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Objective: The role of intraoperative radiation therapy (IORT) in the management of resectable pancreatic cancer (RPC) remains unclear. To date, the application of IORT using a low-energy X-ray source has not been extensively investigated. Therefore, this study was conducted to evaluate the safety and efficacy of IORT using a 50 kV X-ray source in treating RPC. Methods: Patients with RPC who underwent radical pancreatectomy and IORT were enrolled. The primary endpoint was time to treatment failure (TTF) survival, whereas the secondary endpoints were safety and overall survival (OS). Results: By November 2023, 35 patients with RPC were treated according to the study protocol. The median TTF was 11.67 months, whereas the median OS for the cohort was 22.2 months. The local recurrence rate was 20%. The most common postoperative complication was pancreatic fistula. The incidence of delayed gastric emptying was 20%. Within 30 days after surgery, one patient experienced abdominal pain, another experienced vomiting, and one died because of abdominal infection and a grade C pancreatic fistula. Carcinoembryonic antigen (CEA) and D-dimer levels significantly correlated with TTF and OS in multivariate analyses. The carbohydrate antigen 19-9 (CA19-9) level was another prognostic factor significantly associated with OS. Patients with low D-dimer and normal CA19-9 levels showed prolonged OS with an IORT dose ≤ 15 Gy. Conclusions: This study supports use of IORT with a 50 kV X-ray source in treating RPC. IORT using a low-energy X-ray source was well-tolerated and feasible. Additionally, D-dimer, CEA, and CA19-9 levels may help identify patient profiles potentially benefitting from IORT.

In this study, we investigate the burning behavior of titanium during the electroslag remelting (ESR) process and its impact on the titanium content at the endpoint using machine learning. Initially, a comprehensive database was established by collecting data from literature and experiments, encompassing slag system composition, smelting temperature, and material composition content. Subsequently, six machine learning algorithms, including random forest and Bayesian regression, were employed to model the burning loss behavior of titanium. The random forest model, which exhibited optimal mean square error (MSE) performance, was utilized to generate partial dependence plots. These plots, in conjunction with experimental observations and existing studies, facilitated the analysis of key factors influencing titanium burn loss. Furthermore, the same six machine learning models were applied to predict the endpoint titanium content. The Bayesian regression model demonstrated superior performance in terms of R2 and MSE, leading to the derivation of an empirical formula for predicting endpoint titanium content. This empirical formula was subsequently validated, refined, and optimized using a thermodynamic model based on the theory of molecular ion coexistence. The final prediction formula achieved an error margin of 0.123%.

Objective: Little progress has been made in recent years using first-line chemotherapy, including gemcitabine combined with nab-paclitaxel, FOLFIRINOX, and NALIRIFOX, for advanced pancreatic adenocarcinoma (APC). In addition, the optimal second-line chemotherapy regimen has not been determined. This study aimed to compare the effectiveness of different types of second-line chemotherapy for APC. Methods: Patients with APC who received first-line treatment from January 2008 to January 2021 were considered eligible for this retrospective analysis. The primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS), respectively. Results: Four hundred and thirty-seven and 617 patients were treated with 5-fluorouracil- and gemcitabine-based chemotherapy as first-line treatment, respectively. Demographic and clinical features, except age and liver metastasis, were comparable between the two groups (P < 0.05). The median OS was 8.8 and 7.8 months in patients who received a 5-fluorouracil- and gemcitabine-based combined regimen for first-line therapy, respectively (HR = 1.244, 95% CI = 1.090–1.419; P < 0.001). The median OS was 5.6 and 1.9 months in patients who received second-line chemotherapy and supportive care, respectively (HR = 0.766, 95% CI = 0.677–0.867; P < 0.001). The median PFS was not significantly differently between gemcitabine or 5-fluorouracil monotherapy and combination therapy. Conclusions: A 5-fluorouracil- or gemcitabine-based combined regimen was shown to be as effective as a single 5-fluorouracil or gemcitabine regimen as second-line therapy for patients with APC.

