First report of molecular epidemiology and phylogenetic characteristics of feline herpesvirus (FHV-1) from naturally infected cats in Kunshan, China.

BACKGROUND: Feline herpesvirus type 1 (FHV-1) is a life threatening highly contagious virus in cats and typically causes upper respiratory tract infections as well as conjunctival and corneal ulcers. Genetic variability could alter the severity of diseases and clinical signs. Despite regular vaccine practices against FHV-1 in China, new FHV-1 cases still commonly occur. The genetic and phylogenetic characteristics of FHV-1 in Kunshan city of China has not been studied yet. Therefore, this study was planned to investigate the prevalence, molecular characteristics of circulating strains, and phylogenetic analyses of FHV-1. This is the first report of molecular epidemiology and phylogenetic characteristics of FHV-1 from naturally infected cats in Kunshan, China. METHODS: The occulo-nasal swabs were collected from diseased cats showing respiratory distress, conjunctivitis, and corneal ulcers at different veterinary clinics in Kunshan from 2022 to 2023. Clinical data and general information were recorded. Swab samples were processed for preliminary detection of FHV-1. Thymidine kinase (TK), glycoprotein B (gB) and glycoprotein D (gD) genes were sequenced and analyzed to investigate genetic diversity and evolution of FHV-1. RESULTS: The FHV-1 genome was detected in 43 (43/200, 21.5%) samples using RT-PCR targeting the TK gene. Statistical analysis showed a significant correlation between age, vaccination status and living environment (p < 0.05) with FHV-1 positivity, while a non-significant correlation was observed for FHV-1 positivity and sex of cats (p > 0.05). Additionally, eight FHV-1 positive cats were co-infected with feline calicivirus (8/43,18.6%). FHV-1 identified in the present study was confirmed as FHV-1 based on phylogenetic analyses. The sequence analyses revealed that 43 FHV-1 strains identified in the present study did not differ much with reference strains within China and worldwide. A nucleotide homology of 99-100% was determined among gB, TK and gD genes nucleotide sequences when compared with standard strain C-27 and vaccine strains. Amino acid analysis showed some amino acid substitutions in TK, gB and gD protein sequences. A potential N-linked glycosylation site was observed in all TK protein sequences. Phylogenetic analyses revealed minor variations and short evolutionary distance among FHV-1 strains detected in this study. CONCLUSIONS: Our findings indicate that genomes of 43 FHV-1 strains are highly homogenous and antigenically similar, and the degree of variation in major envelope proteins between strains is low. This study demonstrated some useful data about prevalence, genetic characteristics, and evolution of FHV-1 in Kunshan, which may aid in future vaccine development.

Molecular epidemiology and phylogenetic analysis of feline calicivirus in Kunshan, China.

Feline calicivirus (FCV) is a highly contagious virus in cats, which typically causes respiratory tract and oral infections. Despite vaccination against FCV being a regular practice in China, new FCV cases still occur. Antigenic diversity of FCV hinders the effective control by vaccination. This is first report which aims to investigate the molecular epidemiology and molecular characteristics of FCV in Kunshan, China. The nasopharyngeal swabs were collected from cats showing variable clinical signs from different animal clinics in Kunshan from 2022 to 2023. Preliminary detection and sequencing of the FCV capsid gene were performed to study genetic diversity and evolutionary characteristics. FCV-RNA was identified in 52 (26%) of the samples using RT-PCR. A significant association was found between FCV-positive detection rate, age, gender, vaccination status and living environment, while a non-significant association was found with breed of cats. Nucleotide analysis revealed two genotypes, GI and GII. GII predominated in Kunshan, with diverse strains and amino acid variations potentially affecting vaccination efficacy and FCV detection. Notably, analysis pinpointed certain strains' association with FCV-virulent systemic disease pathotypes. This investigation sheds light on FCV dynamics, which may aid in developing better prevention strategies and future vaccine designs against circulating FCV genotypes.

Neuroendocrinology of bone.

