Complexity in physiological outputs is believed to be a hallmark of healthy physiological control. How to accurately quantify the degree of complexity in physiological signals with outliers remains a major barrier for translating this novel concept of nonlinear dynamic theory to clinical practice. Here we propose a new approach to estimate the complexity in a signal by analyzing the irregularity of the sign time series of its coarse-grained time series at different time scales. Using surrogate data, we show that the method can reliably assess the complexity in noisy data while being highly resilient to outliers. We further apply this method to the analysis of human heartbeat recordings. Without removing any outliers due to ectopic beats, the method is able to detect a degradation of cardiac control in patients with congestive heart failure and a more degradation in critically ill patients whose life continuation relies on extracorporeal membrane oxygenator (ECMO). Moreover, the derived complexity measures can predict the mortality of ECMO patients. These results indicate that the proposed method may serve as a promising tool for monitoring cardiac function of patients in clinical settings.

Follistatin (FST) performs several vital functions in the cells, including protection from apoptosis during stress. The expression of FST is up-regulated in response to glucose deprivation by an unknown mechanism. We herein showed that the induction of FST by glucose deprivation was due to an increase in the half-life of its mRNA. We further identified an AU-rich element (ARE) in the 3'UTR of FST mRNA that mediated its decay. The expression of FST was elevated after knocking down AUF1 and reduced when AUF1 was further expressed. In vitro binding assays and RNA pull-down assays revealed that AUF1 interacted with FST mRNA directly via its ARE. During glucose deprivation, a majority of AUF1 shuttled from cytoplasm to nucleus, resulting in dissociation of AUF1 from FST mRNA and thus stabilization of FST mRNA. Finally, knockdown of AUF1 decreased whereas overexpression of AUF1 increased glucose deprivation-induced apoptosis. The apoptosis promoting effect of AUF1 was eliminated in FST expressing cells. Collectively, this study provided evidence that AUF1 is a negative regulator of FST expression and participates in the regulation of cell survival under glucose deprivation.

Gemcitabine-based chemotherapy remains one of the standards in management of metastatic breast cancer. However, intrinsic and acquired resistance to gemcitabine inevitably occurs. The aims of this study were to assess the efficacy of the combination of src inhibition and gemcitabine in gemcitabine-resistant breast cancer cells.

The Rearranged during transfection (RET) fusion gene is a newly identified oncogenic mutation in non-small cell lung cancer (NSCLC). The aim of this study is to explore the biological functions of the gene in tumorigenesis and metastasis in RET gene fusion-driven preclinical models. We also investigate the anti-tumor activity of Apatinib, a potent inhibitor of VEGFR-2, PDGFR-β, c-Src and RET, in RET-rearranged lung adenocarcinoma, together with the mechanisms underlying. Our results suggested that KIF5B-RET fusion gene promoted cell invasion and migration, which were probably mediated through Src signaling pathway. Apatinib exerted its anti-cancer effect not only via cytotoxicity, but also via inhibition of migration and invasion by suppressing RET/Src signaling pathway, supporting a potential role for Apatinib in the treatment of KIF5B-RET driven tumors.

This work sought to determine the crosstalk between the Notch and Wnt signaling pathways in regulating supporting cell (SC) proliferation and hair cell (HC) regeneration in mouse utricles. We cultured postnatal day (P)3 and P60 mouse utricles, damaged the HCs with gentamicin, and treated the utricles with the γ-secretase inhibitor DAPT to inhibit the Notch pathway and with the Wnt agonist QS11 to active the Wnt pathway. We also used Sox2-CreER, Notch1-flox (exon 1), and Catnb-flox (exon 3) transgenic mice to knock out the Notch pathway and activate the Wnt pathway in Sox2+ SCs. Notch inhibition alone increased SC proliferation and HC number in both undamaged and damaged utricles. Wnt activation alone promoted SC proliferation, but the HC number was not significantly increased. Here we demonstrated the cumulative effects of Notch inhibition and Wnt activation in regulating SC proliferation and HC regeneration. Simultaneously inhibiting Notch and overexpressing Wnt led to significantly greater SC proliferation and greater numbers of HCs than manipulating either pathway alone. Similar results were observed in the transgenic mice. This study suggests that the combination of Notch inhibition and Wnt activation can significantly promote SC proliferation and increase the number of regenerated HCs in mouse utricle.