Abstract Aberrant upregulation of hepatic lipogenesis induced by chronic and excessive alcohol consumption is a critical driver of the progression of alcohol‐associated liver disease (ALD), however, no effective approaches inhibiting lipogenesis are currently available for treating ALD patients. Moreover, little is known about whether and how nonethanol ingredients in alcoholic beverages regulate the pathogenesis of ALD. Here the discovery of a small molecule that activates the production and secretion of fibroblast growth factor 21 (FGF21) is reported. It is shown that the activator ethyl lactate, a nonethanol ingredient found in distilled liquors, ameliorates alcoholic hepatosteatosis, inflammation and acute‐on‐chronic liver injury by stimulating FGF21. In response to chronic‐plus‐binge ethanol feeding or fasting, ethyl lactate mimics lipogenesis lowering effects by stimulating FGF21 production through the NAD+‐dependent deacetylase sirtuin 1 (SIRT1) signaling pathway. These ethyl lactate‐mediated beneficial effects are abolished by inhibition of SIRT1 through injection of EX527. Importantly, FGF21 deficiency in hepatocytes blocks the downregulation of lipogenesis by ethyl lactate and exacerbates alcoholic steatosis, inflammation and liver injury. The regulatory mechanism is discussed during the pathophysiological conditions and suggests new lines of research into the therapeutic use of a foodborne small molecule ethyl lactate.

Critical-size bone defects (CSDs), which are those that do not self-repair in a given period, are essential for evaluating bone-regeneration strategies. We established CSDs models in the rabbit cranium and ulna, and the bone-regeneration capacities of porous calcium phosphate (CaP) ceramics were assessed. A 12.6-mm cranial defect was confirmed as a CSDs after 12 weeks, with submicron surface-structured biphasic calcium-phosphate (BCP) implants [consisting of 20% hydroxyapatite and 80% tricalcium phosphate (TCP)] demonstrating significantly higher bone formation (32.2% ± 10.6%) than micron surface-structured TCP (TCP-B) implants (17.8% ± 4.6%, p = 0.0121). Ulna defects (15.0 mm in length) failed to heal spontaneously within 24 weeks when the periosteum was removed from both the ulna and radius, and the radius was covered with an expanded polytetrafluoroethylene (ePTFE) membrane. No bone bridging (i.e., union) was observed in the BCP implants at 12 weeks, whereas 80% of BCP implants (four out of five) achieved union by 24 weeks. Furthermore, the bone area within the available space of BCP implants increased significantly from 19.3% ± 7.3% at 12 weeks to 37.7% ± 8.5% at 24 weeks (p = 0.0063), accompanied by significant BCP resorption (14.8% at 12 weeks and 30.2% at 24 weeks). This study offers two rabbit CSDs models for evaluating bone-regeneration strategies (including bone substitution), and the overall data obtained in the current study indicate the possibility of repairing CSDs with CaP ceramics demonstrating improved bone-forming ability given adequate implantation time.

Medical images and radiology reports are essential for physicians to diagnose medical conditions. However, the vast diversity and cross-source heterogeneity inherent in these data have posed significant challenges to the generalizability of current data-mining methods for clinical decision-making. Recently, multimodal large language models (MLLMs), especially Gemini-Vision-series (Gemini) and GPT-4-series (GPT-4) models, have revolutionized numerous domains, significantly impacting the medical field. In this study, we conducted a detailed evaluation of the performance of the Gemini series models (including Gemini-1.0-Pro-Vision, Gemini-1.5-Pro, and Gemini-1.5-Flash) and GPT series models (including GPT-4o, GPT-4-Turbo, and GPT-3.5-Turbo) across 14 medical datasets, covering 5 medical imaging categories (dermatology, radiology, dentistry, ophthalmology, and endoscopy) and 3 radiology report datasets. The investigated tasks encompass disease classification, lesion segmentation, anatomical localization, disease diagnosis, report generation, and lesion detection. Moreover, we also validated the performance of the Claude-3-Opus, Yi-Large, Yi-Large-Turbo, and LLaMA 3 models to gain a comprehensive understanding of the MLLM models in the medical field. Our experimental results demonstrated that Gemini-series models excelled in report generation and lesion detection but faces challenges in disease classification and anatomical localization. Conversely, GPT-series models exhibited proficiency in lesion segmentation and anatomical localization but encountered difficulties in disease diagnosis and lesion detection. Additionally, both the Gemini series and GPT series contain models that have demonstrated commendable generation efficiency. While both models hold promise in reducing physician workload, alleviating pressure on limited healthcare resources, and fostering collaboration between clinical practitioners and artificial intelligence technologies, substantial enhancements and comprehensive validations remain imperative before clinical deployment.

