An RNase produced by Bacillus safensis RB-5 was purified up to 22.32-fold by successive techniques of salting out, DEAE-anion exchange and gel permeation (Sephadex G-100) chromatography techniques with a yield of 2.27%. The purified RNase possessed a single band in SDS-PAGE (Mr ~ 60 kDa). The purified RNase showed optimal activity at temperature of 37 °C and pH 7.5 in the presence of substrate (Yeast RNA) and Mg2+ ions. The RNase activity was strongly inhibited by Hg2+ and mildly by Fe2+, Ba2+ and Zn2+ ions. Its half-life was found to be 8 h at 37 °C. The RNase kinetics study showed Km and Vmax value of 0.3 mM and 9.2 μmol/mg/min, respectively. The purified RNase also showed cytotoxic and antiproliferative activities towards a few transformed cell lines. The purified RNase (IC50 0.035 U/mL) effectively inhibited RD and Hep-2C cells proliferation & migration, while sparing HEK 293 cells. The purified RNase was cytotoxic as well as effective degrader of the RNA of transformed RD cells at low concentration. Moreover, the purified RNase of B. safensis RB-5 was found to possess a little hemolytic activity towards human RBCs.This research is focused on improving performance of chitosan based functional material by introducing active additive. A series of assays revealed incorporation with clove essential oil (CEO) significantly improved the physical, chemical and antimicrobial performance of chitosan. In this work, the prepared chitosan-CEO film (CH-CEO) showed varieties in color parameters, mechanical strength and water vapor permeability. Moreover, chitosan was endowed with significant antioxidant and antimicrobial activities, thereby it was used as protective coatings for fresh-cutting apple tubes at ~1 °C. Results demonstrated the treatment slowed down the quality deterioration process of preserved apple samples, especially for firmness and color. As well, CH-CEO coating reduced microbial counts in the preserved apple samples and inhibited the varieties in the chemical properties. The overall observations revealed that CH-CEO film has remarkable potential as an antioxidant and antimicrobial material, especially as an active coating for fresh-cutting foods during storage.Secretion-associated and ras-related protein 1 (Sar1) is a small GTPase that plays an important role in the transport of protein coated with coat protein complex II vesicles. However, its alternative roles in the biological processes of Procambarus clarkii remain unclear. Here, a sar1 gene (named as Pc-sar1) with an open reading frame of 582 bp from P. clarkii was identified. Pc-sar1 was expressed in all examined tissues with highest expression levels in muscle, which was determined by real-time PCR and western blotting. After the induction of lipopolysaccharide (LPS) and polycytidylic acid (Poly I C), the transcriptional levels of Pc-sar1 differed in hepatopancreas, gill, muscle and intestine. In contrast, the expression of Pc-sar1 was upregulated by 20-hydroxyecdysone in these four tissues. In addition, the RNA interference of Pc-sar1 significantly affected the expression levels of immune and hormone-related genes. These results indicate that Pc-sar1 is involved in the innate immune response and ecdysteroid signaling pathway.Intrinsically disordered proteins (IDPs) possess a wide range of biological function in all organisms, however the specific functions of most IDPs are still unknown. Soybean LOC protein, LOC for short, is a heat-stable protein, which is more abundant in the stress-resistant radicles. Sequence alignment and phylogenetic analysis showed that LOC is a functionally unknown protein and conserved in Fabaceae. LOC, being enriched in most disorder-promoting residues and depleted in most order-promoting residues, was predicted to contain high levels of intrinsic disorder by several commonly used computational tools. However, it was also predicted to contain two disorder-based protein-protein binding sites and two short α-helical segments. The circular dichroism spectroscopic analysis showed that this protein is mostly disordered in water, but can form more α-helical structure in the presence of SDS and TFE. Functional in vitro studies showed that the LOC protein is able to prevent lactate dehydrogenase inactivation by freeze-thaw at a molar ratio of 101. Furthermore, in vivo analyses revealed the survival rate of Escherichia coli over-expressing LOC protein under the conditions of osmotic stress was noticeably increased in comparison with the control. These observations suggest that the intrinsically disordered protein LOC might serve as a chaperone and/or cell protector.Disease-modifying osteoarthritis (OA) therapy is not yet available. Several adjuvant therapies have demonstrated promising results in the treatment of OA. The present study aimed to investigate the therapeutic effects and underlying mechanisms of a combination of Lactobacillus acidophilus, vitamin B, and curcumin in the treatment of OA. Monosodium iodoacetate (MIA)-induced arthritis of the knee joint in rat was used as an animal model of human OA. The combination of L. acidophilus LA-1, vitamin B, and curcumin or a saline solution was given orally. Pain was measured according to the paw withdrawal latency, and paw withdrawal threshold. Cartilage destruction was analyzed using histomorphological techniques and the Mankin scoring system. Protein expression in the joint was examined using immunohistochemistry. The effects of the combination of L. acidophilus LA-1, vitamin B, and curcumin on mRNA levels in chondrocytes stimulated with interleukin (IL)-1β were analyzed using real-time polymerase chain reaction. Thted the anabolic/catabolic imbalance. These findings indicate the therapeutic potential of combination use of L. acidophilus, vitamin B, and curcumin in patients with OA.

The reduced action of incretin hormones in type 2 diabetes (T2D) is mainly attributed to GIP insensitivity, but efficacy estimates of GIP and GLP-1 differ among studies, and the negligible effects of pharmacological GIP doses remain unexplained. We aimed to characterize incretin action in vivo in subjects with normal glucose tolerance (NGT) or T2D and provide an explanation for the different insulinotropic activity of GIP and GLP-1 in T2D subjects.

