Targeting the STAT3/IL-36G signaling pathway can be a promising approach to treat rosacea.

BACKGROUND: Rosacea is an inflammatory skin disorder characterized by the release of inflammatory mediators from keratinocytes, which are thought to play a crucial role in its pathogenesis. Despite an incidence of approximately 5.5%, rosacea is associated with a poor quality of life. However, as the pathogenesis of rosacea remains enigmatic, treatment options are limited. OBJECTIVES: To investigate the pathogenesis of rosacea and explore new therapeutic strategies. METHODS: Transcriptome data from rosacea patients combined with immunohistochemical staining were used to investigate the activation of STAT3 in rosacea. The role of STAT3 activation in rosacea was subsequently explored by inhibiting STAT3 activation both in vivo and in vitro. The key molecules downstream of STAT3 activation were identified through data analysis and experiments. Dual-luciferase assay and ChIP-qPCR analysis were used to validate the direct binding of STAT3 to the IL-36G promoter. DARTS, in combination with experimental screening, was employed to identify effective drugs targeting STAT3 for rosacea treatment. RESULTS: STAT3 signaling was hyperactivated in rosacea and served as a promoter of the keratinocyte-driven inflammatory response. Mechanistically, activated STAT3 directly bind to the IL-36G promoter region to amplify downstream inflammatory signals by promoting IL-36G transcription, and treatment with a neutralizing antibody (α-IL36γ) could mitigate rosacea-like inflammation. Notably, a natural plant extract (pogostone), which can interact with STAT3 directly to inhibit its activation and affect the STAT3/IL36G signaling pathway, was screened as a promising topical medication for rosacea treatment. CONCLUSIONS: Our study revealed a pivotal role for STAT3/IL36G signaling in the development of rosacea, suggesting that targeting this pathway might be a potential strategy for rosacea treatment.

Correction: Jiménez-Ortigosa et al. Cryo-Electron Tomography of Candida glabrata Plasma Membrane Proteins. J. Fungi 2021, 7, 120.

The authors wish to update the article title to "Cryo-Electron Tomography of Candida glabrata Plasma Membrane Proteins" [...].

Bibliometric analysis of 100 top cited articles of heart failure-associated diseases in combination with machine learning.

Objective: The aim of this paper is to analyze the application of machine learning in heart failure-associated diseases using bibliometric methods and to provide a dynamic and longitudinal bibliometric analysis of heart failure-related machine learning publications. Materials and methods: Web of Science was screened to gather the articles for the study. Based on bibliometric indicators, a search strategy was developed to screen the title for eligibility. Intuitive data analysis was employed to analyze the top-100 cited articles and VOSViewer was used to analyze the relevance and impact of all articles. The two analysis methods were then compared to get conclusions. Results: The search identified 3,312 articles. In the end, 2,392 papers were included in the study, which were published between 1985 and 2023. All articles were analyzed using VOSViewer. Key points of the analysis included the co-authorship map of authors, countries and organizations, the citation map of journal and documents and a visualization of keyword co-occurrence analysis. Among these 100 top-cited papers, with a mean of 122.9 citations, the most-cited article had 1,189, and the least cited article had 47. Harvard University and the University of California topped the list among all institutes with 10 papers each. More than one-ninth of the authors of these 100 top-cited papers wrote three or more articles. The 100 articles came from 49 journals. The articles were divided into seven areas according to the type of machine learning approach employed: Support Vector Machines, Convolutional Neural Networks, Logistic Regression, Recurrent Neural Networks, Random Forest, Naive Bayes, and Decision Tree. Support Vector Machines were the most popular method. Conclusions: This analysis provides a comprehensive overview of the artificial intelligence (AI)-related research conducted in the field of heart failure, which helps healthcare institutions and researchers better understand the prospects of AI in heart failure and formulate more scientific and effective research plans. In addition, our bibliometric evaluation can assist healthcare institutions and researchers in determining the advantages, sustainability, risks, and potential impacts of AI technology in heart failure.

Translational medical bioengineering research of traumatic brain injury among Chinese and American pedestrians caused by vehicle collision based on human body finite element modeling.