IntroductionA variety of studies have shown a link between the gut microbiota and autoimmune diseases, but the causal relationship with Henoch-Schönlein purpura (HSP) and immune thrombocytopenic purpura (ITP) is unknown.MethodsThis study investigated the bidirectional causality between gut microbiota and HSP and ITP using Mendelian randomization (MR). Large-scale genetic data of gut microbiota at phylum to species level from the MiBioGen consortium and the Dutch Microbiome Project were utilized. Genome-wide association studies (GWAS) summary statistics for HSP and ITP came from FinnGen R10. Various MR methods were applied to infer causal relationships, including inverse variance weighted (IVW), maximum likelihood (ML), cML-MA, MR-Egger, weighted median, weighted model, and MR-PRESSO. Multiple sensitivity analyses and Bonferroni correction were conducted to enhance robustness and reliability.ResultsBased on the IVW estimates, 23 bacterial taxa were identified to have suggestive associations with HSP and ITP. Remarkably, after Bonferroni correction, family Alcaligenaceae (OR = 2.86, 95% CI = 1.52–5.37; IVW, p = 1.10 × 10−3, ML, p = 1.40 × 10−3) was significantly associated with ITP as a risk factor, while family Bacteroidales S24 7group (OR = 0.46, 95% CI = 0.29–0.74; IVW, p = 1.40 × 10−3) was significantly associated with ITP as a protective factor. No significant associations between HSP and ITP and gut microbiota were found in reverse analyses.ConclusionOur study provides evidence of causal effects of gut microbiota on HSP and ITP, highlighting the importance of further research to clarify the underlying mechanisms and develop targeted therapeutic interventions for these autoimmune diseases.

Distribution grid topology and admittance information are essential for system planning, operation, and protection. In many distribution grids, missing or inaccurate topology and admittance data call for efficient estimation methods. However, measurement data may be insufficient or contaminated with large noise, which will fundamentally limit the estimation accuracy. This work explores the theoretical precision limits of the topology and admittance estimation (TAE) problem with different measurement devices, noise levels, and numbers of measurements. On this basis, we propose a conservative progressive self-adaptive (CPS) algorithm to estimate the topology and admittance. The results on IEEE 33 and 141-bus systems validate that the proposed CPS method can approach the theoretical precision limits under various measurement settings.

Abstract Chronic adipose tissue inflammation accompanied by macrophage accumulation and activation is implicated in the pathogenesis of insulin resistance and type 2 diabetes in humans. The transcriptional coregulator CREBZF is a key factor in hepatic metabolism, yet its role in modulating adipose tissue inflammation and type 2 diabetes remains elusive. The present study demonstrates that overnutrition‐induced CREBZF links adipose tissue macrophage (ATM) proinflammatory activation to insulin resistance. CREBZF deficiency in macrophages, not in neutrophils, attenuates macrophage infiltration in adipose, proinflammatory activation, and hyperglycemia in diet‐induced insulin‐resistant mice. The coculture assays show that macrophage CREBZF deficiency improves insulin sensitivity in primary adipocytes and adipose tissue. Mechanistically, CREBZF competitively inhibits the binding of IκBα to p65, resulting in enhanced NF‐κB activity. In addition, bromocriptine is identified as a small molecule inhibitor of CREBZF in macrophages, which suppresses the proinflammatory phenotype and improves metabolic dysfunction. Furthermore, CREBZF is highly expressed in ATM of obese humans and mice, which is positively correlated with proinflammatory genes and insulin resistance in humans. This study identifies a previously unknown role of CREBZF coupling ATM activation to systemic insulin resistance and type 2 diabetes.

ObjectiveWith the development of information and communication technology, cyberbullying among Chinese college students has become more frequent, bringing many negative consequences to both society and students themselves. Childhood psychological maltreatment may be one of the influencing factors of cyberbullying, but its internal mechanism remains poorly understood. This study aimed to explore the relationship between childhood psychological maltreatment and cyberbullying among college students and to further explore the mediating effect of negative emotion and the moderating effect of meaning in life.MethodsIn this study, 656 college students (48.7% males) were recruited to complete anonymous questionnaires assessing their perceptions of child psychological maltreatment, negative affect, meaning in life and cyberbullying. SPSS23.0 and Hayes PROCESS macro for SPSS were used to conduct statistical analysis.Results(1) Childhood psychological maltreatment was significantly positively associated with cyberbullying; (2) Negative affect played a partially mediating role between childhood psychological maltreatment and cyberbullying; and (3) Meaning in life moderated the direct association between childhood psychological maltreatment and cyberbullying and moderated the association between negative affect and cyberbullying.ConclusionIn this study, a moderated mediation model was constructed and the internal mechanism of childhood psychological maltreatment and cyberbullying among college students was found. The results provided both theoretical contributions and practical suggestions for preventing cyberbullying.

