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Abstract Background Atherosclerosis is the main cause of carotid artery stenosis (CAS) which mostly occurs in the elderly. In this paper, the expression level of miR-375-3p in asymptomatic CAS patients and its diagnostic value for asymptomatic CAS were investigated, and the effects of miR-375-3p on the cell proliferation and migration of vascular smooth muscle cells (VSMCs) was further explored. Methods 98 healthy subjects and 101 asymptomatic CAS patients were participated in this study. qRT-PCR was used to measure the expression level of serum miR-375-3p, and the ROC curve was established to evaluate the predictive value of miR-375-3p for asymptomatic CAS. After transfection with miR-375-3p mimic or inhibitor in vitro, cell proliferation and migration were detected by CCK-8 assay, colony formation assay, and Transwell assay, respectively. The levels of TNF-α, IL-1β, IL-6 were detected by ELISA. Western blot was used to detect the protein expression of XIAP. Finally, luciferase reporter gene assay was applied to assess the interaction of miR-375-3p with target genes. Results The expression level of serum miR-375-3p in asymptomatic CAS patients was significantly higher than that in healthy controls, and the AUC value of ROC curve was 0.888. The sensitivity and specificity were 80.2 and 86.7%, respectively, indicating that miR-375-3p had high diagnostic value for asymptomatic CAS. In vitro cell experiments showed that up-regulation of miR-375-3p significantly promoted the proliferation and migration of VSMCs, and also promoted the generation of inflammatory factors and phenotypic transformation of VSMCs. Luciferase reporter gene assay confirmed that XIAP was a target gene of miR-375-3p and was negatively regulated by miR-375-3p. Conclusions In this study, miR-375-3p may have a clinical diagnostic value for asymptomatic CAS patients which need further validation. Increased miR-375-3p levels in CAS may be associated with increased proliferation and migration of VSMCs via downregulation of the apoptosis inducing gene XIAP.

Tumor microenvironment (TME)-activated theranostics is a promising strategy to effectively identify small lesions, improve antitumor efficacy, and reduce the risk of undesired side effects. Hypoxia, as a common characteristic of TME, can serve as a preferred site for stimulus-dependent activation; however, tumor-hypoxia levels in various developmental stages exhibit different characteristics, severely limiting the response sensitivity. Herein, a circulating self-reinforcing hypoxic nanoamplifier (CGH NAs) is developed that utilizes a dual-chain reaction process (internal regulation, internal regulation) to achieve precise activation of NIR-II FL/photoacoustic (PA) imaging-guided synergistic therapy. Inspired by the positive correlation of nitroreductase (NTR) with hypoxia, the CGH NAs encapsulate CQ4T and GOx into NTR-sensitive hyaluronic acid-nitroimidazole (HA-NI) shell via a self-assembly approach, enabling aggregation-caused NIR-II FL quenching and tumor-accurate delivery. When CGH NAs efficiently accumulated in the tumor region, the intensive local NTR reduced hydrophobic –NO2 to hydrophilic –NH2, which lead to disassembly of CGH NAs. The released GOx could consume O2 (internal regulation) and glucose to cut off the energy supply, inducing tumor-starvation therapy; generate gluconic acid and H2O2 (oxidative stress). Meanwhile, the released CQ4T promoted rapid recovery of NIR-II FL signals for imaging-guided PDT, which could simultaneously deplete intratumoral O2 (external stimulation). Remarkably, the strengthened tumor-hypoxia levels in turn accelerated the NTR-responsive degradation of the CGH NAs, thereby achieving high-efficiency theranostic.

Phototheranostics, relying on energy conversions of fluorophores upon excitation, integrating diagnostic fluorescence imaging and photo-driven therapy, represents a promising strategy for cancer precision medicine. Compared with the first near-infrared biological window (NIR-I), fluorophores imaged in the second window (NIR-II, 1000–1700 ​nm) exhibit a higher temporal and spatial resolution and tissue penetration depth. Polymethine cyanine-based dye IR1061 is a typical NIR-II small-molecule organic fluorophore, but its low water solubility and short circulation time limiting its biological applications. Therefore, human serum albumin (HSA) nanoparticles with great biocompatibility and biosafety were employed to fabricate hydrophobic IR1061, which exhibited red-shifted absorption band as typical for J-aggregates. Moreover, IR1061@HSA nanoparticles can be successfully used for NIR-II imaging to noninvasively visualize the tumor vascular networks, as well as real-time intraoperative image-guided tumor resection. Interestingly, benefiting from the high photothermal conversion efficiency brought by J-aggregates, IR1061@HSA nanoparticles were also explored for photothermal therapy (PTT) and cause efficient thermal ablation of tumors. Overall, IR1061@HSA, as a novel J-aggregates albumin-based NIR II dye nanoparticle with high biocompatibility, provides an integrated versatile platform for cancer phototheranostics with promising clinical translation prospects.

