Recent advances of NFATc1 in rheumatoid arthritis-related bone destruction: mechanisms and potential therapeutic targets.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by inflammation of the synovial tissue and joint bone destruction, often leading to significant disability. The main pathological manifestation of joint deformity in RA patients is bone destruction, which occurs due to the differentiation and proliferation of osteoclasts. The transcription factor nuclear factor-activated T cell 1 (NFATc1) plays a crucial role in this process. The regulation of NFATc1 in osteoclast differentiation is influenced by three main factors. Firstly, NFATc1 is activated through the upstream nuclear factor kappa-B ligand (RANKL)/RANK signaling pathway. Secondly, the Ca2+-related co-stimulatory signaling pathway amplifies NFATc1 activity. Finally, negative regulation of NFATc1 occurs through the action of cytokines such as B-cell Lymphoma 6 (Bcl-6), interferon regulatory factor 8 (IRF8), MAF basic leucine zipper transcription factor B (MafB), and LIM homeobox 2 (Lhx2). These three phases collectively govern NFATc1 transcription and subsequently affect the expression of downstream target genes including TRAF6 and NF-κB. Ultimately, this intricate regulatory network mediates osteoclast differentiation, fusion, and the degradation of both organic and inorganic components of the bone matrix. This review provides a comprehensive summary of recent advances in understanding the mechanism of NFATc1 in the context of RA-related bone destruction and discusses potential therapeutic agents that target NFATc1, with the aim of offering valuable insights for future research in the field of RA. To assess their potential as therapeutic agents for RA, we conducted a drug-like analysis of potential drugs with precise structures.

Predictive Analysis in Oral Cancer Immunotherapy: Profiling Dual PD-L1-Positive Extracellular Vesicle Subtypes with Step-Wedge Microfluidic Chips.

PD-L1-positive extracellular vesicles (PD-L1+ EVs) play a pivotal role as predictive biomarkers in cancer immunotherapy. These vesicles, originating from immune cells (I-PD-L1+ EVs) and tumor cells (T-PD-L1+ EVs), hold distinct clinical predictive values, emphasizing the importance of deeply differentiating the PD-L1+ EV subtypes for effective liquid biopsy analyses. However, current methods such as ELISA lack the ability to differentiate their cellular sources. In this study, a novel step-wedge microfluidic chip that combines magnetic microsphere separation with single-layer fluorescence counting is developed. This chip integrates magnetic microspheres modified with anti-PD-L1 antibodies and fluorescent nanoparticles targeting EpCAM (tumor cell marker) or CD45 (immunocyte marker), enabling simultaneous quantification and sensitive analysis of PD-L1+ EV subpopulations in oral squamous cell carcinoma (OSCC) patients' saliva without background interference. Analysis results indicate reduced levels of I-PD-L1+ EVs in OSCC patients compared to those in healthy individuals, with varying levels of heterogeneous PD-L1+ EVs observed among different patient groups. During immunotherapy, responders exhibit decreased levels of total PD-L1+ EVs and T-PD-L1+ EVs, accompanied by reduced levels of I-PD-L1+ EVs. Conversely, nonresponders show increased levels of I-PD-L1+ EVs. Utilizing the step-wedge microfluidic chip allows for simultaneous detection of PD-L1+ EV subtypes, facilitating the precise prediction of oral cancer immunotherapy outcomes.

Miniaturized guided-mode resonance laser based on a one-dimensional finite heterostructure cavity.

Lasers based on the resonant nanostructures have attracted much attention due to their low threshold and compact dimensions. Guided-mode resonance (GMR) structures have been studied in lasing configurations because of their optical field enhancement and convenient free space excitation. However, the GMR inherently requires a larger footprint and is not suitable for high-density packaging. Here, we present numerical evidence of a miniaturized laser implemented in a one-dimensional finite heterostructure cavity (FHC). A GMR resonator and distributed Bragg reflectors are integrated to create the FHC, which enables the efficient coupling and localization of the electric field. Numerical findings indicate that the threshold is approximately 22.5 µJ/cm2, while the emission region is confined within a length of 5.4 µm. In addition, by adjusting the coupling strength, it is capable to achieve controllable lasing emission. The proposed structure provides a compact source for high-capacity optical communications, sensing, and quantum information processing.