In this paper, the as-cast microstructure, microsegregation, precipitates and suitable homogenization process of a novel Ni-based wrought superalloy prepared by vacuum induction melting (VIM) + vacuum arc remelting (VAR) were investigated by optical microscope (OM), scanning electron microscope (SEM), electron probe microanalysis (EPMA), differential scanning calorimetry (DSC), high temperature confocal laser scanning microscope (HT-CLSM) and thermal simulation compression. The results show that severe element segregation exists in the ingot. Nb, Ti and Al are mainly segregated in the interdendritic region, while W is mainly segregated in the dendrite arm. The precipitates in the alloy mainly include non-uniform γ′ strengthening phase, coarse (γ + γ′) eutectic phase and MC carbide, among which, the redissolution temperature range of γ′ phase is 1060–1220 °C; the (γ + γ′) eutectic phase can be redissolved obviously above 1180 °C but melted into liquid at 1250 °C; the redissolution temperature range of MC carbide is 1349–1358 °C, exceeding the solidus temperature of the alloy. After homogenization at 1220 °C/10 h, all the γ′ phase and most of the (γ + γ′) eutectic phase can be redissolved, and the element segregation can be significantly alleviated, moreover, the hot deformation resistance of the alloy is lower and the dynamic recrystallization (DRX) degree is higher, indicating that 1220 °C/10 h is an ideal single-stage homogenization process.

In 2020 and 2021, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus, caused a global pandemic. Vaccines are expected to reduce the pressure of prevention and control, and have become the most effective strategy to solve the pandemic crisis. SARS-CoV-2 infects the host by binding to the cellular receptor angiotensin converting enzyme 2 (ACE2) via the receptor-binding domain (RBD) of the surface spike (S) glycoprotein. In this study, a candidate vaccine based on a RBD recombinant subunit was prepared by means of a novel glycoengineered yeast Pichia pastoris expression system with characteristics of glycosylation modification similar to those of mammalian cells. The candidate vaccine effectively stimulated mice to produce high-titer anti-RBD specific antibody. Furthermore, the specific antibody titer and virus-neutralizing antibody (NAb) titer induced by the vaccine were increased significantly by the combination of the double adjuvants Al(OH)3 and CpG. Our results showed that the virus-NAb lasted for more than six months in mice. To summarize, we have obtained a SARS-CoV-2 vaccine based on the RBD of the S glycoprotein expressed in glycoengineered Pichia pastoris, which stimulates neutralizing and protective antibody responses. A technical route for fucose-free complex-type N-glycosylation modified recombinant subunit vaccine preparation has been established.

The aim of this study was to evaluate the influence of 5% (v/v) sea buckthorn on the flavor and consumer acceptance of probiotic yogurts. Eight strains of lactic acid bacteria (LAB) were screened from pickled cowpea, pickles, Tibetan kefir, kurut, Xinjiang condensed yogurt previously and then applied in the fermentation of plain yogurt and sea buckthorn yogurt. Firstly E-nose, E-tongue and fuzzy comprehensive evaluation method were used to evaluate the consumer acceptance of the plain yogurt and sea buckthorn yogurt fermented by different LAB. Then head space-solid phase microextraction-gas chromatography/mass (HS-SPME-GC/MS) method was used to analyze the flavor composition of plain yogurt and sea buckthorn yogurt. The results showed that addition of 5% (v/v) sea buckthorn could significantly affect the flavor of yogurt, including the increase of aroma and the decrease of unpleasant odor, as well as the decrease of bitterness, umami and richness. The results of GC/MS showed that the addition of sea buckthorn could provide more esters and alcohols to yogurt, which were well-known to present fruity, fermentative and floral aroma in many fruits. The results of sensory evaluation showed that among 8 strains of selected LAB, sea buckthorn yogurt fermented by Lactobacillus pentosus Z-14 screened from pickles had the highest score and was best accepted by consumers.

