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Chemistry-alone approach has recently been applied for incepting pluripotency in somatic cells, representing a breakthrough in biology. However, chemical reprogramming is hampered by low efficiency, and the underlying molecular mechanisms remain unclear. Particularly, chemical compounds do not have specific DNA-recognition domains or transcription regulatory domains, and then how do small molecules work as a driving force for reinstating pluripotency in somatic cells? Furthermore, how to efficiently clear materials and structures of an old cell to prepare the rebuilding of a new one? Here, we show that small molecule CD3254 activates endogenous existing transcription factor RXRα to significantly promote mouse chemical reprogramming. Mechanistically, CD3254–RXRα axis can directly activate all the 11 RNA exosome component genes ( Exosc1–10 and Dis3 ) at transcriptional level. Unexpectedly, rather than degrading mRNAs as its substrates, RNA exosome mainly modulates the degradation of transposable element (TE)-associated RNAs, particularly MMVL30 , which is identified as a new barrier for cell-fate determination. In turn, MMVL30 -mediated inflammation (IFN-γ and TNF-α pathways) is reduced, contributing to the promotion of successful reprogramming. Collectively, our study provides conceptual advances for translating environmental cues into pluripotency inception, particularly, identifies that CD3254–RXRα–RNA exosome axis can promote chemical reprogramming, and suggests modulation of TE-mediated inflammation via CD3254-inducible RNA exosome as important opportunities for controlling cell fates and regenerative medicine.

Zero-shot sketch-based image retrieval (ZSSBIR) aims at retrieving natural images given free hand-drawn sketches that may not appear during training. Previous approaches used semantic aligned sketch-image pairs or utilized memory expensive fusion layer for projecting the visual information to a low-dimensional subspace, which ignores the significant heterogeneous cross-domain discrepancy between highly abstract sketch and relevant image. This may yield poor performance in the training phase. To tackle this issue and overcome this drawback, we propose a Wasserstein distance-based cross-modal semantic network (WAD-CMSN) for ZSSBIR. Specifically, it first projects the visual information of each branch (sketch, image) to a common low-dimensional semantic subspace via Wasserstein distance in an adversarial training manner. Furthermore, a novel identity matching loss is employed to select useful features, which can not only capture complete semantic knowledge, but also alleviate the over-fitting phenomenon caused by the WAD-CMSN model. Experimental results on the challenging Sketchy (Extended) and TU-Berlin (Extended) datasets indicate the effectiveness of the proposed WAD-CMSN model over several competitors.

The purpose of this study is to investigate the predictive value of neutrophil-to-lymphocyte ratio (NLR), serum calcium, and serum albumin on the prognosis of patients with diabetic foot. A total of 156 patients who were treated in the Department of Burn and Plastic Surgery of Qilu Hospital of Shandong University from 1 January 2014 to 1 August 2020 were selected. All the patients were randomly divided into a healing group, minor amputation group, major amputation group, and death group according to their treatment outcomes. The levels of NLR, serum calcium and serum albumin in each group were examined and compared. The correlations between NLR, serum calcium, and serum albumin with the prognosis of diabetic foot were analysed to investigate their predictive effects on the prognosis of diabetic foot. The results of one-way ANOVA showed that among the 4 groups of patients, the difference in NLR values between the healing group and the minor amputation group was slightly smaller, but they were significantly different from the major amputation group and the death group, respectively. There was no significant difference in serum calcium levels between the healing group and the minor amputation group, but the serum calcium levels of the major amputation group and the death group gradually decreased. The levels of NLR in the 4 groups gradually increased, while the albumin levels gradually decreased. Spearman's rank correlation test indicated that NLR was significantly related to the prognosis of patients with diabetic foot. The group with higher NLR had a worse prognosis in diabetic foot patients. Serum calcium and serum albumin were strongly correlated with the prognosis of patients with diabetic foot. The group with lower serum calcium and serum albumin values had a worse prognosis in diabetic foot patients. The areas under the receiver operator characteristic curve of NLR, serum calcium and serum albumin were 0.901, 0.803, and 0.816, respectively. NLR, serum calcium and serum albumin can be used as reliable indicators to predict the prognosis of diabetic foot. Preoperative diabetic foot patients with higher NLR values or lower serum calcium and serum albumin have a poorer prognosis.

