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Abstract To emulate the ordered arrangement of monomer units found in natural macromolecules, single-unit monomer insertion (SUMI) have emerged as a potent technique for synthesizing sequence-controlled vinyl polymers. Specifically, numerous applications necessitate vinyl polymers encompassing both radically and cationically polymerizable monomers, posing a formidable challenge due to the distinct thiocarbonylthio end-groups required for efficient control over radical and cationic SUMIs. Herein, we present a breakthrough in the form of interconvertible radical and cationic SUMIs achieved through the manipulation of thiocarbonylthio end-groups. The transition from a trithiocarbonate (for radical SUMI) to a dithiocarbamate (for cationic SUMI) is successfully accomplished via a radical-promoted reaction with bis(thiocarbonyl) disulfide. Conversely, the reverse transformation utilizes the reaction between dithiocarbamate and bistrithiocarbonate disulfide under a cationic mechanism. Employing this strategy, we demonstrate a series of synthetic examples featuring discrete oligomers containing acrylate, maleimide, vinyl ether, and styrene, compositions unattainable through the SUMI of a single mechanism alone.

Abstract As a high‐risk trauma, deep burns are always hindered in their repair process by decreased tissue regeneration capacity and persistent infections. In this study, we developed a simultaneous strategy for deep burn wounds treatment using functional nanovesicles with antibacterial and tissue remodeling properties, delivered via a click‐chemistry hydrogel. An aggregation‐induced emission photosensitizer of 4‐(2‐(5‐(4‐(diphenylamino)phenyl)thiophen‐2‐yl)vinyl)‐1‐(2‐hydroxyethyl) pyridin‐1‐ium bromide (THB) with excellent photodynamic properties was first prepared, and then combined with readily accessible adipose stem cells‐derived nanovesicles to generate the THB functionalized nanovesicles (THB@ANVs). The THB@ANVs showed strong antibacterial activity against Gram‐positive bacteria (up to 100% killing rate), and also beneficial effects on tissue remodeling, including promoting cell migration, cell proliferation, and regulating immunity. In addition, we prepared a click‐hydrogel of carboxymethyl chitosan for effective delivery of THB@ANVs on wounds. This hydrogel could be injected to conform to the wound morphology while responding to the acidic microenvironment. In vivo evaluations of wound healing revealed that the THB@ANVs hydrogel dressing efficiently accelerated the healing of second‐degree burn wounds by reducing bacterial growth, regulating inflammation, promoting early angiogenesis, and collagen deposition. This study provides a promising candidate of wound dressing with diverse functions for deep burn wound repair.

Abstract Early monitoring and warning arrangements are effective ways to distinguish infectious agents and control the spread of epidemic diseases. Current testing technologies, which cannot achieve rapid detection in the field, have a risk of slowing down the response time to the disease. In addition, there is still no epidemic surveillance system, implementing prevention and control measures is slow and inefficient. Motivated by these clinical needs, a sample‐to‐answer genetic diagnosis platform based on light‐controlled capillary modified with a photocleavable linker is first developed, which could perform nucleic acid separation and release by light irradiation in less than 30 seconds. Then, on site polymerase chain reaction was performed in a handheld closed‐loop convective system. Test reports are available within 20 min. Because this method is portable, rapid, and easy to operate, it has great potential for point‐of‐care testing. Additionally, through multiple device networking, a real‐time artificial intelligence monitoring system for pathogens was developed on a cloud server. Through data reception, analysis, and visualization, the system can send early warning signals for disease control and prevention. Thus, anti‐epidemic measures can be implemented effectively, and deploying and running this system can improve the capabilities for the prevention and control of infectious diseases.

Abstract Circulating tumor nucleic acids (CTNAs) have been employed as the potential markers for tumor diagnosis and management, which are highly correlated with the tumorigenesis, progression, and metastasis processes. Therefore, it is important to develop a highly‐sensitive and reliable method for the detection of CTNAs, especially the multiplex point mutation detection of blood‐derived CTNAs. Herein, a versatile gold island‐enhanced multiplex quantum dots (GIEM‐QDs) fluorescent platform was constructed for the highly‐sensitive detection of CTNAs in serum. The GIEM fluorescent strategy was designed as the highly‐efficient signal giving‐out mode which could amplify the fluorescence intensity of QDs, thus realizing a homogeneous platform for the enrichment, multiplex detection, and point mutations monitoring of CTNAs with the principle of base‐stacking. A high sensitivity of 10 amol and desirable specificity was achieved, and the performance index for analysis of clinical tumor patients’ samples indicated that the GIEM‐QDs fluorescent strategy could realize multiplex point mutation detection of CTNAs in complex blood samples. Hence, this platform could achieve a high detection rate in clinical samples that suitably met the clinical requirements for multiplex detection and point mutations monitoring of CTNAs, and thus has the potential to serve as the tumor liquid biopsy strategy based on CTNAs.

Abstract Considering that a unit dual quaternion can describe elegantly the rigid transformation including rotation and translation, the point-wise weighted 3D coordinate transformation using a unit dual quaternion is formulated. The constructed transformation model by a unit dual quaternion does not need differential process to eliminate the three translation parameters, while traditional models do. Based on the Lagrangian extremum law, the analytical dual quaternion algorithm (ADQA) of the point-wise weighted 3D coordinate transformation is proved existed and derived in detail. Four numerical cases, including geodetic datum transformation, the registration of LIDAR point clouds, and two simulated cases, are studied. This study shows that ADQA is valid as well as the modified procrustes algorithm (MPA) and the orthonormal matrix algorithm (OMA). ADQA is suitable for the 3D coordinate transformation with point-wise weight and no matter rotation angles are small or big. In addition, the results also indicate that if the distribution of common points degrades from 3D or 2D space to 1D space, the solvable correct transformation parameters decrease. In other words, all common points should not be located on a line. From the perspective of improving the transformation accuracy, high accurate control points (with small errors in the coordinates) should be chosen, and it is preferred to decrease the rotation angles as much as possible. Graphical Abstract

Wound repair is a complex problem for both clinical practitioners and scientific investigators. Conventional approaches to wound repair have been associated with several limitations, including prolonged treatment duration, high treatment expenses, and significant economic and psychological strain on patients. Consequently, there is a pressing demand for more efficacious and secure treatment modalities to enhance the existing treatment landscapes. In the field of wound repair, cell-free therapy, particularly the use of mesenchymal stem cell-derived exosomes (MSC-Exos), has made notable advancements in recent years. Exosomes, which are small lipid bilayer vesicles discharged by MSCs, harbor bioactive constituents such as proteins, lipids, microRNA (miRNA), and messenger RNA (mRNA). These constituents facilitate material transfer and information exchange between the cells, thereby regulating their biological functions. This article presents a comprehensive survey of the function and mechanisms of MSC-Exos in the context of wound healing, emphasizing their beneficial impact on each phase of the process, including the regulation of the immune response, inhibition of inflammation, promotion of angiogenesis, advancement of cell proliferation and migration, and reduction of scar formation.

