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Abstract Traditional diagnostic strategies for infectious disease detection require benchtop instruments that are inappropriate for point-of-care testing (POCT). Emerging microfluidics, a highly miniaturized, automatic, and integrated technology, are a potential substitute for traditional methods in performing rapid, low-cost, accurate, and on-site diagnoses. Molecular diagnostics are widely used in microfluidic devices as the most effective approaches for pathogen detection. This review summarizes the latest advances in microfluidics-based molecular diagnostics for infectious diseases from academic perspectives and industrial outlooks. First, we introduce the typical on-chip nucleic acid processes, including sample preprocessing, amplification, and signal read-out. Then, four categories of microfluidic platforms are compared with respect to features, merits, and demerits. We further discuss application of the digital assay in absolute nucleic acid quantification. Both the classic and recent microfluidics-based commercial molecular diagnostic devices are summarized as proof of the current market status. Finally, we propose future directions for microfluidics-based infectious disease diagnosis.

Abstract Background To explore the kinetic changes in virology, specific antibody response and imaging during the clinical course of COVID-19. Methods This observational study enrolled 20 patients with COVID-19, who were hospitalized between January 20–April 6, 2020, in the two COVID-19 designated hospitals of Zhoushan, Zhejiang and Rushan, Shandong, China, The laboratory findings, imaging, serum response to viral infection, and viral RNA level in the throat and stool samples were assessed from onset to recovery phase in patients with COVID-19. Results SARS-COV-2 RNA was positive as early as day four. It remained positive until day 55 post-onset in the sputum-throat swabs and became negative in most cases (55%) within 14 days after onset. Lymphocytopenia occurred in 40% (8/20) of patients during the peak infection period and returned to normal at week five. The most severe inflammation in the lungs appeared in week 2 or 3 after onset, and this was completely absorbed between week 6 and 8 in 85.7% of patients. All patients had detectable antibodies to the receptor binding domain (RBD), and 95% of these patients had IgG to viral N proteins. The antibody titer peaked at week four. Anti-S IgM was positive in 7 of 20 patients after week three. Conclusions All COVID-19 patients in this study were self-limiting and recovered well though it may take as long as 6–8 weeks. Our findings on the kinetic changes in imaging, serum response to viral infection and viral RNA level may help understand pathogenesis and define clinical course of COVID-19.

The performance of a plate heat exchanger (PHE) using water as the working fluid with zigzag flow channels was optimized in the present study. The optimal operating conditions of the PHE are explored experimentally by the Taguchi method, with effectiveness as the objective function. The results are further verified by the analysis of variance (ANOVA). In addition, the zigzag flow channel geometry is optimized by the non-dominated sorting genetic algorithm-II (NSGA-II), in which the effectiveness and pressure drop of the PHE are considered the two objective functions in the multi-objective optimization process. The experimental results show that the ratio of flow rates is the most important factor affecting the effectiveness of the PHE. The optimal operating conditions are the temperatures of 95 °C and 10 °C at the inlets of hot and cold water flows, respectively, with a cold/hot flow rate ratio of 0.25. The resultant effectiveness is 0.945. Three geometric parameters of the zigzag flow channel are considered, including the entrance length, the bending angle, and the fillet radius. The sensitivity analysis of the parameters reveals that a conflict exists between the two objective functions, and multi-objective optimization is necessary for the zigzag flow channel geometry. The numerical simulations successfully obtain the Pareto optimal front for the two objective functions, which benefits the determination of the geometric design for the zigzag flow channel.

