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Abstract Background Investigating the unexplored territory of lncRNA m6A modification in colorectal cancer (CRC) vasculature, this study focuses on LINC01106 and YTHDF1. Methods Clinical assessments reveal upregulated LINC01106 promoting vascular generation via the miR-449b-5p-VEGFA pathway. Results YTHDF1, elevated in CRC tissues, emerges as an adverse prognostic factor. Functional experiments showcase YTHDF1’s inhibitory effects on CRC cell dynamics. Mechanistically, Me-CLIP identifies m6A-modified LINC01106, validated as a YTHDF1 target through Me-RIP. Conclusions This study sheds light on the YTHDF1-mediated m6A modification of LINC01106, presenting it as a key player in suppressing CRC vascular generation.

Abstract Background In the realm of assisted reproduction, a subset of infertile patients demonstrates high ovarian response following controlled ovarian stimulation (COS), with approximately 29.7% facing the risk of Ovarian Hyperstimulation Syndrome (OHSS). Management of OHSS risk often necessitates embryo transfer cancellation, leading to delayed prospects of successful pregnancy and significant psychological distress. Regrettably, these patients have received limited research attention, particularly regarding their metabolic profile. In this study, we aim to utilize gas chromatography-mass spectrometry (GC-MS) to reveal these patients’ unique serum metabolic profiles and provide insights into the disease’s pathogenesis. Methods We categorized 145 infertile women into two main groups: the CON infertility group from tubal infertility patients and the Polycystic Ovary Syndrome (PCOS) infertility group. Within these groups, we further subdivided them into four categories: patients with normal ovarian response (CON-NOR group), patients with high ovarian response and at risk for OHSS (CON-HOR group) within the CON group, as well as patients with normal ovarian response (PCOS-NOR group) and patients with high ovarian response and at risk for OHSS (PCOS-HOR group) within the PCOS group. Serum metabolic profiles were analyzed using GC-MS. The risk criteria for OHSS were: the number of developing follicles > 20, peak Estradiol (E2) > 4000pg/mL, and Anti-Müllerian Hormone (AMH) levels > 4.5ng/mL. Results The serum metabolomics analysis revealed four different metabolites within the CON group and 14 within the PCOS group. Remarkably, 10-pentadecenoic acid emerged as a discernible risk metabolite for the CON-HOR, also found to be a differential metabolite between CON-NOR and PCOS groups. cysteine and 5-methoxytryptamine were also identified as risk metabolites for the PCOS-HOR. Furthermore, KEGG analysis unveiled significant enrichment of the aminoacyl-tRNA biosynthesis pathway among the metabolites differing between PCOS-NOR and PCOS-HOR. Conclusion Our study highlights significant metabolite differences between patients with normal ovarian response and those with high ovarian response and at risk for OHSS within both the tubal infertility control group and PCOS infertility group. Importantly, we observe metabolic similarities between patients with PCOS and those with a high ovarian response but without PCOS, suggesting potential parallels in their underlying causes.

Abstract Mechanically interlocked molecules (MIMs) including famous catenanes show switchable physical properties and attract continuous research interest due to their potential application in molecular devices. The advantages of using spin crossover (SCO) materials here are enormous, allowing for control through diverse stimuli and highly specific functions, and enabling the transfer of the internal dynamics of MIMs from solution to solid state, leading to macroscopic applications. Herein, we report the efficient self-assembly of catenated metal-organic frameworks (termed catena-MOFs) induced by stacking interactions, through the combination of rationally selected flexible and conjugated naphthalene diimide-based bis-pyridyl ligand (BPND), [MI(CN)2]− (M = Ag or Au) and Fe2+ in a one-step strategy. The obtained bimetallic Hofmann-type SCO-MOFs [FeII(BPND){Ag(CN)2}2]·3CHCl3 (1Ag) and [FeII(BPND{Au(CN)2}2]·2CHCl3·2H2O (1Au) possess a unique three-dimensional (3D) catena-MOF constructed from the polycatenation of two-dimensional (2D) layers with hxl topology. Both complexes undergo thermal- and light-induced SCO. Significantly, abnormal increases in the maximum emission intensity and dielectric constant can be detected simultaneously with the switching of spin states. This research opens up SCO-actuated bistable MIMs that afford dual functionality of coupled fluorescence emission and dielectricity.

The mechanical properties and insulation damage of stator end windings in permanent magnet synchronous generator (PMSG) are investigated by theoretical analysis, finite element analysis (FEA) and experiment verification. First, a theoretical model of the winding electromagnetic force (EF) and vibration response before and after eccentricity faults are established. Then, the stress/strain distribution of the end windings under different working conditions is analyzed. Finally, the insulation damage behavior of end windings with initial cracks is studied and characterized using the stress intensity factor (SIF). The results indicate that the winding EF and vibration responses vary under different faults. The stress/strain at the joint of the winding is the largest, and the insulation layer has the maximum stress/strain under the same section. Additionally, the SIF amplitude of the crack at the winding joint is the largest. And the SIF amplitude of the crack will increase with the increase of fault degree/crack depth/crack length. The contribution of this paper lies in the comprehensive analysis of the winding EF distribution, vibration response, stress and strain, and insulation damage before and after eccentricity. This analysis can provide valuable reference for the health monitoring of PMSG eccentricity faults and the prevention of winding insulation damage.

Static air-gap eccentricity (SAGE) is a common fault in generators. Current researches primarily focus on the parallel SAGE types, while the inclined static air-gap eccentricity (ISAGE) has been rarely investigated. This paper proposes an improved air-gap eccentricity model and presents a study on the electromagnetic-mechanical properties in synchronous generators under typical ISAGE running conditions. Such electromagnetic-mechanical properties include not only the magnetic flux density (MFD) variations, but also the mechanical responses of the electromagnetic torque (EMT) and rotor unbalanced magnetic pulls (UMP). The typical ISAGE factors include: 1) a varied rotor inclined angle θ, and 2) different values of axial inclined distance z (indicates the offset combination case of the two rotor ends). This work is based on the MFD analysis calculation. Theoretical analysis, finite element analysis, and experimental study are carried out, respectively, by taking a 5 kVA two-pole prototype generator as the study object. It is shown that the electromagnetic-mechanical properties of the generator will change when the inclined eccentricity occurs. The EMT, and the rotor UMP as well as the vibrations will increase as the rotor inclined θ and z increase. Specifically, the 2nd harmonic has the most significant variation.

The static air gap eccentricity is one of the prevalent faults in permanent magnet synchronous generators. In previous studies, the variation of magnetic flux density, stator current and vibration have been studied mostly. However, the temperature characteristic of winding insulation under 3D static air gap eccentricity fault is rarely investigated. As a supplement, this paper comprehensively analyzes the influence of radial static air gap eccentricity, axial static air gap eccentricity and the combined static air gap eccentricity (radial static air gap eccentricity and axial static air gap eccentricity) fault on the winding insulation thermal response. The whole work is based on not only the loss of core and windings but also the temperature rise of the winding insulation, which is carried out through theoretical analysis, finite element calculation, and experiment verification. It is shown that radial static air gap eccentricity will increase the winding insulation temperature whatever in singe radial static air gap eccentricity or combined static air gap eccentricity, while axial static air gap eccentricity has the opposite effect. Specifically, the winding insulation temperature in radial static air gap eccentricity 0.1 mm, 0.2 mm and 0.3 mm cases are 57.18℃, 59.10℃ and 61.04℃, respectively, which is 3.29℃, 5.21℃ and 7.15℃ higher than that under normal condition. However, under axial static air gap eccentricity, winding insulation temperature will decrease by 1.84℃, 4.11℃ and 5.9℃, respectively. When axial static air gap eccentricity is unchanged and radial static air gap eccentricity is increased, the winding insulation temperature will increase by 1.5℃ and 3.23℃, respectively. On the contrary, when radial static air gap eccentricity is unchanged and axial static air gap eccentricity increases, the winding insulation temperature decreases by 2.54℃ and 5.66℃, respectively. The end part and the join between the end and line parts of the winding insulation are the most dangerous positions to suffer from static thermal wear.