BackgroundColon cancer (CC) is a highly heterogeneous malignancy associated with high morbidity and mortality. Pyroptosis is a type of programmed cell death characterized by an inflammatory response that can affect the tumor immune microenvironment and has potential prognostic and therapeutic value. The aim of this study was to evaluate the association between pyroptosis-related gene (PRG) expression and CC.MethodsBased on the expression profiles of PRGs, we classified CC samples from The Cancer Gene Atlas and Gene Expression Omnibus databases into different clusters by unsupervised clustering analysis. The best prognostic signature was screened and established using least absolute shrinkage and selection operator (LASSO) and multivariate COX regression analyses. Subsequently, a nomogram was established based on multivariate COX regression analysis. Next, gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were performed to explore the potential molecular mechanisms between the high- and low-risk groups and to explore the differences in clinicopathological characteristics, gene mutation characteristics, abundance of infiltrating immune cells, and immune microenvironment between the two groups. We also evaluated the association between common immune checkpoints and drug sensitivity using risk scores. The immunohistochemistry staining was utilized to confirm the expression of the selected genes in the prognostic model in CC.ResultsThe 1163 CC samples were divided into two clusters (clusters A and B) based on the expression profiles of the 33 PRGs. Genes with prognostic value were screened from the DEGs between the two clusters, and an eight PRGs prognostic model was constructed. GSEA and GSVA of the high- and low-risk groups revealed that they were mainly enriched in inflammatory response-related pathways. Compared to those in the low-risk group, patients in the high-risk group had worse overall survival, an immunosuppressive microenvironment, and worse sensitivity to immunotherapy and drug treatment.ConclusionOur findings provide a foundation for future research targeting pyroptosis and new insights into prognosis and immunotherapy from the perspective of pyroptosis in CC.

Abstract Background The biological activity and regenerative medicine of bone marrow mesenchymal stem cells (BMSCs) have been focal topics in the broad fields of diabetic wound repair. However, the molecular mechanisms are still largely elusive for other cellular processes that are regulated during BMSC treatment. Our previous studies have shown that hypoxia is not only a typical pathological phenomenon of wounds but also exerts a vital regulatory effect on cellular bioactivity. In this study, the beneficial effects of hypoxic BMSCs on the cellular behaviors of epidermal cells and diabetic wound healing were investigated. Method The viability and secretion ability of hypoxic BMSCs were detected. The autophagy, proliferation and migration of HaCaT cells cultured with hypoxic BMSCs-derived conditioned medium were assessed by estimating the expression of autophagy-related proteins, MTS, EdU proliferation and scratch assays. And the role of the SMAD signaling pathway during hypoxic BMSC-evoked HaCaT cell autophagy was explored through a series of in vitro gain- and loss-of-function experiments. Finally, the therapeutic effects of hypoxic BMSCs were evaluated using full-thickness cutaneous diabetic wound model. Results First, we demonstrated that hypoxic conditions intensify HIF-1α-mediated TGF-β1 secretion by BMSCs. Then, the further data revealed that BMSC-derived TGF-β1 was responsible for the activation of epidermal cell autophagy, which contributed to the induction of epidermal cell proliferation and migration. Here, the SMAD signaling pathway was identified as downstream of BMSC-derived TGF-β1 to regulate HaCaT cell autophagy. Moreover, the administration of BMSCs to diabetic wounds increased epidermal autophagy and the rate of re-epithelialization, leading to accelerated healing, and these effects were significantly attenuated, accompanied by the downregulation of Smad2 phosphorylation levels due to TGF-β1 interference in BMSCs. Conclusion In this report, we present evidence that uncovers a previously unidentified role of hypoxic BMSCs in regulating epidermal cell autophagy. The findings demonstrate that BMSC-based treatment by restoring epidermal cell autophagy could be an attractive therapeutic strategy for diabetic wounds and that the process is mediated by the HIF-1α/TGF-β1/SMAD pathway.

Abstract Owing to the persistent inflammatory microenvironment and unsubstantial dermal tissues, chronic diabetic wounds do not heal easily and their recurrence rate is high. Therefore, a dermal substitute that can induce rapid tissue regeneration and inhibit scar formation is urgently required to address this concern. In this study, we established biologically active dermal substitutes (BADS) by combining novel animal tissue‐derived collagen dermal‐replacement scaffolds (CDRS) and bone marrow mesenchymal stem cells (BMSCs) for the healing and recurrence treatments of chronic diabetic wounds. The collagen scaffolds derived from bovine skin (CBS) displayed good physicochemical properties and superior biocompatibility. CBS loaded with BMSCs (CBS‐MCSs) could inhibit M1 macrophage polarization in vitro. Decreased MMP‐9 and increased Col3 at the protein level were detected in CBS‐MSCs‐treated M1 macrophages, which may be attributed to the suppression of the TNF‐α/NF‐κB signaling pathway (downregulating phospho‐IKKα/β/total IKKα/β, phospho‐IκB/total IκB, and phospho‐NFκB/total NFκB) in M1 macrophages. Moreover, CBS‐MSCs could benefit the transformation of M1 (downregulating iNOS) to M2 (upregulating CD206) macrophages. Wound‐healing evaluations demonstrated that CBS‐MSCs regulated the polarization of macrophages and the balance of inflammatory factors (pro‐inflammatory: IL‐1β, TNF‐α, and MMP‐9; anti‐inflammatory: IL‐10 and TGF‐β3) in db/db mice. Furthermore, CBS‐MSCs facilitated the noncontractile and re‐epithelialized processes, granulation tissue regeneration, and neovascularization of chronic diabetic wounds. Thus, CBS‐MSCs have a potential value for clinical application in promoting the healing of chronic diabetic wounds and preventing the recurrence of ulcers.

Aptamer (Apt) is a kind of recognition molecule with excellent affinity and high specificity. Transmembrane glycoprotein mucin (MUC1) is an important tumor biomarker overexpressed in MCF-7 tumor cells. MUC1 Apt (Apt-M) could specifically target MCF-7 tumor cells. Ti3C2 nanosheets with high photothermal conversion efficiency were considered as a promising therapeutic nanoplatform for tumor therapy. Doxorubicin (DOX) is a common anti-tumor drug. Herein, a novel DOX/Ti3C2/Apt-M therapeutic nanoplatform was successfully fabricated, which could specifically target MCF-7 tumor cells. As expected, the temperature of DOX/Ti3C2/Apt-M therapeutic nanoplatform raised rapidly under laser irradiation. Meanwhile, chemotherapy was triggered through multimodal stimuli-responsive drug release from the DOX/Ti3C2/Apt-M therapeutic nanoplatform under acidic environment and laser-induced local high temperature. Encouragingly, the MCF-7 cell viability of DOX/Ti3C2/Apt-M with laser irradiation was only 26.9%. The tumor surface temperature of MCF-7 xenograft mice in the DOX/Ti3C2/Apt-M + Laser group rose to about 58.3 °C, which was significantly higher than other laser irradiation groups. The experiments in vitro and in vivo indicated that the DOX/Ti3C2/Apt-M therapeutic nanoplatform can rapidly accumulate in MCF-7 tumors with excellent active targeting properties, and display superior tumor suppressive ability through combination therapy. This work provides a new idea of targeted tumor therapy based on Ti3C2 nanosheets.

Abstract Background To explore the genetic and immunophenotyping heterogeneities between patients with intrapulmonary metastasis (IPM) or multiple primary lung cancer (MPLC). Methods Whole exome sequencing (WES) and transcriptome sequencing (RNA‐seq) were performed on the tissue and blood samples of IPM and MPLC patients to comprehensively analyze the clonal evolution, molecular typing and immunophenotyping. Results There was no significant difference in genetic mutation, tumor mutational burden (TMB) value and mutant allele tumor heterogeneity (MATH) value between IPM and MPLC patients. Notably, the loss of heterozygosity (LOH) of human leukocyte antigen (HLA) appeared in all IPM patients, while there was also no significant difference between the two groups. In addition, expression of immune checkpoint‐related genes including CTLA‐4, BTLA, TIGIT and HAVCR2 in the MPLC group was significantly higher than those in IPM group. At the same time, 86 differentially expressed genes (DEGs) were observed between IPM and MPLC patients with transcriptome sequencing, of which 56 DEGs were upregulated and 30 were downregulated in the IPM group compared with the MPLC group. The cluster analysis revealed that the 86 DEGs could be distinguished in IPM and MPLC samples. Moreover, only the infiltration levels of CD56dim natural killer cells in the IPM group was significantly higher than that in the MPLC group, and the infiltration levels of the remaining 27 immune cell subsets were similar in both groups. Conclusions IPM and MPLC are roughly similar in genetic and immune characteristics indicating that genomics alone may not be able to effectively distinguish between IPM and MPLC, which still needs to be comprehensively evaluated with clinical manifestations, imaging, and pathological characteristics.