BackgroundTo compare clinicopathologic feature of rectal neuroendocrine tumor (NET) grade G1 with G2 NET.MethodsSix hundred-one cases of rectal G1 and G2 NETs diagnosed in our center were analyzed.ResultsOf 601 cases of rectal NET, 515 cases were with grade G1 and 86 cases were with grade G2. Median tumor size was 0.7 cm. Compared with G1 NET, G2 tumors were with significantly larger tumor size (0.8 vs 2.2 cm, p < 0.001), less percentages of patients with tumors confined to submucosa (92.6 vs 42.8%, p < 0.001), more frequent presence of microvascular invasion (MVI) (3.6 vs 16.9%, p < 0.001) or peri-neural invasion (PNI) (2.0 vs 24.1%, p < 0.001). Incidence of lymph node and distant metastasis was 5.2 and 2.1% in G1 NET compared with 44.2 and 31.4% in G2 tumor, respectively (p < 0.001). For tumors sized 1–2 cm and confined to submucosa, incidence of lymph node metastasis was 6.1% for G1 NET compared with 21.1% for G2 NET. Status of MVI/PNI was predictive of lymph node metastasis for G2 tumor rather than G1 NET in this subgroup.ConclusionsRectal G2 NET was much more invasive with significantly elevated prevalence of lymph node metastasis compared with G1 tumor.

Hierarchical scheduling model for relay-enhanced cellular network was designed to divide the w e process of resource scheduling in relay-enhanced cell into two parts,which are high-level scheduling accomplished by eNode B and low-level scheduling accomplished by Relay Node.Based on this,a throughput guaranteed proportional fair (TG-PF) scheduling algorithm was also proposed.The algorithm fully takes the advantages of Max C/I algorithm and PF algorithm consideration,so that it can effectively improve cell lay-enhanced cellular network based on TG-PF,PF algorithm and TG-PF algorithm are separately used in high-level and low-level scheduling process to satisfy the system throughput and scheduling fairness requirements of relay-enhanced cell.Simulation results suggest that the proposed method can tremendously improve cell edge throughput with a small size sa-crifice in scheduling fairness.

BACKGROUND: GATA family of transcription factors are critical for organ development and associated with progression of various cancer types. However, their expression patterns and prognostic values for hepatocellular carcinoma (HCC) are still largely unknown. METHODS: Expression of GATA transcription factors in HCC cell lines and tissues (n = 240) were evaluated by RT-qPCR, western blot and immunohistochemistry. Cellular proliferation, migration and invasion of HepG2 was evaluated by CCK-8 kit, scratch wound assay and transwell matrigel invasion assay, respectively. RESULTS: GATA2 expression was decreased in HCC cell lines (p = 0.056 for mRNA, p = 0.040 for protein) and tissues (p = 1.27E-25) compared with normal hepatocytes. Decreased expression of intratumoral GATA2 protein significantly correlated with elevated alpha feto-protein (p = 2.7E-05), tumor size >5 cm (p = 0.049), absence of tumor capsule (p = 0.002), poor differentiation (p = 0.005), presence of tumor thrombi (p = 0.005) and advanced TNM stage (p = 0.001) and was associated with increased recurrence rate and decreased overall survival rate by univariate (p = 1.6E-04 for TTR, p = 1.7E-04 for OS) and multivariate analyses (HR = 0.63, 95% CI = 0.43-0.90, p = 0.012 for TTR; HR = 0.67, 95% CI = 0.47-0.95, p = 0.026 for OS). RNAi-mediated knockdown of GATA2 expression significantly enhanced proliferation, migration and invasion of HepG2 cell in vitro. CONCLUSIONS: Decreased expression of hematopoietic factor GATA2 was associated with poor prognosis of HCC following resection.

PurposeTo investigate the prognostic value of intratumoral invariant natural killer T (iNKT) cells and interferon-gamma (IFN-γ) in hepatocellular carcinoma (HCC) after curative resection.Experimental designExpression of TRAV10, encoding the Vα24 domain of iNKT cells, and IFN-γ mRNA were assessed by quantitative real-time polymerase chain reaction in tumor from 224 HCC patients undergoing curative resection. The prognostic value of these two and other clinicopathologic factors was evaluated.ResultsEither intratumoral iNKT cells and IFN-γ alone or their combination was an independent prognostic factor for OS (P = 0.001) and RFS (P = 0.001) by multivariate Cox proportional hazards analysis. Patients with concurrent low levels of iNKT cells and IFN-γ had a hazard ratio (HR) of 2.784 for OS and 2.673 for RFS. The areas under the curve of iNKT cells, IFN-γand their combination were 0.618 vs 0.608 vs 0.654 for death and 0.591 vs 0.604 vs 0.633 for recurrence respectively by receiver operating characteristic curve analysis. The prognosis was the worst for HCC patients with concurrent low levels of iNKT cells and IFN-γ, which might be related with more advanced pTNM stage and more vascular invasion.ConclusionsCombination of intratumoral iNKT cells and IFN-γ is a promising independent predictor for recurrence and survival in HCC, which has a better power to predict HCC patients' outcome compared with intratumoral iNKT cells or IFN-γ alone.

