Myostatin regulates energy homeostasis through autocrine- and paracrine-mediated microenvironment communications.

Myostatin (MSTN) has long been recognized as a critical regulator of muscle mass. Recently, there has been an increasing interest in its role in metabolism. In our study, we specifically knocked out MSTN in brown adipose tissue (BAT) from mice (MSTNΔUCP1) and found that the mice gained more weight than controls when fed a high-fat diet, with progressive hepatosteatosis and impaired skeletal muscle activity. RNA-seq analysis indicated signatures of mitochondrial dysfunction and inflammation in the MSTN-ablation BAT. Further studies demonstrated that the the Kruppel-like factor 4 (KLF4) was responsible for the metabolic phenotypes observed, while FGF21 contributed to the microenvironment communication between adipocytes and macrophages induced by the loss of MSTN. Moreover, the MSTN-SMAD2/3-p38 signaling pathway mediated the expression of KLF4 and FGF21 in adipocytes. In summary, our findings suggest that brown adipocytes-derived MSTN regulates BAT thermogenesis via autocrine and paracrine effects on adipocytes or macrophages, ultimately regulating systemic energy homeostasis.

Exploring the roles and potential therapeutic strategies of inflammation and metabolism in the pathogenesis of vitiligo: a mendelian randomization and bioinformatics-based investigation.

Introduction: Vitiligo, a common autoimmune acquired pigmentary skin disorder, poses challenges due to its unclear pathogenesis. Evidence suggests inflammation and metabolism's pivotal roles in its onset and progression. This study aims to elucidate the causal relationships between vitiligo and inflammatory proteins, immune cells, and metabolites, exploring bidirectional associations and potential drug targets. Methods: Mendelian Randomization (MR) analysis encompassed 4,907 plasma proteins, 91 inflammatory proteins, 731 immune cell features, and 1400 metabolites. Bioinformatics analysis included Protein-Protein Interaction (PPI) network construction, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Subnetwork discovery and hub protein identification utilized the Molecular Complex Detection (MCODE) plugin. Colocalization analysis and drug target exploration, including molecular docking validation, were performed. Results: MR analysis identified 49 proteins, 39 immune cell features, and 59 metabolites causally related to vitiligo. Bioinformatics analysis revealed significant involvement in PPI, GO enrichment, and KEGG pathways. Subnetwork analysis identified six central proteins, with Interferon Regulatory Factor 3 (IRF3) exhibiting strong colocalization evidence. Molecular docking validated Piceatannol's binding to IRF3, indicating a stable interaction. Conclusion: This study comprehensively elucidates inflammation, immune response, and metabolism's intricate involvement in vitiligo pathogenesis. Identified proteins and pathways offer potential therapeutic targets, with IRF3 emerging as a promising candidate. These findings deepen our understanding of vitiligo's etiology, informing future research and drug development endeavors.

Relationship between bullous pemphigoid and malignancy: A Mendelian randomization study.

Bullous pemphigoid (BP) is the most common autoimmune blistering disease, which primarily affects the elderly. However, the relationship between BP and malignancy remains controversial in traditional observational studies. The aim of this study, which included only European populations, was to assess the potential causative link between BP and 13 types of malignant tumors in a two-sample Mendelian randomization (MR) study. BP was not associated with an increased risk of developing 13 types of malignant tumors. This study did not find a causal relationship between BP and malignant tumors. However, further research is warranted to examine the generalizability of this conclusion in non-European populations.

Engineering A Boron-Rich Interphase with Nonflammable Electrolyte toward Stable Li||NCM811 Cells Under Elevated Temperature.