In microsurgery, it is always difficult to accurately identify the blood supply with ease, such as vascular anastomosis, digit replantation, skin avulsion reconstruction and flap transplantation. Near-infrared window I (NIR-I, 700—900 nm) imaging has many clinical applications, whereas near-infrared window II (NIR-II, 1,000–1700 nm) imaging has emerged as a highly promising novel optical imaging modality and used in a few clinical fields recently, especially its penetration distance and noninvasive characteristics coincide with the needs of microsurgery. Therefore, a portable NIR-II imaging instrument and the Food and Drug Administration (FDA) approved indocyanine green (ICG) were used to improve the operation efficiency in microsurgery of 39 patients in this study. The anastomotic vessels and the salvaged distal limbs were clearly visualized after intravenous injection of ICG. The technique enabled identification of perforator vessels and estimation of perforator areas prior to the flap obtention and made it easier to monitor the prognosis. Overall, this study highlights the use of the portable NIR- II imaging with ICG as an operative evaluation tool can enhance the safety and accuracy of microsurgery.

Microfluidic droplets accommodating a single cell as independent microreactors are frequently demanded for single-cell analysis of phenotype and genotype. However, challenges exist in identifying and reducing the covalence probability (following Poisson’s distribution) of more than two cells encapsulated in one droplet. It is of great significance to monitor and control the quantity of encapsulated content inside each droplet. We demonstrated a microfluidic system embedded with a weakly supervised cell counting network (WSCNet) to generate microfluidic droplets, evaluate their quality, and further recognize the locations of encapsulated cells. Here, we systematically verified our approach using encapsulated droplets from three different microfluidic structures. Quantitative experimental results showed that our approach can not only distinguish droplet encapsulations (F1 score > 0.88) but also locate each cell without any supervised location information (accuracy > 89%). The probability of a “single cell in one droplet” encapsulation is systematically verified under different parameters, which shows good agreement with the distribution of the passive method (Residual Sum of Squares, RSS < 0.5). This study offers a comprehensive platform for the quantitative assessment of encapsulated microfluidic droplets.

Adzuki bean (Vigna angularis (Willd.) Ohwi & Ohashi) is an annual cultivated leguminous crop commonly grown in Asia and consumed worldwide. However, there has been limited research regarding adzuki bean genetics, which has prevented the efficient application of genes during breeding. In the present study, we constructed a high-density genetic map based on whole genome re-sequencing technology and validated its utility by mining QTLs related to seed size. Moreover, we analyzed the sequences flanking insertions/deletions (InDels) to develop a set of PCR-based markers useful for characterizing adzuki bean genetics. A total of 2904 markers were mapped to 11 linkage groups (LGs). The total length of the map was 1365.0 cM, with an average distance between markers of 0.47 cM. Among the LGs, the number of markers ranged from 208 (LG7) to 397 (LG1) and the total distance ranged from 97.4 cM (LG9) to 155.6 cM (LG1). Twelve QTLs related to seed size were identified using the constructed map. The two major QTLs in LG2 and LG9 explained 22.1 and 18.8% of the total phenotypic variation, respectively. Ten minor QTLs in LG4, LG5 and LG6 explained 3.0–10.4% of the total phenotypic variation. A total of 9718 primer pairs were designed based on the sequences flanking InDels. Among the 200 selected primer pairs, 75 revealed polymorphisms in 24 adzuki bean germplasms. The genetic map constructed in this study will be useful for screening genes related to other traits. Furthermore, the QTL analysis of seed size and the novel markers described herein may be relevant for future molecular investigations of adzuki bean and will be useful for exploiting the mechanisms underlying legume seed development.