Miniaturized quasi-BICs based on a two-dimensional heterostructure to realize a low-threshold nanolaser.

Bound states in the continuum (BICs) have been demonstrated as an effective mechanism to achieve high quality (Q)-factor cavities for nanolasers. However, the development of a compact BIC laser with a low threshold has remained elusive. Here, we numerically report lasing action from symmetry-protected BICs in a two-dimensional heterostructure, which consists of compound gratings with finite cells surrounded by orthogonal distributed Bragg reflectors (DBRs). The compound grating is used to excite quasi-BIC resonance with a high Q-factor, and DBRs enable light confinement and localized electric fields to enhance light-matter interaction. The nanolaser with a threshold of 16.8 µJ/cm2 is achieved within a footprint as small as 3.35 × 3.35 µm2. By changing the phase adjusting gap or asymmetry degree, it is possible to control the lasing emission. This work reveals a new, to our knowledge, path toward compact BIC lasers with a simple scheme for applications that require a small footprint and low threshold.

Construction of Functionalized Oxindoles by Quinone-Carbonate Synergistically Triggered Intermolecular Radical Coupling.

We disclose a rapid and nontoxic procedure to construct various oxindoles. This method harnesses the power of a catalytic amount of quinone in synergy with Cs2CO3, showcasing remarkable compatibility with a wide range of functional groups. Mechanistic investigations reveal that it operates via a radical pathway, likely initiated by the single-electron transfer from quinone-Cs2CO3 complexes. This pivotal electron transfer event leads to the generation of a crucial alkyl radical intermediate, contributing to the overall success and efficacy of the transformation.

Repair-driven DNA tetrahedral nanomachine combined with DNAzyme for 8-oxo guanine DNA glycosylase activity assay, drug screening and intracellular imaging.

8-oxo guanine DNA glycosylase (8-oxoG DNA glycosylase), a crucial DNA repair enzyme, is essential for maintaining genome integrity and preventing diseases caused by DNA oxidative damage. Imaging 8-oxoG DNA glycosylase in living cells requires a dependable technique. In this study, we designed a DNAzyme-modified DNA tetrahedral nanomachine (DTDN) powered by 8-oxoG restoration. Incorporating a molecular beacon probe (MB), the constructed platform was used for amplified in situ monitoring of 8-oxoG DNA glycosylase. Under normal conditions, duplexing with a complementary strand modified with two 8-oxoG sites inhibited the activity of DNAzyme. The restoration of DNAzyme activity by the repair of intracellular 8-oxoG DNA glycosylase on 8-oxoG bases can initiate a signal amplification reaction. This detection system can detect 8-oxoG DNA glycosylase activity linearly between 0 and 20 U mL-1, with a detection limit as low as 0.52 U mL-1. Using this method, we were able to screen 14 natural compounds and identify 6 of them as 8-oxoG DNA glycosylase inhibitors. In addition, a novel approach was utilized to assess the activity of 8-oxoG DNA glycosylase in living cells. In conclusion, this method provides a universal tool for monitoring the activity of 8-oxoG DNA glycosylase in vitro and in living cells, which holds great promise for elucidating the enzyme's functionality and facilitating drug screening endeavors.

Inhibiting the Otub1/phosphorylated STAT3 axis for the treatment of non-small cell lung cancer.