Pancreatic differentiation from human pluripotent stem cells (hPSCs) provides promising avenues for investigating development and treating diseases. N6-methyladenosine (m6A) is the most prevalent internal messenger RNA (mRNA) modification and plays pivotal roles in regulation of mRNA metabolism, while its functions remain elusive. Here, we profile the dynamic landscapes of m6A transcriptome-wide during pancreatic differentiation. Next, we generate knockout hPSC lines of the major m6A demethylase ALKBH5, and find that ALKBH5 plays significant regulatory roles in pancreatic organogenesis. Mechanistic studies reveal that ALKBH5 deficiency reduces the mRNA stability of key pancreatic transcription factors in an m6A and YTHDF2-dependent manner. We further identify that ALKBH5 cofactor α-ketoglutarate can be applied to enhance differentiation. Collectively, our findings identify ALKBH5 as an essential regulator of pancreatic differentiation and highlight that m6A modification-mediated mRNA metabolism presents an important layer of regulation during cell-fate specification and holds great potentials for translational applications.

Helpful online product reviews, which include massive information, have large impacts on customers? purchasing decisions. In most of e-commerce platforms, the helpfulness of reviews are decided by the votes from other customers. Making full use of these reviews with votes has enormous commercial value, especially in product recommendation. It drives researchers to study the technologies about how to evaluate the review helpfulness automatically. Although Deep Neural Network(DNN), learning from the historical reviews and labels, computed by the votes, has demonstrated effective results, it still has suffered insufficient labeled reviews problem. When the helpfulness of a large number of reviews is unknown for lack of votes, or some useful latest reviews with less votes are submerged by the past reviews, the accuracy of current DNN model decreases quickly. Therefore, we propose an end-to-end deep semi-supervised learning model with weight map, which makes full use of the unlabeled reviews. The training process in this model is divided into three stages:obtaining base classifier by less labeled reviews, iteratively applying weight map strategy on large unlabeled reviews to obtain pseudo-labeled reviews, training on above combined reviews to obtain the re-training classifier. Based on this novel model, we develop an algorithm and conduct a series of experiments, on Amazon Review Dataset, from the aspects of the baseline neural network selection and the strategies comparisons, including two labeling and three weighting strategies. The experimental results demonstrate the effectiveness of our method on utilizing the unlabeled data. And our findings show that the model adopted batch labeling strategy and non-linear weight mapping method has achieved the best performance.

Keloid is a common and frequently-occurring disease in plastic surgery, and its ugly appearance and itching symptoms bring mental and life pain to patients. However, the clinical treatment of keloid, such as drug injection treatment, surgical resection, cryotherapy, laser treatment and other therapeutic effects are poor. Since the discovery of tumor necrosis factor related apoptosis inducing ligand (TRAIL) in 1995, its selective apoptosis on tumor cells makes it have a great prospect in the targeted treatment of tumor. In recent years, it has been found that the formation of keloid is related to the imbalance of apoptosis of fibroblasts in scar and the binding of TRAI to its receptor mediates the apoptosis of fibroblasts. Therefore, the use of TRAIL and TRAIL-R2/death receptor 5 (DR5) in the treatment of keloid has become a hot research topic. In this paper, the present situation, mechanism and development prospect of TRAIL and TRAIL-R2/DR5 targeted treatment of keloid were reviewed, which provided a reference for promoting the development of keloid treatment.

Fine-grained sketch-based image retrieval (FG-SBIR) is an important problem that uses free-hand human sketch as queries to perform instance-level retrieval of photos. Human sketches are generally highly abstract and iconic, which makes FG-SBIR a challenging task. Existing FG-SBIR approaches using triplet loss with \begin{document}$ \ell_2 $\end{document} regularization or higher-order energy function to conduct retrieval performance, which neglect the feature gap between different domains (sketches, photos) and need to select the weight layer matrix. This yields high computational complexity. In this paper, we define a new CAT loss function with elastic net regularization based on attention model. It can close the feature gap between different subnetworks and embody the sparsity of the sketches. Experiments demonstrate that the proposed approach is competitive with state-of-the-art methods.