Based on the average human body size in China and the THUMS AM50 finite element model of the human body, the Kriging interpolation algorithm was used to model the Chinese 50th percentile human body, and the biological fidelity of the model was verified. We built three different types of passenger vehicle models, namely, sedan, sports utility vehicle (SUV), and multi-purpose vehicle (MPV), and used mechanical response analysis and finite element simulation to compare and analyze the dynamic differences and head injury differences between the Chinese 50th percentile human body and the THUMS AM50 model during passenger vehicle collisions. The results showed that there are obvious differences between the Chinese mannequin and THUMS in terms of collision time, collision position, invasion speed, and angle. When a sedan collided with the mannequins, the skull damage to the Chinese human body model was more severe, and when a sedan or SUV collided, the brain damage to the Chinese human body was more severe. The abovementioned results suggest that the existing C-NCAP pedestrian protection testing regulations may not provide the best protection for Chinese human bodies, and that the regulations need to be improved by combining collision damage mechanisms and the physical characteristics of Chinese pedestrians. This thorough investigation is positioned to shed light on the fundamental biomechanics and injury mechanisms at play. Furthermore, the amalgamation of clinically rooted translational and engineering research in the realm of traumatic brain injury has the potential to establish a solid foundation for discerning preventive methodologies. Ultimately, this endeavor holds the potential to introduce effective strategies aimed at preventing and safeguarding against traumatic brain injuries.

Academic Publication of Neurodegenerative Diseases From a Bibliographic Perspective: A Comparative Scientometric Analysis.

Background: For measuring the impact in clinical and scientific research, the citation count of the articles is used in the bibliometric analysis, although there is no comprehensive summary of neurodegenerative disease research. This study intends to provide the neuroscientists and investigators with a practical reference guide to appraise the most important and influential articles written on this subject through a macroscopic view of the research activities on neurodegenerative diseases. Materials and Methods: The Clarivate Analytics Web of Science was searched in July 2020. To ensure the breadth of the search scope, the search terms were confirmed as "multiple sclerosis" (MS) or "amyotrophic lateral sclerosis" (ALS) or "Parkinson's" or "Alzheimer's" or "Huntington's" or "neurodegenerative." After excluding completely unrelated articles, the top-cited articles were collected and evaluated from special characteristics. The data analysis was performed using SPSS 18.0. The articles were characterized by citation number, publication year, topic, study type, authorship, journal, country, and institute of responding author and foundation. Results: The query identified 593,050 articles. A total of 45% of the top-cited articles were published during 2000-2009, followed by 30 articles from 1990-1999. Diagnosis and pathology were the main research categories (n = 62). Alzheimer's disease (AD) was the main study topic (n = 43). Meanwhile, the United States confirmed the tremendous impact on the field of neurodegenerative diseases. Notably, 69 of 100 articles were studied in the United States, and the National Institutes of Health sponsored 49 articles. There were only 22 articles that can be divided by evidence level. No article was categorized as level 1 evidence. In the journal list with multiple articles, seven of 15 were general journals. The 58 authors, who contributed to more than one article, have been identified by VOSviewer, and the clusters of authors reveal the evolution of research focus in neurodegenerative diseases. Conclusions: This study analyzed the bibliometric characteristics and connections of 100 top-cited articles in the field of neurodegenerative diseases in the Web of Science. Their main outcomes were as follows: First, the pathology and diagnostic researches took a major role in top-cited articles while the therapy articles are relatively less. Second, the United States confirmed the tremendous impact on the field of neurodegenerative diseases. Third, researchers also submitted their researches to general journals, not just focused on specialty journals.

The structure-function relationship of a signaling-competent, dimeric Reelin fragment.

Reelin operates through canonical and non-canonical pathways that mediate several aspects of brain development and function. Reelin's dimeric central fragment (CF), generated through proteolytic cleavage, is required for the lipoprotein-receptor-dependent canonical pathway activation. Here, we analyze the signaling properties of a variety of Reelin fragments and measure the differential binding affinities of monomeric and dimeric CF fragments to lipoprotein receptors to investigate the mode of canonical signal activation. We also present the cryoelectron tomography-solved dimeric structure of Reelin CF and support it using several other biophysical techniques. Our findings suggest that Reelin CF forms a covalent parallel dimer with some degree of flexibility between the two protein chains. As a result of this conformation, Reelin binds to lipoprotein receptors in a manner inaccessible to its monomeric form and is capable of stimulating canonical pathway signaling.

Structural insight into transmissive mutant huntingtin species by correlative light and electron microscopy and cryo-electron tomography.

Aggregates of mutant huntingtin (mHTT) containing an expanded polyglutamine (polyQ) tract are hallmarks of Huntington's Disease (HD). Studies have shown that mHTT can spread between cells, leading to the propagation of misfolded protein pathology. However, the structure of transmissive mHTT species, and the molecular mechanisms underlying their transmission remain unknown. Using correlative light and electron microscopy (CLEM) and cryo-electron tomography (cryo-ET), we identified two types of aggregation-prone granules in conditioned medium from PC12 cells expressing a mHTT N-terminal fragment: densities enclosed by extracellular vesicles (EVs), and uncoated, amorphous meshworks of heterogeneous oligomers that co-localize with clusters of EVs. In vitro assays confirmed that liposomes induce condensation of polyQ oligomers into higher-order assemblies, resembling the uncoated meshworks observed in PC12 conditioned medium. Our findings provide novel insights into formation and architecture of transmissive mHTT proteins, and highlight the potential role of EVs as both carriers and modulators of transmissive mHTT proteins.