We used in vivo data from ten studies employing hormone infusion or an oral glucose test (OGTT). To homogeneously interpret and compare the results of the studies we performed the analysis using a mathematical model of the β-cell incorporating the effects of incretins on the triggering and amplifying pathways. The effect on the amplifying pathway was quantified by a time-dependent factor that is greater than one when insulin secretion (ISR) is amplified by incretins. To validate the model results for GIP in NGT subjects, we performed an extensive literature search of the available data.

a) the stimulatory effects of GIP and GLP-1 differ markedly ISR potentiation increases linearly with GLP-1 over the whole dose range, while with GIP infusion it reaches a plateau at ~100 pmol/L GIP, with ISR potentiation of ~2 fold; b) ISR potentiation in T2D is reduced by ~50% for GIP and by ~40% for GLP-1; c) the literature search of GIP in NGT subjects confirmed the saturative effect on insulin secretion.

We show that incretin potentiation of ISR is reduced in T2D, but not abolished, and that the lack of effects of pharmacological GIP doses is due to saturation of the GIP effect more than insensitivity to GIP in T2D.

We show that incretin potentiation of ISR is reduced in T2D, but not abolished, and that the lack of effects of pharmacological GIP doses is due to saturation of the GIP effect more than insensitivity to GIP in T2D.

In this study, we aimed to identify the determinants of mitochondrial dysfunction in skeletal muscle (SKLM) of subjects with type 2 diabetes (T2DM), and to evaluate the effect of pioglitazone (PIO) on SKLM mitochondrial proteome.

Two different groups of adults were studied. Group I consisted of 8 individuals with normal glucose tolerance (NGT) and 8 with T2DM, subjected to SKLM mitochondrial proteome analysis by 2D-gel electrophoresis followed by mass spectrometry-based protein identification. Group II included 24 individuals with NGT and 24 with T2DM, whose SKLM biopsies were subjected to immunoblot analysis. Of the 24 subjects with T2DM, 20 were randomized to receive placebo or PIO (15 mg daily) for 6 months. After 6 months of treatment, SKLM biopsy was repeated.

Mitochondrial proteomic analysis on Group I revealed that several mitochondrial proteins involved in oxidative metabolism were differentially expressed between T2DM and NGT groups, with a downregulation of ATP synthase alpha chain (ATP5A), el treated with PIO for 6 months we found a restored SKLM protein abundance of ATP5A, ETFA, CX6B1, and mitofilin. Moreover, protein levels of HCDH and ECH1 were reduced by -10% and - 15% respectively (P ≤ 0.05 for both) after PIO treatment.

Type 2 diabetes is associated with reduced levels of mitochondrial proteins involved in oxidative phosphorylation and an increased abundance of enzymes implicated in fatty acid catabolism in SKLM. PIO treatment is able to improve SKLM mitochondrial proteomic profile in subjects with T2DM.

Type 2 diabetes is associated with reduced levels of mitochondrial proteins involved in oxidative phosphorylation and an increased abundance of enzymes implicated in fatty acid catabolism in SKLM. PIO treatment is able to improve SKLM mitochondrial proteomic profile in subjects with T2DM.Transcription factors (TFs) are major contributors to cancer risk and somatic development. In preclinical and clinical studies, direct or indirect inhibition of TF-mediated oncogenic gene expression profiles have proven to be effective in many tumor types, highlighting this group of proteins as valuable therapeutic targets. In spite of this, our understanding of TFs in epithelial ovarian cancer (EOC) is relatively limited. EOC is a heterogeneous disease composed of five major histologic subtypes; high-grade serous, low-grade serous, endometrioid, clear cell and mucinous. Each histology is associated with unique clinical etiologies, sensitivity to therapies, and molecular signatures – including diverse transcriptional regulatory programs. While some TFs are shared across EOC subtypes, a set of TFs are expressed in a histotype-specific manner and likely explain part of the histologic diversity of EOC subtypes. Targeting TFs present with unique opportunities for development of novel precision medicine strategies for ovarian cancer. This article reviews the critical TFs in EOC subtypes and highlights the potential of exploiting TFs as biomarkers and therapeutic targets.Myeloperoxidase (MPO) is a prominent mammalian heme peroxidase and a fundamental component of the innate immune response against microbial pathogens. In recent times, MPO has received considerable attention as a key oxidative enzyme capable of impairing the bioactivity of nitric oxide (NO) and promoting endothelial dysfunction; a clinically relevant event that manifests throughout the development of inflammatory cardiovascular disease. Increasing evidence indicates that during cardiovascular disease, MPO is released intravascularly by activated leukocytes resulting in its transport and sequestration within the vascular endothelium. At this site, MPO catalyzes various oxidative reactions that are capable of promoting vascular inflammation and impairing NO bioactivity and endothelial function. In particular, MPO catalyzes the production of the potent oxidant hypochlorous acid (HOCl) and the catalytic consumption of NO via the enzyme’s NO oxidase activity. An emerging paradigm is the ability of MPO to also influunction. Finally, we deliver a detailed appraisal of the different pharmacological strategies available for targeting the catalytic and non-catalytic modes-of-action of MPO in order to protect against endothelial dysfunction in cardiovascular disease.A novel series of deoxyvasicinone-tetrahydro-beta-carboline hybrids were synthesized and evaluated as acetylcholinesterase (AChE) and β-amyloid peptide (Aβ) aggregation inhibitors for the treatment of Alzheimer’s disease. The results revealed that the derivatives had multifunctional profiles, including AChE inhibition, Aβ1-42 aggregation inhibition, and neuroprotective properties. Inspiringly, hybrids 8b and 8d displayed excellent inhibitory activities against hAChE (IC50 = 0.93 and 1.08 nM, respectively) and Aβ1-42 self-aggregation (IC50 = 19.71 and 2.05 μM, respectively). In addition, 8b and 8d showed low cytotoxicity and good neuroprotective activity against Aβ1-42-induced damage in SH-SY5Y cells.