Traditional Chinese Medicine (TCM) is extensively utilized in clinical practice due to its therapeutic and preventative treatments for various diseases. With the development of high-throughput sequencing and systems biology, TCM research was transformed from traditional experiment-based approaches to a combination of experiment-based and omics-based approaches. Numerous academics have explored the therapeutic mechanism of TCM formula by omics approaches, shifting TCM research from the “one-target, one-drug” to “multi-targets, multi-components” paradigm, which has greatly boosted the digitalization and internationalization of TCM. In this review, we concentrated on multi-omics approaches in principles and applications to gain a better understanding of TCM formulas against various diseases from several aspects. We first summarized frequently used TCM quality assessment methods, and suggested that incorporating both chemical and biological ingredients analytical methods could lead to a more comprehensive assessment of TCM. Secondly, we emphasized the significance of multi-omics approaches in deciphering the therapeutic mechanism of TCM formulas. Thirdly, we focused on TCM network analysis, which plays a vital role in TCM-diseases interaction, and serves for new drug discovery. Finally, as an essential source for storing multi-omics data, we evaluated and compared several TCM databases in terms of completeness and reliability. In summary, multi-omics approaches have infiltrated many aspects of TCM research. With the accumulation of omics data and data-mining resources, deeper understandings of the therapeutic mechanism of TCM have been acquired or will be gained in the future.

BackgroundLung adenocarcinoma (LA) with a micropapillary component (LAMPC) is a histological subtype of lung cancer that has received increasing attention due to its correlation with poor prognosis, and its tendency to recur and metastasize. At present, comprehensive genomic profiles and clinicopathological features for LAMPC remain unclear and require further investigation.MethodsFrom September 2009 to October 2020, a total of 465 LAMPC patients were recruited and divided into four groups according to MPC proportions, and the correlations between varying proportions of MPCs and clinicopathological characteristics were analyzed. Twenty-nine (29) LAMPC patients and 89 LA patients without MPC (non-MPC) that had undergone NGS testing were selected for further study The comprehensively analyze genomic variations and the difference between LAMPC and MPC were determined. In addition, Gene alterations of LAMPC between Chinese and Western populations were also compared using cBioPortal data.ResultsA higher proportion of MPCs, associated with higher tumor stage, pleural invasion, and vascular tumor thrombus formation, was determined in LA patients. Compared to non-MPC patients, LAMPC patients were determined to have a lower frequency of single nucleotide variants and a higher frequency of insertion-deletion mutations. Mutations in TP53, CTNNB1, and SMAD4, and ALK rearrangements/fusions were significantly more frequent in LAMPC patients. ERBB2 mutations were only detected in non-MPC patients. Gene mutations in the Wnt pathway were significantly more common in LAMPC patients as compared to non-MPC patients. ALK fusions were more prevalent in younger patients. Patients with KRAS or LBP1B mutations had significantly larger tumor diameters than patients with wild-type KRAS or LBP1B. Patients with KRAS mutations were more likely to develop vascular tumor thrombus. Using the cBioPortal public database, we determined that mutations in EGFR were significantly higher in Chinese patients than in a Memorial Sloan Kettering Cancer Center (MSKCC) Western cohort. ALK fusions were exclusively detected in the Chinese cohort, while mutations in KEAP1 and NOTCH4 were only detected in the MSKCC cohort. Our analysis of signaling pathways revealed that Wnt pathway gene mutations were significantly higher in the Chinese cohort.ConclusionLA patients with higher proportions of MPCs were determined to have a higher tumor stage, pleural invasion, and vascular tumor thrombosis formation. We comprehensively analyzed the genomic mutation characteristics of LAMPC patients and identified multiple, novel MPC-related gene alterations and pathway changes. Our data provide further understanding of the nature of the LAMPC and potential drug-targeted gene alterations, which may lead to new therapeutic strategies.

IntroductionSkin cancer is one of the most common types of cancer. An accessible tool to the public can help screening for malign lesion. We aimed to develop a deep learning model to classify skin lesion using clinical images and meta information collected from smartphones.MethodsA deep neural network was developed with two encoders for extracting information from image data and metadata. A multimodal fusion module with intra-modality self-attention and inter-modality cross-attention was proposed to effectively combine image features and meta features. The model was trained on tested on a public dataset and compared with other state-of-the-art methods using five-fold cross-validation.ResultsIncluding metadata is shown to significantly improve a model's performance. Our model outperformed other metadata fusion methods in terms of accuracy, balanced accuracy and area under the receiver-operating characteristic curve, with an averaged value of 0.768±0.022, 0.775±0.022 and 0.947±0.007.ConclusionA deep learning model using smartphone collected images and metadata for skin lesion diagnosis was successfully developed. The proposed model showed promising performance and could be a potential tool for skin cancer screening.

Chronic wound healing remains a challenging medical problem affecting society, which urgently requires anatomical and functional solutions. Adipose-derived stem cells (ADSCs), mesenchymal stem cells with self-renewal and multiple differentiation ability, play essential roles in wound healing and tissue regeneration. The exosomes from ADSCs (ADSC-EXOs) are extracellular vesicles that are essential for communication between cells. ADSC-EXOs release various bioactive molecules and subsequently restore tissue homeostasis and accelerate wound healing, by promoting various stages of wound repair, including regulating the inflammatory response, promoting wound angiogenesis, accelerating cell proliferation, and modulating wound remodeling. Compared with ADSCs, ADSC-EXOs have the advantages of avoiding ethical issues, being easily stored, and having high stability. In this review, a literature search of PubMed, Medline, and Google Scholar was performed for articles before August 1, 2022 focusing on exosomes from ADSCs, chronic wound repair, and therapeutic potential. This review aimed to provide new therapeutic strategies to help investigators explore how ADSC-EXOs regulate intercellular communication in chronic wounds.

ObjectiveProviding protection against aggregation and guiding hydrophobic precursors through the mitochondria’s intermembrane space, this protein functions as a chaperone-like protein. SLC25A12 is imported by TIMM8 as a result of its interaction with TIMM13. In spite of this, it is still unknown how TIMM13 interacts with skin cutaneous melanoma (SKCM) and tumor-infiltrating lymphocytes (TILs).MethodsAberrant expression of TIMM13 in SKCM and its clinical outcome was evaluated with the help of multiple databases, including the Xiantao tool (https://www.xiantao.love/), HPA, and UALCAN. TISIDB and Tumor Immune Estimation Resources (TIMER) databases were applied to explore the association between TIMM13 and tumor infiltration immune cells. OS nomogram was constructed, and model performance was examined. Finally, TIMM13 protein expression was validated by immunohistochemistry (IHC).ResultsTIMM13 expression was higher in SKCM samples than in peritumor samples. TIMM13 was strongly associated with sample type, subgroup, cancer stage, lymph node stage, and worse survival. Further, upregulation of TIMM13 was significantly associated with immunoregulators, and chemokines, as well as T cells, B cells, monocytes, neutrophils, macrophages, and T-cell regulators. An analysis of bioinformatic data uncovered that TIMM13 expression was strongly associated with PD1 (T-cell exhaustion marker). The nomogram showed good predictive performance based on calibration plot. TIMM13 was highly expressed in melanoma tissue samples than in normal samples.ConclusionIn brief, TIMM13 may be a prognostic biomarker for SKCM. It might modulate the tumor immune microenvironment and lead to a poorer prognosis. In addition, it is necessary to study the targeted therapy of TIMM13.