Abstract Bone defects caused by trauma, tumor, or osteoarthritis remain challenging due to the lack of effective treatments in clinic. Stem cell transplantation has emerged as an alternative approach for bone repair and attracted widespread attention owing to its excellent biological activities and therapy effect. The attempts to develop this therapeutic approach focus on the generation of effective cell delivery vehicles, since the shortcomings of direct injection of stem cells into target tissues. Here, we developed a novel core-shell microcapsule with a stem cell-laden core and a biomass shell by using all-aqueous phase microfluidic electrospray technology. The designed core-shell microcapsules showed a high cell viability during the culture procedure. In addition, the animal experiments exhibited that stem cell-laden core-shell microcapsules have good biocompatibility and therapeutic effect for bone defects. This study indicated that the core-shell biomass microcapsules generated by microfluidic electrospray have promising potential in tissue engineering and regenerative medicine.

Implantation of cardiovascular stents is an important therapeutic method to treat coronary artery diseases. Bare-metal and drug-eluting stents show promising clinical outcomes, however, their permanent presence may create complications. In recent years, numerous preclinical and clinical trials have evaluated the properties of bioresorbable stents, including polymer and magnesium-based stents. Three-dimensional (3D) printed-shape-memory polymeric materials enable the self-deployment of stents and provide a novel approach for individualized treatment. Novel bioresorbable metallic stents such as iron- and zinc-based stents have also been investigated and refined. However, the development of novel bioresorbable stents accompanied by clinical translation remains time-consuming and challenging. This review comprehensively summarizes the development of bioresorbable stents based on their preclinical/clinical trials and highlights translational research as well as novel technologies for stents (e.g., bioresorbable electronic stents integrated with biosensors). These findings are expected to inspire the design of novel stents and optimization approaches to improve the efficacy of treatments for cardiovascular diseases.

Abstract Angelica sinensis (Oliv.) Diels root part is an integral component of traditional Chinese medicine, widely prescribed to improve blood circulation and blood stasis. However, early bolting of A. sinensis compromises the quality of the roots and hence is a major limitation for yield of medicinal materials. To date, little information about the molecular mechanisms underlying bolting is available for this important medicinal plant. To identify genes putatively involved in early bolting, we have conducted the transcriptome analysis of the shoot tips of the early-bolting plants and non-bolting (normal) plants of A. sinensis, respectively, using a combination of third-generation sequencing and next-generation sequencing. A total of 43,438 non-redundant transcripts were collected and 475 unique differentially expressed genes (DEGs) were identified. Gene annotation and functional analyses revealed that DEGs were highly involved in plant hormone signaling and biosynthesis pathways, three main flowering pathways, pollen formation, and very-long-chain fatty acids biosynthesis pathways. The levels of endogenous hormones were also changed significantly in the early bolting stage of A. sinensis. This study provided new insights into the transcriptomic control of early bolting in A. sinensis, which could be further applied to enhance the yield of medicinally important raw materials.

In this paper, a design of a silicon mode (de)multiplexer based on cascaded counter-tapered couplers is proposed and investigated. By using the particle swarm optimization algorithm and finite difference time domain method, structural parameters of each counter-tapered coupler in our proposed mode (de)multiplexer are optimized so that high conversion efficiencies can be obtained and coupling lengths can be significantly shortened. The coupling lengths of counter-tapered couplers in the proposed silicon four-mode (de)multiplexer operating in transverse-electric polarization are 8 μm, 9 μm, and 10 μm. The corresponding conversion efficiencies are respectively 98.98%, 99.98%, and 98.68%. Experimental results show that, the fabricated device exhibits a demultiplexed crosstalk of -32.76 dB, -27.10 dB, -32.45 dB, or -33.29 dB at 1550 nm wavelength, when the fundamental transverse-electric mode is respectively launched into the ports Input0, Input1, Input2, or Input3. The measured demultiplexed crosstalk is less than -15.15 dB from 1525 to 1596 nm and lower than -18.12 dB from 1525 to 1561 nm.

