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Abstract The trillions of microorganisms inhabiting the human gut are intricately linked to human health. While specific microbes have been associated with diseases, microbial abundance alone cannot reveal the molecular mechanisms involved. One such important mechanism is the biosynthesis of functional metabolites. Here, we develop a biosynthetic enzyme-guided disease correlation approach to uncover microbial functional metabolites linked to disease. Applying this approach, we negatively correlate the expression of gut microbial sulfonolipid (SoL) biosynthetic enzymes to inflammatory bowel disease (IBD). Targeted chemoinformatics and metabolomics then confirm that SoL abundance is significantly decreased in IBD patient data and samples. In a mouse model of IBD, we further validate that SoL abundance is decreased while inflammation is increased in diseased mice. We show that SoLs consistently contribute to the immunoregulatory activity of different SoL-producing human microbes. We further reveal that sulfobacins A and B, representative SoLs, act on Toll-like receptor 4 (TLR4) and block lipopolysaccharide (LPS) binding, suppressing both LPS-induced inflammation and macrophage M1 polarization. Together, these results suggest that SoLs mediate a protective effect against IBD through TLR4 signaling and showcase a widely applicable biosynthetic enzyme-guided disease correlation approach to directly link the biosynthesis of gut microbial functional metabolites to human health.

Abstract Non-alcoholic fatty liver disease (NAFLD) is becoming a significant global public health threat. Seabuckthorn (Hippophae rhamnoides L.) has been used in traditional Chinese medicine (TCM). The hypolipidemic effects of Seabuckthorn polysaccharides (SP) against high-fat diets (HFD)-induced NAFLD were systematically explored and compared with that of Bifidobacterium lactis V9 (B. Lactis V9). Results showed that HFD-induced alanine transaminase (ALT) and aspartate aminotransferase (AST) levels decreased by 2.8-fold and 4.5-fold, respectively, after SP supplementation. Moreover, the alleviating effect on hepatic lipid accumulation is better than that of B. Lactis V9. The ACC and FASN mRNA levels were significantly reduced by 1.8 fold (P

Abstract Luminescent metal halides are attracting growing attention as scintillators for X-ray imaging in safety inspection, medical diagnosis, etc. Here we present brand-new hybrid Eu(II)-bromide scintillators, 1D type [Et4N]EuBr3·MeOH and 0D type [Me4N]6Eu5Br16·MeOH, with spin-allowed 5d-4f bandgap transition emission toward simplified carrier transport during scintillation process. The 1D/0D structures with edge/face -sharing [EuBr6]4− octahedra further contribute to lowing bandgaps and enhancing quantum confinement effect, enabling efficient scintillation performance (light yield ~73100 ± 800 Ph MeV−1, detect limit ~18.6 nGy s−1, X-ray afterglow ~ 1% @ 9.6 μs). We demonstrate the X-ray imaging with 27.3 lp mm−1 resolution by embedding Eu(II)-based scintillators into AAO film. Our results create the new family of low-dimensional rare-earth-based halides for scintillation and related optoelectronic applications.

Abstract In this work, the impact of physicochemical modifications on pharmacokinetics and in vivo targeting of a small molecule fibroblast activation protein inhibitor (FAPI) imaging ligand in a murine model of rheumatoid arthritis was evaluated. While similar ligands have been well-reported in oncology for molecular imaging and radiotherapy, there are limited reports of FAPI derivatives in targeted applications in immunology. As inflammation may increase both specific and non-specific delivery of targeted agents in general, we sought to identify the optimal targeted molecular imaging probe characteristics for efficient cell surface engagement. A series of FAPI derivatives were synthesized and their physicochemical properties modified via conjugation of fluorescent dyes and/or an albumin-binding small molecule. The impact of these modifications on cell surface binding affinity was assessed using an overexpressing cell line. Additionally, a thorough mechanistic characterization of fibroblast activation protein (FAP) cell surface internalization was evaluated in both overexpressing and endogenously expressing cells. Lastly, the pharmacokinetics and in vivo uptake in inflamed arthritic paws were characterized via near-infrared (NIR) imaging. All targeted molecular imaging agents tested maintained strong nanomolar binding affinity to cell surface FAP independent of chemical modification. The murine fibroblast-like synoviocytes expressed lower absolute cell-surface FAP compared to a transfected line, and the net internalization half-life measured for the transfected cells via flow cytometry was 7.2 h. The unmodified FAPI ligand exhibited the poorest in vivo targeting, likely resulting from its large apparent volume of distribution (62.7 ml) and rapid systemic clearance (t 1/2 = 0.5 h). Conjugation of a charged, hydrophilic AF647 fluorophore decreased systemic clearance (t 1/2 = 2.1 h) and demonstrated a 2-fold improvement in blocking FAPI-800CW engagement of FAP in vivo when compared to blocking of FAPI-800CW with FAPI with up to 2.8-fold improvements noted for the equivalent albumin binding construct comparison.

Background: Stomach adenocarcinoma (STAD) is one of the most common malignancies. Infection of helicobacter pylori (H. pylori) is a major risk factor that leads to the development of STAD. This study constructed a risk model based on the H. pylori-related macrophages for predicting STAD prognosis. Methods: The single-cell RNA sequencing (scRNA-seq) dataset and the clinic information and RNA-seq datasets of STAD patients were collected for establishing a prognostic model and for validation. The “Seurat” and “harmony” packages were used to process the scRNA-seq data. Key gene modules were sectioned using the “limma” package and the “WGCNA” package. Kaplan-Meier (KM) and Receiver Operating Characteristic Curve (ROC) analyses were performed with “survminer” package. The “GSVA” package was employed for single sample gene set enrichment analysis (ssGSEA). Cell migration and invasion were measured by carrying out wound healing and trans-well assays. Results: A total of 17397 were screened and classified into 8 cell type clusters, among which the macrophage cluster was closely associated with the H. pylori infection. Macrophages were further categorized into four subtypes (including C1, C2, C3, and C4), and highly variable genes of macrophage subtype C4 could serve as an indicator of the prognosis of STAD. Subsequently, we developed a RiskScore model based on six H. pylori -associated genes (TNFRSF1B, CTLA4, ABCA1, IKBIP, AKAP5, and NPC2) and observed that the high-risk patients exhibited poor prognosis, higher suppressive immune infiltration, and were closely associated with cancer activation-related pathways. Furthermore, a nomogram combining the RiskScore was developed to accurately predict the survival of STAD patients. ABCA1 in the RiskScore model significantly affected the migration and invasion of tumor cells. Conclusion: The gene expression profile served as an indicator of the survival for patients with STAD and addressed the clinical significance of using H. pylori-associated genes to treat STAD. The current findings provided novel understandings for the clinical evaluation and management of STAD.

Abstract Understanding the endogenous mechanism of adaptive response to drug‐induced liver injury (arDILI) may discover innovative strategies to manage DILI. To gain mechanistic insight into arDILI, we investigated exosomal miRNAs in the adaptive response to toosendanin‐induced liver injury (TILI) of mice. Exosomal miR‐106b‐5p was identified as a specific regulator of arDILI by comprehensive miRNA profiling. Outstandingly, miR‐106b‐5p agomir treatment alleviated TILI and other DILI by inhibiting apoptosis and promoting hepatocyte proliferation. Conversely, antagomir treatments had opposite effects, indicating that miR‐106b‐5p protects mice from liver injury. Injured hepatocytes released miR‐106b‐5p‐enriched exosomes taken up by surrounding hepatocytes. Vim (encodes vimentin) was identified as an important target of miR‐106b‐5p by dual luciferase reporter and siRNA assays. Furthermore, single‐cell RNA‐sequencing analysis of toosendanin‐injured mouse liver revealed a cluster of Vim+ hepatocytes; nonetheless declined following miR‐106b‐5p cotreatment. More importantly, Vim knockout protected mice from acetaminophen poisoning and TILI. In the clinic, serum miR‐106b‐5p expression levels correlated with the severity of DILI. Indeed, liver biopsies of clinical cases exposed to different DILI causing drugs revealed marked vimentin expression among harmed hepatocytes, confirming clinical relevance. Together, we report mechanisms of arDILI whereby miR‐106b‐5p safeguards restorative tissue repair by targeting vimentin.