Background: Hepatoblastoma (HB) is the most common primary malignant liver tumor in children. The prognosis of HB metastasis is poor, despite the increasing diversity of treatment. Piezo, a ubiquitously expressed membrane mechano-transduction protein, is involved in the process of tumor cell migration. Under the gene expression profiling interactive analysis (GEPIA) database, Piezo1 was highly expressed in HB and negatively correlated with the overall survival time. Methods: Firstly, the expression of Piezo1 in both paracancerous and HB tissues (n = 7) was detected, and the prognostic value of Piezo1 was assessed in HB (n = 160) patients. Secondly, the inhibition and overexpression of Piezo1were executed in two HB cell lines, HepG2 and Huh 6. Methyl thiazolyl tetrazolium (MTT), wound healing and trans-well assays were performed to identify the effect of Piezo1 on the proliferation and metastasis of HB cells, respectively. In addition, a co-immunoprecipitation assay was performed to determine whether Piezo1 has an interaction with HIF-1α. Finally, the expressions level of Piezo1, HIF-1α, and VEGF by overexpression/inhibition each other were detected by RT-qPCR and western blots to find a possible signaling channel in HB metastasis. Results: We found that Piezo1 was highly expressed in HB tissues and associated with poor prognosis of patients. Piezo1 was related to cell proliferation in HepG2 and Huh 6 cells. We also found that Piezo1 stimulated HIF-1α expression. Meanwhile, overexpression of Piezo1 promoted the migration and invasion of HB cells, while the promotion was not detected when HIF-1α was suppressed. Additionally, the silencing of HIF-1α inhibited the expression of VEGF, but showed no effect on Piezo1 expression. Conclusion: In this study, we identified that Piezo1 was involved in HB metastasis, and the Piezo1-HIF-1α-VEGF axis could be a possible signaling pathway in HB metastasis.

Germline-mutation in BRCA1 tumor suppressor gene is an established risk for carcinogenesis not only in females but also in males. Deficiency in the repair of DNA double-strand breaks is hypothesized as a responsible mechanism for carcinogenesis. However, supporting data is insufficient both in the mutation spectra of cancers in the patients with BRCA1 germline-mutation and in murine knockout/knock-in models of Brca1 haploinsufficiency. Furthermore, information on the driving force toward carcinogenesis in BRCA1 mutation carriers is lacking. Here we applied Fenton reaction-based renal carcinogenesis to a rat heterozygously knockout model of BRCA1 haploinsufficiency (mutant [MUT] model; L63X/+). Rat MUT model revealed significant promotion of renal cell carcinoma (RCC) induced by ferric nitrilotriacetate (Fe-NTA). Array-based comparative genome hybridization of the RCCs identified significant increase in chromosomal amplification, syntenic to those in breast cancers of BRCA1 mutation carriers, including c-Myc, in comparison to those in the wild-type. Subacute-phase analysis of the kidney after repeated Fe-NTA treatment in the MUT model revealed dysregulated iron metabolism with mitochondrial malfunction assessed by expression microarray and electron microscopy, leading to renal tubular proliferation with iron overload. In conclusion, we for the first time demonstrate that biallelic wild-type BRCA1 provides more robust protection for mitochondrial metabolism under iron-catalyzed oxidative stress, preventing the emergence of neoplastic cells with chromosomal amplification. Our results suggest that oxidative stress via excess iron is a major driving force for carcinogenesis in BRCA1 haploinsufficiency, which can be a target for cancer prevention and therapeutics.

Investigation of extreme precipitation events in arid and semiarid regions, especially for occurrence time and the associated circulation mechanisms, is vital to support the forecasting of and the advanced response to resultant disasters. In this study, the spatiotemporal pattern of occurrence time of extreme precipitation and atmospheric circulation mechanisms in the Arid Region of Northwest China (ARNC) were analyzed using two indicators (precipitation concentration degree and period) and the climate diagnosis method. Results showed that the significant scattered pattern of extreme precipitation occurrence time (EPOT) in Northern Xinjiang and the postponed pattern of maximum extreme precipitation occurrence (MEPO) from southern to northern Xinjiang are consistent with the input pathway of the Arctic air mass. During the anomaly dispersion year of EPOT and the anomaly delay year of MEPO, the Arctic air mass carried sufficient water vapor is transported to ARNC for triggering extreme precipitation events. Meanwhile, the pattern of concentration–dispersion–concentration in eastern ARNC demonstrates interaction between the westerlies and the summer monsoon. Sufficient water vapor is transported to southwestern ARNC by the southwest monsoon during the anomaly delay year of MEPO and the anomaly concentration year of EPOT. The findings of this study suggest that invasion of the Arctic air mass and the summer monsoon could influence extreme precipitation in ARNC.