Background and Aims: Butyric acid is an intestinal microbiota-produced short-chain fatty acid, which exerts salutary effects on alleviating nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanism of butyrate on regulating hepatic lipid metabolism is largely unexplored. Methods: A mouse model of NAFLD was induced with high-fat diet feeding, and sodium butyrate (NaB) intervention was initiated at the eighth week and lasted for 8 weeks. Hepatic steatosis was evaluated and metabolic pathways concerning lipid homeostasis were analyzed. Results: Here, we report that administration of NaB by gavage once daily for 8 weeks causes an augmentation of insulin-induced gene (Insig) activity and inhibition of lipogenic gene in mice fed with high-fat diet. Mechanistically, NaB is sufficient to enhance the interaction between Insig and its upstream kinase AMP-activated protein kinase (AMPK). The stimulatory effects of NaB on Insig-1 activity are abolished in AMPKα1/α2 double knockout (AMPK−/−) mouse primary hepatocytes. Moreover, AMPK activation by NaB is mediated by LKB1, as evidenced by the observations showing NaB-mediated induction of phosphorylation of AMPK, and its downstream target acetyl-CoA carboxylase is diminished in LKB1–/– mouse embryonic fibroblasts. Conclusions: These studies indicate that NaB serves as a negative regulator of hepatic lipogenesis in NAFLD and that NaB attenuates hepatic steatosis and improves lipid profile and liver function largely through the activation of LKB1-AMPK-Insig signaling pathway. Therefore, NaB has therapeutic potential for treating NAFLD and related metabolic diseases.

Because of the unique features of spherical symmetry, angle-independency, good monodispersity, controllable components and morphologies, structural color particles (SCPs) have found great significances in various fields such as sensing, monitoring, biological assays, etc. Here, inspired by the melanosome-derived bright structural colors and the self-adhesivity of mussels, we present a kind of bioinspired SCPs assembled from polydopamine (PDA)-adhered multi-layer graphene oxide (GO) encapsulated silica nanoparticles (SNs). It is demonstrated that compared with traditional SCPs, the designed particles possess brighter and more vibrant structural colors, and no complicated modification is required during the functionalization process due to the abundant inherent functional groups of GO. The resultant SCPs are verified to be capable for direct hybridization chain reaction and multiplexed nucleic acid assays. These properties indicate the promising prospects of our designed SCPs.

Abstract Wound dressing with the capacities of antioxidation, antiinflammation, and efficient angiogenesis induction is expected for effectively promoting wound healing. Herein, a novel core‐shell hyaluronic acid (HA) microneedle (MN) patch with ferrum‐mesenchymal stem cell‐derived artificial nanovesicles (Fe‐MSC‐NVs) and polydopamine nanoparticles (PDA NPs) encapsulated in the needle tips is presented for wound healing. Fe‐MSC‐NVs containing multifunctional therapeutic cytokines are encapsulated in the inner HA core of the MN tips for accelerating angiogenesis. The PDA NPs are encapsulated in the outer methacrylated hyaluronic acid (HAMA) shell of the MN tips to overcome the adverse impacts from reactive oxygen species (ROS)‐derived oxidative stress. With the gradual degradation of HAMA patch tips in the skin, the PDA NPs are sustainably released at the lesion to suppress the ROS‐induced inflammation reaction, while the Fe‐MSC‐NVs significantly increase the migration, proliferation, and tube formation of human umbilical vein endothelial cells (HUVEC). More attractively, the combination of PDA NPs and Fe‐MSC‐NVs further promotes M2 macrophage polarization, thereby suppressing wound inflammation. Through in vivo experiment, the Fe‐MSC‐NVs/PDA MN patch shows an excellent effect for diabetic wound healing. These features of antioxidation, antiinflammation, and pro‐angiogenesis indicate the proposed composite core‐shell MN patch is valuable for clinical wound healing applications.

Glioma represents the most common primary intracranial malignancy worldwide, with low overall survival rates and limited therapeutic options. The protein CD101, mainly expressed on several immune cells, has been demonstrated to exert potent effects on blunting T cell immune responses across infectious and autoimmunity diseases. Nevertheless, the prognostic value of CD101 expression and its role in the immune microenvironment of various malignancies currently remains elusive. Herein, by adopting bioinformatics methodology, we comprehensively illustrated the potential function and predictive value of CD101 in stratifying clinical prognosis among patients with glioma, for which a high CD101 level predicted an unfavorable clinical outcome in glioma patients. Results from enrichment analyses manifested that CD101 predominantly expressed on the tumor-associated macrophages and was significantly associated with the immune regulatory processes, as evidenced by its positive correlation with immune-related genes and the putative infiltration of immune cells. Evidence provided by in-situ multicolor immunofluorescence staining further validated our findings at the protein level. Taken together, CD101 may serve as a novel biomarker in predicting clinical prognosis and immune status for glioma patients.