AIM: To evaluate the effectiveness and safety of early lens extraction during pars plana vitrectomy (PPV) for proliferative diabetic retinopathy (PDR) compared to those of PPV with subsequent cataract surgery. METHODS: This multicenter randomized controlled trial was conducted in three Chinese hospitals on patients with PDR, aged >45y, with mild cataracts. The participants were randomly assigned to the combined (PPV combined with simultaneously cataract surgery, i.e., phacovitrectomy) or subsequent (PPV with subsequent cataract surgery 6mo later) group and followed up for 12mo. The primary outcome was the change in best-corrected visual acuity (BCVA) from baseline to 6mo, and the secondary outcomes included complication rates and medical expenses. RESULTS: In total, 129 patients with PDR were recruited and equally randomized (66 and 63 in the combined and subsequent groups respectively). The change in BCVA in the combined group [mean, 36.90 letters; 95% confidence interval (CI), 30.35–43.45] was significantly better (adjusted difference, 16.43; 95%CI, 8.77–24.08; P

Abstract Additive manufacturing (AM), known as 3D printing, enables rapid fabrication of geometrically complex copper (Cu) components for electrical conduction and heat management applications. However, pure Cu or Cu alloys produced by 3D printing often suffer from either low strength or low conductivity at room and elevated temperatures. Here, we demonstrate a design strategy for 3D printing of high strength, high conductivity Cu by uniformly dispersing a minor portion of lanthanum hexaboride (LaB6) nanoparticles in pure Cu through laser powder bed fusion (L-PBF). We show that trace additions of LaB6 to pure Cu results in an improved L-PBF processability, an enhanced strength, an improved thermal stability, all whilst maintaining a high conductivity. The presented strategy could expand the applicability of 3D printed Cu components to more demanding conditions where high strength, high conductivity and thermal stability are required.

Cryptococcus neoformans is at the top of the list of “most wanted” human pathogens. Only three classes of antifungal drugs are available for the treatment of cryptococcosis. Studies on antifungal resistance mechanisms are limited to the investigation of how a particular antifungal drug induces resistance to a particular drug, and the impact of stresses other than antifungals on the development of antifungal resistance and even cross-resistance is largely unexplored. The endoplasmic reticulum (ER) is a ubiquitous subcellular organelle of eukaryotic cells. Brefeldin A (BFA) is a widely used chemical inducer of ER stress. Here, we found that both weak and strong selection by BFA caused aneuploidy formation in C. neoformans, mainly disomy of chromosome 1, chromosome 3, and chromosome 7. Disomy of chromosome 1 conferred cross-resistance to two classes of antifungal drugs: fluconazole and 5-flucytosine, as well as hypersensitivity to amphotericin B. However, drug resistance was unstable, due to the intrinsic instability of aneuploidy. We found overexpression of AFR1 on Chr1 and GEA2 on Chr3 phenocopied BFA resistance conferred by chromosome disomy. Overexpression of AFR1 also caused resistance to fluconazole and hypersensitivity to amphotericin B. Furthermore, a strain with a deletion of AFR1 failed to form chromosome 1 disomy upon BFA treatment. Transcriptome analysis indicated that chromosome 1 disomy simultaneously upregulated AFR1, ERG11, and other efflux and ERG genes. Thus, we posit that BFA has the potential to drive the rapid development of drug resistance and even cross-resistance in C. neoformans, with genome plasticity as the accomplice.

Summary: Quantum thermodynamic process involves manipulating and controlling quantum states to extract energy or perform computational tasks with high efficiency. There is still no efficient general method to theoretically quantify the effect of the quantumness of coherence and entanglement in work extraction. In this work, we propose a thermodynamics speed to quantify the extracting work. We show that the coherence of quantum systems can speed up work extracting with respect to some cyclic evolution beyond all incoherent states. We further show the genuine entanglement of quantum systems may speed up work extracting beyond any bi-separable states. This provides a new thermodynamic method to witness entangled systems with physical quantities.

Abstract The soft theorem states that scattering amplitude in gauge theory with a soft gauge-boson emission can be factorized into a hard scattering amplitude and a soft factor. In this paper, we present calculations of the soft factor for processes involving two hard colored partons, up to three loops in QCD. To accomplish this, we developed a systematic method for recursively calculating relevant Feynman integrals using the Feynman-Parameter representation. Our results constitute an important ingredient for the subtraction of infrared singularities at N4LO in perturbative QCD. Using the principle of leading transcendentality between QCD and N $$ \mathcal{N} $$ = 4 super Yang-Mills theory, we determine the soft factor in the latter case to three loops with full-color dependence. As a by-product, we also obtain the finite constant f 2 3 $$ {f}_2^{(3)} $$ in the Bern-Dixon-Smirnov ansatz analytically, which was previously known numerically only.

Abstract Introduction We developed a convolutional neural network (CNN) model to predict treatment outcomes of transforaminal epidural steroid injection (TFESI) for controlling cervical radicular pain due to cervical foraminal stenosis. Methods We retrospectively recruited 293 patients with cervical TFESI due to cervical radicular pain caused by cervical foraminal stenosis. We obtained a single oblique cervical radiograph from each patient. We cut each oblique cervical radiograph image into a square shape, including the foramen that was targeted for TFESI, the intervertebral disc, the facet joint of the corresponding level with the targeted foramen, and the pedicles of the vertebral bodies just above and below the targeted foramen. Therefore, images including the targeted foramen and structures around the targeted foramen were used as input data. A favorable outcome was defined as a ≥ 50% reduction in the numeric rating scale (NRS) score at 2 months post TFESI compared to the pretreatment NRS score. A poor outcome was defined as a

Bayan Obo, located in the north margin of the Yinshan Block, North China Craton (NCC), contains the Archean to Paleoproterozoic basement rocks which may shed light on the early crustal evolution of the NCC. In this paper, to reveal the formation and modification of the basements, we report Hf isotope of zircons from the biotite plagiogneisses in Bayan Obo. Combined with the published U–Pb ages and Hf isotope compositions of the zircons from the Bayan Obo basement rocks, a comprehensive review was employed to provide new insights into the formation and modification of the basement in this area. The oldest formation age of the basement rocks was found to be approximately 2.6 Ga, with positive εHf(t) values indicating the contribution from the depleted mantle to the rocks. The age of ∼2.0 Ga marks the major formation period of the basement rocks. The varied εHf(t) values (−17.2 to +8.9) of the magmatic zircons suggest a mixture origin between the depleted mantle and crustal rocks for the gneiss. The basement went through extensive metamorphism during 1.95–1.9 Ga. In addition, zircon U–Pb–Hf isotope data of the Precambrian units in Guyang and Wuchuan, which are adjacent to Bayan Obo, were compiled for comparison. The comprehensive review on the data of the concordant magmatic zircons indicates the existence of 3.5 Ga crustal fragments in the Yinshan Block. The melting of the depleted mantle and the addition of juvenile materials into the crust at 2.6–2.9 Ga and 2.45–2.55 Ga were confirmed by the high positive εHf(t) values of the magmatic and inherited zircons. An increase in remelting of the crust at 2.0 Ga is deduced from the extremely unradiogenic Hf isotope of the magmatic zircons.

Abstract Pulmonary fibrosis (PF) is a severe chronic interstitial lung disease with high mortality, and there is currently a lack of definite and effective treatment methods. Studies have found that gentiopicroside, a secoiridoid glycoside compound derived from plants of the Gentiana genus, can significantly improve pulmonary inflammation and fibrosis lesions in mice with pulmonary fibrosis. However, the mechanism of its anti-fibrotic effect is unclear. Therefore, in this study, we employed network pharmacology's virtual computer technology to investigate the potential mechanism underlying the anti-pulmonary fibrosis effect of Gentianae Radix et Rhizome (Longdan in Chinese, GRR). Our findings offer valuable theoretical insights and serve as a guiding reference for future experimental investigations. A total of 10 active compounds and 920 drug-target proteins were identified from the TCMSP database. The compound-target-pathway-disease network showed that GRR could potentially treat PF by regulating the MDM2, ERBB2 and VEGFA, signaling pathways through its key targets, including AKT1, TNF, and MAPK1. The protein‒protein interaction network revealed that these targets had strong interactions with each other, indicating a potential synergistic effect of GRR in treating PF. The GO and KEGG enrichment analyses further supported the potential anti-pulmonary fibrosis mechanisms of GRR, including regulating the inflammatory response, ECM-receptor interaction, and TGF-beta signaling pathways. Our study provides a systematic analysis of the potential anti-pulmonary fibrosis mechanisms of GRR based on network pharmacology. These findings could contribute to the development of novel treatments for PF and provide a basis for further experimental studies.

