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To effectively promote antitumor potency of doxorubicin (DOX), a regularly used chemotherapy drug, the tumor acidity-responsive polymeric nanomicelles from self-assembly of the as-synthesized amphiphilic benzoic imine-containing PEGylated chitosan-g-poly(lactic-co-glycolic acid) (PLGA) conjugates were developed as vehicles of DOX. The attained PEGylated chitosan-g-PLGA nanomicelles with high PEGylation degree (H-PEG-CSPNs) were characterized to exhibit a "onion-like" core-shell-corona structure consisting of a hydrophobic PLGA core covered by benzoic imine-rich chitosan shell and outer hydrophilic PEG corona. The DOX-carrying H-PEG-CSPNs (DOX@H-PEG-CSPNs) displayed robust colloidal stability under large-volume dilution condition and in a serum-containing aqueous solution of physiological salt concentration. Importantly, the DOX@H-PEG-CSPNs in weak acidic milieu undergoing the hydrolysis of benzoic imine bonds and increased protonation of chitosan shell showed dePEGylation and surface charge conversion. Also, the considerable swelling of protonated chitosan shell within DOX@H-PEG-CSPNs accelerated drug release. Notably, the cellular internalization of DOX@H-PEG-CSPNs by TRAMP-C1 prostate cancer cells under mimic acidic tumor microenvironment was efficiently boosted upon acidity-triggered detachment of PEG corona and exposure of positively-charged chitosan shell, thus augmenting DOX-mediated anticancer effect. Compared to free DOX molecules, the DOX@H-PEG-CSPNs appreciably suppressed TRAMP-C1 tumor growth in vivo, thereby showing great promise in improving DOX chemotherapy.

The study aimed to describe central nervous system (CNS) progression in patients with infantile-onset Pompe disease (IOPD) and explore the potential clinical impact and predictors.Patients with IOPD treated with enzyme replacement therapy were longitudinally followed with brain magnetic resonance imaging (MRI) and evaluation for IQ scores from 2004 to 2021. Investigation of CNS involvement focused on white matter (WM) abnormalities and was quantified using a scoring system for metachromatic leukodystrophy. MRI scores were correlated with plasma neurofilament light chain (NfL) concentration and IQ scores.A total of 19 patients who started enzyme replacement therapy at a mean age of 26 days were analyzed; the median age at last examination was 12.1 (range = 1.7-19) years. MRI abnormalities were found in all patients, from supratentorial central WM to U-fibers, then to infratentorial WM, and eventually to gray matter. MRI scores progressed (n = 16) at variable rates (range = 0.8-2.7/y) and were positively correlated with age (n = 16) and negatively correlated with IQ scores (n = 8). Plasma NfL concentration was positively correlated with MRI scores (rOur results suggest that the progression of CNS involvement in IOPD may be associated with neuroaxonal injury and decreased IQ scores. NfL could serve as a biomarker for CNS involvement in IOPD.

Atherosclerotic complications represent the leading cause of cardiovascular mortality globally. Dysfunction of endothelial cells (ECs) often initiates the pathological events in atherosclerosis.In this study, we sought to investigate the transcriptional profile of atherosclerotic aortae, identify novel regulator in dysfunctional ECs and hence provide mechanistic insights into atherosclerotic progression.We applied single-cell RNA sequencing (scRNA-seq) on aortic cells from Western diet-fed apolipoprotein E-deficient (ApoEAmong the compendium of aortic cells, mesenchymal markers in ECs were significantly enriched. Two EC subsets were subsequently distinguished, as the 'endothelial-like' and 'mesenchymal-like' subsets. Conventional assays consistently identified SOX4 as a novel atherosclerotic marker in mouse and different human arteries, additional to a cancer marker. EC-specific SOX4 overexpression promoted atherogenesis and endothelial-to-mesenchymal transition (EndoMT). Importantly, hyperlipidemia-associated cytokines and oscillatory blood flow upregulated, whereas the anti-diabetic drug metformin pharmacologically suppressed SOX4 level in ECs.Our study unravels SOX4 as a novel phenotypic regulator during endothelial dysfunction, which exacerbates atherogenesis. Our study also pinpoints hyperlipidemia-associated cytokines and oscillatory blood flow as endogenous SOX4 inducers, providing more therapeutic insights against atherosclerotic diseases.