Abstract Porous particles have found widespread applications in therapeutic diagnosis, drug delivery, and tissue engineering due to their typical properties of large surface area, extensive loading capacity, and hierarchical microstructures. Attempts in this aspect are focusing on the development of effective methods to generate functional porous particles. Herein, a simple droplet microfluidics for continuously and directly generating porous particles by introducing bubble‐propelled nanomotors into the system is presented. As the nanomotors can continuously generate gas bubbles in the unsolidified droplet templates, the desirable porous microparticles can be obtained after droplet polymerization. It is demonstrated that the generation process is highly controlled and the resultant microparticles show excellent porosity and monodispersity. In addition, the obtained porous microparticles can serve as microcarriers for 3D cell culture, because of their characteristic porous structures and favorable biocompatibility. Moreover, owing to the existence of oxygen in these microparticles, they can be used to improve the healing effects of wounds in the type I diabetes rat models. These remarkable features of the generation strategy and the porous microparticles point to their potential values in various biomedical fields.

Fatty liver disease: Bacterial metabolite protects liver by maintaining gut integrity A molecule made by beneficial microbes in the gut helps protect against a severe form of fatty liver disease by preventing bacterial toxins from leaking out of the intestines into the bloodstream. A research team in China led by Yu Li from the Shanghai Institute of Nutrition and Health (CAS) and Jian-Gao Fan from Xinhua Hospital (SJTU) showed in a rat model of non-alcoholic steatohepatitis that indole-3-propionic acid (IPA), a metabolite produced by gut bacteria, helps maintain the integrity of the intestinal inner lining. The more robust intestinal barrier ensures that bacterial toxins do not enter the bloodstream and eventually reach the liver, where they can trigger injury-inducing inflammation. The findings reveal an interaction between the gut microbiome and the liver, and suggest a role for IPA in the treatment of fatty liver disease.

Background: Nonalcoholic fatty liver disease (NAFLD) is associated with altered production of secreted proteins. Increased understanding of secreted proteins could lead to improved prediction and treatment of NAFLD. Here, we aimed to discover novel secreted proteins in humans that are associated with hepatic fat content using unbiased proteomic profiling strategy, and how the identified Thbs1 modulates lipid metabolism and hepatic steatosis. Method: NAFLD patients were enrolled and treated with lifestyle intervention. Patients who underwent liver biopsy were enrolled for analyzing the correlation between circulating Thbs1 and liver steatosis. Mice were fed on high-fat, high-sucrose diet and treated with recombinant Thbs1. Primary hepatocytes isolated from CD36 knockout (CD36-/-) mice and their wild-type littermates (controls) were treated with glucose plus insulin for 24 h together with or without recombinant Thbs1. Finding: Serum Thbs1 levels are increased in participants with NAFLD and positively associated with liver steatosis grades. Improvement of liver steatosis after lifestyle intervention was accompanied with significant reduction of serum Thbs1 levels. Pharmacological administration of recombinant human Thbs1 attenuates hepatic steatosis in diet-induced obese mice. Treatment with Thbs1 protein or stably overexpression of Thbs1 causes a significant reduction of lipid accumulation in primary hepatocytes or HepG2 cells exposed to high glucose plus insulin, suggesting that Thbs1 regulates lipid metabolism in a hepatocyte-autonomous manner. Mechanistically, Thbs1 inhibits cleavage and processing of SREBP-1, leading to a reduction of target lipogenic gene expression and hepatic steatosis. Inhibitory effects of Thbs1 on lipogenesis and triglyceride accumulation are abrogated in CD36 deficient primary hepatocytes exposed to high glucose plus insulin. Interestingly, beneficial effects of Thbs1 on lipid accumulation are observed in primary hepatocytes treated with a Thbs1 nonapeptide mimetic ABT-526. Interpretation: Thbs1 is a biomarker for NAFLD in humans, and pharmacological and genetic approaches for the modulation of Thbs1 activity may have the therapeutic potential for treating hepatic steatosis. Fund: A full list of funding bodies that contributed to this study can be found in the Funding Sources section.