BackgroundCarotid Intima-Media Thickness (CIMT) is a key marker for atherosclerosis, with its modulation being crucial for cardiovascular disease (CVD) risk assessment. While thyroid function’s impact on cardiovascular health is recognized, the causal relationship and underlying mechanisms influencing CIMT remain to be elucidated.MethodsIn this study, Mendelian Randomization (MR) was employed to assess the causal relationship between thyroid function and CIMT. Thyroid hormone data were sourced from the Thyroidomics Consortium, while lipid traits and CIMT measurements were obtained from the UK Biobank. The primary analysis method was a two-sample MR using multiplicative random effects inverse variance weighting (IVW-MRE). Additionally, the study explored the influence of thyroid hormones on lipid profiles and assessed their potential mediating role in the thyroid function-CIMT relationship through multivariate MR analysis.ResultsThe study revealed that lower levels of Free Thyroxine (FT4) within the normal range are significantly associated with increased CIMT. This association was not observed with free triiodothyronine (FT3), thyroid-stimulating hormone (TSH), or TPOAb. Additionally, mediation analysis suggested that apolipoprotein A-I and B are involved in the relationship between thyroid function and CIMT. The findings indicate a potential U-shaped curve relationship between FT4 levels and CIMT, with thyroid hormone supplementation in hypothyroid patients showing benefits in reducing CIMT.ConclusionThis research establishes a causal link between thyroid function and CIMT using MR methods, underscoring the importance of monitoring thyroid function for early cardiovascular risk assessment. The results advocate for the consideration of thyroid hormone supplementation in hypothyroid patients as a strategy to mitigate the risk of carotid atherosclerosis. These insights pave the way for more targeted approaches in managing patients with thyroid dysfunction to prevent cardiovascular complications.

Triple-negative breast cancer (TNBC) is more prone to recurrence and metastasis relative to other subtypes of breast cancer, leading to an extremely poor prognosis. The increasing potential chemoresistance of TNBC patients is mainly due to that tumor cells escape from apoptosis. In recent years, statins have demonstrated extensive anti-tumor effects. It is worth noting that statins have more effective anti-tumor effects on TNBC cells and drug-resistant breast cancer cells. Therefore, this study examines the superior cytotoxic effects of statins on TNBC cell lines and further explores their potential therapeutic mechanisms. We detected different cell phenotypes and found that statins significantly reduced the cell viability of TNBC cells. Specifically, pitavastatin showed an obvious induction in cell death, cell cycle arrest and oxidative stress in TNBC MDA-MB-231 cells. The reversal effect of iron chelator desferrioxamine (DFO) on the morphological and molecular biological changes induced by pitavastatin has revealed a new mode of cell death induced by pitavastatin: ferroptosis. This ferroptotic effect was strengthened by the decreased expression of glutathione peroxidase 4 (GPx4) as well as newly discovered ferroptosis suppressor protein 1 (FSP1). The data showed that ferroptotic death of MDA-MB-231 cells is autophagy-dependent and mediated by the mevalonate pathway. Finally, we found that therapeutic oral doses of statins can inhibit the growth of transplanted tumors, which establishes statins as a potential treatment for TNBC patients. In conclusion, we found pitavastatin could induce autophagy-dependent ferroptosis in TNBC cells via the mevalonate pathway which may become a potential adjuvant treatment option for TNBC patients.

Inhibitor of apoptosis proteins (IAPs) are crucial components of apoptosis that perform vital roles in the regulation of caspase activity in organisms. In this study, two IAPs genes were identified from Cotesia chilonis, the dominant parasitic wasp of Chilo suppressalis. CcIAP1 gene is a typical IAP and contains two BIR domains and a RING domain, whereas CcIAP gene is an atypical IAP1 only containing two BIR domains. Phylogenetic analysis indicated that CcIAP1 and CcIAP were grouped with other Hymenopteran IAPs and IAP1 in C. suppressalis. Real-time quantitative PCR revealed that CcIAP1 and CcIAP genes were both highly induced at −6°C and 30°C, and expression was highest at the third instar stage. The expression of CcIAP1 and CcIAP genes were significantly induced during parasitism of C. suppressalis, and the 7-d time point resulted in the highest expression levels for both genes, in which was an advanced stage of larval development of C. chilonis. RNAi experiments showed that CcIAP1 gene was the key IAP in the regulation of apoptosis of C. chilonis and its host. In conclusion, CcIAP1 and CcIAP correlate with the development of C. chilonis and their responses to temperature stress.

Background: Tumor antigenicity and efficiency of antigen presentation jointly influence tumor immunogenicity, which largely determines the effectiveness of immune checkpoint blockade (ICB). However, the role of altered antigen processing and presentation machinery (APM) in breast cancer (BRCA) has not been fully elucidated. Methods: A series of bioinformatic analyses and machine learning strategies were performed to construct APM-related gene signatures to guide personalized treatment for BRCA patients. A single-sample gene set enrichment analysis (ssGSEA) algorithm and weighted gene co-expression network analysis (WGCNA) were combined to screen for BRCA-specific APM-related genes. The non-negative matrix factorization (NMF) algorithm was used to divide the cohort into different clusters and the fgsea algorithm was applied to investigate the altered signaling pathways. Random survival forest (RSF) and the least absolute shrinkage and selection operator (Lasso) Cox regression analysis were combined to construct an APM-related risk score (APMrs) signature to predict overall survival. Furthermore, a nomogram and decision tree were generated to improve predictive accuracy and risk stratification for individual patients. Based on Tumor Immune Dysfunction and Exclusion (TIDE) method, random forest (RF) and Lasso logistic regression model were combined to establish an APM-related immunotherapeutic response score (APMis). Finally, immune infiltration, immunomodulators, mutational patterns, and potentially applicable drugs were comprehensively analyzed in different APM-related risk groups. IHC staining was used to assess the expression of APM-related genes in clinical samples. Results: In this study, APMrs and APMis showed favorable performances in risk stratification and therapeutic prediction for BRCA patients. APMrs exhibited more powerful prognostic capacity and accurate survival prediction compared to conventional clinicopathological features. APMrs was closely associated with distinct mutational patterns, immune cell infiltration and immunomodulators expression. Furthermore, the two APM-related gene signatures were independently validated in external cohorts with prognosis or immunotherapeutic responses. Potential applicable drugs and targets were mined in the APMrs-high group. APM-related genes were further validated in our in-house samples. Conclusion: The APM-related gene signatures established in our study could improve the personalized assessment of survival risk and guide ICB decision-making for BRCA patients.

Abstract Background The metastasis of breast cancer (BC) is a complex multi-step pathological process, strictly dependent on the intrinsic characteristics of BC cells and promoted by a predisposing microenvironment. Although immunotherapy has made important progress in metastasis BC, the heterogeneity of PD-L1 in tumor associated macrophages (TAMs) in BC and the underlying mechanisms in the metastasis development of BC are still not completely elucidated. Small extracellular vesicles (sEVs) represent essential interaction mediators between BC cells and TAMs. It is worth noting to explore the underlying mechanisms typical of sEVs and their role in the metastasis development of BC. Methods The structure of sEVs was identified by TEM, while the particle size and amounts of sEVs were detected by BCA and NTA analysis. The specific PD-L1 + CD163 + TAM subpopulation in metastasis BC was identified by scRNA-seq data of GEO datasets and verified by IHC and IF. The function of TAMs and sEVs in metastasis BC was explored by RT-qPCR, WB, IF, flow cytometry and in vivo experiment. The expression profiles of plasma sEVs-miRNA in relation to BC metastasis was analyzed using next-generation sequencing. Further detailed mechanisms of sEVs in the metastasis development of BC were explored by bioinformatics analysis, RT-qPCR, WB and luciferase reporter assay. Results In this study, we identified that the immunosuppressive molecule PD-L1 was more abundant in TAMs than in BC cells, and a specific PD-L1 + CD163 + TAM subpopulation was found to be associated with metastasis BC. Additionally, we found that BC cells-derived sEVs can upregulate the PD-L1 expression and induce the M2 polarization, enhancing the metastasis development both in vitro and in vivo. Also, Clinical data showed that sEV-miR-106b-5p and sEV-miR-18a-5p was in relation to BC metastasis development and poor prognosis of BC patients. Further mechanistic experiments revealed that BC-derived sEV-miR-106b-5p and sEV-miR-18a-5p could synergistically promoted the PD-L1 expression in M2 TAMs by modulating the PTEN/AKT and PIAS3/STAT3 pathways, resulting in the enhancement of the BC cells invasion and metastasis. Conclusions Our study demonstrated that BC-derived sEVs can induce metastasis in BC through miR-106b-5p/PTEN/AKT/PD-L1 and miR-18a-5p/PIAS3/STAT3/PD-L1 pathways in TAMs. Therefore, the inhibition of these specific interactions of signaling pathways would represent a promising target for future therapeutic strategies for treatment of BC.