Despite the high energy of LiNi0.8 Co0.1 Mn0.1 O2 (NCM811) cathode, it still suffers serious decay due to the continuous solvents decomposition and unstable cathode electrolyte interphase (CEI) layers, especially under high temperatures. The intense exothermic reaction between delithiated NCM811 and flammable electrolyte, on the other hand, pushes the batteries to their safety limit. Herein, these two issues are tackled via engineering the electrolytes, that is, utilizing salts with higher HOMO levels and nonflammable solvents with lower HOMO levels, to reduce the massive decomposition of solvents and improve battery safety under elevated temperatures. Consequently, a thin and boron-rich CEI is generated, which effectively inhibited the side reactions, thus improving the cycling stability and safety. Deviated from the highly concentrated electrolytes which heavily relies on the usage of massive salts, the electrolyte recipe can introduce a robust inorganic-rich CEI but use much less salt (i.e., dilute electrolyte), and thus, offer an encouraging alternative toward practical applications. As such, the NCM811 cathode exhibits a high-capacity retention of 81.2% after 950 cycles at 25 °C and 75% after 300 cycles at 55 °C. This work provides a universal electrolyte design strategy for designing stable and safe high-temperature electrolytes for the NCM811 cathode.

Bioengineering Techniques to Improve Nitrogen Transformation and Utilization: Implications for Nitrogen Use Efficiency and Future Sustainable Crop Production.

Nitrogen (N) is crucial for plant growth and development, especially in physiological and biochemical processes such as component of different proteins, enzymes, nucleic acids, and plant growth regulators. Six categories, such as transporters, nitrate absorption, signal molecules, amino acid biosynthesis, transcription factors, and miscellaneous genes, broadly encompass the genes regulating NUE in various cereal crops. Herein, we outline detailed research on bioengineering modifications of N metabolism to improve the different crop yields and biomass. We emphasize effective and precise molecular approaches and technologies, including N transporters, transgenics, omics, etc., which are opening up fascinating opportunities for a complete analysis of the molecular elements that contribute to NUE. Moreover, the detection of various types of N compounds and associated signaling pathways within plant organs have been discussed. Finally, we highlight the broader impacts of increasing NUE in crops, crucial for better agricultural yield and in the greater context of global climate change.

Identification of GOLDEN2-like transcription factor genes in soybeans and their role in regulating plant development and metal ion stresses.

The Golden 2-Like (G2-like or GLK) transcription factors are essential for plant growth, development, and many stress responses as well as heavy metal stress. However, G2-like regulatory genes have not been studied in soybean. This study identified the genes for 130 G2-Like candidates' in the genome of Glycine max (soybean). These GLK genes were located on all 20 chromosomes, and several of them were segmentally duplicated. Most GLK family proteins are highly conserved in Arabidopsis and soybean and were classified into five major groups based on phylogenetic analysis. These GmGLK gene promoters share cis-acting elements involved in plant responses to abscisic acid, methyl jasmonate, auxin signaling, low temperature, and biotic and abiotic stresses. RNA-seq expression data revealed that the GLK genes were classified into 12 major groups and differentially expressed in different tissues or organs. The co-expression network complex revealed that the GmGLK genes encode proteins involved in the interaction of genes related to chlorophyll biosynthesis, circadian rhythms, and flowering regulation. Real-time quantitative PCR analysis confirmed the expression profiles of eight GLK genes in response to cadmium (Cd) and copper (Cu) stress, with some GLK genes significantly induced by both Cd and Cu stress treatments, implying a functional role in defense responsiveness. Thus, we present a comprehensive perspective of the GLK genes in soybean and emphasize their important role in crop development and metal ion stresses.

A Clinical Predictive Model of Central Lymph Node Metastases in Papillary Thyroid Carcinoma.