Hydrogen treatment: a novel option in liver diseases.

Hydrogen therapy is a very promising treatment against several diseases due to its mild attributes, high affinity and inherent biosafety. However, there is little elaboration about current hydrogen treatment in liver diseases. This article introduces the administration of hydrogen and mechanisms of hydrogen therapy in vivo, including modulating reactive oxygen species, apoptosis and autophagy, and inflammation, affecting mitochondria, as well as protein transporters. The major focus is clinical hydrogen use and related mechanisms in liver dysfunction or diseases, including non-alcoholic fatty liver disease, hepatitis B, liver dysfunction caused by liver tumour and colorectal tumour chemotherapy. Further, the article reveals ex vivo hydrogen application in liver protection. Finally, the article discusses the current and future challenges of hydrogen therapy in liver diseases, aiming to improve knowledge of hydrogen therapy and provide some insights into this burgeoning field.

Preliminary Structural Elucidation of ß-(1,3)-glucan Synthase from Candida glabrata Using Cryo-Electron Tomography.

Echinocandin drugs have become a front-line therapy against Candida spp. infections due to the increased incidence of infections by species with elevated azole resistance, such as Candida glabrata. Echinocandins target the fungal-specific enzyme ß-(1,3)-glucan synthase (GS), which is located in the plasma membrane and catalyzes the biosynthesis of ß-(1,3)-glucan, the major component of the fungal cell wall. However, resistance to echinocandin drugs, which results from hotspot mutations in the catalytic subunits of GS, is an emerging problem. Little structural information on GS is currently available because, thus far, the GS enzyme complex has resisted homogenous purification, limiting our understanding of GS as a major biosynthetic apparatus for cell wall assembly and an important therapeutic drug target. Here, by applying cryo-electron tomography (cryo-ET) and subtomogram analysis, we provide a preliminary structure of the putative C. glabrata GS complex as clusters of hexamers, each subunit with two notable cytosolic domains, the N-terminal and central catalytic domains. This study lays the foundation for structural and functional studies of this elusive protein complex, which will provide insight into fungal cell wall synthesis and the development of more efficacious antifungal therapeutics.

Structural and functional analyses of photosystem II in the marine diatom Phaeodactylum tricornutum.

A descendant of the red algal lineage, diatoms are unicellular eukaryotic algae characterized by thylakoid membranes that lack the spatial differentiation of stroma and grana stacks found in green algae and higher plants. While the photophysiology of diatoms has been studied extensively, very little is known about the spatial organization of the multimeric photosynthetic protein complexes within their thylakoid membranes. Here, using cryo-electron tomography, proteomics, and biophysical analyses, we elucidate the macromolecular composition, architecture, and spatial distribution of photosystem II complexes in diatom thylakoid membranes. Structural analyses reveal 2 distinct photosystem II populations: loose clusters of complexes associated with antenna proteins and compact 2D crystalline arrays of dimeric cores. Biophysical measurements reveal only 1 photosystem II functional absorption cross section, suggesting that only the former population is photosynthetically active. The tomographic data indicate that the arrays of photosystem II cores are physically separated from those associated with antenna proteins. We hypothesize that the islands of photosystem cores are repair stations, where photodamaged proteins can be replaced. Our results strongly imply convergent evolution between the red and the green photosynthetic lineages toward spatial segregation of dynamic, functional microdomains of photosystem II supercomplexes.

Integrated analysis of microRNA and mRNA expression profiles in HBx-expressing hepatic cells.

AIM: To identify the miRNA-mRNA regulatory network in hepatitis B virus X (HBx)-expressing hepatic cells. METHODS: A stable HBx-expressing human liver cell line L02 was established. The mRNA and miRNA expression profiles of L02/HBx and L02/pcDNA liver cells were identified by RNA-sequencing analysis. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was performed to investigate the function of candidate biomarkers, and the relationship between miRNA and mRNA was studied by network analysis. RESULTS: Compared with L02/pcDNA cells, 742 unregulated genes and 501 downregulated genes were determined as differentially expressed in L02/HBx cells. Gene ontology analysis suggested that the differentially expressed genes were relevant to different biological processes. Concurrently, 22 differential miRNAs were also determined in L02/HBx cells. Furthermore, integrated analysis of miRNA and mRNA expression profiles identified a core miRNA-mRNA regulatory network that is correlated with the carcinogenic role of HBx. CONCLUSION: Collectively, the miRNA-mRNA network-based analysis could be useful to elucidate the potential role of HBx in liver cell malignant transformation and shed light on the underlying molecular mechanism and novel therapy targets for hepatocellular carcinoma.