The defensive skin secretions of amphibians are a rich resource for the discovery of novel, bioactive peptides. Here we report the identification of a novel vascular smooth muscle-relaxing peptide, named vasorelaxin, from the skin secretion of the Chinese piebald odorous frog, Odorrana schmackeri. Vasorelaxin consists of 20 amino acid residues, SRVVKCSGFRPGSPDSREFC, with a disulfide-bridge between Cys-6 and Cys-20. The structure of its biosynthetic precursor was deduced from cloned skin cDNA and consists of 67 amino acid residues encoding a single copy of vasorelaxin (vasorelaxin, accession number: HE860494). Synthetic vasorelaxin caused a profound relaxation of rat arterial smooth muscle with an EC(50) of 6.76 nM.

DNA vaccines provide an attractive technology against cancer because of their safety record in humans and ease of construction, testing and manufacture. In this study, several DNA fragments encoding multiple cytotoxic T lymphocyte (CTL) and T helper cell epitopes were selected from human prostate-specific membrane antigen (hPSM), mouse prostatic acid phosphatase (mPAP), and human prostate-specific antigen (hPSA). These DNA fragments were ligated together to form a novel fusion gene, termed the 3P gene. The secondary lymphoid tissue chemokine (SLC), 3P and human immunoglobulin G Fc genes were inserted into pcDNA3.1 to construct a DNA vaccine, designated pSLC-3P-Fc. After vaccination, the DNA is taken up by cells that produce and secrete the SLC-3P-Fc fusion proteins, termed chemotactic antigen (chemo-antigen). The secreted chemo-antigens, in addition to promoting the co-localization of naive, non-polarized memory T cells and dendritic cells, are efficiently captured and processed by dendritic cells via receptor-mediated endocytosis and then cross-presented to both major histocompatibility complex class I and class II in a cognate manner. The results of this study demonstrate that vaccination with pSLC-3P-Fc by gene gun inoculation induced a strong antitumour response in a mouse tumour model, which significantly inhibited tumour growth and prolonged the survival time of the tumour-bearing mice. In vitro, the secreted SLC-3P-Fc fusion protein can attract lymphocytes from human peripheral blood mononuclear cells (PBMC); when human lymphocytes were stimulated by pSLC-3P-Fc-transfected autologous PBMC, CTLs were induced which could specifically kill hPSM-, hPAP-, or hPSA-expressing tumour cells. These observations provide a new vaccine strategy for cancer therapy through promoting the co-localization of lymphocytes and the concomitant enhancement of antigen-specific CD4+ helper and CD8+ cytotoxic T-cell responses against tumour.

Agkistrodon in Chinese medicine has long been used as an effective treatment against rheumatoid arthritis (RA). The present research further investigated the effects of peptides extracted from the crude Agkistrodon on the RA rat model. Extracted peptides were separated by parameter-optimized ion-exchange chromatography (IEC), peptide fractions were further analysed by MALDI-TOF/TOF MS, and nano-LC-MS/MS acquired mass spectra were further characterized using Mascot software, which ranks the best matches in the NCBI database. RT-PCR results in RAW264.7 cells indicated that Agkistrodon peptide components had inhibitory effects against inflammatory cytokines. The therapeutic efficacy of Agkistrodon peptides was evaluated on the Wistar rats with collagen-induced arthritis. Symptom relief and reduced cartilage destruction and bone erosion were observed, which can be explained by the direct suppression of inflammatory cytokines in the joints. Agkistrodon peptides downregulate the expression of TNF-α, IL-1β, and IL-6, which may alleviate cartilage destruction and bone erosion, thus relieving symptoms of RA.

Regulation of Nuclear Pre-mRNA Domain Containing 1B (RPRD1B) has been of great interest in the field of oncology in recent years. The relationship between miRNAs and RPRD1B in gastric cancer (GC) has not been adequately reported. This study was designed to screen RPRD1B-targeted miRNAs and investigate its regulatory mechanism in GC cells. Quantitative RT-PCR and in situ hybridization were used to detect miRNA expression in GC tissues. Colony formation, EdU cell proliferation assay, and flow cytometry were used to analyze the cell cycle. Database-assisted gene expression analysis revealed that RPRD1B was targeted and regulated by miRNA-139-5p in GC. miRNA-139-5p expression was higher in GC tissue than in normal tissues and significantly correlated with tumor size, pathological stage, and disease-free survival of GC (p < 0.05). MiRNA-139-5p regulates GC cell proliferation and affects the transition from G1 to S phase. It binds explicitly to the 2013-2019 sites of the 3'UTR of RPRD1B and negatively regulates RPRD1B expression. We demonstrated that the ability of miR-139-5p to regulate GC cell proliferation depends on RPRD1B. This process is accompanied by changes in Cyclin D1 protein expression. We established a miR-139-5p/RPRD1B/tumor proliferation axis in GC, which may serve as novel biomarkers and drug targets for GC.