Abstract Phosphor-glass composites (PGC) are excellent candidates for highly efficient and stable photonic converters; however, their synthesis generally requires harsh procedures and long time, resulting in additional performance loss and energy consumption. Here we develop a rapid synthetic route to PGC within about 10 seconds, which enables uniform dispersion of Y3Al5O12:Ce3+ (YAG:Ce) phosphor particles through a particle self-stabilization model in molten tellurite glass. Thanks for good wettability between YAG:Ce micro-particles and tellurite glass melt, it creates an energy barrier of 6.94 × 105 zJ to prevent atomic-scale contact and sintering of particles in the melt. This in turn allows the generation of YAG:Ce-based PGC as attractive emitters with high quantum efficiency (98.4%) and absorption coefficient (86.8%) that can produce bright white light with luminous flux of 1227 lm and luminous efficiency of 276 lm W−1 under blue laser driving. This work shows a generalizable synthetic strategy for the development of functional glass composites.

Abstract Quality control often employs memory-type control charts, including the exponentially weighted moving average (EWMA) and Shewhart control charts, to identify shifts in the location parameter of a process. This article pioneers a new Bayesian Adaptive EWMA (AEWMA) control chart, built on diverse loss functions (LFs) such as the square error loss function (SELF) and the Linex loss function (LLF). The proposed chart aims to enhance the process of identifying small to moderate as well as significant shifts in the mean, signifying a notable advancement in the field of quality control. These are implemented utilizing an informative prior for both posterior and posterior predictive distributions, employing various paired ranked set sampling (PRSS) schemes. The effectiveness of the suggested chart is appraised using average run length (ARL) and the standard deviation of run length (SDRL). Monte Carlo simulations are employed to contrast the recommended approach against other control charts. The outcomes demonstrate the dignitary performance of the recommended chart in identifying out-of-control signals, especially applying PRSS designs, in comparison to simple random sampling (SRS). Finally, a practical application was conducted in the semiconductor manufacturing context to appraise the efficacy of the offered chart using various paired ranked set sampling strategies. The results reveal that the suggested control chart performed well in capturing the out-of-control signals far better than the already in use control charts. Overall, this study interposes a new technique with diverse LFs and PRSS designs, improving the precision and effectiveness in detecting process mean shifts, thereby contributing to advancements in quality control and process monitoring.

Adaptation to thermal conditions in tidal mudflats always involves tolerating frequent fluctuations and often extreme environmental temperatures. Regulation of gene expression plays a fundamental role in the evolution of these thermal adaptations. To identify the key gene regulatory networks associated with the thermal adaptation, we investigated the capability of cold tolerance, as well as the transcriptomic changes under cold stress in two mudflat inhabitants (Odontamblyopus lacepedii and O. rebecca) with contrasting latitude affinity. Our results revealed a remarkable divergent capacity of cold tolerance (CTmin: 0.61 °C vs. 9.57 °C) between the two gobies. Analysis of transcriptomic changes under cold stress unveiled 193 differentially expressed genes exhibiting similar expression profiles across all tissues and species, including several classic metabolic and circadian rhythm molecules such as ACOD and CIART that may represent the core cold response machinery in eel gobies. Meanwhile, some genes show a unique expression spectrum in the more cold-tolerant O. lacepedii suggesting their roles in the enhanced cold tolerance and hence the extreme thermal adaptations. In addition, a weighted gene co-expression network analysis (WGCNA) revealed a subset of metabolic hub genes including MYH11 and LIPT2 showing distinct down-regulation in O. lacepedii when exposed to cold stress which highlights the role of reduced energy consumption in the enhanced cold tolerance of eel gobies. These findings not only provide new insights into how mudflat teleosts could cope with cold stress and their potential evolutionary strategies for adapting to their thermal environment, but also have important implications for sound management and conservation of their fishery resources in a scenario of global climate warming in the marine realm.

Traditional Chinese medicine (TCM) has a long history and particular advantages in the diagnosis and treatment of diabetic foot gangrene (DFG). Patients with DFG are mainly divided into two subtypes, tendon lesion with edema (GT) and ischemic lesion without edema (GI), which are suitable for different medical strategies. Metabolomics has special significance in unravelling the complexities of multifactorial and multisystemic disorders. This study acquired the serum metabolomic profiles of two traditional Chinese medicine subtypes of DFG to explore potential molecular evidence for subtype characterization, which may contribute to the personalized treatment of DFG. A total of 70 participants were recruited, including 20 with DM and 50 with DFG (20 with GI and 30 with GT). Conventional gas chromatography-mass spectrometry (GC-MS) followed by orthogonal partial least-squares discriminant analysis (OPLS-DA) were used as untargeted metabolomics approaches to explore the serum metabolomic profiles. Kyoto encyclopedia of genes and genomes (KEGG) and MetaboAnalyst were used to identify the related metabolic pathways. Compared with DM patients, the levels of 14 metabolites were altered in the DFG group, which were also belonged to the differential metabolites of GI (13) and GT (7) subtypes, respectively. Among these, urea, α-D-mannose, cadaverine, glutamine, L-asparagine, D-gluconic acid, and indole could be regarded as specific potential metabolic markers for GI, as well as L-leucine for GT. In the GI subtype, D-gluconic acid and L-asparagine are positively correlated with activated partial thromboplastin time (APTT) and fibrinogen (FIB). In the GT subtype, L-leucine is positively correlated with the inflammatory marker C-reactive protein (CRP). Arginine and proline metabolism, glycine, serine and threonine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis are the most important metabolic pathways associated with GI. The main metabolic pathways related to GT include pyrimidine metabolism, glutathione metabolism, biosynthesis of valine, leucine, and isoleucine, as well as valine, serine, and isoleucine with metabolites. The results of this study indicate that patients with different DFG subtypes have distinct metabolic profiles, which reflect the pathological characteristics of each subtype respectively. These findings will help us explore therapeutic targets for DFG and develop precise treatment strategies.

Abstract Hypertrophic scar formation is influenced by the intricate interplay between fibroblasts and endothelial cells. In this study, we investigated this relationship using in vitro and in vivo models. Clinical observations revealed distinct morphological changes and increased vascularity at pathological scar sites. Further analysis using OCTA, immunohistochemistry, and immunofluorescence confirmed the involvement of angiogenesis in scar formation. Our indirect co‐culture systems demonstrated that endothelial cells enhance the proliferation and migration of fibroblasts through the secretion of cytokines including VEGF, PDGF, bFGF, and TGF‐β. Additionally, a suspended co‐culture multicellular spheroid model revealed molecular‐level changes associated with extracellular matrix remodeling, cellular behaviors, inflammatory response, and pro‐angiogenic activity. Furthermore, KEGG pathway analysis identified the involvement of TGF‐β, IL‐17, Wnt, Notch, PI3K‐Akt, and MAPK pathways in regulating fibroblasts activity. These findings underscore the critical role of fibroblasts‐endothelial cells crosstalk in scar formation and provide potential targets for therapeutic intervention. Understanding the molecular mechanisms underlying this interplay holds promise for the development of innovative approaches to treat tissue injuries and diseases.