Background: Thyroid carcinoma is one of the most common endocrine tumors, and papillary thyroid carcinoma (PTC) is the most common pathological type. Current studies have reported that PTC has a strong propensity for central lymph node metastases (CLNMs). Whether to prophylactically dissect the central lymph nodes in PTC remains controversial. This study aimed to explore the risk factors and develop a predictive model of CLNM in PTC. Methods: A total of 2,554 patients were enrolled in this study. The basic information, laboratory examination, characteristics of cervical ultrasound, genetic test, and pathological diagnosis were collected. The collected data were analyzed by univariate logistic analysis and multivariate logistic analysis. The risk factors were evaluated, and the predictive model was constructed of CLNM. Results: The multivariate logistic analysis showed that Age (p < 0.001), Gender (p < 0.001), Multifocality (p < 0.001), BRAF (p = 0.027), and Tumor size (p < 0.001) were associated with CLNM. The receiver operating characteristic curve (ROC curve) showed high efficiency with an area under the ROC (AUC) of 0.781 in the training group. The calibration curve and the calibration of the model were evaluated. The decision curve analysis (DCA) for the nomogram showed that the nomogram can provide benefits in this study. Conclusion: The predictive model of CLNM constructed and visualized based on the evaluated risk factors was confirmed to be a practical and convenient tool for clinicians to predict the CLNM in PTC.

Optimizing the Region for Evaluation of Global Gamma Analysis for Nasopharyngeal Cancer (NPC) Pretreatment IMRT QA by COMPASS: A Retrospective Study.

Background: The global gamma passing rate is the most commonly used metric for patient-specific pretreatment quality assurance in radiation therapy. However, the optimal region for evaluation and specific action limits (ALs) need to be explored. Therefore, this study was carried out to explore the optimal region for evaluation of the global gamma passing rate and define ALs by using the COMPASS software. Methods: A total of 93 intensity-modulated radiation therapy (IMRT) plans for nasopharyngeal cancer (NPC) patients, including 61 original plans and 32 multileaf collimator (MLC) error-introduced test plans, were selected for retrospective analysis. Firstly, the dose distribution was divided into six isodose regions ("≥10%", "≥20%", "≥30%", "≥40%", "≥50%", and "≥60%") based on the prescribed dose and one clinically oriented region for evaluation ("whole") to perform the three-dimensional (3D) global gamma reanalysis. Meanwhile, the percentage gamma passing rate (%GP), mean gamma index (µGI) based on 3%/2 mm criteria, and percentage dose error (%DE) of the dose-volume histogram (DVH) metrics were recorded by COMPASS application. Secondly, the Pearson's correlation coefficient was used to analyze the correlation between %GP and %DE and between µGI and %DE in different regions. Additionally, receiver operating characteristic (ROC) methodology was applied to quantify the fraction of patient-specific plans evaluated as "fail" and "pass". In order to improve the correlation between gamma analysis result and clinical criteria, ROC analysis was carried out in accordance with hybridization analysis criteria (%DE ≤3%, %GP ≥90% and %DE ≤3%, µGI ≤0.6). ROC was performed for two purposes: 1) to analyze the sensitivity and specificity of %GP and µGI in different regions for evaluation and 2) to define the ALs of %GP and µGI in the optimal region for evaluation. Finally, the plans introduced with MLC errors were prepared for validation. Moreover, we also compared the positive rate of ALs of both %GP and µGI in detecting MLC error-introduced plans in different regions. Results: 1) In our study, a number of DVH-based metrics were found to be correlated with the evaluation parameters. The corresponding number was 4, 2, 1, 1, 1, 1, and 3 in γwhole, γ10%, γ20%, γ30%, γ40%, γ50%, and γ60%, respectively, and 5, 3, 0, 1, 1, 4, and 2 in µGIwhole, µGI10%, µGI20%, µGI30%, µGI40%, µGI50%, and µGI60%, respectively. The results by COMPASS have revealed that the %DE of specific structures has a slightly higher correlation with both %GP and µGI of the "whole" region compared with that of any other region. However, it is a moderate correlation (0.5 ≤ |r| < 0.8). 2) The areas under the curves (AUCs) of γwhole, µGIwhole, µGI40%, µGI50%, and µGI60% were >0.7 based on 3%/2 mm criteria. According to the Youden coefficient, we defined the ALs of γwhole ≥92%, µGIwhole ≤0.36, µGI40% ≤0.43, and µGI60% ≤0.40 based on 3%/2 mm criteria. 3) In the validation, for original plans, the accuracy of ALγwhole, ALγ10%, ALµGIwhole, ALµGI40%, ALµGI50%, and ALµGI60% was 23%, 9.8%, 90%, 80.3%, 9.8%, and 88.5%, respectively. For test plans with systematic MLC errors smaller than 0.8 mm, the positive rates of ALγwhole, ALγ10%, ALµGIwhole, ALµGI40%, ALµGI50%, and ALµGI60% were 25%, 58%, 92%, 92%, 42%, and 100%, respectively. For the plans with systematic MLC errors higher than 0.8 mm, the positive rates of all AL%GP and ALµGI were 100%. From the COMPASS validation results, the accuracy of γwhole, µGIwhole, µGI40%, and µGI60% was higher than that of the conventional γ10% and commonly used µGI50%. Conclusions: Compared with the traditional evaluation region (i.e., the criteria with a threshold of 10% or a threshold of 50%, it was the same with the isodose regions of "≥10%", "≥50%" based on the prescribed dose in our study), the "whole" region is more meaningful to the clinic by COMPASS. The accuracy of µGIwhole is higher than that of the conventional γ10% and the commonly used µGI50%.