A keloid is a fibroproliferative disorder of unknown etiopathogenesis that requires ill-defined treatment. Existing evidence indicates that the immune system plays an important role in the occurrence and development of keloid. However, there is still a lack of research on the immune-related signatures of keloid. Here we identified immune-related signatures in keloid and explored their pathological mechanisms. Transcriptomic datasets (GSE7890, GSE92566, and GSE44270) of keloid and normal skin tissues were obtained from the Gene Expression Omnibus database. The overlap of differentially expressed genes and immune-related genes was considered as differentially expressed immune-related genes (DEIGs). Functional analysis, expression, and distribution were applied to explore the function and characteristics of DEIGs, and the expression of these DEIGs in keloid and normal skin tissues was verified by immunohistochemistry. Finally, we conducted interactive network analysis and immune infiltration analysis to determine the therapeutic potential and immune correlation. We identified four DEIGs (LGR5, PTN, JAG1, and DKK1). In these datasets, only GSE7890 met the screening criteria. In the GSE7890 dataset, DKK1 and PTN were downregulated in keloid, whereas JAG1 and LGR5 were upregulated in keloid. In addition, we obtained the same conclusion through immunohistochemistry. Functional analysis indicated that these four DEIGs were mainly involved in stem cell, cell cycle, UV response, and therapy resistance. Through interactive network analysis, we found that these DEIGs were associated with drugs currently used to treat keloid, such as hydrocortisone, androstanolone, irinotecan, oxaliplatin, BHQ-880, and lecoleucovorin. Finally, many immune cells, including CD8+ T cells, resting memory CD4+ T cells, and M1 macrophages, were obtained by immune infiltration analysis. In conclusion, we identified four immune signaling molecules associated with keloid (LGR5, PTN, JAG1, and DKK1). These immune-related signaling molecules may be important modules in the pathogenesis of keloid. Additionally, we developed novel therapeutic targets for the treatment of this challenging disease.

Zika virus (ZIKV) is a re-emerging flavivirus that leads to devastating consequences for fetal development. It is crucial to visualize the pathogenicity activities of ZIKV ranging from infection pathways to immunity processes, but the accurate labeling of ZIKV remains challenging due to the lack of a reliable labeling technique. We introduce the photo-activated bio-orthogonal cycloaddition to construct a fluorogenic probe for the labeling and visualizing of ZIKV. Via a simple UV photoirradiation, the fluorogenic probes could be effectively labeled on the ZIKV. We demonstrated that it can be used for investigating the interaction between ZIKV and diverse cells and avoiding the autofluorescence phenomenon in traditional immunofluorescence assay. Thus, this bioorthogonal-enabled labeling strategy can serve as a promising approach to monitor and understand the interaction between the ZIKV and host cells.

Abstract Background The FOCUS study evaluated the efficacy of migraine preventive medications across different countries within the same patient population, particularly for patients with difficult-to-treat migraine. These prespecified subgroup analyses evaluated efficacy by country in the FOCUS study of fremanezumab in adults with episodic migraine or chronic migraine and documented inadequate response to 2 to 4 migraine preventive medication classes. Methods Overall, 838 participants were enrolled in the FOCUS study, a randomized, double-blind, placebo-controlled, parallel-group, phase 3b study performed at 104 sites. For 12 weeks of double-blind treatment, patients were randomized (1:1:1) to quarterly fremanezumab, monthly fremanezumab, or matched placebo. The primary efficacy endpoint was the mean change from baseline in monthly average migraine days over 12 weeks of double-blind treatment, evaluated by country in these subgroup analyses. Results Of 14 countries contributing data, the Czech Republic (n = 188/838; 22%), the United States (n = 120/838; 14%), and Finland (n = 85/838; 10%) enrolled the most patients. Changes from baseline in monthly average migraine days over 12 weeks were significantly greater with fremanezumab versus placebo for patients in these countries: Czech Republic (least-squares mean difference versus placebo [95% confidence interval]: quarterly fremanezumab, − 1.9 [− 3.25, − 0.47]; P = 0.009; monthly fremanezumab, − 3.0 [− 4.39, − 1.59]; P

Abstract Background Utrophin (UTRN), as a tumor suppressor gene, is involved in various cancer progression. The function of UTRN in the melanoma process and the related molecular mechanisms are still unclear. Herein, we studied the function of UTRN in melanoma growth and the relevant molecular mechanisms. Methods Using the GEO database and UCSC Xena project, we compared the expression of UTRN in non-cancerous and melanoma tissues. Immunohistochemistry (IHC) staining, qRT-PCR and Western Blot (WB) were performed to evaluate UTRN expression in clinical samples. A total of 447 cases with UTRN expression data, patient characteristics and survival data were extracted from TCGA database and analyzed. After stable transduction and single cell cloning, the proliferation ability of A375 human melanoma cells was analyzed by Cell Counting Kit‑8 (CCK) and 5‑ethynyl‑2′‑deoxyuridine (EdU) incorporation assays. GSEA was performed to predict the mechanism by which UTRN regulated melanoma growth. Then WB analysis was used to assess the protein expression levels of pathway signaling in overexpression (EXP) melanoma cells. Epac activator 8-pCPT-2′-O-Me-cAMP was then used to evaluate the proliferation ability by activation of p38 and JNK/c-Jun signaling pathways. Results Data from GEO and UCSC Xena project indicated that UTRN expression was decreased in melanoma. Experiment on clinical samples further confirmed our finding. TCGA results showed that a reduced expression of UTRN in 447 melanoma samples was associated with advanced clinical characteristics (T stage, Clark level, ulceration), shorter survival time and poorer prognosis. In addition, up-regulated UTRN expression inhibited melanoma cell proliferation when compared to control group. MAPK signaling pathway was presented in both KEGG and BioCarta databases by using GSEA tool. WB results confirmed the down-regulated expression of p38, JNK1 and c-Jun in EXP group when compared to control group. Epac activator 8-pCPT-2′-O-Me-cAMP treatment could partially rescue proliferation of tumor cells. Conclusion We have demonstrated that reduced UTRN predicted poorer prognosis and UTRN inhibited melanoma growth via p38 and JNK1/c-Jun pathways. Therefore, UTRN could serve as a tumor suppressor and novel prognostic biomarker for melanoma patients.

Abstract Background Monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway, including the fully humanized monoclonal antibody (IgG2Δa) fremanezumab, have demonstrated safety and efficacy for migraine prevention. Clinical trials include responders and nonresponders; efficacy outcomes describe mean values across both groups and thus provide little insight into the clinical benefit in responders. Clinicians and their patients want to understand the extent of clinical improvement in patients who respond. This post hoc analysis of fremanezumab treatment attempts to answer this question: what is the benefit in subjects who responded to treatment during the two, phase 3 HALO clinical trials? Methods We included subjects with episodic migraine (EM) or chronic migraine (CM) who received fremanezumab quarterly (675 mg/placebo/placebo) or monthly (EM: 225 mg/225 mg/225 mg; CM: 675 mg/225 mg/225 mg) during the 12-week randomized, double-blind, placebo-controlled HALO EM and HALO CM clinical trials. EM and CM responders were defined as participants with a reduction of ≥ 2 or ≥ 4 monthly migraine days, respectively. Treatment benefits evaluated included reductions in monthly migraine days, acute headache medication use, and headache-related disability, and changes in health-related quality of life (HRQoL). Results Overall, 857 participants from the HALO trials were identified as responders (EM: 429 [73.8%]; CM: 428 [56.7%]). Reductions in the monthly average number of migraine days were greater among EM (quarterly: 5.4 days; monthly: 5.5 days) and CM (quarterly: 8.7 days; monthly: 9.1 days) responders compared with the overall population. The proportion of participants achieving ≥ 50% reduction in the average monthly number of migraine days was also greater in responders (EM: quarterly, 59.8%; monthly, 63.7%; CM: quarterly, 52.8%; monthly, 59.0%) than in the overall population. Greater reductions in the average number of days of acute headache medication use, greater reductions in headache-related disability scores, and larger improvements in HRQoL were observed among EM and CM responders compared with the overall populations. Conclusions Fremanezumab responders achieved clinically meaningful improvements in all outcomes. The magnitude of improvements with fremanezumab across efficacy outcomes was far greater in responders than in the overall trial population, providing insight into expected treatment benefits in participants who respond to fremanezumab in clinical practice. Trial registration ClinicalTrials.gov identifiers: NCT02629861 (HALO EM) and NCT02621931 (HALO CM).