Introduction: There are few studies on the relationship between the occurrence of clopidogrel-related high residual platelet reactivity (HRPR) and estimated glomerular filtration rate (eGFR) at admission in patients with ischemic stroke. The aim of this study was to investigate the possible relationship between the two. Methods: Patients who were hospitalized and diagnosed with acute ischemic stroke were recruited from July 1, 2017, to June 30, 2018, at Shanghai TCM-Integrated Hospital. Renal function was measured within 24 h of enrollment and eGFR was calculated. Patients were tested for platelet reactivity using the VerifyNow system after 7 days of antiplatelet therapy with clopidogrel 75 mg/d alone, and patients with P2Y12 reaction unit values ≥230 were diagnosed with HRPR. The association between HRPR and eGFR was analyzed. Results: A total of 274 patients were enrolled in the study, of whom 91 (33.21%) had HRPR. Multivariate logistic regression analysis suggested that an increased risk of HRPR was independently associated with female sex and reduced eGFR (female sex: OR = 2.24, 95% CI: 1.26–3.99, p = 0.006; mild chronic kidney disease [CKD]: OR = 2.95, 95% CI: 1.47–5.93, p = 0.002; moderate CKD: OR = 3.07, 95% CI: 1.08–8.75, p = 0.04). Conclusion: Decreased eGFR is an independent risk factor for the occurrence of HRPR in patients with ischemic stroke.

Abstract The objective of this study is to investigate the behavior of the Bayesian exponentially weighted moving average (EWMA) control chart in the presence of measurement error (ME). It explores the impact of different ranked set sampling designs and loss functions on the performance of the control chart when ME is present. The analysis incorporates a covariate model, multiple measurement methods, and a conjugate prior to account for ME. The performance evaluation of the proposed Bayesian EWMA control chart with ME includes metrics such as average run length and standard deviation of run lengths. The findings, obtained through Monte Carlo simulation and real data application, indicated that ME significantly affects the performance of the Bayesian EWMA control chart when RSS schemes are employed. Particularly noteworthy is the superior performance of the median RSS scheme compared to the other two schemes in the presence of ME.

New drug discovery is under growing pressure to satisfy the demand from a wide range of domains, especially from the pharmaceutical industry and healthcare services. Assessment of drug efficacy and safety prior to human clinical trials is a crucial part of drug development, which deserves greater emphasis to reduce the cost and time in drug discovery. Recent advances in microfabrication and tissue engineering have given rise to organ-on-a-chip, an in vitro model capable of recapitulating human organ functions in vivo and providing insight into disease pathophysiology, which offers a potential alternative to animal models for more efficient pre-clinical screening of drug candidates. In this review, we first give a snapshot of general considerations for organ-on-a-chip device design. Then, we comprehensively review the recent advances in organ-on-a-chip for drug screening. Finally, we summarize some key challenges of the progress in this field and discuss future prospects of organ-on-a-chip development. Overall, this review highlights the new avenue that organ-on-a-chip opens for drug development, therapeutic innovation, and precision medicine.

Liver-resident natural killer cells develop locally and have multiple immunological roles in situ. Here the authors investigate the gut-liver axis and show the impact of the intestinal microbiota on the development of liver-resident natural killer cells.

The incorporation of vasculature is known to be effective in tissue or organ functional regeneration. However, a vague understanding of the interaction between epidermal appendages and their vascular niches is a foremost obstacle to obtaining sweat gland (SG)-specific vasculature units. Here, we map their precise anatomical connections and report that the interplay between SG cells (SGCs) and the surrounding vascular niche is key for glandular development and homeostasis maintenance. To replicate this interplay in vitro, we used three-dimensional (3D) bioprinting to generate reproducible SGC spheroids from differentiated adipose-derived mesenchymal stem cells (ADSCs). With dermal microvascular endothelial cells (DMECs), sacrificial templates made from poly (ε-caprolactone) (PCL) were fabricated to pattern the vascular niche. This interplay model promoted physiologically relevant vascularized glandular morphogenesis in vitro and in vivo. We identified a reciprocal regulatory mechanism for promoting SGs regeneration via contact-independent cell communication and direct cell-cell interactions between SGs and the vasculature. We envision the successful use of our approach for vascularized organ regeneration in the near future.

Introduction Diabetic foot ulcer (DFU) stands as a severe diabetic lower extremity complication, characterized by high amputation rates, mortality, and economic burden. We propose using Mendelian randomization studies to explore shared and distinct risk factors for diabetic lower extremity complications.Research design and methods We selected uncorrelated genetic variants associated with 85 phenotypes in five categories at the genome-wide significance level as instrumental variables. Genetic associations with DFU, diabetic polyneuropathy (DPN), and diabetic peripheral artery disease (DPAD) were obtained from the FinnGen and UK Biobank studies.Results Body mass index (BMI) emerged as the only significant risk factor for DPAD, DPN, and DFU, independent of type 2 diabetes, fasting glucose, fasting insulin, and HbA1c. Educational attainment stood out as the sole significant protective factor against DPAD, DPN, and DFU. Glycemic traits below the type 2 diabetes diagnosis threshold showed associations with DPAD and DPN. While smoking history exhibited suggestive associations with DFU, indicators of poor nutrition, particularly total protein, mean corpuscular hemoglobin, and mean corpuscular volume, may also signal potential DFU occurrence.Conclusions Enhanced glycemic control and foot care are essential for the diabetic population with high BMI, limited education, smoking history, and indicators of poor nutrition. By focusing on these specific risk factors, healthcare interventions can be better tailored to prevent and manage DFU effectively.

Soil salinization and the shortage of water resources have become important factors affecting the sustainable development of agriculture in the southern Xinjiang. Agricultural flooding in winter or spring is the main means to reduce the damage of secondary soil salinization in southern Xinjiang. However, the spatial heterogeneity of soil salinization is not considered in previous irrigation strategy. Excessive irrigation always leads to a serious waste of agricultural water resources. Irrigation zones delineation based on the degree of soil salinization is beneficial for the management of agricultural salinized land and the improvement of water use efficiency in arid areas. This study used 1599 sets of apparent electrical conductivity (ECa) data obtained before winter irrigation and after crop harvest to characterize soil salinity directly. And the spatial heterogeneity of soil salinity in the study area was analyzed directly using ECa values and statistical as well as geostatistical methods. Three main variables obtained from apparent electrical conductivity measurements (EC0.375, EC0.75, EC1.5), vegetation information (NDVI, GNDVI, SAVI), which indirectly reflected the degree of salinity, and environmental factors (Clay, Sand, Silt, DEM), which affecting the distribution of salinity, were used as auxiliary variables. Four zoning models including soil information, soil + vegetation information, soil information + environmental factors and soil + vegetation information + environmental factors were constructed. A multi-scale segmentation algorithm was used to delineate for four zone patterns and evaluate the results of management zones based on the different information. The results showed that there was a strong spatial heterogeneity of soil salinity in the study area, with the coefficients of variation of ECa all higher than 74 %. But the mean of coefficient of variation intra-zone in each zone after delineation was less than 24 %, which was significantly lower than the value before delineation. The zoning result based on only soil information was more fragmented than other zoning results, and the homogeneity intra-zone and heterogeneity among zones were both lower. This result was not desirable to the development and effective implementation of water resource allocation. Management zones delineation with additional vegetation information or environmental factors showed a better zoning result. Delineation using multisource data of soil, vegetation information and environmental factors not only had the highest homogeneity intra-zone and heterogeneity among zones, but also facilitated the implementation of variable-rate irrigation. Consequently, salinity management zoning, which integrates soil, vegetation information and environmental factors, will facilitate the implementation of efficient irrigation with variable irrigating rate.