An unlimited source of human pancreatic β cells is in high demand. Even with recent advances in pancreatic differentiation from human pluripotent stem cells, major hurdles remain in large-scale and cost-effective production of functional β cells. Here, through chemical screening, we demonstrate that the bromodomain and extraterminal domain (BET) inhibitor I-BET151 can robustly promote the expansion of PDX1 + NKX6.1 + pancreatic progenitors (PPs). These expandable PPs (ePPs) maintain pancreatic progenitor cell status in the long term and can efficiently differentiate into functional pancreatic β (ePP-β) cells. Notably, transplantation of ePP-β cells rapidly ameliorated diabetes in mice, suggesting strong potential for cell replacement therapy. Mechanistically, I-BET151 activates Notch signaling and promotes the expression of key PP-associated genes, underscoring the importance of epigenetic and transcriptional modulations for lineage-specific progenitor self-renewal. In summary, our studies achieve the long-term goal of robust expansion of PPs and represent a substantial step toward unlimited supplies of functional β cells for biomedical research and regenerative medicine.

Pathological scars mainly include hyperplastic scars and keloids, and there is no uniform treatment standard for the treatment of pathological scar in clinic now. Drug injection in the treatment of pathological scar is widely used because of its advantages of less trauma and simple operation. Therefore, we used a network meta-analysis to compare the curative effect of four kinds of drugs which are commonly used in the treatment of pathological scar such as botulinum toxin type A, corticosteroids (including diprospan and triamcinolone acetonide (TAC)), verapamil and 5-fluorouracil (5-FU), systematically. It is hoped that our study will provide evidence for the choice of drugs in the treatment of pathological scar by injection. Relevant articles from Wanfang, VIP, CNKI, PubMed, Cochrane Library and Embase databases were extracted by us. They were included into a network meta-analysis to compare the four kinds of drugs which are commonly used in the treatment of pathological scar. The network meta-analysis included a total of 1513 patients from 23 studies. Through meta-analysis, we found that the efficacy of botulinum toxin type A combined with corticosteroid drugs was best in the treatment of pathological scar by injection. There was no significant difference between botulinum toxin type A, corticosteroids combined with 5 Fu, verapamil and 5-FU. The efficacy of corticosteroids combined with 5-FU was better than that of corticosteroids alone and verapamil alone, but there was no significant difference between them and 5-FU. Further, the order of efficacy predicted by the SUCRA curve was as follows: botulinum toxin type A combined with corticosteroids > corticosteroids combined with 5-FU > botulinum toxin type A > corticosteroids > 5-FU > verapamil. Moreover, no publication bias was found in the funnel diagram. In the injection treatment of pathological scar, we recommend the combined injection of two drugs, especially botulinum toxin type A combined with corticosteroids. The effective treatment of botulinum toxin type A combined with corticosteroids in the treatment of pathological scar is as follows: Patients were treated once monthly with intralesional injection of TAC (0.1 ml/cm3) mixed with botulinum toxin type A (2.5 IU/cm3) for a total of 3 treatments. However, there are still limitations in this network meta-analysis, and its conclusion still needs to be further confirmed by more randomized controlled trials. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

OBJECTIVES The symptoms associated with microtia are ever-changing and not to stick to 1 pattern. The symptoms associated with microtia are constantly changing and are not set in stone. The aim of this article was to describe the various phenotypes from multiple systems found in microtitis patients included in the DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources database, and to analyze possible pathogenic mutations. METHODS DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources is an interactive web-based database, which incorporates a suite of tools designed to aid the interpretation of genomic variants. The term "microtia" was used as the search term, and the data extracted from the DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources for this study was updated until October 2020. Pearson chi-squared test was used to test associations between types of genomic variants and the pathogenicity of variants. RESULTS Of the 386 cases enrolled in the study, 99% (n = 382) had 1 or more associated abnormalities. The most frequently detected abnormalities were those of the face and neck (n = 362 [93.8% of all cases]); musculoskeletal system (n = 337 [87.3%]); and nervous system (n = 334 [86.5%]), followed by abnormalities of limbs (n = 252 [65.3%]); the eye (n = 212 [54.9%]); and the integument (n = 200 [51.8%]). Besides, a total of 479 genomic variants were determined, including sequence variants and copy number variants (loss and gain). The pathogenicity of loss-type variants was significantly higher among other types (P