The transcription factor STAT3 is a promising target for the treatment of non-small cell lung cancer (NSCLC). STAT3 activity is mainly dependent on phosphorylation at tyrosine 705 (pSTAT3-Y705), but the modulation on pSTAT3-Y705 is elusive. By screening a library of deubiquitinases (Dubs), we found that the Otub1 increases STAT3 transcriptional activity. As a Dub, Otub1 binds to pSTAT3-Y705 and specifically abolishes its K48-linked ubiquitination, therefore preventing its degradation and promoting NSCLC cell survival. The Otub1/pSTAT3-Y705 axis could be a potential target for the treatment of NSCLC. To explore this concept, we screen libraries of FDA-approved drugs and natural products based on STAT3-recognition element-driven luciferase assay, from which crizotinib is found to block pSTAT3-Y705 deubiquitination and promotes its degradation. Different from its known action to induce ALK positive NSCLC cell apoptosis, crizotinib suppresses ALK-intact NSCLC cell proliferation and colony formation but not apoptosis. Furthermore, crizotinib also suppresses NSCLC xenograft growth in mice. Taken together, these findings identify Otub1 as the first deubiquitinase of pSTAT3-Y705 and provide that the Otub1/pSTAT3-Y705 axis is a promising target for the treatment of NSCLC.

G protein-coupled receptor kinase 2 as a novel therapeutic target for gland fibrosis of Sjögren's syndrome.

Sjogren's syndrome (SS) is a chronic, progressive autoimmune disorder characterized by gland fibrosis. We previously found a close correlation between gland fibrosis and the expression of G protein-coupled receptor kinase 2 (GRK2). In this study we explored the pathological and therapeutic significance of GRK2 in SS. Submandibular gland (SMG) antigen-induced SS mouse model was established in WT and GRK2+/- mice. We showed that the expression levels of GRK2 were significantly up-regulated in glandular tissue and positively correlated with fibrotic morphology in SS patients and mice. Hemizygous knockout of GRK2 significantly inhibited the gland fibrosis. In mouse salivary gland epithelial cells (SGECs), we demonstrated that GRK2 interacted with Smad2/3 to positively regulate the activation of TGF-ß-Smad signaling with a TGF-ß-GRK2 positive feedback loop contributing to gland fibrosis. Hemizygous knockout of GRK2 attenuated TGF-ß-induced collagen I production in SGECs in vitro and hindered gland fibrosis in murine SS though preventing Smad2/3 nuclear translocation. Around 28 days post immunization with SMG antigen, WT SS mice were treated with a specific GRK2 inhibitor paroxetine (Par, 5 mg·kg-1·d-1, i.g. for 19 days). We found that Par administration significantly attenuated gland fibrosis and alleviated the progression of SS in mice. We conclude that genetic knockdown or pharmacological inhibition of GRK2 significantly attenuates gland fibrosis and alleviates the progression of SS. GRK2 binds to Smad2/3 and positively regulates the activation of TGF-ß-Smad signaling. A TGF-ß-GRK2 positive feedback loop contributes to gland fibrosis. Our research points out that GRK2 could be a promising therapeutic target for treating SS.

Assessment of Endoscopy-Based Scoring Systems for Prognostication in Ulcerative Colitis: A Comparative Analysis.

BACKGROUND AND OBJECTIVE: Endoscopy-based scoring systems, including Mayo Endoscopic Score (MES), Modified Mayo Endoscopic Score (MMES), and Degree of Ulcerative Colitis Burden of Luminal Inflammation (DUBLIN) Score, have been introduced to evaluate UC prognosis. This study aims to compare their predictive capacity for clinical outcomes in UC patients. METHODS: Consecutive UC patients from a tertiary hospital were included. The primary outcome was acute severe ulcerative colitis (ASUC), and secondary outcomes were UC-related admission, medication treatment escalation, disease extension and surgery. Predictive performance was assessed using receiver operating characteristic (ROC) curves. RESULTS: Among 300 patients, 15.3% developed ASUC. Robust correlations were observed among the three scoring systems and were with elevated serum inflammatory markers. The DUBLIN score exhibited superior predictive ability for UC-related admission (AUC 0.751; 95%CI 0.698-0.799) and medication treatment escalation (AUC 0.735; 95% CI 0.681-0.784). No statistical differences were found among three scoring systems for predicting ASUC, disease extension, and surgery. Employing respective cut-offs of 2, 11.25, and 3, higher MES (HR = 3.859, 95% CI 1.636-9.107, p = 0.002), MMES (HR = 3.352, 95% CI 1.879-5.980, p < 0.001), and DUBLIN score (HR = 5.619, 95% CI 2.378-13.277, p < 0.001) were associated with an increased risk of developing ASUC. CONCLUSION: The DUBLIN score, assessing the overall inflammatory burden of the intestinal tract, outperforms the MMES in predicting admission and medication treatment escalation related to UC. Its integration into clinical practice has the potential to enhance risk stratification for patients with UC.