Burn injury is an intractable problem in the field of surgery where screening relevant target genes and exploring pathological mechanisms through bioinformatic methods has become a necessity. Herein, we integrated three burn injury mRNA microarray datasets from the Gene Expression Omnibus database to analyze the hub differentially expressed genes (DEGs) between burn injury patient samples and healthy human samples; we conducted multiple functional enrichment analyses and constructed the protein–protein interaction (PPI) network. Finally, we evaluated the immune infiltration in the burn injury microenvironment. A total of 84 intersection DEGs (32 upregulated and 52 downregulated) were screened in burn injury patients via integrated analyses. Upregulated genes were primarily enriched in regulation of T cell activation, regulation of response to DNA damage stimulus, positive regulation of innate immune response, positive regulation of defense response. We also identified 10 hub genes from the PPI network (CCNB2, MYO10, TTK, POLQ, VASP, TIMP1, CDK16, MMP1, ZYX, and PKMYT1). Next, we found that 22 immune cells were substantially changed during the burn injury by CIBERSORT. In addition, we verified that VASP and POLQ are two novel diagnostic markers in burn processes with high diagnostic efficacy via immunohistochemistry. In summary, we identified several key genes involved in burn injury and provided a favorable basis for elucidating the molecular mechanisms of burn injury through comprehensive bioinformatic analysis.

Increasing evidence has demonstrated that pyroptosis, a type of inflammatory programmed cell death, plays an important role in the pathogenesis and progression of gastric cancer. However, it remains unclear whether pyroptosis-related long non-coding RNAs (lncRNAs) can be used to predict the diagnosis and prognosis of gastric adenocarcinoma. This study aimed to evaluate and test the role of the lncRNA signature associated with pyroptosis as a prognostic tool for stomach adenocarcinoma (STAD) and to ascertain their immune value. Relative RNA-sequencing data were extracted from The Cancer Genome Atlas database (TCGA), and data preprocessing was performed for STAD. Pearson correlation analysis was used to determine whether lncRNAs were significantly correlated with pyroptosis based on 23 genes related to pyroptosis. Univariate Cox regression and least absolute shrinkage and selection operator(LASSO) analyses were both adopted to select features and establish the pyroptosis-related lncRNA (PRL) prognostic signature. Kaplan–Meier(KM) survival analysis of the different risk groups was conducted according to the risk scores. We further examined the functional enrichment, tumor microenvironment, and landscape of mutation status among the different risk groups, and these analyses further explained the reasons for the differences in the prediction as well as survival value of the different risk groups. Four lncRNAs, including HAND2-AS1, LINC01354, RP11-276H19.1, and PGM5-AS1, were involved in the PRL signature and used to split STAD patients into two risk groups. Overall survival time(OS) was significantly higher in the low-risk group than in the high-risk group in both the training and validation groups. Functional enrichment analysis was further employed to analyze differentially expressed genes in high- and low-risk groups to identify potential molecular functions and pathways associated with pyroptosis in the gastric cancer microenvironment. Protein-protein interaction (PPI) and Friends analysis identified hub genes that may play a key role in differentially expressed genes in high- and low-risk groups. In addition, there were remarkable discrepancies between the different risk groups in the tumor stage (P

Abstract Background We evaluated the efficacy of fremanezumab, a fully humanized monoclonal antibody that selectively targets calcitonin gene-related peptide, in patients with chronic migraine (CM) with and without medication overuse (MO). Methods In a 12-week, phase 3 trial, patients with CM were randomized to fremanezumab quarterly (675 mg/placebo/placebo), monthly (675 mg/225 mg/225 mg), or placebo. Post hoc analyses assessed the impact of fremanezumab in patients with and without MO (monthly use of acute headache medication ≥15 days, migraine-specific acute medication ≥10 days, or combination medication ≥10 days) on efficacy outcomes, including headache days of at least moderate severity (HDs), and six-item Headache Impact Test (HIT-6) and Migraine-Specific Quality of Life (MSQoL) questionnaire scores. Results Of 1130 patients enrolled, 587 (51.9%) had baseline MO. Fremanezumab reduced placebo-adjusted least-squares mean (95% confidence interval) monthly HDs (− 2.2 [− 3.1 to − 1.2] and − 2.7 [− 3.7 to − 1.8]; P

Abstract Background The long-term safety and efficacy of fremanezumab were evaluated in a 52-week extension study (NCT02638103). Patient satisfaction with fremanezumab, dosing preferences, and patient-reported outcomes were assessed in a subpopulation who completed the extension study and consented to a follow-up questionnaire. Methods In the extension study (N = 1842), adults with migraine were randomized to quarterly or monthly fremanezumab. After completing active treatment, patients answered a survey evaluating patient satisfaction, treatment and dosing preferences, and changes in patient-reported outcomes. Results Of the 557 patients who could have been contacted upon completing the extension study, 302 consented and 253 completed the survey. The mean (standard deviation) satisfaction rating for fremanezumab was 6.1 (1.4; 1 = “extremely dissatisfied” to 7 = “extremely satisfied”). Most patients (175 [69.2%]) preferred quarterly over monthly fremanezumab dosing. Among patients taking antiepileptics (most common class of prior preventive medication; n = 130), 91.5% preferred fremanezumab. Patients reported improvements in anxiety (74 [67.9%]), sleep quality (143 [56.5%]), and quality of time spent with others (210 [83.0%]) with fremanezumab. Conclusion In this study, treatment satisfaction with fremanezumab was high, most patients preferred quarterly fremanezumab dosing, and fremanezumab was generally preferred to prior preventive medications. Trial registration ClinicalTrials.gov NCT02638103 (HALO LTS), registered December 22, 2015.

Abstract The epidermis, which is the outermost layer of mammalian skin, provides an essential barrier that is essential for maintenance of life. The epidermis is a stratified epithelium, which is maintained by the proliferation of epidermal stem cells (EPSCs) at the basal layer of the epidermis. As a unique cell population characterized by self-renewal and differentiation capabilities, EPSCs ensure the maintenance of adult skin homeostasis and participate in repair of the epidermis after injury. Recently, the utilization of EPSCs for wound healing and tissue regeneration has been attracting increased attention from researchers. In addition, the advances in tissue engineering have increased the interest in applying EPSCs in tissue-engineered scaffolds to further reconstitute injured tissues. In this review, we introduce research developments related to EPSCs, including methods recently used in the culture and enrichment of EPSCs, as well as advanced tools to study EPSCs. The function and mechanism of the EPSC-dermal units in the development and homeostasis of the skin are also summarized. Finally, the potential applications of EPSCs in skin tissue engineering are discussed.