Abstract Colorectal cancer (CRC) is a common gastrointestinal malignancy with high morbidity and fatality. Chemotherapy, as traditional therapy for CRC, has exerted well antitumor effect and greatly improved the survival of CRC patients. Nevertheless, chemoresistance is one of the major problems during chemotherapy for CRC and significantly limits the efficacy of the treatment and influences the prognosis of patients. To overcome chemoresistance in CRC, many strategies are being investigated. Here, we review the common and novel measures to combat the resistance, including drug repurposing (nonsteroidal anti‐inflammatory drugs, metformin, dichloroacetate, enalapril, ivermectin, bazedoxifene, melatonin, and S‐adenosylmethionine), gene therapy (ribozymes, RNAi, CRISPR/Cas9, epigenetic therapy, antisense oligonucleotides, and noncoding RNAs), protein inhibitor (EFGR inhibitor, S1PR2 inhibitor, and DNA methyltransferase inhibitor), natural herbal compounds (polyphenols, terpenoids, quinones, alkaloids, and sterols), new drug delivery system (nanocarriers, liposomes, exosomes, and hydrogels), and combination therapy. These common or novel strategies for the reversal of chemoresistance promise to improve the treatment of CRC.

Abstract Purpose To investigate the mechanism underlying the modulation of M1 macrophage polarization by exosomes released from hyperthermia-treated triple-negative breast cancer (TNBC) cells. Materials and methods In this study, the effects of hyperthermia on TNBC cells were examined using cell counting kit-8, apoptosis, and cell cycle assays. Transmission electron microscopy was used to identify the structure of exosomes, while bicinchoninic acid and nanoparticle tracking analysis were used to detect particle size and amounts of exosomes released after hyperthermia. The polarization of macrophages incubated with exosomes derived by hyperthermia-pretreated TNBC cells were assessed by RT-qPCR and flow cytometry analysis. Next, RNA sequencing was performed to determine the targeting molecules changed in hyperthermia-treated TNBC cells in vitro. Finally, the mechanism underlying the modulation of macrophage polarization by exosomes derived from hyperthermia-treated TNBC cells was examined by using RT-qPCR, immunofluorescence and flow cytometry analysis. Results Hyperthermia markedly reduced cell viability in TNBC cells and promoted the secretion of TNBC cell-derived exosomes. The hub genes of hyperthermia-treated TNBC cells were significantly correlated with macrophage infiltration. Additionally, hyperthermia-treated TNBC cell-derived exosomes promoted M1 macrophage polarization. Furthermore, the expression levels of heat shock proteins, including HSPA1A, HSPA1B, HSPA6, and HSPB8, were significantly upregulated upon hyperthermia treatment, with HSPB8 exhibiting the highest upregulation. Moreover, hyperthermia can induce M1 macrophage polarization by promoting exosome-mediated HSPB8 transfer. Conclusion This study demonstrated a novel mechanism that hyperthermia can induce M1 polarization of macrophages via exosome-mediated HSPB8 transfer. These results will help with future development of an optimized hyperthermia treatment regime for clinical application, especially for combination treatment with immunotherapy.

Background: This study aimed to assess the clinical significance of generating a volumetric stent expansion index for tapering lesions through intravascular ultrasound (IVUS). Previous IVUS studies have used minimal stent area (MSA) to predict adverse outcomes. Methods: A total of 251 tapering lesions were treated in this study via IVUS guidance in 232 patients. Eight stent expansion indices were evaluated to determine the association of these indices with device-oriented clinical endpoints (DoCEs) after two-year follow-ups. These were the ILUMIEN III and IV standards, the ULTIMATE (Intravascular Ultrasound Guided Drug Eluting Stents Implantation in “All-Comers” Coronary Lesions) standard, the IVUS-XPL (Impact of Intravascular Ultrasound Guidance on the Outcomes of Xience Prime Stents in Long Lesions) standard, the minimal volumetric expansion index (MVEI) using the Huo-Kassab or linear model, the MSA/vessel area at the MSA cross-section, the traditional stent expansion (MSA/mean proximal and distal reference lumen cross-sectional area), and MSA. Results: The MVEI was the only stent expansion index that correlated significantly with the two-year DoCEs (hazard ratio [HR], 1.91; 95% confidence interval [CI]: 1.16–3.96; p = 0.028). In the ROC analysis, the area under the curve for the MVEI was 0.71 (p = 0.002), with an optimal cut-off value of 62.2 for predicting the DoCEs. Conclusions: This is the first study to use IVUS for tapering lesions and demonstrate that the MVEI is an independent predictor of two-year DoCEs.

Abstract Objective To explore the influence and the underlying mechanism of vaspin (visceral adipose tissue‐derived serpin) on the development of triple‐negative breast malignancy. Methods First, we analyzed medical records and screened out 22 breast cancer patients with different BMI according to inclusion and exclusion criterion, and measured serum vaspin of those patients. Then we studied the effects of vaspin on TNBC cell lines by using EdU assay, colony formation, transwell and wound‐healing assay. Later, we used bioinformatics analysis to identify downstream effectors and verify with qRT‐PCR, luciferase assay, western blot, etc. Results We found the vaspin level was positively correlated with BMI in breast malignant patients and vaspin could significantly enhance the proliferation, infiltration and transferring of triple‐negative breast cancer cells by restraining the expression of miR‐33a‐5p. By using bioinformatic analysis and luciferase assay, we identified miR‐33a‐5p directly regulating ABHD2. Conclusion Vaspin, as a cancer‐promoting cytokine, may inhibit miR‐33a‐5p thus increasing the level of ABHD2 to promote the development of the triple‐negative breast cancer.

IoT device market has grown rapidly in recent years, with many researches have been done to investigate the IoT devices’ adoption factors. However, it is crucial to understand how to maintain the users’ continuance intention. This study, based on the post-acceptance model of the Expectation Confirmation Model (ECM), investigates the impact of early-stage users’ personal traits (personal innovativeness), social influence (normative and informational), and familiarity, on the social diffusion of IoT devices (in particular, smart speakers) measured by the continuation intention of smart speakers. We tested the research model and hypotheses using data from 364 smart speaker users, analyzed with partial least square technique using Smart-PLS. The data analysis results revealed that satisfaction has a very strong and positive impact on continuance intention. Perceived usefulness, confirmation, and personal innovativeness are positively associated with continuance intention via satisfaction. Social influence, represented by normative and informational social influence, showed a significant positive impact on continuance intention, a high degree of familiarity weakens the influence of normative social influence on continuance intention; however, familiarity has no impact on the relationship between informational social influence and continuance intention.

This paper mainly focuses on the impact of inclined static air gap eccentricity (ISAGE) on the electromagnetic characteristics and mechanical performances (vibration, deformation, strain and stress). Considering different ISAGE fault types in the theoretical and finite element analysis (FEA) model of synchronous generators, the effects of intersection position of the rotor center axis and stator center axis, rotor inclined angle, and the combination of the previous two fault types on MFD, phase current and radial magnetic pulling per unit area (MPPUA) are analyzed and compared. Then, based on the stator model used uniformly in three physical fields, the harmonic response and mechanical response are investigated with loads imported by the electromagnetic field. Finally, the stator radial vibration measurement experiments are carried out to verify the results obtained by theoretical analysis and FEA. It is shown that ISAGE will considerably enlarge the fluctuation of MPPUA and intensify the radial vibration of the stator, especially at the 2nd harmonic. The probability of failure at tooth tip and inner slot wall of the stator will increase.