Association between dietary retinol intake and rheumatoid arthritis based on NHANES database.

OBJECTIVE: This study focused on the investigation of the correlation between dietary retinol intake and rheumatoid arthritis (RA) using the National Health and Nutrition Examination Survey (NHANES) database. METHODS: Data from five NHANES cycles from 2003 to 2012 were utilized for this study. Dietary retinol intake was considered as the independent variable, and RA was the dependent variable. A weighted logistic regression method was applied to construct the relational model of the two variables. Stratified analysis without adjusting for confounding factors and subgroup analysis with confounding factors adjusted were conducted to explore the association between dietary retinol intake and RA. The optimal intake of dietary retinol was determined by the restricted cubic splines (RCS) analysis. RESULTS: 22,971 samples were included in this study. The weighted logistic regression model was employed to construct the relational model of dietary retinol intake and RA (OR: 0.95, 95% CI: 0.91-0.99, p = 0.019). Stratified analysis displayed a great influence on the relational model exerted by the interaction between gender and retinol intake (p for interaction = 0.014). A significant association between retinol intake and RA was also indicated in the model adjusted for demographic characteristics (OR: 0.95, 95% CI: 0.90-1.00, p = 0.029). Subgroup analysis by gender showed that in the female population, unadjusted model (OR: 0.90, 95% CI: 0.84-0.96, p = 0.002), model adjusted for demographic characteristics only (OR: 0.89, 95% CI: 0.83-0.96, p = 0.002), and model adjusted for all confounding factors (OR: 0.91, 95% CI: 0.85-0.99, p = 0.019) indicated dietary retinol intake as a protective factor against RA. RCS analysis demonstrated that in the female population, regardless of the model used (Crude, Model I, and Model II), an intake of dietary retinol > 354.86 mcg was associated with RA disease reduction (OR < 1.0, p-non-linear < 0.05, p-overall < 0.05). CONCLUSION: Increased dietary retinol intake was associated with RA disease reduction, particularly in the female population. Women are recommended to increase their dietary retinol intake (> 354.86 mcg) to reduce the risk of RA.

The Minhang Pediatric Biobank cohort study: protocol overview and baseline characteristics.

BACKGROUND: Little has been done to establish biobanks for studying the environment and lifestyle risk factors for diseases among the school-age children. The Minhang Pediatric Biobank (MPB) cohort study aims to identify factors associated with health and diseases of school-aged children living in the urban or suburban area of Shanghai. METHODS: This population-based cohort study was started in all sub-districts/towns of Minhang district of Shanghai in 2014. First-grade students in elementary school were enrolled during the time of their routine physical examinations, with self-administered questionnaires completed by their primary caregivers. Additional information was extracted from multiple health information systems. Urine and saliva samples were collected during the baseline survey and follow-up visits. RESULTS: At the end of 2014 academic year, a total number of 8412 children and their parents were recruited, including 4339 boys and 4073 girls. All the participants completed the baseline survey and physical examination, and 7128 urine and 2767 saliva samples were collected. The five most prevalent childhood diseases in this population were dental caries, bronchitis, pneumonia, asthma and overweight/obese. CONCLUSIONS: The MPB cohort has been successfully established, serving as a useful platform for future research relating to the genetic, environmental and lifestyle risk factors for childhood diseases.

[Mechanism of Huangqin Qingre Chubi Capsules in improving rheumatoid arthritis based on METTL3-SFRP4/Wnt/ß-catenin pathway].