Nitric oxide (NO), a free radical labile gas, is involved in the regulation of various biological functions and physiological processes during animal reproduction. Recently, increasing evidence suggests that the biological role and chemical fate of NO is dependent on dynamic regulation of its biosynthetic enzyme, three distinct nitric oxide synthase (NOS) according to their structure, location and function. The impact of NOS isoforms on reproductive functions need to be timely elucidated. Here, we focus on and the basic background and latest studies on the development, structure, importance inhibitor, location pattern, complex functions. Moreover, we summarize the exactly mechanisms which involved some cell signal pathways in the regulation of NOS with cellular and molecular level in the animal reproduction. Therefore, this growing research area provides the new insight into the important role of NOS male and female reproduction system. It also provides the treatment evidence on targeting NOS of reproductive regulation and diseases. [ABSTRACT FROM AUTHOR]

Abstract Colorectal cancer (CRC) is one of the most common malignant tumors worldwide, with a high incidence rate and mortality. The analysis of serum biomarkers for colorectal cancer diagnosis has attracted more and more attention because of its low cost, repeatability, and quantification. This study was aimed to evaluate the diagnostic performance of serum Ephrin-A1 in patients with CRC. We retrospectively analyzed CRC cases in a test cohort (121 patients and 108 controls) and validated them in a validation cohort (119 patients and 118 controls). The concentration of Ephrin-A1 in serum was detected by Enzyme-linked immunosorbent assay (ELISA) and the diagnostic performance of serum Ephrin-A1 was evaluated by receiver operating characteristic (ROC) analysis. In the test cohort, serum Ephrin-A1 levels in patients with all-stage CRC and early-stage CRC were significantly higher than those in healthy controls. The area under the ROC curve (AUC), sensitivity and specificity of all-stage CRC and early-stage CRC were 0.709 (95% CI 0.644–0.775) and 0.660 (95% CI 0.530–0.790), 48.76% and 45.00%, 81.48% and 81.48%, respectively. Similar results were observed in the validation cohort. Serum Ephrin-A1 might be served as a potential biomarker in the diagnosis of CRC.

Abstract Atrial fibrillation (AF) is the most common arrhythmia and its incidence increases with sepsis. However, data on new-onset AF during sepsis hospitalization remain limited in China. We aimed to evaluate the incidence, risk factors, and associated mortality of new-onset AF in sepsis patients in China. We conducted a retrospective study using the National Data Center for Medical Service system, from 1923 tertiary and 2363 secondary hospitals from 31 provinces in China from 2017 to 2019.In total we included 1,425,055 sepsis patients ≥ 18 years without prior AF. The incidence of new-onset AF was 1.49%. Older age, male sex, hypertension, heart failure, coronary disease, valvular disease, and mechanical ventilation were independent risk factor. New-onset AF was associated with a slight increased risk of mortality (adjusted RR 1.03, 95% CI 1.01–1.06). Population attributable fraction suggested AF accounted for 0.2% of sepsis deaths. In this large nationwide cohort, new-onset AF occurred in 1.49% of sepsis admissions and was associated with a small mortality increase. Further research should examine whether optimized AF management can improve sepsis outcomes in China.