α-Melanocyte-stimulating hormone (α-MSH) is a well-studied neuropeptide controlling skin and hair color. Besides, numerous immunomodulation roles of α-MSH were recorded in humans and mice. However, the regulatory effects of α-MSH in teleost immunity haven't been well elucidated. In this study, several precursor molecules of α-MSH (POMCs) and its receptors (MCRs) in Nile tilapia (Oreochromis niloticus) were characterized, and their expression characteristics and specific functions on antibacterial immunity were determined. Overall, POMCs and MCRs were principally detected in the brain, skin, and liver, and were remarkably promoted post Streptococcus agalactiae infection. However, tiny POMCs and MCRs were observed in tilapia immune organs (head kidney and spleen) or lymphocytes, and no evident immunomodulation effect was detected in vitro. Moreover, the in vivo challenge experiments revealed that α-MSH protects tilapia from bacterial infection by regulating responses in the brain and intestine. This study lays theoretical data for a deeper comprehension of the immunomodulation mechanisms of teleost α-MSH and the evolutional process of the vertebrate melanocortin system.

Pyroptosis is an inflammatory and programmed cell death initiated by the formation of the inflammasome, which consists of NLR, ASC, and Caspase. Pyroptosis has received growing attention due to its association with innate immunity and various diseases. However, the involvement and induction of the NLRCs and pyroptosis-related genes in fish immunity remain poorly studied. In this study, several NLRCs and pyroptosis-related genes in Nile tilapia (Oreochromis niloticus) were identified and characterized. Their involvement in bacterial infection and expression profiles in Nile tilapia lymphocyte responses were also assessed. Overall, three NLRC members (NOD1, NOD2, and NLRC3) and five pyroptosis-related genes (ASC1, Caspase1, Gsdme, NLRP3, and NLRP14) in Nile tilapia were cloned and characterized. The transcript levels of these molecules were broadly distributed in various tissues with comparatively high expression in the gills, intestine, and spleen. Their transcripts were also induced during Streptococcus agalactiae or Aeromonas hydrophila infection. Moreover, they were primarily expressed in T cells, NCCs, and Mo/Mφ and showed antibacterial and partially antiviral responses. The present study lays a theoretical foundation for further investigation of the pyroptosis mechanisms in fish as well as the evolution of the antiviral roles of pyroptosis in vertebrates.

We develop a simple and efficient route for the fabrication of water-soluble metallosupramolecular polymers. We demonstrate that the introduction of environment-responsive metal-organic complexes within supramolecular polymers endows the resulting self-assembled nano-objects with outstanding antibacterial activity and may significantly improve the efficacy and safety of selective cancer therapy. Herein, we successfully developed a silver-containing supramolecular polymer (Ag-Cy-J) possessing a hydrophilic Jeffamine backbone and highly sensitive pH-responsive cytosine-silver-cytosine (Cy-Ag-Cy) linkages, which spontaneously self-assemble to produce sterically stabilized spherical nanogels in water. The resulting nanogels exhibit several attractive features such as unique fluorescence behavior in water, highly stable self-assembled structures in biological media, significant antihemolytic capability, highly sensitive pH-responsiveness and broad-spectrum antibacterial activity against various bacteria strains. Importantly, in vitro cellular assays clearly demonstrated Ag-Cy-J nanogels highly selectively target and induce cytotoxicity in cancer cells, without affecting normal cells. The selective cytotoxic activity in cancer cells is attributed to rapid dissociation of the Cy-Ag-Cy complexes within the nanogels in the cancer cell microenvironment, followed by the intracellular release of silver ions and induction of rapid, massive apoptosis. Overall, the pH-sensitive Cy-Ag-Cy complexes within this supramolecular nanogel system may provide a route to remarkably improve the efficacy of both antibacterial and cancer drug therapies. STATEMENT OF SIGNIFICANCE: We present a significant breakthrough in the development of a water-soluble silver-containing metallosupramolecular polymer (Ag-Cy-J) that spontaneously self-assembles in water into a spherical nanogel with unique physical characteristics due to the existence of highly sensitive pH-responsive cytosine-silver-cytosine (Cy-Ag-Cy) linkages within the nanogels. Importantly, a series of in vitro antibacterial and anticancer assays demonstrated the Ag-Cy-J nanogels not only exert strong antibacterial activity against various bacterial strains, but also exhibit a high degree of selective uptake and rapidly induce massive apoptosis in cancer cells without harming normal cells. Thus, this newly discovered supramolecular system may potentially provide a multi-biofunctional soft nanomaterial for efficient and safe antibacterial and cancer therapies.