The past decade has witnessed significant advances in our understanding of skeletal homeostasis and the mechanisms that mediate the loss of bone in primary and secondary osteoporosis. Recent breakthroughs have primarily emerged from identifying disease-causing mutations and phenocopying human bone disease in rodents. Notably, using genetically-modified rodent models, disrupting the reciprocal relationship with tropic pituitary hormone and effector hormones, we have learned that pituitary hormones have independent roles in skeletal physiology, beyond their effects exerted through target endocrine glands. The rise of follicle-stimulating hormone (FSH) in the late perimenopause may account, at least in part, for the rapid bone loss when estrogen is normal, while low thyroid-stimulating hormone (TSH) levels may contribute to the bone loss in thyrotoxicosis. Admittedly speculative, suppressed levels of adrenocorticotropic hormone (ACTH) may directly exacerbate bone loss in the setting of glucocorticoid-induced osteoporosis. Furthermore, beyond their established roles in reproduction and lactation, oxytocin and prolactin may affect intergenerational calcium transfer and therefore fetal skeletal mineralization, whereas elevated vasopressin levels in chronic hyponatremic states may increase the risk of bone loss.. Here, we discuss the interaction of each pituitary hormone in relation to its role in bone physiology and pathophysiology.

Generation of skin tone and pigmented region-modified images using a pigment discrimination model trained with an optical approach.

BACKGROUND: Skin tone and pigmented regions, associated with melanin and hemoglobin, are critical indicators of skin condition. While most prior research focuses on pigment analysis, the capability to simulate diverse pigmentation conditions could greatly broaden the range of applications. However, current methodologies have limitations in terms of numerical control and versatility. METHODS: We introduce a hybrid technique that integrates optical methods with deep learning to produce skin tone and pigmented region-modified images with numerical control. The pigment discrimination model produces melanin, hemoglobin, and shading maps from skin images. The outputs are reconstructed into skin images using a forward problem-solving approach, with model training aimed at minimizing the discrepancy between the reconstructed and input images. By adjusting the melanin and hemoglobin maps, we create pigment-modified images, allowing precise control over changes in melanin and hemoglobin levels. Changes in pigmentation are quantified using the individual typology angle (ITA) for skin tone and melanin and erythema indices for pigmented regions, validating the intended modifications. RESULTS: The pigment discrimination model achieved correlation coefficients with clinical equipment of 0.915 for melanin and 0.931 for hemoglobin. The alterations in the melanin and hemoglobin maps exhibit a proportional correlation with the ITA and pigment indices in both quantitative and qualitative assessments. Additionally, regions overlaying melanin and hemoglobin are demonstrated to verify independent adjustments. CONCLUSION: The proposed method offers an approach to generate modified images of skin tone and pigmented regions. Potential applications include visualizing alterations for clinical assessments, simulating the effects of skincare products, and generating datasets for deep learning.

Repurposing erectile dysfunction drugs tadalafil and vardenafil to increase bone mass.

We report that two widely-used drugs for erectile dysfunction, tadalafil and vardenafil, trigger bone gain in mice through a combination of anabolic and antiresorptive actions on the skeleton. Both drugs were found to enhance osteoblastic bone formation in vivo using a unique gene footprint and to inhibit osteoclast formation. The target enzyme, phosphodiesterase 5A (PDE5A), was found to be expressed in mouse and human bone as well as in specific brain regions, namely the locus coeruleus, raphe pallidus, and paraventricular nucleus of the hypothalamus. Localization of PDE5A in sympathetic neurons was confirmed by coimmunolabeling with dopamine ß-hydroxylase, as well as by retrograde bone-brain tracing using a sympathetic nerve-specific pseudorabies virus, PRV152. Both drugs elicited an antianabolic sympathetic imprint in osteoblasts, but with net bone gain. Unlike in humans, in whom vardenafil is more potent than tadalafil, the relative potencies were reversed with respect to their osteoprotective actions in mice. Structural modeling revealed a higher binding energy of tadalafil to mouse PDE5A compared with vardenafil, due to steric clashes of vardenafil with a single methionine residue at position 806 in mouse PDE5A. Collectively, our findings suggest that a balance between peripheral and central actions of PDE5A inhibitors on bone formation together with their antiresorptive actions specify the osteoprotective action of PDE5A blockade.

First-in-class humanized FSH blocking antibody targets bone and fat.

Blocking the action of FSH genetically or pharmacologically in mice reduces body fat, lowers serum cholesterol, and increases bone mass, making an anti-FSH agent a potential therapeutic for three global epidemics: obesity, osteoporosis, and hypercholesterolemia. Here, we report the generation, structure, and function of a first-in-class, fully humanized, epitope-specific FSH blocking antibody with a KD of 7 nM. Protein thermal shift, molecular dynamics, and fine mapping of the FSH-FSH receptor interface confirm stable binding of the Fab domain to two of five receptor-interacting residues of the FSHß subunit, which is sufficient to block its interaction with the FSH receptor. In doing so, the humanized antibody profoundly inhibited FSH action in cell-based assays, a prelude to further preclinical and clinical testing.