Abstract Background Acute myeloid leukemia (AML) is recognized as a hematological neoplasm with heterogenetic cytology and short-term outcome. HCP5 has been proven to be related with the pathogenesis of AML. However, the underlying mechanism of HCP5 in AML remains unclear. Methods Clinical profiles of AML patients were downloaded from TCGA and GTEx databases. LncBase and TargetScan online tools were utilized to predict potential targets, and dual-luciferase reporter assay was performed to verify the association between miR-1291 and HCP5 or PIK3R5. Cell Counting Kit 8 and flow cytometry tests were implemented to evaluate the effects of HCP5/miR-1291/PIK3R5 axis in AML cells. Quantitative RT-PCR and Western blot were conducted to detect the expression levels of genes. Results HCP5 and PIK3R5 were significantly increased in AML tissue samples compared with healthy controls. HCP5 facilitated AML cells viability and inhibited apoptosis. There was a positive relationship between HCP5 and PIK3R5, but miR-1291 negatively regulated PIK3R5. Overexpression of PIK3R5 enhanced the promoting effect of HCP5 in the development of AML, while weakened the suppression of miR-1291 to AML progression. Conclusion Our findings manifested that HCP5 was remarkably upregulated in AML and upregulated HCP5 promoted the malignant behaviors of AML cells by mediating miR-1291/PIK3R5 axis, which would provide a new insight for the treatment of AML.

Candidiasis, which presents a substantial risk to human well‐being, is frequently treated with azoles. However, drug‐drug interactions caused by azoles inhibiting the human CYP3A4 enzyme, together with increasing resistance of Candida species to azoles, represent serious issues with this class of drug, making it imperative to develop innovative antifungal drugs to tackle this growing clinical challenge. A drug repurposing approach is used to examine a library of Food and Drug Administration (FDA)‐approved drugs, ultimately identifying otilonium bromide (OTB) as an exceptionally encouraging antifungal agent. Mechanistically, OTB impairs vesicle‐mediated trafficking by targeting Sec31, thereby impeding the plasma membrane (PM) localization of the ergosterol transporters, such as Sip3. Consequently, OTB obstructs the movement of ergosterol across membranes and triggers cytotoxic autophagy. It is noteworthy that C. albicans encounters challenges in developing resistance to OTB because it is not a substrate for drug transporters. This study opens a new door for antifungal therapy, wherein OTB disrupts ergosterol subcellular distribution and induces cytotoxic autophagy. Additionally, it circumvents the hepatotoxicity associated with azole‐mediated liver enzyme inhibition and avoids export‐mediated drug resistance in C. albicans. [ABSTRACT FROM AUTHOR]

Electrosynthesis of hydrogen peroxide (H2O2) based on proton exchange membrane (PEM) reactor represents a promising approach to industrial‐level H2O2 production, while it is hampered by the lack of high‐efficiency electrocatalysts in acidic medium. Herein, we present a strategy for the specific oxygen functional group (OFG) regulation to promote the H2O2 selectivity up to 92 % in acid on cobalt‐porphyrin molecular assembled with reduced graphene oxide. In situ X‐ray adsorption spectroscopy, in situ Raman spectroscopy and Kelvin probe force microscopy combined with theoretical calculation unravel that different OFGs exert distinctive regulation effects on the electronic structure of Co center through either remote (carboxyl and epoxy) or vicinal (hydroxyl) interaction manners, thus leading to the opposite influences on the promotion in 2e− ORR selectivity. As a consequence, the PEM electrolyzer integrated with the optimized catalyst can continuously and stably produce the high‐concentration of ca. 7 wt % pure H2O2 aqueous solution at 400 mA cm−2 over 200 h with a cell voltage as low as ca. 2.1 V, suggesting the application potential in industrial‐scale H2O2 electrosynthesis. [ABSTRACT FROM AUTHOR]