Neutrophil extracellular traps (NETs) play important roles in sepsis and deep-seated infections, but whether NET formation correlates with clinical outcomes of patients with streptococcal bloodstream infections (BSIs) is unclear.We analyzed serum levels of complexes of myeloperoxidase and DNA (MPO-DNA) in patients with streptococcal-BSIs. In vitro assay of NET induction by serum from BSI patients was performed.MPO-DNA values for the Streptococci-BSI group (n = 59) were significantly higher than those for healthy controls (p 0.00001) and matched control groups (n = 59, p = 0.004). The rate of higher MPO-DNA levels (1.87 μg/mL) were higher in abscess-prone streptococcal groups (streptococcus milleri group) (72.2% vs. 52.5%, p = 0.02). For patients with BSIs due to highly infective endocarditis (IE)-prone pathogens, the values of serum MPO-DNA were also higher in patients diagnosed of IE compared to their counterparts (p = 0.009). Notably, serum from patients with leukopenia could induce higher amounts of in vitro NET formation, despite having low MPO-DNA levels, suggesting that NET formation could be influenced by WBC counts. Therefore, we combined WBC counts with MPO-DNA to predict all-cause 30-day mortality in patients with commensal streptococcal-BSIs. The mortality risk was lowest among patients who had neither high MPO-DNA levels nor abnormal WBC counts (p = 0.058). Furthermore, this group of patients also had a favorable composite outcome consisting of major adverse cardiovascular events (MACE) and all-cause mortality (p = 0.026).Together, these study data suggested that serum MPO-DNA can be a biomarker for predicting a composite outcome consisting of MACE and all-cause mortality in patients with commensal streptococcal-BSIs.

In this study, we investigated various pubertal presentations and progressions before and after estrogen induction therapy and the correlations with Turner syndrome karyotypes.We reviewed the medical records of patients with Turner syndrome diagnosed before the age of 18 years between 2000 and 2019. Sixty-six patients were enrolled and distributed into 45,X monosomy group, X chromosome structural abnormalities group and X mosaicism group. The pubertal presentations were classified into spontaneous puberty, arrested puberty and no spontaneous puberty. All patients' karyotypes, pubertal progressions and laboratory data were collected and analyzed.The karyotypes were highly correlated with pubertal presentations. No spontaneous puberty was noticed in 58.3% 45,X monosomy patients, 50% patients with X chromosome structural abnormalities had arrested puberty, whereas 70% patients with X mosaicism had spontaneous puberty. Estrogen induction therapy in patients with no spontaneous puberty could induce puberty and the tempo of puberty may approximate to the spontaneous puberty group (median, 2.3 vs. 2.2 years, P = 0.95). In both interventional groups, the FSH level was distinguishable before treatment (median, 65.1 vs. 100.4 mIU/mL, P = 0.02). After long term estrogen therapy, the FSH could be suppressed to similar level in both interventional groups (median, 37.5 vs 34.5 mIU/mL, P = 0.84). Neither LH nor E2 level provided valuable information before and after treatment.The karyotypes were highly correlated with pubertal presentations at Turner syndrome patients. The integrity of 2nd X chromosome plays an important role. Low dose estrogen could mimic the tempo of puberty even delay induction age at Taiwan. The FSH data could provide predictive information of pubertal induction for both interventional groups.