Optical temperature sensors, which can accurately detect temperature in biological systems, are crucial to the development of healthcare monitoring. To challenge the state-of-art technology, it is necessary to design single luminescence center doped materials with multi-wavelength emission for optical temperature sensors with more modes and higher resolution. Here, an Er3+ single-doped KYF4 nanocrystals glass ceramic with an obvious thermochromic phenomenon is reported for the first time, which shows a different temperature-dependent green, red, and near-infrared luminescence behavior based on thermal disturbance model. In addition, Er3+ single-doped GC fiber was drawn and fabricated into multi-mode optical fiber temperature sensor, which has superior measured temperature resolution (＜0.5 ​°C), excellent detection limit (0.077 ​°C), and high correlation coefficient (R2) of 0.99997. More importantly, this sensor can monitor temperature in different scenarios with great environmental interference resistance and repeatability. These results indicate that our sensor shows great promise as a technology for environmental and healthcare monitoring, and it provides a route for the design of optical fiber temperature sensors with multi-mode and high resolution.

Vaccines play a crucial role in mitigating the transmission of COVID-19. The primary objective of COVID-19 vaccination campaigns is to induce immunity in individuals, thereby reducing the risk of infection, severe illness, and subsequent transmission within communities. The present study mainly focuses on examining the impact of multiple vaccinations on the transmission dynamics of COVID-19 using a new epidemic modeling approach. The vaccinated individuals are divided into three subclasses according to their vaccination status. The primary, secondary and booster shots of COVID-19 vaccines are considered in the construction of the model. Initially, the model is constructed using classical integer order differential equations and basic necessary properties are carried out. Furthermore, utilizing a fractional and fractal–fractional epidemiological approach with an exponential kernel, the model is extended with these operators in order to provide insights into the potential benefits of this vaccination strategy in controlling the spread of the disease. The uniqueness and existence criteria of the fractional and fractal–fractional models are presented and an efficient numerical solution is investigated using the modified Adams–Bashforth method. The impact of both fractional (memory index) and fractal parameters is demonstrated graphically for R01 showing the converges of solution trajectories to the disease-free and endemic steady states respectively. Moreover, we examine the impact of various vaccination rates (first and second dose, and booster short) on the reduction and mitigation of the disease incidence.

Abstract Nutritional status is an independent predictor of outcome in cirrhosis patients. Nutritional Risk Screening 2002 (NRS2002), Royal Free Hospital-Nutritional Prioritizing Tool (RFH-NPT), and Liver Disease Undernutrition Screening Tool (LDUST) were employed to detect cirrhosis with malnutrition risk in this work. Meanwhile, their diagnostic performances were compared to find the best screening method. This work aimed to establish the sarcopenia cut-off value of the transversal psoas thickness index (TPTI), and identify the risk factors for malnutrition. Cirrhosis patients who were admitted to Heibei Gerneral hospital from April 2021 to October 2021 and underwent abdominal CT examination were enrolled. 78 patients were assessed by NRS2002, RFH-NPT, and LDUST. The Global Leadership Initiative for Malnutrition (GLIM) criteria were selected as the gold standard for the diagnosis of malnutrition. Meanwhile the cut-off value of sarcopenia was established based on the TPTI of malnourished patients. Logistic regression analysis was adopted to assess the influencing factors of malnutrition risk and malnutrition. The prevalence of malnutrition was 42.31%. The prevalence of malnutrition risk was 32.1%, 61.5%, and 62.8% with NRS2002, RFH-NPT, and LDUST, respectively. NRS2002 presented the best specificity compared with the other methods, while RFH-NPT showed the highest sensitivity. The optimal gender-specific TPTI cut-off value for diagnosing sarcopenia was determined as TPTI

Abstract Mitochondrial function and homeostasis are critical to the proliferation of lung cancer cells. T-cell immunoglobulin and mucin domain-containing molecule 4 (TIM-4) promotes the development and progression of lung cancer. However, the role of TIM-4 in mitochondria homeostasis in tumor cells remains completely unknown. In this study, we found that TIM-4 promoted growth and proliferation of lung cancer cells by the oxidative phosphorylation (OXPHOS) pathway. Consistently, inhibition of OXPHOS reversed TIM-4-induced proliferation of lung cancer cells. Notably, TIM-4 promoted mitochondrial fusion via enhancing L-OPA1 protein expression. Mechanistically, TIM-4 regulated protein of L-OPA1 through the PI3K/AKT pathway, and TIM-4 interacted with ANXA2 to promote the activation of PI3K/AKT signaling. Collectively, TIM-4 promotes oxidative phosphorylation of lung cancer cells to accelerate tumor progress via ANXA2/PI3K/AKT/OPA1 axis, which sheds significant new lights on the potential role of TIM-4 in regulating tumor cell metabolism.

Oxidative stress due to excessive reactive oxygen species (ROS) production in the skin microenvironment is one of the main mechanisms in psoriasis pathogenesis. A nano drug delivery system based on ROS-responsive release can enhance drug release at the target site. In this study, a ROS-sensitive material methoxypolyethylene glycol-thioether-thiol (mPEG-SS) was synthesized using mPEG as the parent structure with sulfide structural modification. An mPEG-SS-calcipotriol (mPEG-SS-CPT, PSC) nano-micelle percutaneous delivery system was prepared by encapsulating CPT. A small animal imaging system was used to study PSC’s the ROS-sensitive drug release process. It is shown that endogenous ROS mainly affects PSC and releases drugs. Finally, the therapeutic effect of PSC on psoriasis was explored by animal experiments. Ultimately, it ameliorates imiquimod-induced psoriasis-like inflammation. Overall, PSC is an effective ROS-sensitive transdermal drug delivery system that is expected to provide a new strategy for treating psoriasis.

Acute myocardial infarction (AMI) is one of the most common ischemic heart diseases. However, lack of sufficient drug concentration (in the ischemic heart) is the major factor of treatment failure. It is urgent for researchers to engineer novel drug delivery systems to enhance the targeted delivery of cardioprotective agents. The aim of the present study was to investigate the anti-AMI ability of calycosin (CAL) and tanshinone (TAN) co-loaded; mitochondrion-targeted tetrapeptide (MTP) and cyclic arginyl-glycyl-aspartic acid (RGD) peptide co-modified nano-system.: We prepared CAL and TAN combined lipid-polymer hybrid nano-system, and RGD was modified to the system to achieve RGD-CAL/TAN NS. MTP-131 was conjugated with PEG and modified onto the nanoparticles to achieve dual ligands co-modified MTP/RGD-CAL/TAN NS. The physicochemical properties of nano-systems were characterized. The AMI therapy ability of the systems was investigated in AMI rats’ model. The size of MTP/RGD-CAL/TAN NS was 170.2 ± 5.6 nm, with a surface charge of −18.9 ± 1.9 mV. The area under the curve (AUC) and blood circulation half-life (T1/2) of MTP/RGD-CAL/TAN NS was 178.86 ± 6.62 μg·min/mL and 0.47 h, respectively. MTP/RGD-CAL/TAN NS exhibited the most significant infarct size reduction effect of 22.9%. MTP/RGD-CAL/TAN NS exhibited the highest heart accumulation and best infarct size reduction effect, which could be used as a promising system for efficient treatment of cardiovascular diseases.