Background: Auxin, a plant hormone, plays diverse roles in the modulation of plant growth and development. The transport and signal transduction of auxin are regulated by various factors involved in shaping plant morphology and responding to external environmental conditions. The auxin signal transduction is primarily governed by the following two gene families: the auxin response factor (ARF) and auxin/indole-3-acetic acid (AUX/IAA). However, a comprehensive genomic analysis involving the expression profiles, structures, and functional features of the ARF and AUX/IAA gene families in Vaccinium bracteatum has not been carried out to date. Results: Through the acquisition of genomic and expression data, coupled with an analysis using online tools, two gene family members were identified. This groundwork provides a distinguishing characterization of the chosen gene families in terms of expression, interaction, and response in the growth and development of plant fruits. In our genome-wide search of the VaARF and VaIAA genes in Vaccinium bracteatum, we identified 26 VaARF and 17 VaIAA genes. We analyzed the sequence and structural characteristics of these VaARF and VaIAA genes. We found that 26 VaARF and 17 VaIAA genes were divided into six subfamilies. Based on protein interaction predictions, VaIAA1 and VaIAA20 were designated core members of VaIAA gene families. Moreover, an analysis of expression patterns showed that 14 ARF genes and 12 IAA genes exhibited significantly varied expressions during fruit development. Conclusion: Two key genes, namely, VaIAA1 and VaIAA20, belonging to a gene family, play a potentially crucial role in fruit development through 26 VaARF-IAAs. This study provides a valuable reference for investigating the molecular mechanism of fruit development and lays the foundation for further research on Vaccinium bracteatum. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OC) is one of the most commonplace gynecological malignancies. This study explored the effects of resveratrol (RES) on OC cell proliferation and apoptosis. Proliferation activity was measured for A2780 cells treated with RES for 24 h and 48 h at concentrations of 0, 10, 25, 50, 75, 100, 150, 200, and 300 µM. RNA sequencing (RNA-seq) was performed to analyze the circular RNA (circRNA), microRNA (miRNA), and messenger RNA (mRNA) expression spectrum. The differentially expressed genes included 460 circRNAs, 1988 miRNAs, and 1671 mRNAs, and they were subjected to analyses including Gene Ontology, the Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome enrichment. We selected signaling pathways enriched in the cell processes by mRNA KEGG, comprehensively analyzed the circRNA-miRNA-mRNA regulatory network, and verified several miRNAs expressed in the regulatory network diagram using the quantitative real-time polymerase chain reaction. The data showed that the cell proliferation of A2780 cells treated with RES for 24 h or 48 h decreased with increasing concentrations of RES. The circRNA-miRNA-mRNA regulatory network that we constructed provides new insights into the ability of RES to inhibit cell proliferation and promote apoptosis in A2780 cells. [ABSTRACT FROM AUTHOR]

Background In recent decades, considerable attention has been paid to exploring the population genetic characteristics of Han Chinese, mainly documenting a north-south genetic substructure. However, the central Han Chinese have been largely underrepresented in previous studies. Aim To infer a comprehensive understanding of the homogenisation process and population history of Han Chinese. Subjects and methods We collected samples from 122 Han Chinese from seven counties of Hubei province in central China and genotyped 534,000 genome-wide SNPs. We compared Hubei Han with both ancient and present-day Eurasian populations using Principal Component Analysis, ADMIXTURE, f statistics, qpWave and qpAdm. Results We observed Hubei Han Chinese are at a genetically intermediate position on the north-south Han Chinese cline. We have not detected any significant genetic substructure in the studied groups from seven different counties. Hubei Han show significant evidence of genetic admixture deriving about 63% of ancestry from Tai-Kadai or Austronesian-speaking southern indigenous groups and 37% from Tungusic or Mongolic related northern populations. Conclusions The formation of Han Chinese has involved extensive admixture with Tai-Kadai or Austronesian-speaking populations in the south and Tungusic or Mongolic speaking populations in the north. The convenient transportation and central location of Hubei make it the key region for the homogenisation of Han Chinese.

Histone acetylation is a ubiquitous hallmark of transcription. Here the authors provide evidence that the majority of histone acetylation is dependent on transcription, specifically due to the requirement of RNAPII for the recruitment and activity of histone acetyltransferases.