Objectives: Acupuncture is a promising therapy for amnestic mild cognitive impairment (aMCI). Growing evidence suggest that alterations in the microbiota-gut-brain (MGB) axis contribute to the development and progression of aMCI. However, little is known about whether and how acupuncture change the MGB axis of aMCI individuals. Methods: This was a randomized, controlled, clinical trial. Forty patients with aMCI were randomly allocated to either the acupuncture group or the waitlist group. The primary outcome was the change in the Alzheimer’s Disease Assessment Scale-Cognitive Scale (ADAS-Cog) score. In addition, multi-omics was performed to detect changes in brain function, gut microbiota, and serum metabolites. Generalized estimating equations were used to estimate the outcomes, and correlational analyses were performed to explore the relationships between the clinical and multi-omics data. Results: Compared to a mean baseline to week 12 change of –3.94 in the acupuncture group, the mean change in the waitlist group was 1.72 (net difference, –5.66 [95 % CI, –6.98 to –4.35]). Compared to the waitlist group, acupuncture’s MGB axis modulatory effect exhibited altered the regional homogeneity values of Frontal_Med_Orb_L, Cingulum_Mid_L, and Frontal_Sup_Medial_L, relative abundance of gut Ruminococcus_sp_AF43_11 and s_Eubacterium_coprostanoligenes, and levels of serum (11E,15Z)-9,10,13-trihydroxyoctadeca-11,15-dienoic acid, dipropylene glycol dimethyl ether, N6-Me-dA, and DPK, which correlated with changes in ADAS-Cog scores. Conclusions: Our data imply that acupuncture ameliorates overall cognitive function, along with changes in brain activity, gut microbiota, and serum metabolites, providing preliminary evidence of the mechanisms acting through the MGB axis underlying the effects of acupuncture on aMCI.

BackgroundAcupuncture is a promising non-pharmaceutical complementary therapy in treating prolonged Disorders of consciousness (pDOC), but solid evidence to support its effectiveness and safety is still lacking. Thus, the purpose of this study is to investigate the efficacy and safety of acupuncture-assisted therapy for pDOC patients.MethodsA single-center, prospective, randomized, conventional-controlled, assessor-and-statistician-blinded trial has been designed and is being conducted at West China Hospital of Sichuan University. A total of 110 participants will be randomly assigned to the experimental group and the control group in a 1:1 allocation ratio and evaluated using Coma Recovery Scale-Revised (CRS-R) at 8 a.m., 12 p.m., and 4 p.m. on 2 consecutive days before enrollment to determine the consciousness level. The experimental group will receive acupuncture combined with conventional treatment, while the control group will receive only conventional treatment during the trial observation period. The treatment duration of both groups will be 20 days. Among them, the frequency of acupuncture-assisted therapy is once a day, with 10 consecutive sessions followed by a day’s rest for a total of 24 days. Data will be collected separately during baseline and after the final treatment. For data analysis, both Full Analysis Set (FAS) and Per Protocol Set (PPS) principles will be performed together by applying SPSS 27.0 software. The primary outcome measures are the changes of CRS-R before and after treatment, while the secondary outcome measures are the changes of Full Outline of Unresponsiveness Scale (FOUR), the changes of Nociception Coma Scale-Revised (NCS-R), the changes of Disability Rating Scale (DRS), the changes of Mismatch Negativity (MMN) and P300 before and after treatment, respectively.DiscussionThis trial aims to rationally assess the consciousness level from multiple 2 perspectives through subjective evaluation and objective detection by selecting several standardized clinical scales combined with Event-Related Potential (ERP) detection technology. In this way, we will be able to reduce the subjectivity of consciousness assessment and objectively evaluate the clinical efficacy of acupuncture-assisted therapy for pDOC. The study, if proven to be effective and safe enough, will provide a favorable evidence to guide medical decision-making choices and future researches.Clinical trial registrationhttps://www.chictr.org.cn/, identifier ChiCTR2300076180.