Noninvasive imaging plays a pivotal role in assessing the brain structural and functional changes in presurgical mesial temporal lobe epilepsy (MTLE) patients. Our goal was to study the relationship between the changes of cerebral white matter (WM) and cognitive functions in MTLE patients.Voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) MRI were performed on 24 right-handed MTLE patients (12 with left MTLE and 12 with right MTLE) and 12 matching healthy controls. Gray matter (GM), WM, and whole brain (WB) volumes were measured with VBM while fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were measured with TBSS. All patients and controls also underwent Montreal Cognitive Assessment (MoCA) before MRI.WM volume and the ratio of WM volume versus WB volume were significantly lower in MTLE patients compared with controls. WM volume in MTLE patients had a positive correlation with MoCA score (r = 0.71, P < .001) and a negative correlation with the duration of epilepsy (r = -0.693, P < .001). Volumetric differences were mainly located in the corpus callosum, uncinate fasciculus, inferior longitudinal fasciculus, and superior longitudinal fasciculus. FA of both left MTLE and right MTLE groups was significantly decreased, while MD, AD, and RD were significantly increased. Most left MTLE patients showed bilateral WM fiber tract changes versus ipsilateral changes for right MTLE patients.Changes in DTI parameters and WM volume were found in MTLE patients and more ipsilateral changes were seen with right-sided MTLE. Cognitive changes of MTLE patients were found to be correlated with the changes in WM structure. These findings not only provide useful information for lateralization of the seizure focus but can also be used to explain functional connectivity disorders which may be an important physiological basis for cognitive changes in patients with MTLE.

Dysregulation of microRNAs has been demonstrated to be involved in a variety of biological events related to cancer, including proliferation, metastasis, angiogenesis and immune escape. MiR-616-3p is located on the chromosome region 12q13.3, however, its potential role and clinical implications in gastric cancer remain poorly understood. The current study aimed to investigate the potential role of miR-616-3p in gastric cancer. The results showed that miR-616-3p was up-regulated in cancer tissues. Higher expression of miR-616-3p in tumor tissues also predicted poor prognosis. Furthermore, loss- and gain-of-function in vitro revealed that miR-616-3p promoted angiogenesis and EMT in gastric cancer cells. Mechanistically, further analysis demonstrated that the effects of miR-616-3p on metastasis and angiogenesis occurred through the down-regulation of PTEN, a direct target of miR-616-3p. We propose that the restoration of PTEN expression may block miR-616-3p-induced EMT and angiogenesis. Collectively, our findings suggest that the miR-616-3p-PTEN signaling axis might be a potential therapeutic target for gastric cancer.

Squamous non-small cell lung cancer (SqNSCLC), as a leading cause of cancer-related deaths worldwide, has limited treatment options and poor prognosis. Thus, novel targeted therapies are desperately needed.

Glaucoma is a leading cause of blindness characterized by progressive degeneration of retinal ganglion cells (RGCs). A well-established risk factor for the development and progression of glaucoma is elevation of intraocular pressure (IOP). However, how elevated IOP leads to RGC degeneration remains poorly understood. Here, we fabricate a facile, tunable hydrostatic pressure platform to study the effect of increased hydrostatic pressure on RGC axon and total neurite length, cell body area, dendritic branching, and cell survival. The hydrostatic pressure can be adjusted by varying the height of a liquid reservoir attached to a three-dimensional (3D)-printed adapter. The proposed platform enables long-term monitoring of primary RGCs in response to various pressure levels. Our results showed pressure-dependent changes in the axon length, and the total neurite length. The proportion of RGCs with neurite extensions significantly decreased by an average of 38 ± 2% (mean ± SEM) at pressures 30 mmHg and above (p < 0.05). The axon length and total neurite length decreased at a rate of 1.65 ± 0.18 μm and 4.07 ± 0.34 μm, respectively (p < 0.001), for each mmHg increase in pressure after 72 hours pressure treatment. Dendritic branching increased by 0.20 ± 0.05 intersections/day at pressures below 25 mmHg, and decreased by 0.07 ± 0.01 intersections/day at pressures above 25 mmHg (p < 0.001). There were no significant changes in cell body area under different levels of hydrostatic pressure (p ≥ 0.05). Application of this model will facilitate studies on the biophysical mechanisms that contribute to the pathophysiology of glaucoma and provide a channel for the screening of potential pharmacological agents for neuroprotection.

