexpectedly, 3-MA or RAP retreatment did not have any impact on the changes in IL-33 among these inflammatory indicators. Furthermore, elevated expression of IL-33 promoted wound closure and alleviated the pathological damage, whereas, its antagonist Anti-IL-33 treatment overtly reversed the above-mentioned effects of IL-33. Moreover, 3-MA in combination with anti-IL-33 treatment reversed the role of 3-MA alone in mitigated pathological changes, but they failed to revert the effect of anti-IL-33 alone on worsening pathological damage. In sum, emerging data support the novel contribution of the YAP/IL-33 pathway in autophagy inhibition against SWH-induced pathological damage, and highlight that the autophagy/YAP/IL-33 signal axis is expected to become a new therapeutic target for SWH.

Tumor-associated macrophages promote resistance of hepatocellular carcinoma cells against sorafenib by activating CXCR2 signaling.

BACKGROUND: Sorafenib (SOR) is the first line treatment for advanced hepatocellular carcinoma (HCC), but resistance develops frequently. Tumor-associated macrophages (TAMs) have been reported to affect the progression of HCC. We therefore aimed to study the role of TAMs in promoting SOR resistance. METHODS: Immunofluorescence staining for the M2 marker CD204 and the cancer stem cell (CSC) markers CD44 and CD133 was performed in paired HCC and adjacent noncancerous tissues and HCC tissues stratified by response of SOR treatment. HCC/U937 coculture system and cytokines were used to induce M2 polarization for studying the effects of M2 TAMs on CSC properties and apoptotic death of HCC cells after SOR treatment. RESULTS: Higher expression of CD204, CD44, and CD133 was observed in patients with SOR nonresponse (SNR) than in those with SOR response (SR), suggesting that SNR is positively correlated to levels of CSCs and M2 TAMs. After coculture, M2 TAMs could increase the level of CSCs but decrease SOR-induced apoptosis. Incubation of HCC cells with coculture conditioned medium increased the formation of spheres that were resistant to SOR. Furthermore, CXCL1 and CXCL2 were found to be the potential paracrine factors released by M2 TAMs to upregulate SOR resistance in HCC cells. Treatment with CXCL1 and CXCL2 could increase HCC CSC activity but decrease SOR-induced apoptosis by affecting BCL-2 family gene expression. Using pharmacological inhibitors, CXCR2/ERK signaling was found to be critical to CXCL1- and CXCL2-mediated SOR resistance. CONCLUSION: This study identified CXCL1, CXCL2, and their downstream CXCR2/ERK signaling as potential therapeutic targets to overcome SOR resistance in HCC.

Adherence to prescribed antihypertensive medication among patients with depression in the United States.

BACKGROUND: Hypertensive patients with depression have a higher mortality rate and a worse prognosis compared with hypertensive only. Depression may reduce medication adherence in hypertension patients. METHODS: This study includes respondents in the National Health and Nutritional Examination Survey (NHANES) database from 2005 to 2018 who had previously been diagnosed with hypertension. Medication adherence was defined as taking medication as recommended by a physician. The depressive state was assessed using the patient health questionnaire (PHQ)-9. RESULTS: Nine thousand one hundred eighty-six respondents were included in the analysis. Medication adherence was associated with depression (odds ratio [OR]: 1.48, 95% confidence interval [CI]: 1.26 to1.75) and depression score (OR: 1.04 per each point increase, 1.03 to 1.05) in the unadjusted analyses. After adjusting for clinical and socioeconomic/demographic factors, there were significant statistical correlations between depression score and medication adherence (aOR: 1.02 per each point increase, 1.00 to 1.03, p < 0.05), but there was no significant statistical correlation between depression and medication adherence (p > 0.05). It was still statistically significant relationships between sex, age, body mass index (BMI), race, marital status, and health insurance with medication adherence after adjusted socioeconomic/demographic factors. CONCLUSION: Depression was marginally associated with poor medication adherence in hypertensive patients, and the correlation increased with depression degree. Moreover, socioeconomic/demographic factors have an independent impact on medication adherence including sex, age, BMI, race, marital status, and health insurance.