To investigate the possible influence of polycyclic aromatic hydrocarbons (PAHs) exposure on neurodevelopment of toddlers at the age of 12 months.

Totally 306 subjects were recruited from the Qingdao Birth Cohort established in 2014. PAH-DNA adducts in toddlers’ umbilical cord blood samples, hydroxyl-PAH metabolites in their urine samples and the developmental quotients (DQs) were measured. Sex, gestational age, birth weight, and maternal educational background were adjusted to analyze the influence of the PAH exposure on the neurodevelopment of the toddlers using multivariate linear regression model.

Pearson correlation test showed that the logarithmic values of hydroxyl-PAH were negatively correlated with the DQs. Multivariate linear regression analysis indicated that logarithmic concentration of 1(9)- hydroxyphenanthrene was still associated with the DQs of the fine motor behaviors with β and 95% confidential interval (CI) of -1.137 (-2.053, -0.222), together with PAH-DNA adducts [β (95% CI) -0.577 (-0.930, -0.225)]. PAH-DNA adducts presented an independently negative influence on the DQs of the gross motor and personal social behaviors with β (95%CI) of -0.470 (-0.814, -0.126) and -0.526 (-0.859, -0.193), respectively.

The exposure to PAHs in toddlers at 12 months could influence their neurodevelopment. Additionally, prenatal exposure to PAHs should also be considered.

The exposure to PAHs in toddlers at 12 months could influence their neurodevelopment. Additionally, prenatal exposure to PAHs should also be considered.To identify oral drugs that likely display nonlinear pharmacokinetics due to saturable metabolism by intestinal CYP3A, our previous report using CYP3A substrate drugs proposed an approach using thresholds for the linear index number (LIN3A = dose/Km; Km, Michaelis-Menten constant for CYP3A) and the intestinal availability (FaFg). Here, we aimed to extend the validity of the previous approach using both CYP3A substrate and non-substrate drugs and to devise a decision tree suited for early drug candidates using in vitro metabolic intrinsic clearance (CLint, vitro) instead of FaFg. Out of 152 oral drugs (including 136 drugs approved in Japan, US or both), type I nonlinearity (in which systemic drug exposure increases in a more than dose-proportional manner) was noted with 82 drugs (54%), among which 58 drugs were identified as CYP3A substrates based on public information. Based on practical feasibility, 41 drugs were selected from CYP3A substrates and subjected to in-house metabolic assessment. The results were used to determine the thresholds for CLint, vitro (0.45 μL/min/pmol CYP3A4) and LIN3A (1.0 L). For four drugs incorrectly predicted, potential mechanisms were looked up. Overall, our proposed decision tree may aid in the identification of early drug candidates with intestinal CYP3A-derived type I nonlinearity.Formulation of protein-based therapeutics employ advanced formulation and analytical technologies for screening various parameters such as buffer, pH, and excipients. At a molecular level, physico-chemical properties of a protein formulation depend on self-interaction between protein molecules, protein-solvent and protein-excipient interactions. This work describes a novel in silico approach, SILCS-Biologics, for structure-based modeling of protein formulations. SILCS Biologics is based on the Site-Identification by Ligand Competitive Saturation (SILCS) technology and enables modeling of interactions among different components of a formulation at an atomistic level while accounting for protein flexibility. It predicts potential hotspot regions on the protein surface for protein-protein and protein-excipient interactions. Here we apply SILCS-Biologics on a Fab domain of a monoclonal antibody (mAbN) to model Fab-Fab interactions and interactions with three amino acid excipients, namely, arginine HCl, proline and lysine HCl. Experiments on 100 mg/ml formulations of mAbN showed that arginine increased, lysine reduced, and proline did not impact viscosity. We use SILCS-Biologics modeling to explore a structure-based hypothesis for the viscosity modulating effect of these excipients. Current efforts are aimed at further validation of this novel computational framework and expanding the scope to model full mAb and other protein therapeutics.There has been rapid growth in the use of larval zebrafish as a complementary vertebrate model for drug discovery, abuse liability and pharmacological toxicology, resulting in a huge increase in zebrafish facilities worldwide. However, many research groups working with zebrafish do not typically report the pH of husbandry conditions in methodologies, nor are the pH of drug treatments reported in many research articles. This unknown factor can be a major contributor in the differential effects of drug treatments. Therefore, as a case study, we tested the impact of altering pH of several drugs of abuse and assessed locomotor changes associated with a single drug concentration delivered at different pHs. We found that a change of a single pH unit, within the pH ranges commonly used in zebrafish husbandry, was enough to alter locomotor activity at a fixed drug concentration. Many pharmacological agents are dependent on environmental factors, such as pH, to determine bioavailability. Efficaciousness for many classes of drug is dependent on their ionization state in which shifts towards uncharged species can influence the easy of a drug crossing biological membranes. Thus, we urge users to report pH in husbandry methods and drug treatments to improve replicability and inter-study comparisons.

To investigate the effects of aerobic exercise training on cardiomyocyte ultrastructure, oxidative stress, and activation of protein synthesis pathways in a model of cardiomyopathy induced by doxorubicin (Dox).