Extrusion-based bioprinting (EBB) holds potential for regenerative medicine. However, the widely-used bioinks of EBB exhibit some limitations for skin regeneration, such as unsatisfactory bio-physical (i.e., mechanical, structural, biodegradable) properties and compromised cellular compatibilities, and the EBB-based bioinks with therapeutic effects targeting cutaneous wounds still remain largely undiscussed. In this review, the printability considerations for skin bioprinting were discussed. Then, current strategies for improving the physical properties of bioinks and for reinforcing bioinks in EBB approaches were introduced, respectively. Notably, we highlighted the applications and effects of current EBB-based bioinks on wound healing, wound scar formation, vascularization and the regeneration of skin appendages (i.e., sweat glands and hair follicles) and discussed the challenges and future perspectives. This review aims to provide an overall view of the applications, challenges and promising solutions about the EBB-based bioinks for cutaneous wound healing and skin regeneration.

With the modernization and internationalization of traditional Chinese medicine (TCM), the requirement for quality control has increased. The quality marker (Q-marker) is an important standard in this field and has been implemented with remarkable success in recent years. However, the establishment of Q-markers remains fragmented and the process lacks systematicity, resulting in inconsistent quality control and insufficient correlation with clinical efficacy and safety of TCM. This review introduces four multimodal integrated approaches that contribute to the discovery of more comprehensive and accurate Q-markers, thus aiding in the establishment of new quality control patterns based on the characteristics and principles of TCM. These include the whole-process quality control strategy, chemical-activity-based screening method, efficacy, safety, and consistent combination strategy, and TCM theory-guided approach. Furthermore, methodologies and representative examples of these strategies are described, and important future directions and questions in this field are also proposed.

Summary: Emerging evidence shows that pancreatic β-cell function and quality are key determinants in the progression of type 2 diabetes (T2D). The transcription factor zinc finger homeobox 2 (Zhx2) is involved in proliferation and development of multiple cells. However, the exact role of Zhx2 in β-cells and T2D remains completely unknown. Here, we report that Zhx2 orchestrates β-cell mass and function by regulating paired box protein pax-6 (Pax6). We found that β-cell-specific knockout Zhx2 (Zhx2BKO) mice showed a decrease in β-cell proliferation and glucose homeostasis. Under prediabetic and diabetic conditions, we discovered glucose intolerance in both Zhx2BKO-HFD mice and Zhx2BKO-db/db mice, with reduced β-cell mass and insulin secretion. Mechanistically, we demonstrated that Zhx2 targeted the Pax6 promoter region (−1740∼-1563; −862∼-559; −251∼+75), enhanced promoter activity. Overall, Zhx2 maintains β-cell function by transcriptionally regulating Pax6, which provides a therapeutic target for diabetes intervention.

Graphene oxide (GO) films mixed with polyethylenimine (PEI) were prepared by a layer-by-layer assembly (LBL) method, in which the GO component is then converted to reduced GO (rGO) in situ through an electron transfer interaction with a polyoxometalate (POM) that is assembled on the outer surface. With this, devices were manufactured by spreading composite films of (PEI/rGO)n-POM with different numbers of PEI/rGO layers on ITO substrates. Cyclic voltammetry (CV) reveals that the catalytic activity for H2O2 of (PEI/rGO)n-POM films was significantly higher than that of similar films of (PEI/GO)n/PEI/POM manufactured LBL with the same number of layers, although the catalyst POM content of (PEI/rGO)n-POM was only half that of (PEI/GO)n/PEI/POM. The catalytic activity of (PEI/rGO)n-POM films first increases and then decreases as the number of PEI/rGO layers increases. The result shows that (PEI/rGO)3-POM films with three PEI/rGO layers exhibit the highest efficiency. Amperometric measurements of the (PEI/rGO)3-POM films showed improved current response, high sensitivity, wide linear range, low detection limit, and fast response for H2O2 detection. The enhanced catalytic property of (PEI/rGO)n-POM films is attributed to the electron transfer interaction and electrostatic interaction between POM and rGO.

Deciphering the role of climate adaptation in generating genetic divergence and hence speciation is a central question in evolution. Comparisons of genomes of closely related species spanning selective climate gradients are particularly informative in discerning the signatures of selection and thereby providing valuable information concerning the role of climate adaptation in speciation. Here we re-sequenced 99 genomes of the two sister eel-goby species Odontamblyopus lacepedii and O. rebecca, which are endemic to tidal mudflats spanning contrasting latitude gradients, to estimate the influence of divergent climate selection on shaping genome-wide patterns of divergence. The results indicated that genome-wide differentiation between the two species was evident (genome-wide FST = 0.313). Against a background of high baseline genomic divergence, 588 and 1202 elevated divergent loci were detected to be widespread throughout their genomes, as opposed to focused within small islands of genomic regions. These patterns of divergence may arise from divergent climate selection in addition to genetic drift acting through past glacial segregation (1.46 million years ago). We identified several candidate genes that exhibited elevated divergence between the two species, including genes associated with substance metabolism, energy production, and response to environmental cues, all putative candidates closely linked to thermal adaptation expected from the latitude gradient. Interestingly, several candidates related to gamete recognition and time of puberty, and also exhibited elevated divergence, indicating their possible role in pre-zygote isolation and speciation of the two species. Our results would expand our knowledge on the roles of latitude climate adaptation and genetic drift in generating and maintaining biodiversity in marine teleosts.

The influence of some seemingly anomalous samples on modeling is often ignored in the quantitative prediction of soil composition modeling with hyperspectral data. Soil spectral transformation based on wavelet packet technology only performs pruning and threshold filtering based on experience. The feature bands selected by the Pearson correlation coefficient method often have high redundancy. To solve these problems, this paper carried out a study of the prediction of soil total iron composition based on a new method. First, regarding the problem of abnormal samples, the Monte Carlo method based on particle swarm optimization (PSO) is used to screen abnormal samples. Second, feature representation based on Shannon entropy is adopted for wavelet packet processing. The amount of information held by the wavelet packet node is used to decide whether to cut the node. Third, the feature bands selected based on the correlation coefficient and the competitive adaptive reweighted sampling (CARS) algorithm using the least squares support vector regression (LSSVR) are applied to the soil spectra before and after wavelet packet processing. Finally, the Fe content was calculated based on a 1D convolutional neural network (1D-CNN). The results show that: (1) The Monte Carlo method based on particle swarm optimization and modeling multiple times was able to handle the abnormal samples. (2) Based on the Shannon entropy wavelet packet transformation, simple operations could simultaneously preserve the spectral information while removing high-frequency noise from the spectrum, effectively improving the correlation between soil spectra and content. (3) The 1D-CNN with added residual blocks could also achieve better results in soil hyperspectral modeling with few samples.