Abstract Background Bone marrow mesenchymal stem cells (BMSCs) can undergo inadequate osteogenesis or excessive adipogenesis as they age due to changes in the bone microenvironment, ultimately resulting in decreased bone density and elevated risk of fractures in senile osteoporosis. This study aims to investigate the effects of osteocyte senescence on the bone microenvironment and its influence on BMSCs during aging. Results Primary osteocytes were isolated from 2-month-old and 16-month-old mice to obtain young osteocyte-derived extracellular vesicles (YO-EVs) and senescent osteocyte-derived EVs (SO-EVs), respectively. YO-EVs were found to significantly increase alkaline phosphatase activity, mineralization deposition, and the expression of osteogenesis-related genes in BMSCs, while SO-EVs promoted BMSC adipogenesis. Neither YO-EVs nor SO-EVs exerted an effect on the osteoclastogenesis of primary macrophages/monocytes. Our constructed transgenic mice, designed to trace osteocyte-derived EV distribution, revealed abundant osteocyte-derived EVs embedded in the bone matrix. Moreover, mature osteoclasts were found to release osteocyte-derived EVs from bone slices, playing a pivotal role in regulating the functions of the surrounding culture medium. Following intravenous injection into young and elderly mouse models, YO-EVs demonstrated a significant enhancement of bone mass and biomechanical strength compared to SO-EVs. Immunostaining of bone sections revealed that YO-EV treatment augmented the number of osteoblasts on the bone surface, while SO-EV treatment promoted adipocyte formation in the bone marrow. Proteomics analysis of YO-EVs and SO-EVs showed that tropomyosin-1 (TPM1) was enriched in YO-EVs, which increased the matrix stiffness of BMSCs, consequently promoting osteogenesis. Specifically, the siRNA-mediated depletion of Tpm1 eliminated pro-osteogenic activity of YO-EVs both in vitro and in vivo. Conclusions Our findings suggested that YO-EVs played a crucial role in maintaining the balance between bone resorption and formation, and their pro-osteogenic activity declining with aging. Therefore, YO-EVs and the delivered TPM1 hold potential as therapeutic targets for senile osteoporosis. Graphical abstract

Abstract Background Growing evidence showed that acupuncture may improve cognitive function by reducing oxidative stress, key to the pathogenesis in vascular dementia (VaD), but this is yet to be systematically analysed. This study aimed to summarize and evaluate the effect of acupuncture on oxidative stress in animal models of VaD. Method Eight databases including PubMed, Embase, Web of Science, Cochrane library, CNKI, Wan Fang, CBM, and VIP were searched since their establishment until April 2023, for studies that reported the effect of acupuncture on oxidative stress in VaD animal models. Relevant literature was screened, and information was extracted by two reviewers. The primary outcomes were the levels of oxidative stress indicators. The methodological quality was assessed via the SYRCLE Risk of Bias Tool. Statistical analyses were performed using the RevMan and Stata software. Results In total, 22 studies with 747 animals were included. The methodology of most studies had flaws or uncertainties. The meta-analysis indicated that, overall, acupuncture significantly reduced the expression of pro-oxidants including reactive oxygen species (standardized mean differences [SMDs] = -4.29, 95% confidence interval [CI]: -6.26, -2.31), malondialdehyde (SMD = -2.27, 95% CI: -3.07, -1.47), nitric oxide (SMD = -0.85, 95% CI: -1.50, -0.20), and nitric oxide synthase (SMD = -1.01, 95% CI: -1.69, -0.34) and enhanced the levels of anti-oxidants including super oxide dismutase (SMD = 2.80, 95% CI: 1.98, 3.61), glutathione peroxidase (SMD = 1.32, 95% CI: -0.11, 2.76), and catalase (SMD = 1.31, 95% CI: 0.05, 2.58) in VaD animal models. In subgroup analyses, acupuncture showed significant effects on most variables. Only partial modelling methods and treatment duration could interpret the heterogeneity of some outcomes. Conclusion Acupuncture may inhibit oxidative stress to improve cognitive deficits in animal models of VaD. Nevertheless, the methodological quality is unsatisfactory. More high-quality research with a rigorous design and further experimental researches and clinical trials are needed to confirm these findings. Systematic review registration This study was registered in PROSPERO (CRD42023411720).

Knowing how functional diversity varies across environmental gradients is crucial in investigating biodiversity formation and community assembly processes. The majority of studies concerning functional diversity are based on one fixed plot size, resulting in weakened sensitivity of the spatial patterns to sampling resolution. This weakness may obscure the true mechanisms behind community assemblage. In this study, we utilized hyperspectral imagery collected by Orbita hyperspectral satellites (OHS) to explore the spatial distribution patterns of functional traits and diversity in alpine meadows at four sampling radii (25 m, 50 m, 100 m, 200 m). We examined how functional traits and their diversity responded to variations in climatic and soil conditions at different sampling resolutions. Our findings revealed a significant influence of solar radiation and soil depth on the patterns of functional traits in alpine meadows. Scale dependency was evident in the functional richness (FRic), functional evenness (FEve), and functional dispersion (FDis) of different traits, indicated by a notable difference from the null model. In the presence of stronger soil nutrient and water limitation, chlorophyll a content (CAC), specific leaf area (SLA), leaf thickness (LT), and plant height (Height) exhibited increased clustering and convergence at larger sampling resolutions, illustrating environmental filtering in habitat patch assembly in the alpine meadow. For the first time, this study explores scale dependency in functional diversity patterns in alpine meadows using satellite-based hyperspectral imagery. It unveils the environmental filtering effect of soil nutrient limitation on shaping vegetation patch structures at a landscape level from a remote sensing perspective. The study underscores the significance of accounting for sampling resolution in future related research.