Male Sprague Dawley rats were randomly assigned to Control (saline, sedentary), Dox/sedentary (DoxSed), or Dox/exercise (DoxEx) groups. Saline or Dox were injected i.p. for 10days (1mg/kg/d). Aerobic exercise training was performed for 9 wks (starting with drug administration) on a treadmill, 5 d/wk, 30min/d at 60% of maximum velocity. After euthanasia, the left ventricle (LV) was dissected, and processed for microscopy or frozen for Western blot and kinetic measurement of antioxidant enzymes activity.

Dox resulted in a mortality of 31.2% of sedentary animals, whilst all animals from both Control and DoxEx groups survived. DoxSed animals presented increased LV connective tissue deposition alongside with massive sarcomeric disorganization with dissolution of myofibrils and wavy Z-lines. There was an increase in oxidative damage and a reduction in the activation of both Akt and ERK pathways in LV from DoxSed compared to Control group. Aerobic training caused notable changes in myocardial structure with reduced fibrosis and preservation of myofibrils integrity and sarcomere organization. This was associated with reduced LV oxidative damage and increased activity of antioxidant enzymes, and an increase in the activation of PI3K-Akt pathway.

Aerobic exercise training was effective in preventing mortality caused by Dox and in preserving LV ultrastructure, partially via activation of the physiological protein synthesis pathway, PI3K-Akt, and reducing oxidative stress.

Aerobic exercise training was effective in preventing mortality caused by Dox and in preserving LV ultrastructure, partially via activation of the physiological protein synthesis pathway, PI3K-Akt, and reducing oxidative stress.

Differentiation of bone marrow eosinophils (BM-EO) and its trafficking to peripheral blood and respiratory mucosa are a hallmark of inflammatory diseases. Staphylococcal enterotoxin B (SEB) has been shown to aggravate airways eosinophilic inflammation. This study aimed to investigate the effects of mouse airways SEB exposure on BM-EO population, as well as its adhesive properties and release of cytokines/chemokines that orchestrate BM-EO trafficking to lungs.

Male BALB/c mice were intranasally exposed to SEB (1μg), and at 4, 16, 24 and 48h thereafter, bone marrow (BM), circulating blood and bronchoalveolar lavage (BAL) fluid were collected. Levels of cytokines/chemokines and expressions of VLA-4 and CCR3 in BM were evaluated. Adhesion of BM to ICAM-1 and VCAM-1 were also evaluated.

SEB exposure promoted a marked eosinophil influx to BAL at 16 and 24h after exposure, which was accompanied by significant increases in counts of immature (16h) and mature (4 to 48h) forms of eosinophil in BM, along with blood eosinophilia (16h). In BM, higher levels of eotaxin, IL-5, IL-4, IL-3 and IL-7 were detected at 16 to 48h. SEB also significantly increased CCR3 expression and calcium levels in BM-EO, and enhanced the cell adhesion to ICAM-1 (24h) and ICAM-1 (48h).

Airways SEB exposure increases the number of eosinophils in BM by mechanisms involving a network of cytokine and chemokine release, facilitating the BM-EO adhesion to ICAM-1 and VCAM-1 to gain access to the peripheral blood and lung tissues.