Pancreatic differentiation from human pluripotent stem cells (hPSCs) provides promising avenues for investigating development and treating diseases. N

Background: Necrotizing fasciitis(NF) is a severe progressive infectious disease where a synergistic action of multiple bacteria results in suppurative necrosis of the skin and soft tissue. Despite being a relatively uncommon infection, its mortality is significantly high. In this case report ,we describe the clinical presentation, management and outcome of a patient with NF of the left lower limb complicated with the abscess of retroperitoneal space and ensuing septic shock and dysfunction of heart and liver. Finally, we analyzed six cases we have treated before including this one and a retrospective study was performed.Case presentation: A 69-year-old male patient, complaining about the pain of left lower limb and high fever due to uncertain reasons, featuring the tenderness of affected limb and left lower abdomen , was diagnosed with the NF complicated with the abscess of retroperitoneal space. The patient then develop septic shock and dysfunction of heart and liver. After repeated debridement of necrosis tissue, in combination with multiple antibiotics, laboratory test methods and the vacuum-assisted closure(VAC) therapy, the patient survived ,gradually improved and finally got a full recovery.Methods: A retrospective study was performed on six patients with NF of unilateral lower limb from March 2018 to October 2019. All patients were given systemic antibiotics and nutrition support. During the first stage, repeated surgical debridement with negative-pressure wound therapy(NPWT) was performed. Direct suture of the wound was performed in the second stage. Results: The incision healed well in all patients, and no infection or necrosis occurred in the wound. During the follow-up of 6.5 months (range, 5-9 months), no recurrence of infection or incision rupture occurred.Discussion: Although prompt diagnosis and adequate antibiotic therapy are basic for the treatment of patients with NF, early and repeated surgical intervention is vital for a favorable outcome. Thus, adjuvant treatment for NF such as negative pressure wound therapy (NPWT) using the VAC are very useful to accelerate wound healing.Conclusions: Prompt diagnosis, adequate antibiotic therapy and more crucially, early and repeated surgical debridement of the necrotic tissue combined with VAC therapy play a collaborative role in the successful treatment of NF.

Chemical compounds have recently been introduced as alternative and non‐integrating inducers of pluripotent stem cell fate. However, chemical reprogramming is hampered by low efficiency and the molecular mechanisms remain poorly characterized. Here, we show that inhibition of spleen tyrosine kinase (Syk) by R406 significantly promotes mouse chemical reprogramming. Mechanistically, R406 alleviates Syk / calcineurin (Cn) / nuclear factor of activated T cells (NFAT) signaling‐mediated suppression of glycine, serine, and threonine metabolic genes and dependent metabolites. Syk inhibition upregulates glycine level and downstream transsulfuration cysteine biosynthesis, promoting cysteine metabolism and cellular hydrogen sulfide (H(2)S) production. This metabolic rewiring decreased oxidative phosphorylation and ROS levels, enhancing chemical reprogramming. In sum, our study identifies Syk‐Cn‐NFAT signaling axis as a new barrier of chemical reprogramming and suggests metabolic rewiring and redox homeostasis as important opportunities for controlling cell fates.

Growing number of enterprises nowadays are pursuing online marketing strategies, with their eyes focusing on the effectiveness of opinion leader value-creation on social media platform. Therefore, how to accurately identify opinion leaders on social media platforms is of great significance. The emotional value generated by communication between opinion leaders and fans will have a significant impact on the potential consumption behavior of fans. Most of the existing research on opinion leader identification is to establish models based on the existing indicator data of the platform, without taking the value of emotional communication into account. This paper proposes a social media opinion leader identification model based on online comment sentiment analysis. We first crawl online comments, then analyze the text data characteristics, establish emotional indicators of different attributes, calculate the sentiment value of the text data, and finally use artificial neural network technology to train to form an opinion leader recognition model. The experimental results show that emotional communication is a very important factor in opinion leader identification, and the proposed model can identify opinion leaders more accurately.