Bone-modifying agents for bone loss in patients with prostate cancer receiving androgen deprivation therapy; insights from a network meta-analysis.

BACKGROUND: The data of head-to-head comparisons of the effect of bone-modifying agents (BMAs) in patients with androgen deprivation therapy (ADT) for prostate cancer without skeletal metastasis is limited. Thus, we conducted a network meta-analysis to compare each BMA for the efficacy of bone mineral densities (BMDs) and the risk of fracture. METHODS: We performed a network meta-analysis to compare the change of BMDs and the risk of vertebral fracture in the studies included using a random-effect model. The primary outcomes are the change of BMD of the lumbar spine (LS) and the total hip (TH) from the baseline at 1 year from the initiation of the BMA and the risk of vertebral fracture. RESULTS: We identified and included 15 studies in this analysis. All BMAs except risedronate showed a significant increase of BMD of the LS compared with groups without BMA, among which zoledronate showed the most BMD gain. At TH, bisphosphonates (alendronate, pamidronate, and zoledronate) and denosumab showed significant elevation compared with the no-BMA group. Denosumab was associated with the most BMD gain at the TH. Only denosumab reduced the risk of vertebral fracture (relative risk [95% confidence interval]: 0.40 [0.20-0.81]). Although zoledronate showed the highest BMD gain at the LS, it did not reduce the risk of vertebral fracture in this analysis. CONCLUSION: Most bisphosphonates and denosumab significantly increased BMD at the LS and the TH in patients receiving ADT for prostate cancer without skeletal metastasis. In particular, zoledronate and denosumab were the most potent BMAs in terms of BMD increment at the LS and the TH, respectively. However, denosumab, not zoledronate, was the only BMA that showed a significant risk reduction of vertebral fracture. We need further studies to examine the change of bone quality and the effect on the risk of non-vertebral and hip fractures.

Mechanism of glucocerebrosidase activation and dysfunction in Gaucher disease unraveled by molecular dynamics and deep learning.

The lysosomal enzyme glucocerebrosidase-1 (GCase) catalyzes the cleavage of a major glycolipid glucosylceramide into glucose and ceramide. The absence of fully functional GCase leads to the accumulation of its lipid substrates in lysosomes, causing Gaucher disease, an autosomal recessive disorder that displays profound genotype-phenotype nonconcordance. More than 250 disease-causing mutations in GBA1, the gene encoding GCase, have been discovered, although only one of these, N370S, causes 70% of disease. Here, we have used a knowledge-based docking protocol that considers experimental data of protein-protein binding to generate a complex between GCase and its known facilitator protein saposin C (SAPC). Multiscale molecular-dynamics simulations were used to study lipid self-assembly, membrane insertion, and the dynamics of the interactions between different components of the complex. Deep learning was applied to propose a model that explains the mechanism of GCase activation, which requires SAPC. Notably, we find that conformational changes in the loops at the entrance of the substrate-binding site are stabilized by direct interactions with SAPC and that the loss of such interactions induced by N370S and another common mutation, L444P, result in destabilization of the complex and reduced GCase activation. Our findings provide an atomistic-level explanation for GCase activation and the precise mechanism through which N370S and L444P cause Gaucher disease.

Oxytocin regulates body composition.

The primitive neurohypophyseal nonapeptide oxytocin (OXT) has established functions in parturition, lactation, appetite, and social behavior. We have shown that OXT has direct actions on the mammalian skeleton, stimulating bone formation by osteoblasts and modulating the genesis and function of bone-resorbing osteoclasts. We deleted OXT receptors (OXTRs) selectively in osteoblasts and osteoclasts using Col2.3Cre and Acp5Cre mice, respectively. Both male and female Col2.3Cre+:Oxtrfl/fl mice recapitulate the low-bone mass phenotype of Oxtr+/- mice, suggesting that OXT has a prominent osteoblastic action in vivo. Furthermore, abolishment of the anabolic effect of estrogen in Col2.3Cre+:Oxtrfl/fl mice suggests that osteoblastic OXTRs are necessary for estrogen action. In addition, the high bone mass in Acp5Cre+:Oxtrfl/fl mice indicates a prominent action of OXT in stimulating osteoclastogenesis. In contrast, we found that in pregnant and lactating Col2.3Cre+:Oxtrfl/fl mice, elevated OXT inhibits bone resorption and rescues the bone loss otherwise noted during pregnancy and lactation. However, OXT does not contribute to ovariectomy-induced bone loss. Finally, we show that OXT acts directly on OXTRs on adipocytes to suppress the white-to-beige transition gene program. Despite this direct antibeiging action, injected OXT reduces total body fat, likely through an action on OXT-ergic neurons. Consistent with an antiobesity action of OXT, Oxt-/- and Oxtr-/- mice display increased total body fat. Overall, the actions of OXT on bone mass and body composition provide the framework for future therapies for osteoporosis and obesity.