Abstract Objective The purpose of this study was to compare imaging features between COVID-19 and mycoplasma pneumonia (MP). Materials and methods The data of patients with mild COVID-19 and MP who underwent chest computed tomography (CT) examination from February 1, 2020 to April 17, 2020 were retrospectively analyzed. The Pneumonia-CT-LKM-PP model based on a deep learning algorithm was used to automatically quantify the number, volume, and involved lobes of pulmonary lesions, and longitudinal changes in quantitative parameters were assessed in three CT follow-ups. Results A total of 10 patients with mild COVID-19 and 13 patients with MP were included in this study. There was no difference in lymphocyte counts at baseline between the two groups (1.43 ± 0.45 vs. 1.44 ± 0.50, p = 0.279). C-reactive protein levels were significantly higher in MP group than in COVID-19 group (p

Abstract Autophagy predominantly promotes cell survival by recycling cell components, while it kills cells in specific contexts. Cell death related to autophagy plays important roles in multiple physiological and pathological situations including tumorigenesis, and the mechanism needs to be defined further. PRAS40 was found to be crucial in various cancers, and phosphorylation was reported to be involved in autophagy inhibition in monocytes. However, the detailed role of PRAS40 in autophagy and the relationship to tumorigenesis remain largely unknown. Herein we screened the binding partners of PRAS40, and found that PRAS40 interacted with Phosphoglycerate kinase 1 (PGK1). PGK1 phosphorylated PRAS40 at Threonine 246, which could be inhibited by blocking the interaction. Both in vitro and in vivo results revealed that PRAS40 mediated PGK1-induced cell growth. By tracing the mechanism, we found that PGK1 suppressed autophagy-mediated cell death, in which PRAS40 was crucial. Thus PGK1 phosphorylates PRAS40 to repress autophagy-mediated cell death under normoxia, promoting cellular proliferation. The binding of PGK1 to PRAS40 was transferred to Beclin1 under hypoxia, resulting in the increase of Beclin1 phosphorylation. These results suggest a novel model of tumorigenesis, in which PGK1 switches between repressing autophagy-mediated cell death via PRAS40 and inducing autophagy through Beclin1 according to the environmental oxygen level. Our study is anticipated to be able to offer novel insights in understanding PGK1/PRAS40 signaling hyperactivated cancers.

Purpose: Understanding the inflammation and histopathological changes in vivo caused by Escherichia coli infection is of great significance for scientific research and clinical diagnosis. Methods: Mice were randomly divided into 6 groups (N = 10) after adaptive feeding, and it challenged by intraperitoneal injection with different concentrations of E. coli ATCC25922. The survival situation within 7 days was recorded, and the half-lethal dose (LD50) was calculated by Karber's method. After the end, the blood, heart, liver, spleen, lung, and kidney of the mice were collected. We detected the concentration of inflammatory cytokines (IL-6, IL-β, and TNF-α) and inducible nitric oxide synthase (iNOS) in serum by ELSIA. Organs were observed by histopathological staining and electron microscope observation. Results: The LD50 of mice infected with E. coli was 1.371∗106 CFU/kg. The concentrations of IL-6, IL-β, and TNF-α increased with time after infection in mice, reaching the highest concentration on the 7th day. iNOS was significantly increased on the 1st day of infection, and then decreased over time (P < 0.01). Within a week after infection, the colony counts of the heart, liver, spleen, lung and kidney showed a first decrease, and then reached a surge on the 7th day. Pathological results showed that a small amount of mitochondrial swelling and autophagy were seen in the spleen, lung and kidney tissues of the infected group; and a small amount of secondary lysosomes and autophagy were also seen; but no pathological changes were found in the liver and heart. Conclusion: Escherichia coli can cause inflammation and oxidative stress in mice, causing different degrees of damage to the spleen, lung, and kidney tissues, which provides theoretical support for inflammatory and pathological changes caused by Escherichia coli infection in vivo.

Background: Acute myocardial infarction (AMI) is one of the most common ischemic heart diseases. However, lack of sufficient drug concentrations in the ischemic heart may led to treatment failure. It is urgent for researchers to engineer novel drug delivery systems to enhance the targeted delivery of cardioprotective agents. Objective: The aim of the present study was to investigate the anti-AMI ability of calycosin (CAL) and tanshinone (TAN) co-loaded mitochondria targeted lipid-polymer hybrid nano-system. Methods: CAL and TAN combined lipid-polymer hybrid nano-systems were prepared and MTP-131 was conjugated with PEG and modified onto the nanoparticles to achieve MTP-CAL/TAN NS. The physicochemical properties of nano-systems were characterized, the AMI therapy ability of the systems was investigated in AMI rats’ model. Results: The size of MTP-CAL/TAN NS was 168.7 ± 5.1 nm, with a surface charge of − 21.3 ± 2.3 mV. The area under the curve (AUC) and blood circulation half-life (T1/2) of MTP-CAL/TAN NS was 178.86 ± 6.62 μg·min/mL and 0.47 h, respectively. MTP-CAL/TAN NS exhibited the most significant infarct size reduction effect of 23.9 %. Conclusion: MTP-CAL/TAN NS exhibited the highest heart accumulation and best infarct size reduction effect, which could be used as a promising system for efficient treatment of cardiovascular diseases.

Evidence suggests that increased microRNA-155 (miR-155) expression in immune cells enhances antitumor immune responses. However, given the reported association of miR-155 with tumorigenesis in various cancers, a debate is provoked on whether miR-155 is oncogenic or tumor suppressive. We aimed to interrogate the impact of tumor miR-155 expression, particularly that of cancer cell–derived miR-155, on antitumor immunity in breast cancer. We performed bioinformatic analysis of human breast cancer databases, murine experiments, and human specimen examination. We revealed that higher tumor miR-155 levels correlate with a favorable antitumor immune profile and better patient outcomes. Murine experiments demonstrated that miR-155 overexpression in breast cancer cells enhanced T cell influx, delayed tumor growth, and sensitized the tumors to immune checkpoint blockade (ICB) therapy. Mechanistically, miR-155 overexpression in breast cancer cells upregulated their CXCL9/10/11 production, which was mediated by SOCS1 inhibition and increased phosphorylated STAT1 (p-STAT1)/p-STAT3 ratios. We further found that serum miR-155 levels in breast cancer patients correlated with tumor miR-155 levels and tumor immune status. Our findings suggest that high serum and tumor miR-155 levels may be a favorable prognostic marker for breast cancer patients and that therapeutic elevation of miR-155 in breast tumors may improve the efficacy of ICB therapy via remodeling the antitumor immune landscape.

Abstract Background Lung adenocarcinoma (LUAD) is the most common pathology subtype of lung cancer. In recent years, immunotherapy, targeted therapy and chemotherapeutics conferred a certain curative effects. However, the effect and prognosis of LUAD patients are different, and the efficacy of existing LUAD risk prediction models is unsatisfactory. Methods The Cancer Genome Atlas (TCGA) LUAD dataset was downloaded. The differentially expressed immune genes (DEIGs) were analyzed with edgeR and DESeq2. The prognostic DEIGs were identified by COX regression. Protein-protein interaction (PPI) network was inferred by STRING using prognostic DEIGs with p value

The accurate estimation of rock strength is an essential task in almost all rock-based projects, such as tunnelling and excavation. Numerous efforts to create indirect techniques for calculating unconfined compressive strength (UCS) have been attempted. This is often due to the complexity of collecting and completing the abovementioned lab tests. This study applied two advanced machine learning techniques, including the extreme gradient boosting trees and random forest, for predicting the UCS based on non-destructive tests and petrographic studies. Before applying these models, a feature selection was conducted using a Pearson’s Chi-Square test. This technique selected the following inputs for the development of the gradient boosting tree (XGBT) and random forest (RF) models: dry density and ultrasonic velocity as non-destructive tests, and mica, quartz, and plagioclase as petrographic results. In addition to XGBT and RF models, some empirical equations and two single decision trees (DTs) were developed to predict UCS values. The results of this study showed that the XGBT model outperforms the RF for UCS prediction in terms of both system accuracy and error. The linear correlation of XGBT was 0.994, and its mean absolute error was 0.113. In addition, the XGBT model outperformed single DTs and empirical equations. The XGBT and RF models also outperformed KNN (R = 0.708), ANN (R = 0.625), and SVM (R = 0.816) models. The findings of this study imply that the XGBT and RF can be employed efficiently for predicting the UCS values.