The effect and mechanism of Huangqin Qingre Chubi Capsules(HQC) on rheumatoid arthritis(RA) were studied.Seventy male SPF rats were randomly divided into normal group, model group, low-(0. 18 g·kg~(-1)), middle-(0. 36 g·kg~(-1)), and high-(0. 72 g·kg~(-1)) dose groups of HQC, methotrexate group(MTX, 0. 75 mg·kg~(-1)), and negative control group(NC group, model +saline). Adjuvant arthritis fibroblast-like synoviocytes(AA-FLS) were divided into normal group, model group, low-, middle-, and high-dose groups of HQC, and negative control group. RT-qPCR and Western blot were used to detect the m RNA and protein expressions of METTL3, SFRP4, ß-catenin, CCND1, c-Myc, MMP3, and fibronectin. The protein expression of MMP3 and ß-catenin was detected by immunofluorescence. The gene expression level of METTL3 on AA-FLS was knocked down to further examine the expression of each gene. ELISA measured the levels of IL-1ß, IL-6, and IL-8. The results showed that compared with the normal group, rats in the model group found redness and swelling in their limbs and significantly increased joint swelling. Compared with the model group, the joint swelling degree of each treatment group significantly decreased(P<0. 05). The paw retraction threshold and body weight mass index both significantly increased(P<0. 05). METTL3 was highly expressed on AA and negatively correlated with the expression of SFRP4. After treatment, the m RNA and protein expression of METTL3, ß-catenin, CCND1, c-Myc, fibronectin, and MMP3 were significantly decreased on AA-FLS(P< 0. 05). Compared with the model group, knocking down METTL3 resulted in reduced m RNA and protein expression of ß-catenin, CCND1, c-Myc, fibronectin, and MMP3(P< 0. 05). At the same time, the m RNA and protein expressions of ß-catenin, CCND1, c-Myc, fibronectin, and MMP3 in the HQC+METTL3 knockdown group were significantly lower than those in the METTL3 knockdown group(P<0. 05). HQC could reduce the levels of IL-1ß, IL-6, and IL-8 to varying degrees(P<0. 05). The results indicate that HQC has a significant improvement effect on arthritis in AA rats. The expression of METTL3 is significantly increased in synovial tissue and AA-FLS of AA rats, which may be a potential target for the diagnosis and treatment of RA. HQC improves RA through the METTL3-SFRP4/Wnt/ß-catenin signaling pathway and has significant antiinflammatory and anti-rheumatic effects.

Immunosuppressive effect of small extracellular vesicle PD-L1 is restricted by co-expression of CD80.

BACKGROUND: The PD-L1 on tumor cell-derived small extracellular vesicles (sEVs) can suppress the proliferation and cytokine production of T cells. However, PD-L1 can also be expressed by non-tumor cells. The present study is designed to test whether immunocytes release immunosuppressive PD-L1-positive sEVs. METHODS: sEVs were isolated from different clinical samples of head and neck squamous cell carcinoma (HNSCC) patients, the level and cellular origins of PD-L1-positive sEVs were assessed. Co-expression of CD80 on PD-L1-positive sEVs was examined to evaluate the immunosuppressive and tumor-promotive effects. RESULTS: PD-L1-positive sEVs in HNSCC patients had various cellular origins, including tumor cell, T cell, B cell, dendritic cell and monocyte/macrophage. However, PD-L1-positive sEVs derived from immune cells did not exert immunosuppressive functions due to the co-expression of CD80. It was verified that co-expression of CD80 disrupted the binding of sEV PD-L1 to its receptor PD-1 on T cells and attenuated the immunosuppression mediated by sEV PD-L1 both in vitro and in vivo. CONCLUSION: The study suggests that PD-L1-positive sEVs have the cellular origin and functional heterogeneity. Co-expression of CD80 could restrict the immunosuppressive effect of sEV PD-L1. A greater understanding of PD-L1-positive sEV subsets is required to further improve their clinical application.

Metabolomics reveals arbuscular mycorrhizal fungi-mediated tolerance of walnut to soil drought.