Assessment of Statistical Process Control Based DVH Action Levels for Systematic Multi-Leaf Collimator Errors in Cervical Cancer RapidArc Plans.

Background: In the patient-specific quality assurance (QA), DVH is a critical clinically relevant parameter that is finally used to determine the safety and effectiveness of radiotherapy. However, a consensus on DVH-based action levels has not been reached yet. The aim of this study is to explore reasonable DVH-based action levels and optimal DVH metrics in detecting systematic MLC errors for cervical cancer RapidArc plans. Methods: In this study, a total of 148 cervical cancer RapidArc plans were selected and measured with COMPASS 3D dosimetry system. Firstly, the patient-specific QA results of 110 RapidArc plans were retrospectively reviewed. Then, DVH-based action limits (AL) and tolerance limits (TL) were obtained by statistical process control. Secondly, systematic MLC errors were introduced in 20 RapidArc plans, generating 380 modified plans. Then, the dose difference (%DE) in DVH metrics between modified plans and original plans was extracted from measurement results. After that, the linear regression model was used to investigate the detection limits of DVH-based action levels between %DE and systematic MLC errors. Finally, a total of 180 test plans (including 162 error-introduced plans and 18 original plans) were prepared for validation. The error detection rate of DVH-based action levels was compared in different DVH metrics of 180 test plans. Results: A linear correlation was found between systematic MLC errors and %DE in all DVH metrics. Based on linear regression model, the systematic MLC errors between -0.94 mm and 0.88 mm could be caught by the TL of PTV95 ([-1.54%, 1.51%]), and the systematic MLC errors between -1.00 mm and 0.80 mm could also be caught by the TL of PTVmean ([-2.06%, 0.38%]). In the validation, for original plans, PTV95 showed the minimum error detection rate of 5.56%. For error-introduced plans with systematic MLC errors more than 1mm, PTVmean showed the maximum error detection rate of 88.89%, and then was followed by PTV95 (86.67%). All the TL of DVH metrics showed a poor error detection rate in identifying error-induced plans with systematic MLC errors less than 1mm. Conclusion: In 3D quality assurance of cervical cancer RapidArc plans, process-based tolerance limits showed greater advantages in distinguishing plans introduced with systematic MLC errors more than 1mm, and reasonable DVH-based action levels can be acquired through statistical process control. During DVH-based verification, main focus should be on the DVH metrics of target volume. OARs in low-dose regions were found to have a relatively higher dose sensitivity to smaller systematic MLC errors, but may be accompanied with higher false error detection rate.

A Case of CD5-Positive Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type Secondary to Chronic Lymphedema.