Gene mutations play an important role in tumor progression. This study aimed to identify genes that were mutated in colorectal cancer (CRC) and to explore their biological effects and prognostic value in CRC patients. We performed somatic mutation analysis using data sets from The Cancer Genome Atlas and International Cancer Genome Consortium, and identified that FREM2 had the highest mutation frequency in patients with colon adenocarcinoma (COAD). COAD patients were divided into FREM2-mutated type (n = 36) and FREM2-wild type (n = 278), and a Kaplan-Meier survival curve was generated to perform prognostic analysis. A FREM2-mutation prognosis model was constructed using random forest method, and the performance of the model was evaluated using receiver operating characteristic curve. Next, the random forest method and Cox regression analysis were used to construct a prognostic model based on the gene expression data of 36 FREM2-mutant COAD patients. The model showed a high prediction accuracy (83.9%), and 13 prognostic model characteristic genes related to overall survival were identified. Then, the results of tumor mutation burden (TMB) and microsatellite instability (MSI) analyses revealed significant differences in TMB and MSI among the risk scores of different prognostic models. Differentially expressed genes were identified and analyzed for functional enrichment and immune infiltration. Finally, 30 samples of CRC patients were collected for immunohistochemical staining to analyze the FREM2 expression levels, which showed that FREM2 was highly expressed in tumor tissues. In conclusion, CRC patients had a high level of FREM2 mutations associated with a worse prognosis, which indicated that FREM2 mutations may be potential prognostic markers in CRC.

Background: Burn injury is a life-threatening disease that does not have ideal biomarkers. Therefore, this study first applied weighted gene co-expression network analysis (WGCNA) and differentially expressed gene (DEG) screening methods to identify pivotal genes and diagnostic biomarkers associated with the skin burn process.Methods: After obtaining transcriptomic datasets of burn patient skin and normal skin from Gene Expression Omnibus (GEO) and performing differential analysis and functional enrichment, WGCNA was used to identify hub gene modules associated with burn skin processes in the burn patient peripheral blood sample dataset and determine the correlation between modules and clinical features. Enrichment analysis was performed to identify the functions and pathways of key module genes. Differential analysis, WGCNA, protein-protein interaction analysis, and enrichment analysis were utilized to screen for hub genes. Hub genes were validated in two other GEO datasets, tested by immunohistochemistry for hub gene expression in burn patients, and receiver operating characteristic curve analysis was performed. Finally, we constructed the specific drug activity, transcription factors, and microRNA regulatory network of the five hub genes.Results: A total of 1,373 DEGs in GSE8056 were obtained, and the top 5 upregulated genes were S100A12, CXCL8, CXCL5, MMP3, and MMP1, whereas the top 5 downregulated genes were SCGB1D2, SCGB2A2, DCD, TSPAN8, and KRT25. DEGs were significantly enriched in the immunity, epidermal development, and skin development processes. In WGCNA, the yellow module was identified as the most closely associated module with tissue damage during the burn process, and the five hub genes (ANXA3, MCEMP1, MMP9, S100A12, and TCN1) were identified as the key genes for burn injury status, which consistently showed high expression in burn patient blood samples in the GSE37069 and GSE13902 datasets. Furthermore, we verified using immunohistochemistry that these five novel hub genes were also significantly elevated in burn patient skin. In addition, MCEMP1, MMP9, and S100A12 showed perfect diagnostic performance in the receiver operating characteristic analysis.Conclusion: In conclusion, we analyzed the changes in genetic processes in the skin during burns and used them to identify five potential novel diagnostic markers in blood samples from burn patients, which are important for burn patient diagnosis. In particular, MCEMP1, MMP9, and S100A12 are three key blood biomarkers that can be used to identify skin damage in burn patients.

Although solid organ transplantation remains the definitive management for patients with end-stage organ failure, this ultimate treatment has been limited by the number of acceptable donor organs. Therefore, efforts have been made to expand the donor pool by utilizing marginal organs from donation after circulatory death or extended criteria donors. However, marginal organs are susceptible to ischemia-reperfusion injury (IRI) and entail higher requirements for organ preservation. Recently, machine perfusion has emerged as a novel preservation strategy for marginal grafts. This technique continually perfuses the organs to mimic the physiologic condition, allows the evaluation of pretransplant graft function, and more excitingly facilitates organ reconditioning during perfusion with pharmacological, gene, and stem cell therapy. As mesenchymal stem cells (MSCs) have anti-oxidative, immunomodulatory, and regenerative properties, mounting studies have demonstrated the therapeutic effects of MSCs on organ IRI and solid organ transplantation. Therefore, MSCs are promising candidates for organ reconditioning during machine perfusion. This review provides an overview of the application of MSCs combined with machine perfusion for lung, kidney, liver, and heart preservation and reconditioning. Promising preclinical results highlight the potential clinical translation of this innovative strategy to improve the quality of marginal grafts.

The tumorigenesis of skin cutaneous melanoma (SKCM) remains unclear. The tumor microenvironment (TME) is well known to play a vital role in the onset and progression of SKCM. However, the dynamic mechanisms of immune regulation are insufficient. We conducted a comprehensive analysis of immune cell infiltration in the TME. Based on the differentially expressed genes (DEGs) in clusters grouped by immune infiltration status, a set of hub genes related to the clinical prognosis of SKCM and tumor immune infiltration was explored.Methods: We analyzed immune cell infiltration in two independent cohorts and assessed the relationship between the internal pattern of immune cell infiltration and SKCM characteristics, including clinicopathological features, potential biological pathways, and gene mutations. Genes related to the infiltration pattern of TME immune cells were determined. Furthermore, the unsupervised clustering method (k-means) was used to divide samples into three different categories according to TME, which were defined as TME cluster-A, -B, and -C. DEGs among three groups of samples were analyzed as signature genes. We further distinguished common DEGs between three groups of samples according to whether differences were significant and divided DEGs into the Signature gene-A group with significant differences and the Signature gene-B group with insignificant differences. The Signature gene-A gene set mainly had exon skipping in SKCM, while the Signature gene-B gene set had no obvious alternative splicing form. Subsequently, we analyzed genetic variations of the two signatures and constructed a competing endogenous RNA (ceRNA) regulatory network. LASSO Cox regression was used to determine the immune infiltration signature and risk score of SKCM. Finally, we obtained 13 hub genes and calculated the risk score based on the coefficient of each gene to explore the impact of the high- and low-risk scores on biologically related functions and prognosis of SKCM patients further. The correlation between the risk score and clinicopathological characteristics of SKCM patients indicated that a low-risk score was associated with TME cluster-A classification (p < 0.001) and metastatic SKCM (p < 0.001). Thirteen hub genes also showed different prognostic effects in pan-cancer. The results of univariate and multivariate Cox analyses revealed that risk score could be used as an independent risk factor for predicting the prognosis of SKCM patients. The nomogram that integrated clinicopathological characteristics and immune characteristics to predict survival probability was based on multivariate Cox regression. Finally, 13 hub genes that showed different prognostic effects in pan-cancers were obtained. According to immunohistochemistry staining results, Ube2L6, SRPX2, and IFIT2 were expressed at higher levels, while CLEC4E, END3, and KIR2DL4 were expressed at lower levels in 25 melanoma specimens.Conclusion: We performed a comprehensive assessment of the immune-associated TME. To elucidate the potential development of immune-genomic features in SKCM, we constructed an unprecedented set of immune characteristic genes (EDN3, CLEC4E, SRPX2, KIR2DL4, UBE2L6, and IFIT2) related to the immune landscape of TME. These genes are related to different prognoses and drug responses of SKCM. The immune gene signature constructed can be used as a robust prognostic biomarker of SKCM and a predictor of an immunotherapy effect.