Abstract To minimize surgical complications and staged procedures halo-traction is often used during deformity corrections. But the use of halo-traction in the treatment of refractory cervical kyphosis secondary to infections has never been reported. This study investigated the role of halo-traction in the treatment of cervical infection patients associated with refractory kyphosis. We retrospectively reviewed 48 patients with cervical infection associated with refractory kyphosis who were treated in our spine department. Patients were divided into two groups, the traction group (A) and the non-traction group (B). Group A underwent preoperative halo-traction followed by surgery, while group B underwent surgery alone. Between the two groups, we analyzed the kyphosis deformity correction, level of fusions, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), functional improvement by Neck disability index (NDI) score, and complications. Group A had a better correction of kyphosis deformity compared to group B (27.01 ± 11.54)0 versus (18.08 ± 10.04)0 (P = 0.01, Z = − 2.44). No statistically significant differences between the two groups in terms of functional improvement, level of fusions, ESR and CRP. Group B had 3 revision surgery cases. Preoperative halo-traction followed by surgery is superior in kyphosis correction in the treatment of patients with cervical infections with refractory kyphosis.

For the problem that how the grouting reinforcement of a single penetrated structural plane affects the bearing capacity of surrounding rock, an approach of rock samples preparation with single penetrated fracture surface is proposed firstly, and the rock samples are injected with ultrafine cement and epoxy resin, respectively. Then, the strength and deformation characteristics of the consolidated body under uniaxial (triaxial) compression are investigated with the RMT-150C experimental system. Finally, the micro consolidation mechanism of structural plane grouting is revealed using theoretical analysis and electron microscope scanning. It is found that the fracture surface generated under the triaxial loading-unloading condition is closer to the engineering practice and meets the experimental requirements. The stress−strain characteristic curves of the specimens injected with ultrafine cement show phased deformation characteristics, and the curves of the specimens injected with epoxy resin are relatively smooth. For the strength characteristics, the influence of confining pressure is significantly larger than that of grouting material selection. Grouting reinforcement can improve the residual strength of rock mass. With the increase of confining pressure, the increase of improvement coefficient of residual strength is less obvious, and the peak strength of the consolidated body is closer to that of intact rock. For the failure characteristics, the main fracture surface of the specimen injected with ultrafine cement shears and slips along the original fracture surface, and the main fracture surface of the specimen injected with epoxy resin is a new penetrated fracture surface. Finally, based on the Mohr-Coulomb criterion, the relationship between the bonding force of grouting materials and the strength improvement coefficient of structural plane is established. It is found that the strength improvement coefficient of structural plane has a linear relationship with the bonding force of grout. The comparison between the calculation and test results shows that the formula is reasonable and can provide a reference for the optimization of deep surrounding rock support.

AIM: To prepare a folic acid-magnetic dual target, adriamycin(ADM)-loaded phase change liposome nanoparticles(FA-PFH-Fe3O4@ADM), and observe its ability to target retinoblastoma Y79 cells and its three-mode imaging ability of in vitro ultrasound/photoacoustic/magnetic resonance.METHODS: FA-PFH-Fe3O4@ADM was prepared by the double emulsification method, and its basic characteristics were tested. Test the cellular safety of nanoparticles. Observe the heating phenomenon and phase transition of nanoparticles under 808nm laser. Y79 cells in logarithmic growth phase were divided into four groups. The non-targeted group and the single magnetic target group were added with PFH-Fe3O4@ADM nanoparticles(0.625mg/mL). The single folic acid target group and folic acid-magnetic dual target group were added with FA-PFH-Fe3O4@ADM nanoparticles(0.625mg/mL). A 4T magnet was placed at the side of the orifice plate of the single magnetic target group and the folic acid-magnetic double target group to evaluate the targeting ability of nanoparticles on Y79 cells. In addition, the ability of FA-PFH-Fe3O4@ADM nanoparticles ultrasound/photoacoustic/magnetic resonance three-mode imaging in vitro was observed.RESULT: FA-PFH-Fe3O4@ADM nanoparticles were successfully prepared with uniform distribution and uniform spherical structure. The average particle size of nanoparticles was 338.6±2.20 nm. ADM and Fe3O4 were successfully loaded, with an encapsulation efficiency of(41.76±4.12)% and(59.06±13.63)%, respectively. Nanoparticles had good paramagnetic properties and showed no obvious toxicity to Y79 cells. The phagocytic rate of the folic acid-magnetic dual target group(86.19±0.55)% was significantly higher than that of the single folate target group(43.36±5.91)% and single magnetic target group [(28.58±3.23)%, P

Purpose To investigate the mechanism through which hyperthermia promotes exosome secretion and drug sensitivity in adriamycin-resistant breast cancer. Materials and Methods We first evaluated the effect of hyperthermia on adriamycin-resistant breast cancer viability and used transmission electron microscopy, nanoparticle tracking analysis, and a bicinchoninic acid kit to validate the effect of hyperthermia on exosome secretion. The effective targeting molecules and pathways changed by hyperthermia were explored by RNA microarray and verified in vitro. The adriamycin-resistant MCF-7/ADR cells co-incubated with the exosomes produced by MCF-7/ADR cells after hyperthermia were assessed. The uptake of exosomes by MCF-7/ADR cells after hyperthermia treatment was evaluated by confocal microscopy. Finally, the mechanism through which hyperthermia promotes exosome secretion by hyperthermia was determined. Results Hyperthermia significantly suppressed the growth of adriamycin-resistant breast cancer cells and increased drug sensitivity by upregulating FOS and CREB5, genes related to longer overall survival in breast cancer patients. Moreover, hyperthermia promoted exosome secretion through Rab7b, a small GTPase that controls endosome transport. The upregulated FOS and CREB5 antioncogenes can be transferred to MCF-7/ADR cells by hyperthermia-treated MCF-7/ADR cell-secreted exosomes. Conclusions Our results demonstrated a novel function of hyperthermia in promoting exosome secretion in adriamycin-resistant breast cancer cells and revealed the effects of hyperthermia on tumor cell biology. These hyperthermia-triggered exosomes can carry antitumor genes to the residual tumor and tumor microenvironment, which may be more beneficial to the effects of hyperthermia. These results represent an exploration of the relationship between therapeutic strategies and exosome biology.

Abstract Background More initial clinical node‐positive breast cancer patients achieve axillary pathological complete response (ax‐pCR) after neoadjuvant systemic therapy (NST). Restaging axillary status and performing de‐escalated surgical procedures to replace routine axillary lymph nodes dissection (ALND) is urgently needed. Targeted axillary lymph node biopsy (TLNB) is a novel de‐escalated surgical strategy marking metastatic axillary nodes before NST and targeted dissection and biopsy intraoperatively to tailor individual axillary management. Methods This study provided a systematic review and meta‐analysis to evaluate the feasibility and diagnosis accuracy of TLNB. Prospective and retrospective clinical trials on TLNB were searched from Pubmed, Embase, and Cochrane. Identification rate (IFR), false‐negative rate (FNR), negative predictive value (NPV), and rate of ax‐pCR were the outcomes of this meta‐analysis. Results One thousand nine hundred and twenty patients attempted TLNB, with an overall IFR of 93.5% (95% confidence interval [CI] 90.1%–96.2%). IFR of three nodal marking methods, namely iodine seeds, clips, and carbon dye, was 95.6% (95% CI 91.2%–98.7%), 91.7% (95% CI 87.3%–95.4%), and 97.1% (95% CI 89.1%–100.0%), respectively. Of them, 847 patients received ALND, with an overall FNR of 5.5% (95% CI 3.3%–8.0%), and NPV ranged from 90.1% to 96.1%. Regression analysis showed that the overlap of targeted and sentinel biopsied nodes might associate with IFRs and FNRs. Conclusion TLNB is a novel, less invasive surgical approach to distinguish initial node‐positive breast cancer that achieves negative axillary conversion after NST. It yields an excellent IFR with a low FNR and a high NPV. A combination of preoperative imaging, intraoperative TLNB with SLNB, and postoperative nodal radiotherapy might affect the future treatment paradigm of primary breast cancer with nodal metastases.