Potential role of High mobility group box 1 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and is characterized as a typical inflammation-related carcinoma. High mobility group box protein 1 (HMGB1), a non-histone DNA-binding protein, is identified as a potent proinflammatory mediator when presents extracellularly. Recently, a growing body of evidence indicates that HMGB1 plays a potential role in HCC, but many questions remain unanswered about the relationship between HMGB1 and HCC formation and development. This review focuses on the biological effect of HMGB1, and discusses the association of HMGB1 with HCC and potential use of strategies targeting HMGB1 in HCC treatment.

Is insulin-like growth factor binding protein 2 associated with metastasis in lung cancer?

Insulin-like growth factor binding protein 2 (IGFBP2) is involved in the progression of many epithelial cancers. However, its role in non-small cell lung cancer (NSCLC), another type of epithelial cancer, remains unclear. We detected IGFBP2 expression using immunohistochemistry in surgically resected tumors from 110 NSCLC patients, 37 of which had metastases. The positive rate of IGFBP2 expression was compared between the metastatic and the non-metastatic group, and correlations of IGFBP2 expression with metastasis and overall survival were analyzed. We also investigated the expression of IGFBP2 in microvesicles (MVs) collected from primary lung cancer cell cultures, and in different locations of newly resected NSCLC tumors, using immunoblotting. The overall positive rate of IGFBP2 expression in lung cancer was 51.8 % and it was significantly higher in the metastatic group than in the non-metastatic group (70.3 and 42.5 % respectively, p < 0.01). And the higher the lymph node stage, the higher the positive rate. Cytoplasmic expression was predominant in the majority of the tumors. Based on multivariate regression analysis, IGFBP2 was correlated with metastasis and poor overall survival (Hazard ratio: 3.56 and 3.23 respectively). IGFBP2 was detectable in the MVs collected from IGFBP2 positive cell lines, and its expression was most abundant in the marginal region of the newly resected tumors. IGFBP2 is associated with metastasis and poor survival of lung cancer. Its presence in MVs and high abundance in the marginal region of tumors suggest that its association with metastasis may be related to tumor microenviroment remodeling in NSCLC.

[Identification of sarcosaphagous Calliphorid flies by analyzing the sequence of 16S rDNA].

OBJECTIVE: To explore the application of a 289bp fragment of the 16S rDNA gene to identify various species of sarcosaphagous Calliphorid flies. METHODS: Twenty-six Calliphorid flies were collected from 14 Chinese provinces. All specimens were properly assigned into three genera and six species. The DNA of the pectoralis was extracted using CTAB method. Then PCR amplification was done for the 289 bp fragment of the 16S rDNA gene. The PCR products were then purified and sequenced, and the obtained sequences were uploaded to GenBank. The phylogenetic tree was built by the neighbor-joining method and intraspecific and interspecific divergences were calculated by sequence analysis. RESULTS: The above 26 sarcosaphagous flies could be well clustered according to different genera and species. The evolutional intraspecific values were all zero, the evolutional interspecific variations varied from 0.3% to 6.5%. CONCLUSION: The 289 bp fragment of the 16S rDNA of sarcosaphagous flies can be effectively used to identify most of the flies at species level. This method appears to be fast and low dissipative, which might be used to estimate postmortem interval by sarcosaphagous flies.

[Telephone follow-up of 1635 post-surgery lung cancer patients and retrospective study of lung cancer prognosis].

OBJECTIVE: To evaluate the telephone follow-up of surgery patients with lung cancer and to analyze the prognosis factors. METHODS: From October 2011 to January 2012, 1635 post-surgery lung cancer patients from January 2002 to August 2011 were followed up by telephone interview. The data from follow-up and clinical characteristics were collected and analyzed. Among these patients, 116 patients with complete and reliable clinical data were further analyzed to determine the effective factors of lung cancer metastasis and long-term survival. RESULTS: The average response rate in the follow-up was 36.1%, and the response rate was related to the interval time after the operations. The shorter the interval, the higher the response rate. The response rate in female patients was higher than that in male patients (P<0.001).The response rate was higher in patients younger than 40 (56 %) than that in the patients aged between 50-59 and over 60 (39% and 24% respectively, P<0.001). There was no statistical difference between patients from urban and rural areas (P=0.844). In the 116 patients with complete and reliable clinical data, statistical analysis confirmed that the metastasis and high lymph node staging were factors to increase patients' risk of death (with odd ratio 0.212 and 1.818 respectively, P<0.001). The adenocarcinoma grade, high lymph node staging and advanced age were related to the metastasis risk (odds ratio 2.353, 2.181 and 2.908, respectively). CONCLUSION: Time, gender and age are the influencing factors in the telephone follow-up. Metastasis, lymph node metastasis, pathologic type and age are related to the lung cancer prognosis in the small-scale sample.