Abstract Our previous study showed that levels of circulating insulin-like growth factor binding protein-1 (IGFBP-1) has potential diagnostic value for early-stage upper gastrointestinal cancers. This study aimed to assess whether serum IGFBP-1 is a potential diagnostic and prognostic biomarker for CRC patients. IGFBP-1 mRNA expression profile data of peripheral blood in colorectal cancer (CRC) patients were downloaded and analyzed from Gene Expression Omnibus database. We detected serum IGFBP-1 in 138 CRC patients and 190 normal controls using enzyme-linked immunosorbent assay. Blood IGFBP-1 mRNA levels were higher in CRC patients than those in normal controls (P = 0.027). In addition, serum IGFBP-1 protein levels in the CRC group were significantly higher than those in normal control group (P

Abstract Endothelial cells (ECs) and bone marrow stromal cells (BMSCs) play crucial roles in supporting hematopoiesis and hematopoietic regeneration. However, whether ECs are a source of BMSCs remains unclear. Here, we evaluate the contribution of endothelial-to-mesenchymal transition to BMSC generation in postnatal mice. Single-cell RNA sequencing identifies ECs expressing BMSC markers Prrx1 and Lepr; however, this could not be validated using Prrx1-Cre and Lepr-Cre transgenic mice. Additionally, only a minority of BMSCs are marked by EC lineage tracing models using Cdh5-rtTA-tetO-Cre or Tek-CreERT2. Moreover, Cdh5 + BMSCs and Tek + BMSCs show distinct spatial distributions and characteristic mesenchymal markers, suggestive of their origination from different progenitors rather than CDH5+ TEK+ ECs. Furthermore, myeloablation induced by 5-fluorouracil treatment does not increase Cdh5 + BMSCs. Our findings indicate that ECs hardly convert to BMSCs during homeostasis and myeloablation-induced hematopoietic regeneration, highlighting the importance of using appropriate genetic models and conducting careful data interpretation in studies concerning endothelial-to-mesenchymal transition.

Abstract Background Previous studies have shown that ALDH2 and ADH1B genes may be associated with alcohol metabolism and the risk of esophageal squamous cell carcinoma (ESCC), with inconsistent results. This meta‐analysis aimed at comprehensively assessing the associations between ALDH2 and ADH1B polymorphisms and the risk of ESCC to synthesize and clarify the evidence. Methods We calculated summary estimates of the associations between four genetic variants (rs671 and rs674 in ALDH2, and rs1229984 and rs1042026 in ADH1B) and the ESCC risk across 23 publications in the additive model and allelic model. Venice criteria, Bayesian false discovery probability (BFDP), and false‐positive reporting probability (FPRP) were used to assess the strength of epidemiological evidence. Heterogeneity among studies was evaluated by using the Higgin's I2 statistic, and publication bias was assessed by using funnel plots and Begg's test. A Mendelian randomization (MR) analysis was performed to determine the causal association between alcohol intake and esophageal cancer risk. Data from the HaploReg v4.1 and PolyPhen‐2 were analyzed for functional annotations. Results Of the four genetic variants, rs671 of ALDH2 was associated with a significantly reduced risk of ESCC (OR: 0.60, 95% CI: 0.50–0.73), whereas rs1229984 of ADH1B was associated with a significantly increased risk (2.50, 95% CI: 1.70–3.69) in the additive model. In the allelic model, the variant rs1229984 of ADH1B also increased the risk of ESCC (OR: 1.50; 95% CI: 1.21–1.87). The result for the variant rs671 was considered as strong epidemiological evidence. Functional annotations identified that the four variants were related to the enhancer histone marks and motif changes. The other two variants were not associated with the ESCC risk (rs674 of ALDH2 OR: 1.22, 95% CI: 0.71–2.12; rs1042026 of ADH1B OR: 1.28, 95% CI: 0.52–3.14) in the additive model. The MR analysis did not find a causal effect of alcohol on the esophageal cancer risk. Conclusions The results showed that ADH1B rs1229984 was significantly associated with an increased the risk of ESCC.