Insulin-related gene (Insig) negatively regulates hepatic fatty acid synthesis, a process involved in development of non-alcoholic fatty liver disease (NAFLD). Here, the authors show that AMPK activation by metformin promotes Insig phosphorylation, stabilizing it and inhibiting lipogenic gene expression. This is protective against steatosis in diabetic mice.

Abstract Intelligent responsive microcarriers have emerged as a promising class of biomaterials for therapeutic delivery and tissue regeneration, since they can respond to external stimuli and release the loaded drugs in an active manner. Among various available stimuli, near‐infrared (NIR) light is particularly attractive because it can penetrate biotic tissues with sufficient intensity and minimal damage. In this work, a kind of photoresponsive delivery microcarriers (PDMs) is developed using microfluidics. The microcarriers consist of NIR‐absorbing graphene oxide, thermosensitive poly(N‐isopropylacrylamide), and biocompatible gelatin methacrylate. Under NIR light, the PDMs exhibit an evident volume shrinkage and effectively trigger the drug release. After the NIR light is switched off, the shrunken microcarriers return to their original size. This reversible process can be stably repeated for many cycles. An in vitro experiment demonstrates that the NIR‐radiated PDMs can actively release vascular endothelial growth factors and improve the tube formation of human umbilical vein endothelial cells. The results from the in vivo experiment also show an obvious photothermal effect and superior therapeutic efficacy of these PDMs in a rat model of tissue defects. These features make the PDMs an excellent drug delivery system and represent a great potential for clinical applications in tissue repair.

Three-dimensional (3D) porous scaffolds have a demonstrated value for tissue engineering and regenerative medicine. Inspired by the predation processes of marine predators in nature, we present new photocontrolled shrinkable inverse opal graphene oxide (GO) hydrogel scaffolds for cell enrichment and 3D culture. The scaffolds with adjustable pore sizes and morphologies were created using a GO and N-isopropylacrylamide dispersed solution as a continuous phase of microfluidic emulsions for polymerizing and replicating. Because of the interconnected porous structures and the remotely controllable volume responsiveness of the scaffolds, the suspended cells could be enriched into the inner spaces of the scaffolds through predator-like swallowing and discharging processes. Hepatocyte cells concentrated in the scaffold pores could form denser 3D spheroids more quickly via the controlled compression force caused by the shrinking of the dynamic scaffolds. More importantly, with a program of scaffold enrichment with different cells, an unprecedented 3D multilayer coculture system of endothelial-cell-encapsulated hepatocytes and fibroblasts could be generated for applications such as liver-on-a-chip and bioartificial liver. It was demonstrated that the resultant multicellular system offered significant improvements in hepatic functions, such as albumin secretion, urea synthesis, and cytochrome P450 expression. These features of our scaffolds make them highly promising for the biomimetic construction of various physiological and pathophysiological 3D tissue models, which could be used for understanding tissue level biology and in vitro drug testing applications.

INDUCER OF CBF EXPRESSION 1 (ICE1) encodes a MYC-like basic helix-loop-helix (bHLH) transcription factor playing a critical role in plant responses to chilling and freezing stresses and leaf stomata development. However, no information connecting ICE1 and reproductive development has been reported. In this study, we show that ICE1 controls plant male fertility via impacting anther dehydration. The loss-of-function mutation in ICE1 gene in Arabidopsis caused anther indehiscence and decreased pollen viability as well as germination rate. Further analysis revealed that the anthers in the mutant of ICE1 (ice1-2) had the structure of stomium, though the epidermis did not shrink to dehisce. The anther indehiscence and influenced pollen viability as well as germination in ice1-2 were due to abnormal anther dehydration, for most of anthers dehisced with drought treatment and pollen grains from those dehydrated anthers had similar viability and germination rates compared with wild type. Accordingly, the sterility of ice1-2 could be rescued by ambient dehydration treatments. Likewise, the stomatal differentiation of ice1-2 anther epidermis was disrupted in a different manner compared with that in leaves. ICE1 specifically bound to MYC-recognition elements in the promoter of FAMA, a key regulator of guard cell differentiation, to activate FAMA expression. Transcriptome profiling in the anther tissues further exhibited ICE1-modulated genes associated with water transport and ion exchange in the anther. Together, this work reveals the key role of ICE1 in male fertility control and establishes a regulatory network mediated by ICE1 for stomata development and water movement in the anther.