Airways SEB exposure increases the number of eosinophils in BM by mechanisms involving a network of cytokine and chemokine release, facilitating the BM-EO adhesion to ICAM-1 and VCAM-1 to gain access to the peripheral blood and lung tissues.Despite the conventional reputation of neutrophils to have antibacterial properties, recent studies have put emphasis and are interested in the role of neutrophils in the spread and treatment of cancer. It has been shown that the infiltration of neutrophils, either by exerting pro- or anti-tumoral effects, probably affects tumor prognosis. Tumor-associated neutrophils (TANs) probably participate in tumor promotion and development in different ways, such as increasing genomic instability, induction of immunosuppression, and increasing angiogenesis. Despite major advances in breast cancer treatment, it is the second leading cause of death in American women. It has been revealed that inflammation is a fundamental issue in the treatment of this cancer because tumor growth, invasion, metastasis, and vascularization can be affected by inflammatory factors. It is demonstrated that enhanced neutrophil to lymphocyte ratio probably contributes to the raised rate of mortality and decreased survival among breast cancer cases. The present review explores the biology of TANs, their suspected interactions in the breast cancer microenvironment, and their functions in preserving the tumor microenvironment and progression of tumors. Furthermore, their potential as therapeutic targets and clinical biomarkers has been discussed in this paper.Fluorescence is routinely used for in vivo tracking and imaging of molecules and nanostructures with assuming that the fluorescence intensity is proportional to the dye concentration. Herein, we report the unique tumor-specific fluorescence character of rhodamine B isothiocyanate derivatives (RBITCs), which emits fluorescence selectively in cancerous tissues, including small metastatic tumors, but is quenched in blood and healthy tissues. A preliminary mechanism study shows that binding of the thiourea group in the RBITCs on hemoglobin quenches their fluorescence, but the oxidation of the thiourea by the elevated reactive oxygen species in tumor activates the fluorescence. Thus, the fluorescent intensity of RBITCs is associated with the microenvironment of tissues and positively correlates with the cancer stages. These findings suggest that the RBITCs are not suitable for tracking of cargos in the presence of red blood cells but may be useful for cancer imaging and early diagnosis, and probing the tumor microenvironment.Owing to their tremendous potential, the inference of nano-scaled materials has revolutionized many fields including the medicine and health, particularly for development of various types of targeted drug delivery devices for early prognosis and successful treatment of various diseases, including the brain disorders. Owing to their unique characteristic features, a variety of nanomaterials (particularly, ultra-fine particles (UFPs) have shown tremendous success in achieving the prognostic and therapeutic goals for early prognosis and treatment of various brain maladies such as Alzheimer’s disease, Parkinson’s disease, brain lymphomas, and other ailments. However, serious attention is needful due to innumerable after-effects of the nanomaterials. Despite their immense contribution in optimizing the prognostic and therapeutic modalities, biological interaction of nanomaterials with various body tissues may produce severe nanotoxicity of different organs including the heart, liver, kidney, lungs, immune system, gastro-intestinal system, skin as well as nervous system. However, in this review, we have primarily focused on nanomaterials-induced neurotoxicity of the brain. Following their translocation into different regions of the brain, nanomaterials may induce neurotoxicity through multiple mechanisms including the oxidative stress, DNA damage, lysosomal dysfunction, inflammatory cascade, apoptosis, genotoxicity, and ultimately necrosis of neuronal cells. Our findings indicated that rigorous toxicological evaluations must be carried out prior to clinical translation of nanomaterials-based formulations to avoid serious neurotoxic complications, which may further lead to develop various neuro-degenerative disorders.Encapsulation technologies can be used to preserve therapeutic and bioactive compounds from harsh conditions (e.g., light, moisture, and oxygen) and biological destruction (enzymes, metabolism, and phagocytosis). Encapsulation involves the incorporation of the active moieties into a shell structure (e.g., protein, polysaccharide or lipid-based material). These techniques can improve the physicochemical properties of the encapsulated compounds, provide sustained release to specific organs, „cover up” undesirable properties, and improve their solubility, dispersion, and bioavailability. Different techniques have been applied to encapsulate drug compounds, including emulsification, inclusion complexation, nanoparticulate systems (solid lipid nanoparticles and nanostructured lipid carriers), liposome entrapment, nanoprecipitation, freeze drying, spray drying, etc. However, high temperatures or toxic solvents are used in some of these techniques such as spray drying, and liposome entrapment can degrade the bioactiand future perspectives of this technique.Nanomedicines based on synthetic polypeptides are among the most versatile and advanced platforms for tumor therapy. Notably, several polypeptide-based nanodrugs are currently under human clinical assessments. The previous (pre)clinical studies clearly show that dynamic stability (i.e. stable in circulation while destabilized in tumor) of nanomedicines plays a vital role in their anti-tumor performance. Various strategies have recently been developed to design dynamically stabilized polypeptide-based nanomedicines by e.g. crosslinking the nanovehicles with acid, reactive oxygen species (ROS), glutathione (GSH), or photo-sensitive linkers, inter-crosslinking between vehicles and drugs, introducing π-π stacking or lipid-lipid interactions in the nanovehicles, chemically conjugating drugs to vehicles, and forming unimolecular micelles. Interestingly, these robust and smart nanodrugs have demonstrated improved tumor targetability, anti-tumor efficacy, as well as safety profiles in different tumor models. In this review, representative strategies to robust and smart polypeptide-based nanomedicines for targeted treatment of varying malignancies are highlighted. The exciting development of dynamic nanomedicines will foresee further increasing clinical translation in the future.The Coronavirus disease 2019 (COVID-19) pandemic has led to a surge in need for alternative routes of administration of drugs for end of life and palliative care, particularly in community settings. Transmucosal routes include intranasal, buccal, sublingual and rectal. They are non-invasive routes for systemic drug delivery with the possibility of self-administration, or administration by family caregivers. In addition, their ability to offer rapid onset of action with reduced first-pass metabolism make them suitable for use in palliative and end-of-life care to provide fast relief of symptoms. This is particularly important in COVID-19, as patients can deteriorate rapidly. Despite the advantages, these routes of administration face challenges including a relatively small surface area for effective drug absorption, small volume of fluid for drug dissolution and the presence of a mucus barrier, thereby limiting the number of drugs that are suitable to be delivered through the transmucosal route. In this review, the merits, challenges and limitations of each of these transmucosal routes are discussed. The goals are to provide insights into using transmucosal drug delivery to bring about the best possible symptom management for patients at the end of life, and to inspire scientists to develop new delivery systems to provide effective symptom management for this group of patients.Global health is threatened by emerging viruses, many of which lack approved therapies and effective vaccines, including dengue, Ebola, and Venezuelan equine encephalitis. We previously reported that AAK1 and GAK, two of the four members of the understudied Numb-associated kinases (NAK) family, control intracellular trafficking of RNA viruses. Nevertheless, the role of BIKE and STK16 in viral infection remained unknown. Here, we reveal a requirement for BIKE, but not STK-16, in dengue virus (DENV) infection. BIKE mediates both early (postinternalization) and late (assembly/egress) stages in the DENV life cycle, and this effect is mediated in part by phosphorylation of a threonine 156 (T156) residue in the μ subunit of the adaptor protein (AP) 2 complex. Pharmacological compounds with potent anti-BIKE activity, including the investigational anticancer drug 5Z-7-oxozeaenol and more selective inhibitors, suppress DENV infection both in vitro and ex vivo. BIKE overexpression reverses the antiviral activity, validating that the mechanism of antiviral action is, at least in part, mediated by BIKE. Lastly, 5Z-7-oxozeaenol exhibits antiviral activity against viruses from three unrelated RNA viral families with a high genetic barrier to resistance. These findings reveal regulation of poorly understood stages of the DENV life cycle via BIKE signaling and establish a proof-of-principle that pharmacological inhibition of BIKE can be potentially used as a broad-spectrum strategy against acute emerging viral infections.Exposure to hepatitis E virus (HEV) bears a high risk of developing chronic infection in immunocompromised patients, including organ transplant recipients and cancer patients. We aim to identify effective anti-HEV therapies through screening and repurposing safe-in-human broad-spectrum antiviral agents. In this study, a safe-in-human broad-spectrum antiviral drug library comprising of 94 agents was used. Upon screening, we identified gemcitabine, a widely used anti-cancer drug, as a potent inhibitor of HEV replication. The antiviral effect was confirmed in a range of cell culture models with genotype 1 and 3 HEV strains. As a cytidine analog, exogenous supplementation of pyrimidine nucleosides effectively reversed the antiviral activity of gemcitabine, but the level of pyrimidine nucleosides per se does not affect HEV replication. Surprisingly, similar to interferon-alpha (IFNα) treatment, gemcitabine activates STAT1 phosphorylation. This subsequently triggers activation of interferon-sensitive response element (ISRE) and transcription of interferon-stimulated genes (ISGs). Cytidine or uridine effectively inhibits gemcitabine-induced activation of ISRE and ISGs. As expected, JAK inhibitor 1 blocked IFNα, but not gemcitabine-induced STAT1 phosphorylation, ISRE/ISG activation, and anti-HEV activity. These effects of gemcitabine were completely lost in STAT1 knockout cells. In summary, gemcitabine potently inhibits HEV replication by triggering interferon-like response through STAT1 phosphorylation but independent of Janus kinases. This represents a non-canonical antiviral mechanism, which utilizes the innate defense machinery that is distinct from the classical interferon response. These results support repurposing gemcitabine for treating hepatitis E, especially for HEV-infected cancer patients, leading to dual anti-cancer and antiviral effects.