Skin cutaneous melanoma (SKCM) is the most aggressive and fatal type of skin cancer. Its highly heterogeneous features make personalized treatments difficult, so there is an urgent need to identify markers for early diagnosis and therapy. Detailed profiles are useful for assessing malignancy potential and treatment in various cancers. In this study, we constructed a co-expression module using expression data for cutaneous melanoma. A weighted gene co-expression network analysis was used to discover a co-expression gene module for the pathogenesis of this disease, followed by a comprehensive bioinformatics analysis of selected hub genes. A connectivity map (CMap) was used to predict drugs for the treatment of SKCM based on hub genes, and immunohistochemical (IHC) staining was performed to validate the protein levels. After discovering a co-expression gene module for the pathogenesis of this disease, we combined GWAS validation and DEG analysis to identify 10 hub genes in the most relevant module. Survival curves indicated that eight hub genes were significantly and negatively associated with overall survival. A total of eight hub genes were positively correlated with SKCM tumor purity, and 10 hub genes were negatively correlated with the infiltration level of CD4+ T cells and B cells. Methylation levels of seven hub genes in stage 2 SKCM were significantly lower than those in stage 3. We also analyzed the isomer expression levels of 10 hub genes to explore the therapeutic target value of 10 hub genes in terms of alternative splicing (AS). All 10 hub genes had mutations in skin tissue. Furthermore, CMap analysis identified cefamandole, ursolic acid, podophyllotoxin, and Gly-His-Lys as four targeted therapy drugs that may be effective treatments for SKCM. Finally, IHC staining results showed that all 10 molecules were highly expressed in melanoma specimens compared to normal samples. These findings provide new insights into SKCM pathogenesis based on multi-omics profiles of key prognostic biomarkers and drug targets. GPR143 and SLC45A2 may serve as drug targets for immunotherapy and prognostic biomarkers for SKCM. This study identified four drugs with significant potential in treating SKCM patients.

Chronic inflammation increases cancer risk, and cancer development is characterized by stepwise accumulation of genetic and epigenetic alterations. During chronic inflammation, infectious agents and intrinsic mediators of inflammatory responses can induce genetic and epigenetic changes. This study tried to evaluate both the genetic and epigenetic influence of chronic inflammation on colon mucosa cells. Repetitive dextran sulfate sodium (DSS) treatment induced chronic colitis model. Whole-exome sequencing (WES) (200× coverage) was performed to detect somatic variations in colon mucosa cells. With the use of whole-genome bisulfite sequencing (BS) at 34-fold coverage (17-fold per strand), the methylome of both the colitis and control tissue was comparatively analyzed. Bioinformatics assay showed that there was no significant single-nucleotide polymorphism/insertion or deletion (SNP/InDel) mutation accumulation in colitis tissue, while it accumulated in aged mice. Forty-eight genes with SNP/InDel mutation were overlapped in the three colitis tissues, two (Wnt3a and Lama2) of which are in the cancer development-related signaling pathway. Differentially methylated region (DMR) assay showed that many genes in the colitis tissue are enriched in the cancer development-related signaling pathway, such as PI3K–AKT, Ras, Wnt, TGF-beta, and MAPK signaling pathway. Together, these data suggested that even though chronic inflammation did not obviously increase genetic mutation accumulation, it could both genetically and epigenetically alter some genes related to cancer development.

Skin cutaneous melanoma (SKCM) is a highly aggressive and resistant cancer with immense metabolic heterogeneity. Here, we performed a comprehensive examination of the diverse metabolic signatures of SKCM based on non-negative matrix factorization (NMF) categorization, clustering SKCM into three distinct metabolic subtypes (C1, C2, and C3). Next, we evaluated the metadata sets of the metabolic signatures, prognostic values, transcriptomic features, tumor microenvironment signatures, immune infiltration, clinical features, drug sensitivity, and immunotherapy response of the subtypes and compared them with those of prior publications for classification. Subtype C1 was associated with high metabolic activity, low immune scores, and poor prognosis. Subtype C2 displayed low metabolic activity, high immune infiltration, high stromal score, and high expression of immune checkpoints, demonstrating the drug sensitivity to PD-1 inhibitors. The C3 subtype manifested moderate metabolic activity, high enrichment in carcinogenesis-relevant pathways, high levels of CpG island methylator phenotype (CIMP), and poor prognosis. Eventually, a 90-gene classifier was produced to implement the SKCM taxonomy and execute a consistency test in different cohorts to validate its reliability. Preliminary validation was performed to ascertain the role of SLC7A4 in SKCM. These results indicated that the 90-gene signature can be replicated to stably identify the metabolic classification of SKCM. In this study, a novel SKCM classification approach based on metabolic gene expression profiles was established to further understand the metabolic diversity of SKCM and provide guidance on precisely targeted therapy to patients with the disease.

Cardiovascular diseases, including cardiomyopathy, myocardial infarction, myocardial ischemia/reperfusion injury, heart failure, vascular injury, stroke, and arrhythmia, are correlated with cardiac and vascular cell death. Ferroptosis is a novel form of non-apoptotic regulated cell death which is characterized by an iron-driven accumulation of lethal lipid hydroperoxides. The initiation and execution of ferroptosis are under the control of several mechanisms, including iron metabolism, glutamine metabolism, and lipid peroxidation. Recently, emerging evidence has demonstrated that ferroptosis can play an essential role in the development of various cardiovascular diseases. Recent researches have shown the ferroptosis inhibitors, iron chelators, genetic manipulations, and antioxidants can alleviate myocardial injury by blocking ferroptosis pathway. In this review, we systematically described the mechanisms of ferroptosis and discussed the role of ferroptosis as a novel therapeutic strategy in the treatment of cardiovascular diseases.

ObjectiveThe adoption of hearts from donation after circulatory death (DCD) is a promising approach for the shortage of suitable organs in heart transplantation. However, DCD hearts suffer from serious ischemia/reperfusion injury (IRI). Recent studies demonstrate that nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-mediated pyroptosis is a novel target to ameliorate myocardial IRI. Melatonin is shown to inhibit NLRP3 inflammasome-mediated pyroptosis. Therefore, this study is designed to verify the hypothesis that melatonin can protect the heart graft preserved with ex vivo heart perfusion (EVHP) against myocardial IRI via inhibiting NLRP3 inflammasome-mediated pyroptosis in a rat model of DCD.MethodsDonor-heart rats were randomly divided into three groups: (1) Control group: non-DCD hearts were harvested from heart-beating rats and immediately preserved with allogenic blood-based perfusate at constant flow for 105 min in the normothermic EVHP system; (2) DCD-vehicle group; and (3) DCD-melatonin group: rats were subjected to the DCD procedure with 25 min of warm ischemia injury and preserved by the normothermic EVHP system for 105 min. Melatonin (200 μmol/L) or vehicle was perfused in the cardioplegia and throughout the whole EVHP period. Cardiac functional assessment was performed every 30 min during EVHP. The level of oxidative stress, inflammatory response, apoptosis, and NLRP3 inflammasome-mediated pyroptosis of heart grafts submitted to EVHP were evaluated.ResultsTwenty five-minute warm ischemia injury resulted in a significant decrease in the developed pressure (DP), dP/dtmax, and dP/dtmin of left ventricular of the DCD hearts, while the treatment with melatonin significantly increased the DP, dP/dtmax of the left ventricular of DCD hearts compared with DCD-vehicle group. Furthermore, warm ischemia injury led to a significant increase in the level of oxidative stress, inflammatory response, apoptosis, and NLRP3 inflammasome-mediated pyroptosis in the hearts preserved with EVHP. However, melatonin added in the cardioplegia and throughout the EVHP period significantly attenuated the level of oxidative stress, inflammatory response, apoptosis, and NLRP3 inflammasome-mediated pyroptosis compared with DCD-vehicle group.ConclusionEVHP combined with melatonin post-conditioning attenuates myocardial IRI in DCD hearts by inhibiting NLRP3 inflammasome-mediated pyroptosis, which might expand the donor pool by the adoption of transplantable DCD hearts.

Abstract The skin has important barrier, sensory, and immune functions, contributing to the health and integrity of the organism. Extensive skin injuries that threaten the entire organism require immediate and effective treatment. Wound healing is a natural response, but in severe conditions, such as burns and diabetes, this process is insufficient to achieve effective treatment. Epidermal stem cells (EPSCs) are a multipotent cell type and are committed to the formation and differentiation of the functional epidermis. As the contributions of EPSCs in wound healing and tissue regeneration have been increasingly attracting the attention of researchers, a rising number of therapies based on EPSCs are currently under development. In this paper, we review the characteristics of EPSCs and the mechanisms underlying their functions during wound healing. Applications of EPSCs are also discussed to determine the potential and feasibility of using EPSCs clinically in wound healing.