BACKGROUND: Arbuscular mycorrhizal fungi (AMF) have a positive effect on drought tolerance of plants after establishing reciprocal resymbiosis with roots, while the underlying mechanism is not deciphered. Metabolomics can explain the mechanism of plant response to environmental stress by analyzing the changes of all small molecular weight metabolites. The purpose of this study was to use Ultra High Performance Liquid Chromatography Q Exactive Mass Spectrometer to analyze changes in root metabolites of walnut (Juglans regia) after inoculation with an arbuscular mycorrhizal fungus Diversispora spurca under well-watered (WW) and drought stress (DS). RESULTS: Sixty days of soil drought significantly inhibited root mycorrhizal colonization rate, shoot and root biomass production, and leaf water potential in walnut, while AMF inoculation significantly increased biomass production and leaf water potential, accompanied by a higher increase magnitude under DS versus under WW. A total of 3278 metabolites were identified. Under WW, AMF inoculation up-regulated 172 metabolites and down-regulated 61 metabolites, along with no changes in 1104 metabolites. However, under DS, AMF inoculation up-regulated 49 metabolites and down-regulated 116 metabolites, coupled with no changes in 1172 metabolites. Among them, juglone (a quinone found in walnuts) as the first ranked differential metabolite was up-regulated by AMF under WW but not under DS; 2,3,5-trihydroxy-5-7-dimethoxyflavanone as the first ranked differential metabolite was increased by AMF under DS but not under WW. The KEGG annotation showed a large number of metabolic pathways triggered by AMF, accompanied by different metabolic pathways under WW and DS. Among them, oxidative phosphorylation and phenylalanine metabolism and biosynthesis were triggered by AMF in response to WW and DS, where N-acetyl-L-phenylalanine was induced by AMF to increase under DS, while decreasing under WW. CONCLUSION: This study provides new insights into the metabolic mechanisms of mycorrhiza-enhanced drought tolerance in walnuts.

Blockage of PHLPP1 protects against myocardial ischemia/reperfusion injury in diabetic mice via activation of STAT3 signaling.

Diabetes can exacerbate myocardial ischemia/reperfusion (IR) injury. However, the sensitivity to IR injury and the underlying mechanisms in diabetic hearts remain unclear. Inhibition of PH domain leucine-rich repeating protein phosphatase (PHLPP1) could reduce myocardial IR injury, our previous study demonstrated that the expression of PHLPP1 was upregulated in diabetic myocardial IR model. Thus, this study aimed to investigate the mechanism of PHLPP1 in diabetic myocardial IR injury. Nondiabetic and diabetic C57BL/6 mice underwent 45 min of coronary artery occlusion followed by 2 h of reperfusion. Male C57BL/6 mice were injected with streptozotocin for five consecutive days to establish a diabetes model. H9c2 cells were exposed to normal or high glucose and subjected to 4 h of hypoxia followed by 4 h of reoxygenation. Diabetes or hyperglycemia increased postischemic infarct size, cellular injury, release of creatine kinase-MB, apoptosis, and oxidative stress, while exacerbating mitochondrial dysfunction. This was accompanied by enhanced expression of PHLPP1 and decreased levels of p-STAT3 and p-Akt. These effects were counteracted by PHLPP1 knockdown. Moreover, PHLPP1 knockdown resulted in an increase in mitochondrial translocation of p-STAT3 Ser727 and nuclear translocation of p-STAT3 Tyr705 and p-STAT3 Ser727. However, the effect of PHLPP1 knockdown in reducing posthypoxic cellular damage was nullified by either Stattic or LY294002. Additionally, a co-immunoprecipitation assay indicated a direct interaction between PHLPP1 and p-STAT3 Ser727, but not p-STAT3 Tyr705. The abnormal expression of PHLPP1 plays a significant role in exacerbating myocardial IR injury in diabetic mice. Knockdown of PHLPP1 to activate the STAT3 signaling pathway may represent a novel strategy for alleviating myocardial IR injury in diabetes.

A New Pipeline for Removing Paralogs in Target Enrichment Data.