For maritime broadband communications, atmospheric ducts can enable beyond line-of-sight communications or cause severe interference. Due to the strong spatial–temporal variability of atmospheric conditions in near-shore areas, atmospheric ducts have inherent spatial heterogeneity and suddenness. This paper aims to evaluate the effect of horizontally inhomogeneous ducts on maritime radio propagation through theoretical analysis and measurement validation. To make better use of meteorological reanalysis data, we design a range-dependent atmospheric duct model. Then, a sliced parabolic equation algorithm is proposed to improve the prediction accuracy of path loss. We derive the corresponding numerical solution and analyze the feasibility of the proposed algorithm under the range-dependent duct conditions. A 3.5 GHz long-distance radio propagation measurement is utilized to verify the algorithm. The spatial distribution characteristics of atmospheric ducts in the measurements are analyzed. Based on actual duct conditions, the simulation results are consistent with the measured path loss. The proposed algorithm outperforms the existing method during the multiple duct periods. We further investigate the influence of different duct horizontal characteristics on the received signal strength.

Abstract Background Under natural conditions, soil nutrients are heterogeneously distributed, and plants have developed adaptation strategies to efficiently forage patchily distributed nutrient. Most previous studies examined either patch strength or patch size separately and focused mainly on root morphological plasticity (increased root proliferation in nutrient-rich patch), thus the effects of both patch strength and size on morphological and physiological plasticity are not well understood. In this study, we examined the foraging strategy of Neyraudia reynaudiana (Kunth) Keng ex Hithc, a pioneer grass colonizing degraded sites, with respect to patch strength and size in heterogeneously distributed phosphorus (P), and how foraging patchily distributed P affects total plant biomass production. Plants were grown in sand-culture pots divided into ½, ¼, 1/6 compartments and full size and supplied with 0 + 0/30, 0 + 7.5/30 and 7.5 + 0/30 mg P/kg dry soil as KH2PO4 or 0 + 15/15, 0 + 18.5/ 18.5, 7.5 + 15/15 mg kg − 1 in the homogenous treatment. The first amount was the P concentration in the central region, and that the second amount was the P concentration in the outer parts of the pot. Results After 3 months of growth under experimental conditions, significantly (p

Renal tubular epithelial cells (RTECs) are one of the most mitochondria-rich cell types, and are thus vulnerable to mitochondrial dysregulation, which is defined as a pivotal event in tubular damage in diabetic nephropathy (DN). However, the underlying mechanisms remain largely unknown. Here, we investigated the role and mechanisms of tumor necrosis factor alpha-induced protein 8-like 1 (TNFAIP8L1/TIPE1) in high glucose (HG)-induced mitochondrial dysfunction in RTECs and DN progression. TIPE1 expression was predominantly upregulated in RTECs in patients with DN and mice with streptozotocin (STZ)-induced DN. Conditional knockout of Tipe1 in RTECs significantly decreased the urine protein creatinine ratio, renal tubular damage, epithelial-mesenchymal transition, and interstitial fibrosis in STZ-induced mice. RNA sequencing revealed that citrate cycle-related genes were positively enriched in the renal tissues of RTEC-specific Tipe1 knockout mice. Tipe1 deficiency upregulated ATP levels, mitochondrial membrane potential, and respiration rate, but downregulated mitochondrial ROS levels in RTECs. Furthermore, Tipe1 ablation led to enhanced mitophagy in RTECs, indicative of increased LC3II, PINK1, and Parkin expression, but decreased p62 expression in mitochondria. Mechanistically, mass spectrometry screening and co-immunoprecipitation assays revealed the interaction of TIPE1 with prohibitin 2 (PHB2), a crucial mitophagy receptor. Intriguingly, TIPE1 promoted the ubiquitination and proteasomal degradation of PHB2. Subsequently, PHB2 knockdown almost abrogated the improvement of Tipe1 loss on HG-induced tubular cell mitophagy and damage. Thus, TIPE1 disrupts mitochondrial homeostasis in RTECs and promotes tubular damage by destabilizing PHB2 under HG conditions. Hence, TIPE1 may act as a potential therapeutic target to prevent DN progression.

Mean platelet volume (MPV) is an indicator of platelet activation and has been proposed as a diagnostic marker for several kinds of cancers. We investigated the value of MPV as a diagnostic marker for prostate cancer (PCa) and examined whether MPV in combination with prostate-specific antigen (PSA) could increase the sensitivity or specificity of PSA for PCa diagnosis. For this study, 107 pathologically confirmed PCa and 177 non-PCa patients who underwent prostate biopsy were retrospectively studied. Clinical data and pre-biopsy hematological parameters were collected. The above parameters were compared between PCa and non-PCa patients. The correlation between MPV and clinical characteristics was analyzed. Receiver operating characteristic (ROC) analysis was used to explore the diagnostic value of MPV for PCa. Among all parameters analyzed, the difference was only found in MPV, platelet distribution width (PDW), and PSA between PCa and non-PCa patients. MPV was significantly decreased and PDW increased in PCa than that of non-PCa among men. ROC analysis identified MPV ≤ 9.05 fl as a cut-off value for potential PCa with area under the ROC curve (AUC) = 0.783, 95% CI = 0.733–0.833, sensitivity = 0.746, and specificity = 0.708. AUC and the sensitivity of MPV were comparable with total PSA (TPSA) or free PSA (FPSA). However, the specificity of MPV was larger than that of TPSA (0.461) or FPSA (0.561). Furthermore, MPV combined with TPSA or FPSA further enhanced the specificity of TPSA (0.844) or FPSA (0.927), but PDW did not. These findings suggested that MPV could have a predictive value for the diagnosis of PCa. MPV in combination with TPSA or FPSA could enhance the specificity of PSA and may reduce the rate of unnecessary biopsy for patients with high levels of PSA.

T-cell immunoglobulin domain and mucin domain 4 (TIM-4) is a transmembrane protein that promotes epithelial-mesenchymal transition (EMT), migration and invasion of non-small cell lung cancer (NSCLC) cells. Most transmembrane proteins are modified by N-glycosylation and the importance of protein N-glycosylation in cancer cell metastasis has been well appreciated. However, whether TIM-4 is modified by N-glycosylation and the role of TIM-4 N-glycosylation in NSCLC remains largely unknown. In the current study, we reported that TIM-4 was extensively N-glycosylated at Asn291. After the removal of N-glycosylation, the stability of TIM-4 protein was decreased and TIM-4 was more susceptible to degradation by ER-localized ubiquitin ligase-mediated ERAD. Thus, the expression of TIM-4 on the cell surface was decreased, which suppressed TIM-4-mediated metastasis in NSCLC. In summary, the present study identifies TIM-4 N-glycosylation and its role in NSCLS migration, which would provide a valuable biomarker for developing drugs targeting N-glycosylation at Asn291 on TIM-4.