Precise and rapid extraction of spherical target features from laser point clouds is critical for achieving high-precision registration of multiple point clouds. Existing methods often use linear models to represent spherical target characteristics, which have several drawbacks. This paper proposes a rigorous estimation algorithm for spherical target features based on least squares configurations, in which the point-cloud data error is used as a random parameter, while the spherical center coordinates and radius are used as nonrandom parameters, emphasizing correlation between spherical parameters. The implementation details of this algorithm are illustrated by deriving calculation formulas for three variance–covariance matrices: variance–covariance matrices of the new observations, variance–covariance matrices of the new observation noise, and variance–covariance matrices of random parameters and the new observation noise. Experiments show that the estimation accuracy of sphere centers using our method is improved by at least 5.7% compared to classical algorithms, such as least squares, total least squares, and robust weighted total least squares.

Skin stem cells distributed in the basal layer of the epidermis and hair follicles are important cell sources for skin development, metabolism, and injury repair. At present, great progress has been made in the study of epidermal stem cells at the cellular and molecular levels. Stem cell transplantation is reported to promote skin healing, endothelial cell transformation, and vascular formation. Local stem cells can also be transformed into keratinocytes, sebaceous gland, and other skin-associated tissues. However, the mechanism of action of epidermal stem cells on wound healing and regeneration is not completely clear. This review is aimed at briefly summarizing the biological characteristics of epidermal stem cells and their clinical application in wound healing and tissue regeneration. It further discussed the mechanism of action and the development direction in the future.

High-precision coordinate transformation is vital for high-quality data fusion involving different coordinate systems. The transformation precision is mainly evaluated by the transformation parameters’ estimation precision, the root mean square error (RMSE) of the conversion of common points, or the RMSE of the conversion of check points. However, there are a number of issues associated with the rotation parameters’ precision estimated by the existing transformation methods. First, the estimated precision is related to the rotation matrix, so it is not suitable for scenarios where different rotation matrices are used. Second, the RMSE of the conversion of check points may not be consistent with the RMSE of the conversion of common points, so that the RMSE of the conversion of common points should not be used as a transformation precision index. In addition, some engineering applications do not have check points, and many applications need to know which range of points can meet our requirements. To deal with these limitations, this paper proposes a new way to calculate the translation parameters and evaluate the transformation precision. A lot of experimental data was used to verify the effectiveness and applicability of the proposed transformation model.

Focusing on the global integrity monitoring performance of the BDS-3, the integrity failure model and effect analysis (IFMEA) of the system space segment and the ground control segment were carried out, and the system integrity risk tree model was established according to the IFMEA results. To evaluate the system’s integrity risk probability more reasonably, this paper establishes an abnormal event prediction model with a Bayesian method, based on actual operation data, under a situation in which the BDS-3 just opened service. With statistical analysis results of system anomalies since 27 December 2018—which is the date the BDS-3 began providing basic service—according to the anomaly prediction model, the system’s integrity risk probability under the 95% confidence limit was calculated to be approximately 0.9e-7/h, meeting the design index requirements of 1e-7/h. The analysis results also show that the main risk factors affecting the integrity of BDS-3 are ‘pseudorange measurement anomaly’ and ‘miss-detection of satellite autonomous integrity monitoring’. The results are important references with practical engineering significance for improving the integrity performance of BDS-3.

Abstract Rigid transformation including rotation and translation can be elegantly represented by a unit dual quaternion. Thus, a non-differential model of the Helmert transformation (3D seven-parameter similarity transformation) is established based on unit dual quaternion. This paper presents a rigid iterative algorithm of the Helmert transformation using dual quaternion. One small rotation angle Helmert transformation (actual case) and one big rotation angle Helmert transformation (simulative case) are studied. The investigation indicates the presented dual quaternion algorithm (QDA) has an excellent or fast convergence property. If an accurate initial value of scale is provided, e.g., by the solutions no. 2 and 3 of Závoti and Kalmár (Acta Geod Geophys 51:245–256, 2016) in the case that the weights are identical, QDA needs one iteration to obtain the correct result of transformation parameters; in other words, it can be regarded as an analytical algorithm. For other situations, QDA requires two iterations to recover the transformation parameters no matter how big the rotation angles are and how biased the initial value of scale is. Additionally, QDA is capable to deal with point-wise weight transformation which is more rational than those algorithms which simply take identical weights into account or do not consider the weight difference among control points. From the perspective of transformation accuracy, QDA is comparable to the classic Procrustes algorithm (Grafarend and Awange in J Geod 77:66–76, 2003) and orthonormal matrix algorithm from Zeng (Earth Planets Space 67:105, 2015. https://doi.org/10.1186/s40623-015-0263-6).

An amendment to this paper has been published and can be accessed via the original article.

The common feature matching algorithms for street view images are sensitive to the illumination changes in augmented reality (AR), this may cause low accuracy of matching between street view images. This paper proposes a novel illumination insensitive feature descriptor by integrating the center-symmetric local binary pattern (CS-LBP) into a common feature description framework. This proposed descriptor can be used to improve the performance of eight commonly used feature-matching algorithms, e.g., SIFT, SURF, DAISY, BRISK, ORB, FREAK, KAZE, and AKAZE. We perform the experiments on five street view image sequences with different illumination changes. By comparing with the performance of eight original algorithms, the evaluation results show that our improved algorithms can improve the matching accuracy of street view images with changing illumination. Further, the time consumption only increases a little. Therefore, our combined descriptors are much more robust against light changes to satisfy the high precision requirement of augmented reality (AR) system.

The precision of target-based registration is related to the geometry distribution of targets, while the current method of setting the targets mainly depends on experience, and the impact is only evaluated qualitatively by the findings from empirical experiments and through simulations. In this paper, we propose a new quantitative evaluation model, which is comprised of the rotation dilution of precision ( r D O P , assessing the impact of targets’ geometry distribution on the rotation parameters) and the translation dilution of precision ( t D O P , assessing the impact of targets’ geometry distribution on the translation parameters). Here, the definitions and derivation of relevant formulas of the r D O P and t D O P are given, the experience conclusions are theoretically proven by the model of r D O P and t D O P , and an accurate method for determining the optimal placement location of targets and the scanner is proposed by calculating the minimum value of r D O P and t D O P . Furthermore, we can refer to the model ( r D O P and t D O P ) as a unified model of the geometric distribution evaluation model, which includes the D O P model in GPS.

We have demonstrated using immunoprecipitation and immunostaining a novel physical association of the P2X4 receptor (P2X4R), a ligand-gated ion channel, with the cardioprotective, calcium-dependent enzyme endothelial nitric oxide synthase (eNOS). Treatment of murine ventricular myocytes with the P2XR agonist 2-methylthioATP (2-meSATP) to induce a current (mainly Na+) increased the formation of nitric oxide (NO), as measured using a fluorescent probe. Possible candidates for downstream effectors mediating eNOS activity include cyclic GMP and PKG or cellular protein nitrosylation. A cardiac-specific P2X4R overexpressing mouse line was protected from heart failure (HF) with improved cardiac function and survival in post-infarct, pressure overload, and calsequestrin (CSQ) overexpression models of HF. Although the role of the P2X4R in other tissues such as the endothelium and monocytes awaits characterization in tissue-specific KO, cardiac-specific activation of eNOS may be more cardioprotective than an increased activity of global systemic eNOS. The intra-myocyte formation of NO may be more advantageous over NO derived externally from a donor. A small molecule drug stimulating this sarcolemmal pathway or gene therapy-mediated overexpression of the P2X4R in cardiac myocytes may represent a new therapy for both ischemic and pressure overloaded HF.