Smooth muscle cells (SMCs), which form the walls of blood vessels, play an important role in vascular development and the pathogenic process of vascular remodeling. However, the molecular mechanisms governing SMC differentiation remain poorly understood. Glycoprotein M6B (GPM6B) is a four-transmembrane protein that belongs to the proteolipid protein family and is widely expressed in neurons, oligodendrocytes, and astrocytes. Previous studies have revealed that GPM6B plays a role in neuronal differentiation, myelination, and osteoblast differentiation. In the present study, we found that the GPM6B gene and protein expression levels were significantly upregulated during transforming growth factor-β1 (TGF-β1)-induced SMC differentiation. The knockdown of GPM6B resulted in the downregulation of SMC-specific marker expression and repressed the activation of Smad2/3 signaling. Moreover, GPM6B regulates SMC Differentiation by Controlling TGF-β-Smad2/3 Signaling. Furthermore, we demonstrated that similar to p-Smad2/3, GPM6B was profoundly expressed and coexpressed with SMC differentiation markers in embryonic SMCs. Moreover, GPM6B can regulate the tightness between TβRI, TβRII, or Smad2/3 by directly binding to TβRI to activate Smad2/3 signaling during SMC differentiation, and activation of TGF-β-Smad2/3 signaling also facilitate the expression of GPM6B. Taken together, these findings demonstrate that GPM6B plays a crucial role in SMC differentiation and regulates SMC differentiation through the activation of TGF-β-Smad2/3 signaling via direct interactions with TβRI. This finding indicates that GPM6B is a potential target for deriving SMCs from stem cells in cardiovascular regenerative medicine. Stem Cells 2018 Stem Cells 2019;37:190-201.

This study aimed to assess the comparative efficacy of four ablation strategies on the incidence rates of freedom from atrial fibrillation (AF) or atrial tachycardia (AT) through a 3-year follow-up in patients with persistent AF.

Irisin, the cleaved form of the fibronectin type III domain containing 5 (FNDC5) protein, is involved in metabolism and inflammation. Recent findings indicated that irisin participated in cardiovascular physiology and pathology. In this study, we investigated the effects of FNDC5/irisin on diabetic cardiomyopathy (DCM) in type 2 diabetic db/db mice. Downregulation of myocardial FNDC5/irisin protein expression and plasma irisin levels was observed in db/db mice compared to db/+ controls. Moreover, echocardiography revealed that db/db mice exhibited normal cardiac systolic function and impaired diastolic function. Adverse structural remodeling, including cardiomyocyte apoptosis, myocardial fibrosis, and cardiac hypertrophy were observed in the hearts of db/db mice. Sixteen-week-old db/db mice were intramyocardially injected with adenovirus encoding FNDC5 or treated with recombinant human irisin via a peritoneal implant osmotic pump for 4 weeks. Both overexpression of myocardial FNDC5 and exogenous irisin administration attenuated diastolic dysfunction and cardiac structural remodeling in db/db mice. Results from in vitro studies revealed that FNDC5/irisin protein expression was decreased in high glucose (HG)/high fat (HF)-treated cardiomyocytes. Increased levels of inducible nitric oxide synthase (iNOS), NADPH oxidase 2 (NOX2), 3-nitrotyrosine (3-NT), reactive oxygen species (ROS), and peroxynitrite (ONOO-) in HG/HF-treated H9C2 cells provided evidence of oxidative/nitrosative stress, which was alleviated by treatment with FNDC5/irisin. Moreover, the mitochondria membrane potential (ΔΨm) was decreased and cytochrome C was released from mitochondria with increased levels of cleaved caspase-3 in HG/HF-treated H9C2 cells, indicating the presence of mitochondria-dependent apoptosis, which was partially reversed by FNDC5/irisin treatment. Mechanistic studies showed that activation of integrin αVβ5-AKT signaling and attenuation of oxidative/nitrosative stress were responsible for the cardioprotective effects of FNDC5/irisin. Therefore, FNDC5/irisin mediates cardioprotection in DCM by inhibiting myocardial apoptosis, myocardial fibrosis, and cardiac hypertrophy. These findings implicate that FNDC5/irisin as a potential therapeutic intervention for DCM, especially in type 2 diabetes mellitus (T2DM).