Purpose: Venous thromboembolism (VTE) is a major health issue among hip fracture patients. This study aimed to develop an information platform based on a mobile application and then evaluate whether information platform-based nursing could improve patient's drug compliance and reduce the incidence of VTE in hip fracture patients. Methods: This study retrospectively analyzed hip fracture patients who were treated with conventional prevention and intervention methods for VTE (control group) between January 2008 and November 2012, and prospectively analyzed hip fracture patients who were treated with nursing intervention based on the information platform (study group) between January 2016 and September 2017. All the patients included in the both groups were hip fracture patients who had an age over 50 years, treated with surgery, and hospitalized ≥ 48 h. Patients were excluded if they admitted to hospital due to old fractures, had a severe bleeding after 72 h of admission, diagnosed with any type of VTE, or refused to participate in the study. The information platform was divided into medical, nursing, and patient interface. Based on the information platform, medical practitioners and nurses could perform risk assessments, monitoring management and early warnings, preventions and treatments, health educations, follow-up, and other aspects of nursing interventions for patients. This study compared essential characteristics, drug compliance, VTE occurrence, and mean length of hospitalization between the two groups. Besides, a subgroup analysis was performed in the study group according to different drug compliances. SPSS 18.0 software (IBM Corp., NY, and USA) was used for statistical analysis. Results: Altogether 1177 patients were included in the control group, and 491 patients in the study group. Regarding baseline data, patients in the study group had more morbidities than those in the control group (p

Abstract Recurrence, metastasis, and drug resistance are still big challenges in breast cancer therapy. Internal and external stresses have been proven to substantially facilitate breast cancer progression through molecular and systemic mechanisms. For example, endoplasmic reticulum stress (ERS) results in activation of the unfolded protein response (UPR), which are considered an important cellular stress response. More and more reports indicate its key role in protein homeostasis and other diverse functions involved in the process of breast cancer progression. Therefore, therapies targeting the activation of ERS and its downstream signaling pathways are potentially helpful and novel tools to counteract and fight breast cancer. However, recent advances in our understanding of ERS are focused on characterizing and modulating ERS between healthy and disease states, and so little attention has been paid to studying the role and clinical application of targeting ERS in a certain cancer. In this review, we summarize the function and main mechanisms of ERS in different molecular types of breast cancer, and focus on the development of agents targeting ERS to provide new treatment strategies for breast cancer. Video Abstract

Abstract This article has conducted a comprehensive study on the stator and rotor vibration characteristics of the doubly‐fed induction generator (DFIG) in the case of radial air gap eccentricity (RAGE). Differently from other previous studies, this paper not only investigates the vibration characteristics of stator and rotor in radial static air gap eccentricity (RSAGE) and radial dynamic air‐gap eccentricity (RDAGE) fault but also takes the radial hybrid air gap eccentricity (RHAGE) into account. Through theoretical derivation, the detailed expressions of stator magnetic pull per unit area (MPPUA) and rotor unbalanced magnetic pull (UMP) are obtained. The finite element analysis (FEA) and experiment based on a two pairs of poles DFIG, and the results are consistent with theoretical calculations. It is shown that RAGE will enlarge the magnitude of stator MPPUA/vibration and rotor UMP/vibration. Specifically, RSAGE will not change the frequency components of stator MPPUA/vibration but will bring new frequency components to rotor UMP/vibration. However, both stator MPPUA/vibration and rotor UMP/vibration will generate new frequency components during RDAGE fault. In addition, the effect of RHAGE is the superposition of RSAGE and RDAGE. The research conclusions obtained in this paper can be used as a supplementary criterion for diagnosing the eccentricity of DFIG.

Abstract Background Several studies have reported that circulating tumor cells (CTCs) are a promising marker for the diagnosis of thyroid cancer (TC) with recurrence or distant metastasis (DMs). However, some studies emerged with conflicting results. Therefore, we provide a meta-analysis to evaluate the diagnostic performance of CTC for detection of recurrence in patients of TC. Methods We searched PubMed, Web of Science, Cochrane library with the keywords “thyroid cancer” and “circulating tumor cells”. Data extraction and risk of bias assessment were performed independently by two reviewers. The summary receiver operating characteristic curve (SROC) and other parameters were adopted to summarize the overall test performance. The sensitivity of CTCs in the detection of recurrent TC was reviewed. All analyses were performed by STATA 12.0 and Meta-disc software. Results For CTCs expressing epithelial cell adhesion molecule (EpCAM), seven studies were included in our meta-analysis. Pooled sensitivity, specificity, and diagnostic odds ratio were 0.71 (95% CI: 0.63–0.78), 0.89 (95% CI: 0.84–0.94), and 26.75 (95% CI: 9.11–78.53); 0.78 (95% CI: 0.65–0.89), 0.88 (95% CI: 0.76–0.96), and 40.01 (95% CI: 10.49–152.63) for CTCs expressing thyroid stimulating hormone receptor (TSHR). The area under the SROC for EpCAM and TSHR were both 0.91. Conclusion CTC was a reliable marker for the diagnosis of TC patients with recurrence and DMs, and the sensitivity of CTCs expressing TSHR was higher than that of EpCAM. Additional research is warranted in order to establish uniformity in international guidelines, make up the drawbacks of conventional diagnostic methods and to prevent futile surgery.

AIM: To evaluate celastrol's effect on choroidal neovascularization (CNV). METHODS: In this study, neovascular formation in vitro (tube formation and aortic ring culture) and in vivo (laser induced neovascular in mice) was treated with celastrol to evaluate this natural compound's impact on CNV. Western blot was applied to explore the possible mechanism for it. For in vitro assay, triplicate for each group was repeated at least three times. For in vivo assay, each group contains 5 mice. RESULTS: Celastrol supressed tube formation and aortic ring sprout neovascularization. In vitro assay exhibited that celastrol inhibiting vascular endothelial growth factor (VEGF)-induced proliferation and migration of human umbilical vein endothelial cells and human choroidal endothelial cells, and by blocking VEGF signaling. Furthermore, intraperitoneal administration of celastrol significantly reduced the area of laser-induced CNV in an in vivo mouse model. By day 14, the area of CNV had decreased by 49.15% and 80.26% in the 0.1 mg/kg celastrol-treated group (n=5) and in the 0.5 mg/kg celastrol treated group (n=5), respectively, compared to the vehicle-treated group (n=5). CONCLUSION: Celastrol inhibits CNV by inhibiting VEGF-induced proliferation and migration of vascular endothelial cells, indicating that celastrol is a potent, natural therapeutic compound for the prevention of CNV.

Additively manufactured Ti alloys exhibit spatially dependent microstructures and mechanical properties owing to the intrinsic thermal cycling. Here the authors develop new Ti alloys with uniform mechanical properties through a rational alloy design.

Abstract Background Pyogenic vertebral osteomyelitis (PVO), which is a potentially life-threatening condition and is associated with significant morbidity and mortality, is a cause of back pain that can lead to neurologic deficits if not diagnosed in time and effectively treated. The objective of this study is to compare the efficacy of posterior single-segment and short-segment fixation combined with one-stage posterior debridement and fusion for the treatment of mono-segmental lumbar or lumbosacral PVO. Methods Charts of all patients with mono-segmental lumbar or lumbosacral PVO were treated by single-stage posterior debridement, bone graft fusion, and pedicle screw fixation from April 2012 to January 2016. All patients were divided into two groups: sinlge-segment fixation (Group A, n = 31) and short-segment fixation (Group B, n = 36). These patients were followed up for a minimum of five years. The clinical efficacy was evaluated and compared on average operation time, blood loss, visual analog scale (VAS), erythrocyte sedimentation rate (ESR), C-Reactive protein (CRP), neurological function recovery and local lordotic angle. Results All 67 patients were completely cured during the follow-up. All patients had significant improvement of neurological condition and pain relief at the final follow-up. The VAS was 7.1 ± 0.7 in group A and 7.2 ± 0.6 in group B pre-operatively, which decreased to 2.1 ± 0.6 and 2.0 ± 0.7, respectively, at three months after surgery, then reduced to 0.4 ± 0.5 and 0.5 ± 0.5, respectively, at the final follow-up. ESR, CRP returned to normal limits in all patients 3 months after surgery. The mean blood loss and operation time in group A were less than that in group B (P

Hot dry rock (HDR) is a kind of clean energy with significant potential. Since the 1970s, the United States, Japan, France, Australia, and other countries have attempted to conduct several HDR development research projects to extract thermal energy by breaking through key technologies. However, up to now, the development of HDR is still in the research, development, and demonstration stage. An HDR exploration borehole (with 236 °C at a depth of 3705 m) was drilled into Triassic granite in the Gonghe Basin in northwest China in 2017. Subsequently, China Geological Survey (CGS) launched the HDR resources exploration and production demonstration project in 2019. After three years of efforts, a sequence of significant technological breakthroughs have been made, including the genetic model of deep heat sources, directional drilling and well completion in high-temperature hard rock, large-scale reservoir stimulation, reservoir characterization, and productivity evaluation, reservoir connectivity and flow circulation, efficient thermoelectric conversion, monitoring, and geological risk assessment, etc. Then the whole-process technological system for HDR exploration and production has been preliminarily established accordingly. The first power generation test was completed in November 2021. The results of this project will provide scientific support for HDR development and utilization in the future.©2022 China Geology Editorial Office.