Abstract Due to increasing morbidity worldwide, fractures are becoming an emerging public health concern. This study aimed to investigate the effect of metformin on the healing of osteoporotic as well as normal fractures. Type H vessels have recently been identified as a bone-specific vascular subtype that supports osteogenesis. Here, we show that metformin accelerated fracture healing in both osteoporotic and normal mice. Moreover, metformin promoted angiogenesis in vitro under hypoxia as well as type H vessel formation throughout fracture healing. Mechanistically, metformin increased the expression of HIF-1α, an important positive regulator of type H vessel formation, by inhibiting the expression of YAP1/TAZ in calluses and hypoxia-cultured human microvascular endothelial cells (HMECs). The results of HIF-1α or YAP1/TAZ interference in hypoxia-cultured HMECs using siRNA further suggested that the enhancement of HIF-1α and its target genes by metformin is primarily through YAP1/TAZ inhibition. Finally, overexpression of YAP1/TAZ partially counteracted the effect of metformin in promoting type H vessel-induced angiogenesis-osteogenesis coupling during fracture repair. In summary, our findings suggest that metformin has the potential to be a therapeutic agent for fractures by promoting type H vessel formation through YAP1/TAZ inhibition.

Abstract Oral tongue squamous cell carcinoma (OTSCC) is one of the most aggressive oral tumors. The aim of this study was to establish a nomogram to predict overall survival (OS) of TSCC patients after surgery. 169 TSCC patients who underwent surgical treatments in the Cancer Hospital of Shantou University Medical College were included. A nomogram based on Cox regression analysis results was established and internally validated using bootstrap resampling method. pTNM stage, age and total protein, immunoglobulin G, factor B and red blood cell count were identified as independent prognostic factors to create the nomogram. The Akaike Information Criterion and Bayesian Information Criterion of the nomogram were lower than those of pTNM stage, indicating a better goodness-of-fit of the nomogram for predicting OS. The bootstrap-corrected concordance index of nomogram was higher than that of pTNM stage (0.794 vs. 0.665, p = 0.0008). The nomogram also had a good calibration and improved overall net benefit. Based on the cutoff value obtained from the nomogram, the proposed high-risk group had poorer OS than low-risk group (p

Bone regeneration heavily relies on bone marrow mesenchymal stem cells (BMSCs). However, recruiting endogenous BMSCs for in situ bone regeneration remains challenging. In this study, we developed a novel BMSC-aptamer (BMSC-apt) functionalized hydrogel (BMSC-aptgel) and evaluated its functions in recruiting BMSCs and promoting bone regeneration. The functional hydrogels were synthesized between maleimide-terminated 4-arm polyethylene glycols (PEG) and thiol-flanked PEG crosslinker, allowing rapid in situ gel formation. The aldehyde group-modified BMSC-apt was covalently bonded to a thiol-flanked PEG crosslinker to produce high-density aptamer coverage on the hydrogel surface. In vitro and in vivo studies demonstrated that the BMSC-aptgel significantly increased BMSC recruitment, migration, osteogenic differentiation, and biocompatibility. In vivo fluorescence tomography imaging demonstrated that functionalized hydrogels effectively recruited DiR-labeled BMSCs at the fracture site. Consequently, a mouse femur fracture model significantly enhanced new bone formation and mineralization. The aggregated BMSCs stimulated bone regeneration by balancing osteogenic and osteoclastic activities and reduced the local inflammatory response via paracrine effects. This study's findings suggest that the BMSC-aptgel can be a promising and effective strategy for promoting in situ bone regeneration.