Target enrichment (such as Hyb-Seq) is a well-established high throughput sequencing method that has been increasingly used for phylogenomic studies. Unfortunately, current widely used pipelines for analysis of target enrichment data do not have a vigorous procedure to remove paralogs in target enrichment data. In this study, we develop a pipeline we call Putative Paralogs Detection (PPD) to better address putative paralogs from enrichment data. The new pipeline is an add-on to the existing HybPiper pipeline, and the entire pipeline applies criteria in both sequence similarity and heterozygous sites at each locus in the identification of paralogs. Users may adjust the thresholds of sequence identity and heterozygous sites to identify and remove paralogs according to the level of phylogenetic divergence of their group of interest. The new pipeline also removes highly polymorphic sites attributed to errors in sequence assembly and gappy regions in the alignment. We demonstrated the value of the new pipeline using empirical data generated from Hyb-Seq and the Angiosperms353 kit for two woody genera Castanea (Fagaceae, Fagales) and Hamamelis (Hamamelidaceae, Saxifragales). Comparisons of data sets showed that the PPD identified many more putative paralogs than the popular method HybPiper. Comparisons of tree topologies and divergence times showed evident differences between data from HybPiper and data from our new PPD pipeline. We further evaluated the accuracy and error rates of PPD by BLAST mapping of putative paralogous and orthologous sequences to a reference genome sequence of Castanea mollissima. Compared to HybPiper alone, PPD identified substantially more paralogous gene sequences that mapped to multiple regions of the reference genome (31 genes for PPD compared with 4 genes for HybPiper alone). In conjunction with HybPiper, paralogous genes identified by both pipelines can be removed resulting in the construction of more robust orthologous gene data sets for phylogenomic and divergence time analyses. Our study demonstrates the value of Hyb-Seq with data derived from the Angiosperms353 probe set for elucidating species relationships within a genus, and argues for the importance of additional steps to filter paralogous genes and poorly aligned regions (e.g., as occur through assembly errors), such as our new PPD pipeline described in this study. [Angiosperms353; Castanea; divergence time; Hamamelis; Hyb-Seq, paralogs, phylogenomics.].

Resistin-like molecules: a marker, mediator and therapeutic target for multiple diseases.

Resistin-like molecules (RELMs) are highly cysteine-rich proteins, including RELMα, RELMß, Resistin, and RELMγ. However, RELMs exhibit significant differences in structure, distribution, and function. The expression of RELMs is regulated by various signaling molecules, such as IL-4, IL-13, and their receptors. In addition, RELMs can mediate numerous signaling pathways, including HMGB1/RAGE, IL-4/IL-4Rα, PI3K/Akt/mTOR signaling pathways, and so on. RELMs proteins are involved in wide range of physiological and pathological processes, including inflammatory response, cell proliferation, glucose metabolism, barrier defense, etc., and participate in the progression of numerous diseases such as lung diseases, intestinal diseases, cardiovascular diseases, and cancers. Meanwhile, RELMs can serve as biomarkers, risk predictors, and therapeutic targets for these diseases. An in-depth understanding of the role of RELMs may provide novel targets or strategies for the treatment and prevention of related diseases. Video abstract.

An updated phylogeny, biogeography, and PhyloCode-based classification of Cornaceae based on three sets of genomic data.

PREMISE: A major goal of systematic biology is to uncover the evolutionary history of organisms and translate that knowledge into stable classification systems. Here, we integrate three sets of genome-wide data to resolve phylogenetic relationships in Cornaceae (containing only Cornus s.l.), reconstruct the biogeographic history of the clade, and provide a revised classification using the PhyloCode to stabilize names for this taxonomically controversial group. METHODS: We conducted phylogenetic analyses using 312 single-copy nuclear genes and 70 plastid genes from Angiosperms353 Hyb-Seq, plus numerous loci from RAD-Seq. We integrated fossils using morphological data and produced a dated phylogeny for biogeographical analysis. RESULTS: A well-resolved, strongly supported, comprehensive phylogeny was obtained. Biogeographic analyses support an origin and rapid diversification of Cornus into four morphologically distinct major clades in the Northern Hemisphere (with an eastern Asian ancestor) during the late Cretaceous. Dispersal into Africa from eastern Asia likely occurred along the Tethys Seaway during the Paleogene, whereas dispersal into South America likely occurred during the Neogene. Diversification within the northern hemisphere likely involved repeated independent colonization of new areas during the Paleogene and Neogene along the Bering Land Bridge, the North Atlantic Land Bridge, and the Tethys Seaway. Thirteen strongly supported clades were named following rules of the PhyloCode. CONCLUSIONS: Our study provides an example of integrating genomic and morphological data to produce a robust, explicit species phylogeny that includes fossil taxa, which we translate into an updated classification scheme using the PhyloCode to stabilize names.