ABSTRACT: Primary cutaneous lymphoma occurring at the site of lymphedema is a rare complication. A total of 13 cases of primary cutaneous lymphoma associated with chronic lymphedema have been reported in international studies. We reported a case of cutaneous diffuse large B-cell lymphoma (DLBCL) (leg type) secondary to chronic lymphedema of the lower limbs. Histopathology showed hyperkeratosis of epidermis, acanthosis, and significant edema in the superficial dermis, with diffuse mononuclear infiltration in the dermis. Immunohistochemical studies revealed the expression of CD5, CD20, Pax-5, Bcl-2, Bcl-6, MUM-1, c-myc, and Ki-67. Therefore, the diagnosis of cutaneous DLBCL (leg type) was made. The study further confirmed the association between lymphoma and lymphedema. Especially, it showed CD5 expression. CD5-positive DLBCLs is a specific subgroup of DLBCLs, only approximately 10% of DLBCLs express CD5.

How to Build and Regenerate a Functional Skin Barrier: The Adhesive and Cell Shaping Travels of a Keratinocyte.

In this perspective, we focus on the skin epidermis and take you on a journey that highlights the adhesive- and cell shape‒changing adventures of a keratinocyte while it travels through the different layers of the epidermis, which is essential to make, maintain, and repair this barrier.

Mechanistic insights into the dearomative diborylation of pyrazines: a radical or non-radical process?

The mechanisms of the dearomative diborylation of pyrazines were investigated via a combination of density functional theory (DFT) calculations and experimental studies. DFT calculations revealed that a non-radical mechanism involving two successive [3,3]-σ-rearrangement-type processes is responsible for the diborylation of pyrazine with bis(pinacolato)diboron (B2pin2). However, this non-radical process is highly unfavorable for the diborylation reaction of sterically hindered pyrazine (2,3-dimethylpyrazine). For the diboration reaction of 2,3-dimethylpyrazine with B2pin2 in the presence of 2,6-dichloro-4,4'-bipyridine as the catalyst, 4,4'-bipyridine-mediated radical pathway proceeding through a B-B homolytic cleavage/boryl radical addition is preferred. Control experiments combined with kinetic studies provided supportive evidence for the proposed mechanism.

Cigarette smoke extract induces the Pseudomonas aeruginosa nfxC drug-resistant phenotype.

BACKGROUND: There is clinical and epidemiological evidence indicating that cigarette smoke exposure can significantly increase the usage of antibiotics by smokers to treat pulmonary infections, suggesting an increased risk of bacterial drug resistance. Pseudomonas aeruginosa is commonly found in infectious diseases closely related to cigarette smoke exposure and frequently acquires drug resistance. Recently, a study has demonstrated that cigarette smoke extract may induce Pseudomonas aeruginosa antibiotic resistance but the mechanism remain unknown. OBJECTIVES: To explore the effect of cigarette smoke exposure on drug resistance in P. aeruginosa and the underlying mechanism using an in vitro model of cigarette smoke extract (CSE) exposure. METHODS: P. aeruginosa strains PAO1, PA103 and ATCC27853 were used in this study. Changes in drug resistance in P. aeruginosa after CSE exposure were evaluated by antimicrobial susceptibility tests. Additionally, differentially expressed genes related to drug resistance were detected by transcriptome sequencing and qRT-PCR. RESULTS: CSE increased both the MIC and MBC of levofloxacin and imipenem (MIC was not changed in ATCC 27853) against P. aeruginosa. However, CSE could only increase the minimum inhibitory concentration of tigecycline and minocycline against P. aeruginosa. Transcriptome sequencing and qRT-PCR indicated that MvaT and OprD levels decreased and MexEF-OprN levels increased. CONCLUSIONS: Overall, our results showed that CSE may induce antibiotic resistance in P. aeruginosa. The results of antimicrobial susceptibility tests, transcriptome sequencing and qRT-PCR showed that CSE induced P. aeruginosa to the nfxC drug-resistant phenotype.