Background and Objective Lung cancer is the most common cancer worldwide with the highest morbidity and mortality, in which the non-small cell lung cancer accounts for 80% of all cases. The expression of (HOX transcript antisense RNA) HOTAIR were abnormal in a variety of tumor tissues and is involved in the regulation of the occurrence and development of lung cancer. The purpose of this study is to investigate the effect and mechanism of down-regulation of HOTAIR on gefitinib resistance of lung adenocarcinoma HCC827 cells by targeting PTEN. Methods The HOTAIR downstream target gene was predicted by bioinformatics database. The small interfering RNAs (siRNA) which is corresponding to HOTAIR was transfected using LipofectamineTM 2000. Quantitative real-time PCR (RT-qPCR) and Western blot were used to detect the expression of HOTAIR, PTEN, PI3K and AKT in HCC827 and HCC827GR cells. MTT assay was used to detect the changes in drug resistance of HCC827GR cells. Flow cytometry analysis were used to test the cell proliferation and the rate of apoptosis. Results The expression of HOTAIR increased in HCC827GR and the serum of NSCLC patients with gefitinib resistance (P

Background: Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome, which has become one of the globally recognized threats to health in 21st. The aim of this study was to elucidate the protective effects of berberine on intestinal mucosal barrier by regulating the intestinal flora in nonalcoholic fatty liver disease (NAFLD) rats. Methods: A total of 33 rats were randomly divided into the normal control group, high diet model group and berberine group. Changes of intestinal microbiota were detected by the 454 pyrosequencing of the V4 region of 16SrRNA genes. Morphological changes of liver and ileum tissue and serum biochemical markers were observed. Results: Bacteroidetes and Cyanobacteria of M group were significantly decreased as compared to N group, while Firmicutes and Cyanobacteria of B group were significantly decreased as compared to M group. Hepatocytes swelling and number of fat vacuoles of rats in B group were relieved, and hepatocytes were arranged neatly as compared to M group. The intestinal mucosal villi in B group were plump, and arranged tight and neatly, and the tight junctions and smaller gaps were also observed in B group compared to M group. Conclusions: High-fat diet (HFD) can interrupt the intestinal flora and damage intestinal barrier. Berberine can reduce gut permeability and improve intestinal barrier in NAFLD rats. Moreover, berberine can reduce the variability of intestinal flora in NAFLD rats. Our results suggest that berberine may be the protective effects on the intestinal mucosal barrier in NAFLD rats.

Objective: To study the protective role of berberine (BBR) against nonalcoholic fatty liver disease (NAFLD) on intestinal barrier via investigating its effect on intestinal permeability and intestinal innate immune system in a rat model. Method: Sprague-Dawley rats were randomly divided into three groups: control rats (group N), high-fat diet (HFD) model rats (group M) and BBR-treated rats (group B). Rats in group M and group B were fed with HFD for 12 weeks to induce NAFLD. Rats in group B were then received 4 weeks of BBR administration with continuous HFD feeding. Samples were collected at 16th week. Results: HFD feeding increased the body weight of rats and caused liver steatosis as indicated by hematoxylin & eosin (H&E) staining. Analysis of serum parameters showed that alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), endotoxin, interleukin-1β (IL-1β), interleukin-18 (IL-18), and tumor necrosis factor-α (TNF-α) were significantly higher in group M as compared group N. These results confirmed the successful establishment of NAFLD in rats. With 4 weeks of BBR administration, body weight of group B decreased significantly as compared with group M. Serum levels of ALT, AST, TC, TG, endotoxin, IL-1β, IL-18 and TNF-α reduced significantly and hepatocyte steatosis ameliorated. RT-PCR and Western blot analysis showed that BBR reduced the elevated mRNA and protein expressions of innate immune response elements NOD1, NOD2 and NLRP3 that were caused by HFD. BBR also antagonized the effect of NAFLD on Caspase-1 and Claudin-4 protein expressions. Conclusions: BBR alleviates endotoxemia, reduces serum lipids, increases liver function, reduces systemic inflammation and diminishes liver inflammation and steatosis in NAFLD rats. The protective effect of BBR against NALFD is achieved through ameliorating intestinal mucosal barrier dysfunction partly by improving permeability of intestinal mucosa and modulating intestinal innate immune components.

Abstract Both steatosis and inflammation are key pathological events in the progression of non-alcoholic fatty liver disease (NAFLD). Probiotics are beneficial for the prevention and treatment of NAFLD. Bifidobacterium animalis subsp. lactis V9 (V9) is a newly isolated strain with favorable probiotic properties. The study aims to evaluate the effects and mechanisms of V9 on the hepatic steatosis and inflammatory responses in a rat model of NAFLD induced by high-fat diets (HFD). Our results showed that administration of V9 significantly attenuated the HFD-induced increases in alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, resulting in alleviated hepatic steatosis. V9 supplementation reduced the accumulation of hepatic triglyceride and free fatty acid,while increasing the levels of glycogen. Serum levels of glucose were also decreased in HFD rats administrated with V9. Meanwhile, the transcription of SREBP-1c and FAS was reduced, and the hepatic expression of phosphorylated-AMPK and PPAR-α was restored after V9 administration. V9 suppressed the production of inflammatory cytokines (e.g. IL-6, IL-1β, and TNF-α) in HFD-fed rats. The anti-inflammatory effects of V9 was found to be associated with the inhibition of hepatic expression of TLR4, TLR9, NLRP3, and ASC mRNA. Furthermore, the activation of ERK, JNK, AKT and NF-κB were suppressed by V9 treatment. These results indicate that Bifidobacterium lactis V9 improves NAFLD by regulating de novo lipid synthesis and suppressing inflammation through AMPK and TLR-NF-κB pathways, respectively.

Oriented lines impact human cognition subconsciously. This study aimed to determine whether line orientations in the background of Chinese written characters influenced individual’s memory and emotion. Five pictures with Chinese characters as experimental material, in which four had equidistant parallel lines (0°, -45°, 90°, and +45°) as background and the other one had a blank background, were presented on a personal computer screen, for 15 seconds each, to 94 participants. The participants were then given 45 seconds to write down what they had just memorized. Participants’ emotion was identified by their Heart Rate Variability (HRV) simultaneously during the viewing process. The results showed that vertical (90°) and 45° leftward leaning lines (-45°) did not weaken users’ memory, and no significant difference in memory was found between these two states and the blank background, while horizontal (0°) and 45° rightward leaning lines (+45°) weakened the memory effect significantly. Overall, memory decreased in the condition of horizontally lined background while no influence in vertically lined background condition; and it showed asymmetry under leftward and rightward leaning line conditions: memory decreased in rightward leaning lined background while no influence in leftward lined background. Moreover, the results of emotion and memory showed negative similar trend. These findings provide practical suggestions for visual information design.

Objective To evaluate the efficacy and safety of cilostazol, pentoxifylline, beraprost for intermittent claudication due to lower extremity arterial occlusive disease. Methods Randomized controlled clinical trials were identified from PubMed, Scopus, EMbase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, SinoMed, Wanfang and Chongqing VIP databases, from the database inception to 31/12/2021. The outcome measures were walking distance measured by treadmill (maximum and pain-free walking distance), ankle-brachial index and adverse events. The quality of included studies was assessed by the Cochrane bias risk assessment tool. A network meta-analysis was carried out with Stata 16.0 software. Results There were 29 RCTs included in the study, covering total 5352 patients. Cilostazol was ranked first for both maximum and pain-free walking distance, followed by beraprost and pentoxifylline. For cilostazol, pentoxifylline and beraprost, maximum walking distance increased by 62.93 95%CI(44.06, 81.79), 32.72 95%CI(13.51, 55.79) and 43.90 95%CI(2.10, 85.71) meters, respectively relative to placebo, and pain-free walking distance increased by 23.92 95%CI(11.24, 36.61), 15.16 95%CI(2.33, 27.99) and 19.78 95%CI(-3.07, 42.62) meters. For cilostazol, pentoxifylline, beraprost and cilostazol combined with beraprost, ankle-brachial index increased by 0.06 95%CI(0.04, 0.07), -0.01 95%CI(-0.08, 0.05), 0.18 95%CI(0.12, 0.23) and 0.23 95%CI(0.18, 0.27), respectively relative to placebo. The pentoxifylline and cilostazol was associated with a lower ratio of adverse events than beraprost and cilostazol combined with beraprost. Conclusion Cilostazol, pentoxifylline and beraprost were all effective treatments for intermittent claudication; cilostazol with good tolerance was likely to be the most effective in walking distance, while beraprost and cilostazol combined with beraprost were more prominent in the ankle-brachial index.