Macrophages (Mϕ) represent a major component of tumor tissues and play an important role in both tumor progression and therapeutic response. Although tumor Mϕ are generally considered to be derived from circulating monocytes, emerging evidence indicates that tissue Mϕ pools can be maintained by self-renewal. We aimed to elucidate the contribution, phenotype, and regulatory mechanisms of proliferating Mϕ in human hepatocellular carcinoma (HCC).

Flow cytometry analyses were performed to examine the presence and phenotype of proliferating Mϕ in fresh HCC tissues. Dual immunofluorescence staining was applied to analyze the prognostic value of proliferating Mϕ. The underlying regulatory mechanisms were examined using human monocyte-derived Mϕ.

Tumor-infiltrating Mϕ exhibited a significantly higher proliferative capacity than Mϕ in non-tumor tissues. A higher level of Mϕ proliferation was positively correlated with Mϕ density in the tumor and a poor prognosis in patients with HCC. Proliferating Mϕ were less dopment of strategies to target macrophages with high specificity and efficiency. The current study unveils a novel mechanism by which local proliferation is linked to macrophage accumulation in the tumor milieu, identifying potential targets for future immune-based anticancer therapies.

Tumor-associated macrophages (TAMs) have been reported to play an essential role in both tumor progression and therapeutic response. A fundamental understanding of the mechanisms that regulate macrophage accumulation in tumors will undoubtedly lead to the development of strategies to target macrophages with high specificity and efficiency. The current study unveils a novel mechanism by which local proliferation is linked to macrophage accumulation in the tumor milieu, identifying potential targets for future immune-based anticancer therapies.Women represent ⅔ of the cases of Alzheimer’s disease (AD). Current research has focused on differential risks to explain higher rates of AD in women. However, factors that reduce risk for AD, like cognitive/brain reserve, are less well explored. We asked what is known about sex and gender differences in how reserve mitigates risk for AD? We conducted a narrative review of the literature, with keywords „sex/gender differences”, „cognitive/brain reserve”, „Alzheimer’s Disease”, and the following cognitive reserve contributors „education”, „IQ”, „occupation”, „cognitive stimulation”, „bilingualism”, „socioeconomic status”, „physical activity”, „social support”. Sixteen papers disaggregated their data by sex. Those papers observed sex and gender differences in reserve contributors. There is also evidence that greater reserve may be more beneficial in lowering AD risk in women, although more research is needed. We discuss how traditional reserve contributors are gendered and may not capture factors that support cognition in aging women.Biological motion perception-our capacity to perceive the intrinsic motion of humans and animals-has been implicated as a precursor of social development in infancy. In the adult brain, several biological motion neural correlates have been identified; of particular importance, the right posterior superior temporal sulcus (rpSTS). We present a study, conducted with fNIRS, which measured brain activations in infants’ right posterior temporal region to point-light walkers, a standard stimulus category of biological motion perception studies. Seven-month-old infants (n = 23) participated in a within-subject blocked design with three experimental conditions and one baseline. Infants viewed an intact upright point-light walker of a person approaching the observer; the same point-light walker stimulus but inverted; and a selected frame from the point-light walker stimulus, approaching the viewer at constant velocity with no articulated motion, close to object motion. We found activations for both the upright and the inverted point-light walkers. The rigid moving point-light walker frame did not elicit any response consistent with a functional activation in this region. Our results suggest that biological motion is processed differently in the right middle posterior temporal cortex in infancy, and that articulated motion is a critical feature in biological motion processing at this early age.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting women of reproductive age. Cangfu Daotan Decoction (CFDTT) is one of the prescriptions in the stagnation of obesity-type PCOS. Our previous study showed that CFDTT treatment of obese PCOS was correlated with organic anion transporting polypeptides (OATPs).

Here, we studied the effects of CFDTT on obese PCOS and its underlying mechanism. We built an obese PCOS rat model and treated the rats with CFDTT. Then, we detected the serum levels of TCHO, TG, LDL-c, HDL-c, luteinizing hormone (LH), follicle stimulating growth hormone (FSH), testosterone (T), estradiol (E

), IL-1β, IL-6, and TNF-α in each group and adopted RT-PCR, western blotting and immunohistochemical staining to investigate the effects of CFDTT treatment on the expression of OATP2B1 and OATP3A1 in ovarian and uterine tissues. In addition, we compared the pregnancy outcomes of each group.