Hyperglycemia suppresses the regulatory effect of hypoxia-inducible factor-1α in pulmonary Aspergillus fumigatus infection.

Aspergillus fumigatus is one of the most common fungal infections involved in the pulmonary diseases. Hypoxia-inducible factor-1α (HIF-1α) is important for antifungal immunity. Diabetes is a risk factor of pulmonary A. fumigatus infection and could affect the expression of HIF-1α. The aim of this investigation was to evaluate the role of HIF-1α in pulmonary A. fumigatus infection in diabetes. In murine model, we found diabetic mice had aggravated pulmonary A. fumigatus infection and declined expression of HIF-1α following pulmonary A. fumigatus infection. And these changes could be corrected by dimethyloxalylglycine (DMOG), the agonist of HIF-1α. In cell experiment, after A. fumigatus stimulation, hyperglycemic state was with a decreased HIF-1α expression and increased NLRP3/IL-1ß signal pathway. The percentages of Th1 and Treg cells decreased, while percentages of Th2 and Th17 increased in hyperglycemic group. DMOG suppressed A. fumigatus-stimulated NLRP3 and IL-1ß expressions in hyperglycemic group and corrected Th and Treg cells differentiation. These regulatory effects of DMOG could be dampened by activating of NLRP3. These data indicated that hyperglycemia suppressed the regulatory effect of HIF-1α in pulmonary A. fumigatus infection, which can affect Th and Treg cells differentiation by regulating the NLRP3/IL-1ß signal pathway.

EGFR and Ras regulate DDX59 during lung cancer development.

Oncogenes EGFR and ras are frequently mutated and activated in human lung cancers. In this report, we found that both EGFR and Ras signaling can upregulate RNA helicase DDX59 in lung cancer cells. DDX59 can be induced through the mitogen activated protein kinase (MAPK) pathway after EGFR or Ras activation. Inhibitors for Ras/Raf/MAP pathway significantly decreased DDX59 expression at both protein and mRNA levels. Through immunohistochemistry, we found that DDX59 protein expression correlated with Ras and EGFR mutation status in human lung adenocarcinoma. Finally, through a xenograft nude mice model, we demonstrated that DDX59 is pivotal for EGFR mutated lung cancer cell growth in vivo. Our study identified a novel protein downstream of Ras and EGFR, which may serve as a potential therapeutic drug target for lung cancer patients.

A microvolume molecularly imprinted polymer modified fiber-optic evanescent wave sensor for bisphenol A determination.

A fiber-optic evanescent wave sensor for bisphenol A (BPA) determination based on a molecularly imprinted polymer (MIP)-modified fiber column was developed. MIP film immobilized with BPA was synthesized on the fiber column, and the sensor was then constructed by inserting the optical fiber prepared into a transparent capillary. A microchannel (about 2.0 µL) formed between the fiber and the capillary acted as a flow cell. BPA can be selectively adsorbed online by the MIP film and excited to produce fluorescence by the evanescent wave produced on the fiber core surface. The conditions for BPA enrichment, elution, and fluorescence detection are discussed in detail. The analytical measurements were made at 276 nm/306 nm (λ(ex)/λ(em)), and linearity of 3 × 10(-9)-5 × 10(-6) g mL(-1) BPA, a limit of detection of 1.7 × 10(-9) g mL(-1) BPA (3σ), and a relative standard deviation of 2.4% (n = 5) were obtained. The sensor selectivity and MIP binding measurement were also evaluated. The results indicated that the selectivity and sensitivity of the proposed fiber-optic sensor could be greatly improved by using MIP as a recognition and enrichment element. Further, by modification of the sensing and detection elements on the optical fiber, the proposed sensor showed the advantages of easy fabrication and low cost. The novel sensor configuration provided a platform for monitoring other species by simply changing the light source and sensing elements. The sensor presented has been successfully applied to determine BPA released from plastic products treated at different temperatures.