Mounting evidence has reported that microRNAs (miRNAs) play irreplaceable roles in the development of keloid fibrosis. miR-4417 has been reported to contribute to nickel chloride-promoted lung epithelial cell fibrogenesis and tumorigenesis. However, whether miR-4417 is involved in keloid fibrogenesis as well as its underlying mechanisms remain largely elusive. In this study, the expression levels of miR-4417 and CyclinD1 in keloid tissues and fibroblasts were examined by qRT-PCR. Cell proliferation was determined by CCK assay. Western blot and flow cytometry were performed to evaluate cell apoptosis. Cell migration and invasion were measured by Transwell assay. Luciferase reporter assay was used to confirm the relationship between miR4417 and CyclinD1. As a result, we found that miR-4417 was significantly down-regulated in keloid tissues and fibroblasts. miR-4417 up-regulation led to the suppression of proliferation, migration, and invasion, while induced cell apoptosis in keloid fibroblasts. However, miR-4417 depletion exerted an opposite effect. CyclinD1 harbored the binding sites with miR-4417. Besides, the expression of CyclinD1 was evidently decreased in keloid tissues and fibroblasts. Meanwhile, miR-4417 was negatively correlated with CyclinD1 in keloid tissue. The effect of CyclinD1 knockdown on keloid fibroblasts was similar to that of miR-4417 overexpression. Furthermore, the elevated of CyclinD1 expression rescued the effect of miR-4417 up-regulation on keloid fibroblasts. miR-4417/CyclinD1 axis was required for cell proliferation, apoptosis, migration, and invasion in keloid fibroblasts. In conclusion, miR-4417 and CyclinD1 may be potential therapeutic targets for the treatment of keloid.

Joint Entities-relations extraction (JERE), which can solve the error propagation problem in piped-line extraction, uses a single model to combine the two tasks by different strategies. The neural network-based methods for the joint extraction show better performances than the state-of-the-art results, but the constructed model are complicated. hyper-parameters selection and model training are also difficult. For simplifying the model construction and improving the accuracy of extraction, we transferred the joint extraction problem to a sequential label problem formally, combined different strategies in Encoding layer and Decoding Layer of end-to-end model, focused on the using of Bert on Encoding layer with different tagging scheme, then designed the comparative experiments on Chinese text dataset, the empirical results showed that 1)Using Bert as the embedding layer of the model is better than word2vec, but not so significant. 2)The final results of Bert followed by complex neural net-works such as BiLSTM and simple neural networks such as MLP on experiments are very close, which means Bert can simplify the model construction, it also means that we can get a good result with less training time by a simple neural networks. 3)The new tagging scheme is better than the BIO tagging scheme, and if it is combined with the pre-training language model, we can quickly build a simple and sufficiently accurate model on JERE tasks.

Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs/miRs) are noncoding RNAs that function as regulators of tumor suppressors and oncogenes. The aim of the present study was to investigate the potential mechanism associated with the involvement of urothelial cancer associated 1 (UCA1) in melanoma. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were performed in order to determine the expression levels of UCA1, miR-143, miR-216b, and hexokinase 2 (HK2) in the melanoma and control groups, as well as the influence of UCA1, miR-143, and miR-216b on the expression of HK2, and the effect of lactate and UCA1 on the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK). Bioinformatics algorithm analysis and a luciferase assay were performed in order to predict miRNA targets. In addition, an MTT assay was performed in order to determine the effect of lactate and UCA1 expression on cell proliferation. A total of 39 participants, consisting of 18 patients with melanoma and 21 healthy control subjects, were included in the present study. The present study demonstrated that the expression levels of UCA1 mRNA, and HK2 mRNA and protein were enhanced in patients with melanoma compared with healthy controls; whereas the expression levels of miR-143 and miR-216b mRNA were suppressed in patients with melanoma compared with healthy controls. Furthermore, it was revealed that UCA1 negatively modulated the expression of miR-143 and miR-216b, and that miR-143 and miR-216b directly targeted the HK2 protein by binding to the HK2 3′ untranslated region (UTR). In addition, it was demonstrated that miR-143 and miR-216 suppressed the luciferase activity exhibited by wild-type HK2 3′-UTR. Furthermore, it was revealed that transfection with UCA1 small interfering RNA, and miR-143 and miR-216b mimics markedly suppressed HK2 mRNA and protein expression levels as well as lactate levels in human umbilical vein endothelial cells; however, O2 consumption was revealed to be enhanced post transfection. By contrast, transfection with UCA1 enhanced HK2 mRNA and protein expression levels as well as lactate production; however, O2 consumption was revealed to be suppressed post transfection. Lactate-induced phosphorylation of p38 MAPK was revealed to occur in a concentration-dependent manner, and UCA1 enhanced the phosphorylation level of p38 MAPK via the inhibition of miR-143 and miR-216b expression. Lactate and UCA1 were demonstrated to enhance cell proliferation. In conclusion, the present study demonstrated that the lncRNA UCA1/miR-143 miR-216b/HK2/lactic acid/MAPK axis may be involved in the pathogenesis of melanoma via the modulation of endothelial cells, and thus, lncRNA UCA1 may serve as a potential therapeutic target for melanoma treatment.