We found that CFDTT decreased the serum levels of TCHO, TG, LDL-c, LH, T, IL-1β, IL-6, and TNF-α and increased the levels of HDL-c, FSH and E

in a dose-dependent manner. CFDTT could induce the expression of OATP2B1 and OATP3A1 in ovarian and uterine tissues. Moreover, CFDTT could improve pregnancy outcomes.

These data suggested that the therapeutic mechanism of Cangfu Daotan Decoction on PCOS may be correlated with regulating lipid metabolism, sex hormone secretion and the inflammatory response and increasing OATP2B1 and OATP3A1 expression. Cangfu Daotan Decoction can be developed as a PCOS treatment drug.

These data suggested that the therapeutic mechanism of Cangfu Daotan Decoction on PCOS may be correlated with regulating lipid metabolism, sex hormone secretion and the inflammatory response and increasing OATP2B1 and OATP3A1 expression. Cangfu Daotan Decoction can be developed as a PCOS treatment drug.In June 2017, the Pennsylvania Department of Health (PADOH) was notified of multiple norovirus outbreaks associated with 179 ill individuals who attended separate events held at an outdoor venue and campground over a month period. Epidemiologic investigations were unable to identify a single exposure route and therefore unable to determine whether there was a persistent contamination source to target for exposure mitigation. Norovirus was detected in a fresh recreational water designated swimming area and a drinking water well. A hydrogeological site evaluation suggested a nearby septic leach field as a potential contamination source via ground water infiltration. Geological characterization revealed a steep dip of the bedrock beneath the septic leach field toward the well, providing a viral transport pathway in a geologic medium not previously documented as high risk for viral ground water contamination. The human-associated microbial source tracking (MST) genetic marker, HF183, was used as a microbial traceractices to mitigate exposure and prevent future outbreaks associated with human fecal contaminated waters.

Most data for Central Nervous System Tuberculosis (CNS-TB) derive from high-incidence, resource-limited countries. We sought to determine the presentation, management and outcomes of CNS-TB in a low-incidence setting with accessible healthcare.

We undertook a retrospective, observational study of CNS-TB in adults at a single tertiary-referral London hospital (2001-2017). Cases were categorised as either TB meningitis (TBM) or TB mass lesions without meningitis (TBML), applying novel criteria for definite, probable, and possible TBML.

We identified sixty-two cases of TBM (37% definite; 31% probable; 32% possible) alongside 14 TBML cases (36% definite; 29% probable; and 36% possible). Clinical presentation was highly variable. Among CSF parameters, hypoglycorrhachia proved most discriminatory for „definite” TBM. Neurosurgical intervention was required for mass-effect or hydrocephalus in 16%. Mortality was higher in TBM versus TBML (16% vs. 0%) but overall morbidity was significant; 33% of TBM and 29% of TBML survivors suffered persisting neurological disability at 12-months. In TBM, hydrocephalus, infarct, basal enhancement and low CSF white cell count were independently associated with worse neurological outcomes.

Although mortality was lower than previously reported in other settings, morbidity was significant, highlighting the need for improved CNS-TB diagnostics, therapeutics and interventions to mitigate neurological sequelae.

Although mortality was lower than previously reported in other settings, morbidity was significant, highlighting the need for improved CNS-TB diagnostics, therapeutics and interventions to mitigate neurological sequelae.Erol Başar was one of the most significant neuroscientists of the past century. Two main threads of thought guided Başar’s scientific labor i) the study of brain oscillations and ii) its marriage to basic principles of physics. These two threads provided him with the crucial element to introduce nonlinear random theory into brain research. Until the decade of the seventies, the underling paradigm in studying the electrical activity of the brain was dominated by a simplistic linear systems model that entailed absolute separation between a determinist evoked responses to stimuli and a superimposed background electrical activity considered as „noise”. Başar questioned this simplistic linear model and its interpretation. Başar underscored the nonlinear dynamics of the brain, demonstrated for the first time the interaction between evoked and background activity, and widened the study of event-related activity from the time domain to the frequency and time-frequency domain, heralding a new understanding of the event-related dynamics. These advances were a consequence of Başar’s fascination with the physics and mathematics of dynamical physical systems which he rightly believed to be the key to understanding the brain. Here we carry out a selected review, based on a scientometric analysis of Başar’s scientific trajectory in the field of Brain Dynamics as embodied in 278 peer-reviewed papers. We also report the geographical distribution of Başar’s collaborators, distribution of his citations, and his interaction with many international groups. This analysis illustrates the importance of his innovative contributions and the impact it had on our field. It underscores that he is one of the initiators of a „scientific revolution” in neurophysiology from linear systems to random non-linear systems analysis and the new vision of the brain as a dynamical system.We tested the effect of different intensities of acute exercise on hunger, and post-exercise energy intake, and neurophysiological measures of attention towards food- and non-food stimuli in women. In a within-subjects crossover design, forty-two women completed no exercise, moderate-intensity exercise, and vigorous-intensity exercise sessions separated by one week, in a counterbalanced fashion. At each session, participants completed a passive viewing task of food (high- and low-calorie) and non-food pictures while electroencephalogram (EEG) data were recorded. The early posterior negativity (EPN), P3, and late positive potential (LPP) components of the event-related potential (ERP) measured neurophysiological responses. Subjective ratings of hunger were measured before and immediately after each condition using a visual analog scale (VAS) and food intake was measured using an ad libitum snack buffet offered at the end of each condition. Results indicated that hunger levels increased as time passed for all sessions. EPN amplitude was larger to non-food compared to food images; P3 amplitude was larger to food than non-food stimuli. LPP amplitude did not differ by high-calorie, low-calorie, or non-food images. Notably, there were no significant main effects or interactions of any ERP component amplitude as a function of exercise intensity. Food intake also did not differ by rest or moderate or vigorous exercise, although subjective arousal ratings to the images were higher after moderate and vigorous exercise compared to rest. Food images also had higher arousal and valence ratings than non-food images overall. Findings indicate that, in this sample, acute moderate and vigorous exercise compared to rest did not disproportionately affect neurophysiological measures of attention to food or non-food stimuli, caloric intake, or hunger.