Genetic diversity, population structure, and population expansion of goats worldwide (4 165 individuals from 196 breeds) were analyzed using published mitochondrial DNA (mtDNA) D_loop hypervariable region sequences. Results showed that 2 409 haplotypes and 301 polymorphic sites were present within the 401-bp length D_loop region, the nucleotide diversity (Pi) was 0.03471, and the haplotype diversity (Hd) was 0.9983. Phylogenetic analysis revealed that 98.92% of haplotypes were divided into six obvious clusters, consistent with the classification of the known mitochondrial haplogroups of goats. Haplogroup A accounted for the largest proportion (86%). Interestingly, two unknown divisions (Unknown I and Unknown II) were discovered from goats in Southwest China, suggesting that Southwest China has unique maternal haplogroups. Analysis of molecular variance (AMOVA) and the average number of pairwise differences between populations (PiXY) indicated that geographical variation was small but significant. Neutrality tests (Tajima's D and Fu's FS tests) and mismatch distribution showed that haplogroups B, C, and G had expansion histories. In addition, the phylogenetic relationship between domestic and wild goats suggested that Capra aegagrus is the most likely wild ancestor and may have participated in the domestication of ancestral populations of A, B, C, and F haplogroups. A meta-analysis on the mtDNA sequences of goats from international databases was conducted to analyze goats’ genetic diversity, population structure, and matrilineal system evolution worldwide. The results may help further understand the domestication history and gene flow of goats worldwide.

AIM: To investigate whether ultrasound-targeted cationic microbubbles (CMBs) destruction could deliver endostatin-green fluorescent protein (GFP) plasmids efficiently to the human retinal endothelial cells (HRECs) and inhibit retinal neovascularization in mice. METHODS: CMBs were prepared and the presentation of GFP reporter was confirmed by flow cytometry and laser confocal microscopy. Experiments assessing HRECs migration and vascular formation were performed to evaluate gene therapy's efficiency in vitro. A mouse model of oxygen-induced retinopathy was employed and the expression of Bcl-xl, Bcl-2, vascular endothelial growth factor (VEGF) and endostatin in the retina of mice were determined by Western blotting and quantitative polymerase chain reaction (qPCR). The expression of endostatin-GFP in the retina was examined by laser confocal microscopy at 5, 14, and 28d after treatment. RESULTS: The gene expression of endostatin was the highest in the group of the CMBs. Besides, the inhibition and antiangiogenesis effect of the migration and development of HRECs were improved following treatment with CMBs compared with the other groups in vitro. In vivo, retinal neovascularization was significantly inhibited and the fluorescence intensity of endostatin-GFP in the mouse retina was importantly higher in the group of CMBs than that in other groups. CONCLUSION: The research illustrates ultrasound-targeted CMBs destruction possessed distinct effect on the inhibition of the vascular formation and the development of retinal neovascularization both in vitro and in vivo.

The G-protein-coupled receptor GPR84, activated by medium-chain fatty acids, primarily expressed in macrophages and microglia, is involved in inflammatory responses and retinal development in mammals and amphibians. However, our understanding of its structure, function, tissue expression, and signaling pathways in fish is limited. In this study, we cloned and characterized the coding sequence of GPR84 (ciGPR84) in grass carp. A phylogenetic analysis revealed its close relationship with bony fishes. High expression levels of GPR84 were observed in the liver and spleen. The transfection of HEK293T cells with ciGPR84 demonstrated its responsiveness to medium-chain fatty acids and diindolylmethane (DIM). Capric acid, undecanoic acid, and lauric acid activated ERK and inhibited cAMP signaling. Lauric acid showed the highest efficiency in activating the ERK pathway, while capric acid was the most effective in inhibiting cAMP signaling. Notably, DIM did not activate GPR84 in grass carp, unlike in mammals. These findings provide valuable insights for mitigating chronic inflammation in grass carp farming and warrant further exploration of the role of medium-chain fatty acids in inflammation regulation in this species.

The present work aims to boost our understanding of factors governing the grain-refining efficiency of inoculation treatments by comparing the grain-refining efficiencies of two inoculators: Ti nanoparticles and LaB6 nanoparticles, in a 2024 Al alloy during additive manufacturing (AM). Experimental results obtained by scanning electron microscopy show that the LaB6 nanoparticle possessed almost no refining effect on the alloy, with the addition content ranging from 0.5 wt.% to 2 wt.%. Conversely, the Ti nanoparticle resulted in a more pronounced refinement and a fine, fully equiaxed microstructure at 1 wt.% Ti addition. Based on transmission electron microscopy analysis, the higher refining efficiency of Ti inoculation was ascribed to the incorporation of both Ti solute and the in situ-formed L12-Al3Ti nucleation particles. The former significantly increased the overall undercooling ahead of the growing Al grain, which ensured the activation of heterogeneous nucleation on the L12-Al3Ti nanoparticles, leading to grain refinement. This work highlights that despite the addition of nucleation particles, the incorporation of appropriate solutes to generate sufficient undercooling is the prerequisite for the activation of heterogenous nucleation in AM.

Abstract The objective of this study was to provide the characteristics of hepatic computed tomography images and optimize their transition delay with a bolus-tracking technique for triple-phase hepatic computed tomography in cats. Dynamic triple-phase computed tomography was performed in nine healthy cats. The upper third of the liver was dynamically scanned every 0.5 s for 40 s. The time density curves of the aorta and hepatic parenchyma mean enhancement were analyzed. Triple-phase hepatic computed tomography was performed three times with a bolus trigger of 200 Hounsfield units of aortic enhancement. The transition delays of the arterial, portal, and hepatic parenchymal phases were respectively 0, 5 and 60 s in the first scan; 2, 7 and 62 s in the second scan; and 4, 9 and 64 s in the third scan. All computed tomography images were evaluated by a certificated radiologist. The arterial vessels and their main branches were well enhanced at a 2 s transition delay. The contrast of the portal vein to the liver parenchyma was most obvious at a 7 s transition delay. The mean enhancement of the hepatic parenchyma peaked at a 62 s transition delay, whereas the degree of enhancement of the hepatic vasculature decreased. In this study, the recommended transition delays for the arterial, portal, and hepatic parenchymal phases were 2 s, 7 s and 62 s, respectively, after triggering at 200 Hounsfield units of aortic enhancement. This information may be helpful in diagnosing feline liver diseases and provides a key reference for the clinical implementation of CT.

Abstract Heart aging is the main susceptible factor to coronary heart disease and significantly increases the risk of heart failure, especially when the aging heart is suffering from ischemia-reperfusion injury. Numerous studies with NAD+ supplementations have suggested its use in anti-aging treatment. However, systematic reviews regarding the overall role of NAD+ in cardiac aging are scarce. The relationship between NAD+ signaling and heart aging has yet to be clarified. This review comprehensively summarizes the current studies on the role of NAD+ signaling in delaying heart aging from the following aspects: the influence of NAD+ supplementations on the aging heart; the relationship and cross-talks between NAD+ signaling and other cardiac aging-related signaling pathways; Importantly, the therapeutic potential of targeting NAD+ in delaying heart aging will be discussed. In brief, NAD+ plays a vital role in delaying heart aging. However, the abnormalities such as altered glucose and lipid metabolism, oxidative stress, and calcium overload could also interfere with NAD+ function in the heart. Therefore, the specific physiopathology of the aging heart should be considered before applying NAD+ supplementations. We believe that this article will help augment our understanding of heart aging mechanisms. In the meantime, it provides invaluable insights into possible therapeutic strategies for preventing age-related heart diseases in clinical settings.