Objective Ethanol used by women during pregnancy increases the risk for microtia in the foetus. Traditionally, laboratory experiments and Mouse Genome Informatics (MGI) have been used to explore microtia pathogenesis. The aim of this study was to screen and verify hub genes involved in ethanol-induced microtia and to explore the potential molecular mechanisms. Methods Overlapping genes related to ethanol and microtia were acquired from the GeneCards database and filtered by confidence score. These genes were further analysed via bioinformatics. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis results were visualized with the clusterProfiler R package. A protein-protein interaction (PPI) network was constructed based on data from the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. Results Overall, 41 genes related to both ethanol and microtia were identified. The genes most relevant to ethanol-induced microtia pathogenesis included FGFR-2, FGFR-3, FGF-8, TP53, IGF1, SHH, CTNNB1, and PAX6, among others. Most genes were strongly enriched for tissue and organ development in GO analysis. Additionally, many genes were enriched in the Ras, FoxO, MAPK, and PI3K-Akt signalling pathways in KEGG analysis. Conclusions Bioinformatics analysis was conducted on genes currently known to be related to ethanol-induced microtia pathogenesis. We propose that mechanisms involving FGF-family genes, TP53, IGF1 and SHH contribute significantly to ethanol-induced microtia and the accompanying malformation of other structures.

With the development of big data technology, user profile, as an effective method for delineating user characteristics, has attracted extensive attention from researchers and practitioners. Rich related literatures have been accumulated. How to find the key factors and the new direction from such a big library is a difficult problem for a new researcher entering the field. The knowledge map can be used to visualize the development trend, the frontier field and the overall knowledge structure from these researches. Therefore, we choose web of science database as the literature search engine and use CiteSpace to construct the user profile knowledge map. Through these maps, we analyze the important authors and countries, make the common word analysis and co-citation analysis, study the hot spots and important literatures. The time distribution shows that some foundational theories in user profile were produced at the second stage from 2004 to 2013. What’s more, from the geographical distribution, we find that user profile, as an abstract concept, has no unified framework. Each country focuses on the different research points. From the knowledge map of keywords, we find that the top three algorithmic techniques used in constructing user profile are clustering, classification, and collaborative filtering. At the same time, user profile is also used in some specific applications, such as anomaly detection, behavior analysis, and information retrieval.

miR-425 is a potential tumor suppressor in cancer, but its role in melanoma is still unknown. We aim to investigate miR-425 expression in melanoma tissues and cell lines. Next, cell proliferation, cell cycle, apoptosis and metastasis will be studied using lentivirus-mediated gain-of-function studies. The predicted results are stable miR-425 inhibits cell proliferation and metastasis and induced cell apoptosis. It is predicted that IGF-1 is a potential target gene of miR-495 by bioinformatics analysis. Then luciferase assay analysis identifies IGF-1 as a new direct target gene of miR-425 and miR-425 inhibits melanoma cancer progression via IGF-1. Collectively, our findings suggested that miR-425 may function as a tumor suppressor in melanoma by targeting IGF-1.