To determine the sensitivity to change of question 6 (Q6) of the modified short form version of the Urogenital Distress Inventory (UDI-6) before and after synthetic sling removal (SSR).

Following IRB approval, a prospectively maintained database of mid-urethral sling (MUS) complications identified women with UDI-6 Q6 data before and after SSR. Q6 were compared pre- and postoperatively and against patient self-report of pain in women undergoing -SSR for pain (SSR-P) and in a control group when pain was not the primary indication for SSR (SSR-C). Women with missing pre-SSR or insufficient (<6 months) follow-up measures of pain were excluded. Three hypotheses were tested. (1) Correlation of Q6 scores with patients’ self-reported pain pre- and post-SSR, (2) Higher pre-SSR Q6 scores in the SSR-P group than in the SSR-C group, and (3) Decrease in Q6 scores in the SSR-P group.

Between 2005 and 2017, 116 of 435 women referred to our institution met study criteria. Q6 scores were significantly (P <.0001) associated with self-reported pain with increasing likelihood of self-reporting pain as Q6 score increased. Mean pre-SSR Q6 scores in SSR-C (n=42) was 1.0 ± 1.2 while mean pre-SSR Q6 scores in SSR-P (n=74) was 2.3 ± 1.1 (P <.0001). Mean improvement in Q6 score after SSR was -0.19 ± 1.2 (P=0.3) in SSR-C and -0.88 ± 1.4 (P <0.0001) in SSR-P.

In women undergoing SSR for MUS-related complications, Q6 scores were correlated to self-reported pain and responsive to surgical intervention for pain relief.

In women undergoing SSR for MUS-related complications, Q6 scores were correlated to self-reported pain and responsive to surgical intervention for pain relief.

To demonstrate the safety and efficacy of testis-sparing surgery (TSS) in 2 specific circumstances small, nonpalpable masses suspected to be benign and masses suspicious for germ cell tumor in a solitary or functionally solitary testicle or bilateral disease.

Our institutional review board-approved testicular cancer registry was reviewed for men who underwent inguinal exploration with intent for TSS (2013-2020). The attempted TSS and completed TSS groups were evaluated for differences using Student’s t test for normally-distributed variables, chi-squared and Fisher’s exact tests for proportions, and Wilcoxon rank-sum test for nonparametric variables.

TSS was attempted in 28 patients and completed in 14. TSS was completed only if intraoperative frozen section demonstrated benign disease, except for 1 patient with stage I seminoma and solitary testicle. Sensitivity and specificity of frozen section analysis was 100% and 93%, respectively. There were no significant differences in demographics between attempted vs completed TSS cohorts. Median tumor size was significantly smaller in the completed TSS cohort (1.0 cm vs 1.7 cm, P=.03). In patients with unilateral masses without history of testis cancer, the testis was successfully spared in 9 of 22 cases (41%). In patients with bilateral disease or germ cell tumor in solitary testis, the testis was spared in 5 of 6 cases (83%). At a median follow up of 12.2 months, all patients were alive, and 27 of 28 had no evidence of disease (96%).

TSS is safe and effective for small, benign masses and in the setting of bilateral disease or tumor in a solitary testis.

TSS is safe and effective for small, benign masses and in the setting of bilateral disease or tumor in a solitary testis.Pembrolizumab was recently approved for treatment of cancers with high tumor mutational burden (TMB). We conduct a focused literature review of TMB as a predictive biomarker. TMB quantifies the sum of nonsynonymous coding mutations (typically single nucleotide substitutions and short insertion-deletions) per megabase of sequenced DNA. As a proxy for expression of immunogenic neoantigens, TMB may be an effective predictive biomarker for response to immune checkpoint inhibitors. However, like other biomarkers in this setting, TMB has many limitations; the effect of this FDA approval in the current management of genitourinary cancers is likely limited to select situations.

Some evidence suggests that depression is more common in obese patients. This fact gives us a hint that obesity might be a promoter of depression, though a conclusion can not be drawn. The aim of the study was (1) to confirm whether obesity induced by high-fat diet (HFD) promotes depression-like behaviors in mice, (2) to explore the protective role of insulin-like growth factor-1 (IGF-1) in such behavioral disorder of the animals and (3) to reveal whether mitochondrial mechanism was involved in such protective effect of the reagent.

C57BL/6J mice were fed with HFD to establish a model of obesity. Then, the animals were separately or simultaneously treated with PEG-IGF-1, 666-15 (CREB blocker) and SR-18292 (PGC-1α blocker). After that, depression-like behaviors were assessed using sucrose preference test and tail suspension test. In hippocampus, respiratory control ratio, ATP generation and red/green fluorescence ratio were adopted to reveal mitochondrial function. Also in hippocampus, expressions of p-CREB and PGC-1α were measured using western blotting.