How the Dabie Orogenic Belt (DOB) and the Tan-Lu Fault Zone (TLFZ) transformed during the early Indosinian period is the key to reveal the convergence process between the North China Block (NCB) and the South China Block (SCB). Tongcheng area in the eastern margin of northern DOB is the tectonic node that connects the WNW-trending DOB and the NE-trending TLFZ. The typical ENE-NE-trending gneiss belts penetrably developed in Tongcheng area provide an ideal natural lab to decipher the transformation between the DOB and the TLFZ. Here we conduct an integrated structural and geochronological research on the ENE-NE-trending gneiss. Zircon U–Pb dating on the ENE-NE-trending gneiss yielded metamorphic ages ranging from 255 ± 9 Ma to 203 ± 10 Ma. The weakly deformed veins which intruded the surrounding gneiss yielded two groups of ages, 825 ± 29 Ma to 713 ± 7 Ma and 125 ± 2.6 Ma (weighted mean age), which indicate the protolith age of surrounding rocks and the intrusive timing of the vein, respectively. Integrated structural, microstructural and kinematic analysis indicate that no lateral structural superposed on the gneiss or veins. Therefore, it can be speculated that the deformation and metamorphism of the gneiss should simultaneously formed during the Early Triassic, as a result of continuous tearing from the DOB to the northeastern Sulu Orogenic Belt (SOB) during subduction of the Yangtze block beneath the NCB. Formation of the tearing belts, i.e., the ENE-NE-trending gneiss belts, accomplished the tectonic transformation between the DOB and the TLFZ. They could be regarded as an embryonic form of the TLFZ, which are also apparently different from the TLFZ by characteristics of non-strike slipping.

Abstract Background In frozen embryo transfer (FET), there is limited consensus on the best means of endometrial preparation in terms of the reproductive outcomes in women with polycystic ovary syndrome (PCOS). The present study aimed to compare the pregnancy and neonatal outcomes following artificial cycle FET (AC-FET) with or without gonadotropin-releasing hormone agonist (GnRH-a) pretreatment among women with PCOS. Methods A total of 4503 FET cycles that satisfied the inclusion criteria were enrolled in this retrospective cohort study between 2015 and 2020. The GnRH-a group received GnRH-a pretreatment while the AC-FET group did not. Propensity score matching (PSM) method and multivariate logistic regression analysis were performed to adjust for potential confounding factors. Results After PSM, women in the GnRH-a group suffered a significantly lower miscarriage rate (11.2% vs. 17.1%, P = 0.033) and a higher live birth rate (LBR) compared with those in the AC-FET group (63.1% vs. 56.8%, P = 0.043). No differences were observed in the rates of biochemical pregnancy, clinical pregnancy and ectopic pregnancy between the two groups. A higher mean gestational age at birth was observed in the GnRH-a group than in the AC-FET group (39.80 ± 2.01 vs. 38.17 ± 2.13, P = 0.009). The incidence of neonatal preterm birth (PTB) in the GnRH-a group was lower than that in the AC-FET group (7.4% vs. 14.9%, P = 0.009). Singleton newborns conceived after GnRH-a group were more likely to be small for gestational age (SGA) than those born after AC-FET group (16.4% vs. 6.8%, P = 0.009). However, no significant differences were found between the two groups in terms of mean birthweight, apgar score, the rates of macrosomia, large for gestational age and low birth weight. Conclusion(s) In women with PCOS who underwent AC-FET, GnRH-a pretreatment was significantly associated with a higher live birth rate and a reduced risk of neonatal PTB. However, there was a concomitant increase in the risk of developing SGA babies.

ObjectivesResuscitation transfer of embryos after elective cryopreservation has been widely applied in in vitro fertilization-embryo transfer (IVF-ET) therapy for human infertility or sterility owing to higher embryo implantation rates. This method separates oocyte retrieval from embryo transfer. The optimal time for frozen embryo transfer (FET) remains unknown. Therefore, this study mainly compares the advantages and disadvantages of delayed FET and immediate FET through retrospective analysis.MethodsWe analyzed real world data of patients who underwent resuscitation transplantation between October 2019 and July 2021 at the Reproductive Center of Chengdu Jinjiang Hospital for Women’s and Children’s Health. Propensity score matching was applied to control potential confounding factors. A total of 5,549 patients who received at least one FET were analyzed. Patients undergoing transplantation within 60 days of oocyte retrieval were included in the immediate FET group (n = 1,265) and those undergoing transplantation > 60 days after retrieval were included in the delayed FET group (n = 4,284).ResultsLive birth rates between the two groups were comparable (45.25% vs. 45.76%, p = 0.757). Moreover, no difference was observed in the rates of biochemical pregnancy (64.50% vs. 66.80%), clinical pregnancy (55.24% vs. 56.83%), ectopic pregnancy (1.47% vs. 1.39%), early miscarriage (14.41% vs. 16.20%), late miscarriage (2.21% vs. 2.09%), singleton premature delivery (16.67% vs. 18.29%), and neonatal deformity (1.97% vs. 1.80%). After stratifying the patients based on the type of embryo transferred, number of embryos transferred, FET protocol, and good prognosis criteria, live birth rates remained comparable between the two groups (p > 0.05).ConclusionPregnancy outcomes were comparable between the immediate and delayed FET groups.

Various predictive biomarkers are needed to select candidates for optimal and individualized treatments. Tumor‐infiltrating immune cells have gained increasing interest in cancer research for the prediction of therapeutic response and survival. However, the role of dendritic cells (DCs) in PD-1 blockade immunotherapy remains unclear. In this study, we identified a population of PD-1+ DCs in the tumor microenvironment (TME) of cervical cancer (CC). The accumulation of PD-1+ DCs in cervical tumors was correlated with advanced stages, elevated preoperative squamous cell carcinoma antigen levels and lymph-vascular space invasion. PD-1 expression was induced on activated tumor-associated DCs (TADCs) in vitro compared with their resting counterparts. This PD-1+ DC population was characterized by reduced secretion of cytokines (IL-12, TNF-α, and IL-1β) and dysfunctional induction of T cell proliferation and cytotoxic reaction. PD-1 blockade significantly reinvigorated PD-1+ DCs to release IL-12, TNF-α, and IL-1β compared with PD-1- DCs. TILs from samples with higher PD-1+ DC infiltration could be induced to achieve a greater killing effect of PD-1 blockade treatment. Our findings suggested a role for PD-1+ DCs in immune surveillance dysfunction and CC progression. PD-1+ DC density in the TME may serve as a diagnostic factor for predicting the optimal beneficiaries of PD-1/PD-L1 blockade immunotherapy in CC.

Helicobacter pylori (H. pylori) is a Gram-negative anaerobic bacterium that colonizes the human stomach and is the leading cause of gastric diseases such as chronic gastritis and peptic ulcers, as well as the most definite and controllable risk factor for the development of gastric cancer. Currently, the regimen for H. pylori eradication has changed from triple to quadruple, the course of treatment has been extended, and the type and dose of antibiotics have been adjusted, with limited improvement in efficacy but gradually increasing side effects and repeated treatment failures in an increasing number of patients. In recent years, probiotics have become one of the most important tools for supporting intestinal health and immunity. Numerous in vitro studies, animal studies, and clinical observations have demonstrated that probiotics have the advantage of reducing side effects and increasing eradication rates in adjuvant anti-H. pylori therapy and are a valuable supplement to conventional therapy. However, many different types of probiotics are used as adjuncts against H. pylori, in various combinations, with different doses and timing, and the quality of clinical studies varies, making it difficult to standardize the results. In this paper, we focus on the risk, status, prevention, control, and treatment of H. pylori infection and review international consensus guidelines. We also summarize the available scientific evidence on using Limosilactobacillus reuteri (L. reuteri) as a critical probiotic for H. pylori treatment and discuss its clinical research and application from an evidence-based perspective.

7-Ethyl-10-hydroxycamptothecin (SN38), a highly potent metabolite of irinotecan, has an anticancer efficacy 100–1000 folds more than irinotecan in vitro. However, the clinical application of SN38 has been limited due to the very narrow therapeutic window and poor water solubility. Herein, we report the SN38-glucose conjugates (Glu-SN38) that can target cancer cells due to their selective uptake via glucose transporters, which are overexpressed in most cancers. The in vitro antiproliferative activities against human cancer cell lines and normal cells of Glu-SN38 were investigated. One of the conjugates named 5b showed high potency and selectivity against human colorectal cancer cell line HCT116. Furthermore, 5b remarkably inhibited the growth of HCT116 in vivo. These results suggested that 5b could be a promising drug candidate for treating colorectal cancer.