Hyperglycemia-Induced Overexpression of PH Domain Leucine-Rich Repeat Protein Phosphatase 1 (PHLPP1) Compromises the Cardioprotective Effect of Ischemic Postconditioning Via Modulation of the Akt/Mst1 Pathway Signaling.

PURPOSE: Ischemic postconditioning (IPostC) alleviates myocardial ischemia/reperfusion (IR) injury, but the protective effect is lost during diabetes. PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1) is able to inactivate Akt. Our previous study found that PHLPP1 expression was upregulated in diabetic hearts. We presumed that the attenuation of myocardial injury by IPostC might be hindered by PHLPP1 overexpression in diabetic animals. METHODS AND RESULTS: Nondiabetic and diabetic mice were subjected to 45 min of ischemia followed by 2 h of reperfusion with or without IPostC. H9c2 cells were exposed to normal or high glucose and were subjected to 4 h of hypoxia followed by 4 h of reoxygenation with or without hypoxic postconditioning (HPostC). IPostC attenuated postischemic infarction, apoptosis, creatine kinase-MB, and oxidative stress, which were accompanied by increased p-Akt and decreased PHLPP1 expression and p-Mst1 in nondiabetic but not in diabetic mice. PHLPP1 knockdown or an Mst1 inhibitor reduced hypoxia/reoxygenation (HR)-induced cardiomyocyte damage in H9c2 cells exposed to normal glucose, but the effect was abolished by a PI3K/Akt inhibitor. HPostC attenuated HR-induced cardiomyocyte injury and oxidative stress accompanied by increased p-Akt as well as decreased PHLPP1 expression and p-Mst1 in H9c2 cells exposed to normal glucose but not high glucose. In addition, HPostC in combination with PHLPP1 knockdown or PHLPP1 knockdown alone reduced cell death and oxidative stress in H9c2 cells exposed to high glucose, which was hindered by PI3K/Akt inhibitor. CONCLUSION: IPostC prevented myocardial IR injury partly through PHLPP1/Akt/Mst1 signaling, and abnormalities in this pathway may be responsible for the loss of IPostC cardioprotection in diabetes.

Chronic ß-adrenergic stress contributes to cardiomyopathy in rodents with collagen-induced arthritis.

Patients with rheumatoid arthritis (RA) have a much higher incidence of cardiac dysfunction, which contributes to the high mortality rate of RA despite anti-arthritic drug therapy. In this study, we investigated dynamic changes in cardiac function in classic animal models of RA and examined the potential effectors of RA-induced heart failure (HF). Collagen-induced arthritis (CIA) models were established in rats and mice. The cardiac function of CIA animals was dynamically monitored using echocardiography and haemodynamics. We showed that cardiac diastolic and systolic dysfunction occurred in CIA animals and persisted after joint inflammation and that serum proinflammatory cytokine (IL-1ß, TNF-α) levels were decreased. We did not find evidence of atherosclerosis (AS) in arthritic animals even though cardiomyopathy was significant. We observed that an impaired cardiac ß1AR-excitation contraction coupling signal was accompanied by sustained increases in blood epinephrine levels in CIA rats. Furthermore, serum epinephrine concentrations were positively correlated with the heart failure biomarker NT-proBNP in RA patients (r2 = +0.53, P < 0.0001). In CIA mice, treatment with the nonselective ßAR blocker carvedilol (2.5 mg·kg-1·d-1, for 4 weeks) or the specific GRK2 inhibitor paroxetine (2.5 mg·kg-1·d-1, for 4 weeks) effectively rescued heart function. We conclude that chronic and persistent ß-adrenergic stress in CIA animals is a significant contributor to cardiomyopathy, which may be a potential target for protecting RA patients against HF.