The long-legged fly Lichtwardtia dentalis Zhang, Masunaga et Yang, 2009 belongs to the subfamily Dolichopodinae of Dolichopodidae. The newly sequenced mitogenome of L. dentalis is a new representative of the subfamily. The nearly complete mitogenome is 15,124 bp in length, consisting of 13 protein-coding genes (PCGs), 2 ribosomal RNA genes (rRNAs), and 22 transfer RNA genes (tRNAs). All genes have similar locations and encoding directions with that of other published mitogenomes of Dolichopodidae. The nucleotide composition biases toward A and T with the overall A + T % is 73.9%. All protein-coding genes initiate with standard start codon ATN except COI and NAD1, and TAA/TAG are conventionally used as stop codons. All tRNAs, ranging from 62 to 71 bp, have a clover-leaf structure. Based on the result of the phylogenetic analysis, Dolichopodidae and Empididae were monophyletic, and the relationships among subfamilies of Dolichopodidae were Diaphorinae + (Peloropeodinae + (Xanthochlorinae + (Medeterinae + Dolichopodinae))). The monophyly of the subfamily Dolichopodinae and the sister relationship between Dolichopus and Lichtwardtia were also strongly supported.

Granulomas are the pathological hallmark of tuberculosis (TB). In individuals with latent TB infection, Mycobacterium tuberculosis cells reside within granulomas in a nonreplicating dormant state, and a portion of them will develop active TB. Little is known on the bacterial mechanisms/factors involved in this process. In this study, we found that WhiB4, an oxygen sensor and a transcription factor, plays a critical role in disease progression and reactivation of Mycobacterium marinum (M. marinum) infection in zebrafish. We show that the whiB4::Tn mutant of M. marinum caused persistent infection in adult zebrafish, which is characterized by the lower but stable bacterial loads, constant number of nonnecrotized granulomas in fewer organs, and reduced inflammation compared to those of zebrafish infected with the wild-type bacteria or the complemented strain. The mutant bacteria in zebrafish were also less responsive to antibiotic treatments. Moreover, the whiB4::Tn mutant was defective in resuscitation from hypoxia-induced dormancy and the DosR regulon was dysregulated in the mutant. Taken together, our results suggest that WhiB4 is a major driver of reactivation from persistent infection. IMPORTANCE About one-quarter of the world's population has latent TB infection, and 5 to 10% of those individuals will fall ill with TB. Our finding suggests that WhiB4 is an attractive target for the development of novel therapeutics, which may help to prevent the reactivation of latent infection, thereby reducing the incidences of active TB.

This study aimed to find ferroptosis-related genes linked to clinical outcomes of adrenocortical carcinoma (ACC) and assess the prognostic value of the model.

A core-shell-structured Cu2 O@Mn3 Cu3 O8 (CMCO) nanozyme is constructed to serve as a tumor microenvironment (TME)-activated copper ionophore to achieve safe and efficient cuproptosis. The Mn3 Cu3 O8 shell not only prevents exposure of normal tissues to the Cu2 O core to reduce systemic toxicity but also exhibits enhanced enzyme-mimicking activity owing to the better band continuity near the Fermi surface. The glutathione oxidase (GSHOx)-like activity of CMCO depletes glutathione (GSH), which diminishes the ability to chelate Cu ions, thereby exerting Cu toxicity and inducing cuproptosis in cancer cells. The catalase (CAT)-like activity catalyzes the overexpressed H2 O2 in the TME, thereby generating O2 in the tricarboxylic acid (TCA) cycle to enhance cuproptosis. More importantly, the Fenton-like reaction based on the release of Mn ions and the inactivation of glutathione peroxidase 4 induced by the elimination of GSH results in ferroptosis, accompanied by the accumulation of lipid peroxidation and reactive oxygen species that can cleave stress-induced heat shock proteins to compromise their protective capacity of cancer cells and further sensitize cuproptosis. CMCO nanozymes are partially sulfurized by hydrogen sulfide in the colorectal TME, exhibiting excellent photothermal properties and enzyme-mimicking activity. The mild photothermal effect enhances the enzyme-mimicking activity of the CMCO nanozymes, thus inducing high-efficiency ferroptosis-boosted-cuproptosis.