"Sarcopenic obesity" refers to a condition of low muscle mass in the context of obesity, though may be difficult to assess in patients with cirrhosis who are acutely ill. We aimed to define sarcopenic visceral obesity (SVO) using CT-based skeletal muscle index (SMI) and visceral-to-subcutaneous adipose tissue ratio (VSR) to examine its association with post-transplant mortality. We analyzed 116 adult inpatients with cirrhosis who were urgently listed and transplanted between 1/2005 and 12/2017 at 4 North American transplant centers. SVO was defined as patients with sarcopenia (SMI50 cm

The purpose of this study was to examine the in vivo activity of rosmarinic acid (RA) - a phytochemical with antioxidant, anti-inflammatory, and antiviral properties - against influenza virus (IAV). An antibody-based kinase array and different in vitro functional assays were also applied to identify the mechanistic underpinnings by which RA may exert its anti-IAV activity.We initially examined the potential efficacy of RA using an in vivo mouse model. A time-of-addition assay and an antibody-based kinase array were subsequently applied to investigate mechanism-of-action targets for RA. The hemagglutination inhibition assay, neuraminidase inhibition assay, and cellular entry assay were also performed.RA increased survival and prevented body weight loss in IAV-infected mice. In vitro experiments revealed that RA inhibited different IAV viruses - including oseltamivir-resistant strains. From a mechanistic point of view, RA downregulated the GSK3β and Akt signaling pathways - which are known to facilitate IAV entry and replication into host cells.RA has promising preclinical efficacy against IAV, primarily by interfering with the GSK3β and Akt signaling pathways.

This study aimed to develop and validate a machine learning-based short measure to assess 5 functions (the ML-5F) (activities of daily living [ADL], balance, upper extremity [UE] and lower extremity [LE] motor function, and mobility) in patients with stroke.Secondary data from a previous study. A follow-up study assessed patients with stroke using the Barthel Index (BI), Postural Assessment Scale for Stroke (PASS), and Stroke Rehabilitation Assessment of Movement (STREAM) at hospital admission and discharge.A rehabilitation unit in a medical center.Patients (N=307) with stroke.Not applicable.The BI, PASS, and STREAM.A machine learning algorithm, Extreme Gradient Boosting, was used to select 15 items from the BI, PASS, and STREAM, and transformed the raw scores of the selected items into the scores of the ML-5F. The ML-5F demonstrated good concurrent validity (Pearson's r, 0.88-0.98) and responsiveness (standardized response mean, 0.28-1.01).The ML-5F comprises only 15 items but demonstrates sufficient concurrent validity and responsiveness to assess ADL, balance, UE and LE functions, and mobility in patients with stroke. The ML-5F shows great potential as an efficient outcome measure in clinical settings.

Remarkable Li-ion battery(LIB) anode materials need to have long cycle life and fast charge/discharge rate, however they are difficult to be realized in the monolayer anode materials. The monolayer β-Bi has the stiffness of only 33.0 N/m, thus the Bi/G heterostructure is proposed to improve the electronic and mechanical properties and to produce better LIB anode performance in this paper. The calculated results show that Bi/G heterostructure has excellent thermodynamic, dynamical and mechanical stability. The band gap is only 0.04 eV, which ensures remarkable electrical conductivity. In addition, the Bi/G heterostructure has higher stiffness (369.2 N/m) than that of monolayer β-Bi and graphene. The diffusion barrier (Ebarrier) of 0.32 eV and volume expansion ratio(VER) of only 4% can ensure the rapid transport of Li+ ions in the charge/discharge cycling process and long life of the LIB. These calculated theoretical results for describing the detail properties of Li storage and diffusion in the Bi/G heterostructure can supply adequate conclusive evidence for the prediction of remarkable properties of Bi/G heterostructure as an anode material for LIBs.