FSIP1 regulates autophagy in breast cancer.

Fibrous sheath interacting protein 1 (FSIP1) is a cancer antigen expressed in the majority of breast cancer tissues and is associated with poor prognosis. However, the role of FSIP1 in the progression and drug sensitivity of triple-negative breast cancer (TNBC) has not been explored. Here, we show that FSIP1 deficiency by shRNA-mediated knockdown or CRISPR-Cas9-mediated knockout significantly inhibits the proliferation and invasion of TNBC cells and impairs chemotherapy-induced growth inhibition in vivo. Computational modeling predicted that FSIP1 binds to ULK1, and this was established by coimmunoprecipitation. FSIP1 deficiency promoted autophagy, enhanced AMP-activated protein kinase (AMPK) signaling, and decreased mechanistic target of rapamycin (mTOR) and Wnt/ß-catenin activity. In contrast, knockdown of AMPK or inhibition of autophagy restored the sensitivity to chemotherapy drugs in TNBC cells. Our findings uncover a role of FSIP1 as well as mechanisms underlying FSIP1 action in drug sensitivity and may, therefore, aid in design of TNBC therapies.

Epitope-specific monoclonal antibodies to FSHß increase bone mass.

Pituitary hormones have long been thought solely to regulate single targets. Challenging this paradigm, we discovered that both anterior and posterior pituitary hormones, including FSH, had other functions in physiology. We have shown that FSH regulates skeletal integrity, and, more recently, find that FSH inhibition reduces body fat and induces thermogenic adipose tissue. A polyclonal antibody raised against a short, receptor-binding epitope of FSHß was found not only to rescue bone loss postovariectomy, but also to display marked antiobesity and probeiging actions. Questioning whether a single agent could be used to treat two medical conditions of public health importance--osteoporosis and obesity--we developed two further monoclonal antibodies, Hf2 and Mf4, against computationally defined receptor-binding epitopes of FSHß. Hf2 has already been shown to reduce body weight and fat mass and cause beiging in mice on a high-fat diet. Here, we show that Hf2, which binds mouse Fsh in immunoprecipitation assays, also increases cortical thickness and trabecular bone volume, and microstructural parameters, in sham-operated and ovariectomized mice, noted on microcomputed tomography. This effect was largely recapitulated with Mf4, which inhibited bone resorption by osteoclasts and stimulated new bone formation by osteoblasts. These effects were exerted in the absence of alterations in serum estrogen in wild-type mice. We also reconfirm the existence of Fshrs in bone by documenting the specific binding of fluorescently labeled FSH, FSH-CH, in vivo. Our study provides the framework for the future development of an FSH-based therapeutic that could potentially target both bone and fat.

Bone modifying agents for bone loss in patients with aromatase inhibitor as adjuvant treatment for breast cancer; insights from a network meta-analysis.

PURPOSE: The data of head-to-head comparisons of the anti-fracture efficacy of bone modifying agents (BMAs) in patients with hormone receptor-positive breast cancer receiving aromatase inhibitor (AI) are not available. Therefore, we conducted a network meta-analysis to compare the efficacy of different BMAs in patients with breast cancer receiving adjuvant AI. METHODS: We performed a network meta-analysis to compare the change of bone mineral densities (BMDs) and the risk of fracture in the selected studies using a random effect model. The primary outcomes are the change of BMD of lumbar spine (LS) and total hip (TH) from the baseline (ΔBMD, %) at 1 and 2 years and the risk of fracture. RESULTS: We identified and included a total of 16 randomized controlled trials for this analysis. All BMAs included (risedronate, zoledronate, and denosumab) were associated with a significant increase in BMD of LS and TH at 1 and 2 years compared with no upfront treatment group. Among BMAs, zoledronate and denosumab use resulted in significantly higher BMD of LS and TH at 1 and 2 years compared with risedronate. The risk of fracture was significantly lower in the patients who received denosumab or risedronate compared with the patients without upfront treatment (Relative risk (RR) [95% CI] 0.51 [0.38-0.67] and 0.54 [0.35-0.83], respectively). CONCLUSION: Among the bisphosphonates, zoledronate increased BMD the most, but risedronate, not zoledronate, use was associated with lower risk of fracture. Denosumab increased BMD not only of LS but also of the cortical-bone-rich hip, and showed a significant reduction of fracture risk.

Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11ß-hydroxysteroid dehydrogenase type 2 deficiency.

Mutations in 11ß-hydroxysteroid dehydrogenase type 2 gene (HSD11B2) cause an extraordinarily rare autosomal recessive disorder, apparent mineralocorticoid excess (AME). AME is a form of low renin hypertension that is potentially fatal if untreated. Mutations in the HSD11B2 gene result either in severe AME or a milder phenotype (type 2 AME). To date, ∼40 causative mutations have been identified. As part of the International Consortium for Rare Steroid Disorders, we have diagnosed and followed the largest single worldwide cohort of 36 AME patients. Here, we present the genotype and clinical phenotype of these patients, prominently from consanguineous marriages in the Middle East, who display profound hypertension and hypokalemic alkalosis. To correlate mutations with phenotypic severity, we constructed a computational model of the HSD11B2 protein. Having used a similar strategy for the in silico evaluation of 150 mutations of CYP21A2, the disease-causing gene in congenital adrenal hyperplasia, we now provide a full structural explanation for the clinical severity of AME resulting from each known HSD11B2 missense mutation. We find that mutations that allow the formation of an inactive dimer, alter substrate/coenzyme binding, or impair structural stability of HSD11B2 yield severe AME. In contrast, mutations that cause an indirect disruption of substrate binding or mildly alter intramolecular interactions result in type 2 AME. A simple in silico evaluation of novel missense mutations could help predict the often-diverse phenotypes of an extremely rare monogenic disorder.

Combining SWNT and Graphene in Polymer Nanofibers: A Route to Unique Carbon Precursors for Electrochemical Capacitor Electrodes.

It is important to fabricate nanostructured architectures comprised of functional components for a wide variety of applications because precise structural control in the nanometer regime can yield unprecedented, fascinating properties. Owing to their well-defined microstructural characteristics, it has been popular to use carbon nanospecies, such as nanotubes and graphene, in fabricating nanocomposites and nanohybrids. Nevertheless, it still remains hard to control and manipulate nanospecies for specific applications, thus preventing their commercialization. Herein, first, we report unique one-dimensional nanoarchitectures with meso-/macropores, consisting of single-walled nanotubes (SWNTs), graphene, and polyacrylonitrile, in which poly(vinyl alcohol) was employed as a dispersing agent and sacrificial porogen. One-dimensional SWNTs and two-dimensional graphene pieces were combined in the confined interior space of electrospun nanofibers, which led to unique microstructural characteristics such as enhanced ordering of SWNTs, graphene pieces, and polymer chains in the nanofiber interior. Next, the SWNT/graphene-in-polymer nanofiber (SGPNF) structures were converted into carbonized products (SGCNFs) with effective porosity and tunable electrochemical properties. Similar to SGPNFs, the microstructural and electrical properties of the SGCNFs depended on the incorporated amount of SWNT and graphene. At higher SWNT content, the mesopore volume proportion and specific discharge capacitance of the SGCNFs increased by max. 63 and 598%, respectively. The SGCNFs showed strong potential as a high-performance electrode material for electrochemical capacitors (max. capacitance: nonactivated ∼390 F g-1 and activated ∼750 F g-1). Flexible, all solid-state capacitor cells based on SGCNFs were also successfully demonstrated as a model application. The SGCNFs can be further functionalized by various methods, which will impart attractive properties for extended applications.

Association between site-specific bone mineral density and glucose homeostasis and anthropometric traits in healthy men and women.

OBJECTIVE: Patients with type 2 diabetes mellitus have an increased risk of fracture despite normal or increased bone mineral density (BMD). Studies on the relationship of glucose homeostasis with BMD phenotypes have been inconclusive because distinguishing the roles of insulin resistance and hyperglycaemia in bone remodelling is challenging. In this study, we sought to define the relationship of site-specific BMD with glucose homeostasis traits and anthropometric traits. DESIGN/PATIENTS/MEASUREMENTS: In a cross-sectional study, we examined 787 subjects from the Mexican-American Coronary Artery Disease (MACAD) cohort who had undergone euglycaemic-hyperinsulinaemic clamps, oral glucose tolerance testing and dual X-ray absorptiometry. Glucose homeostasis traits included insulinogenic index (IGI30), insulin sensitivity (M value), insulin clearance (MCRI), fasting insulin, fasting glucose and 2-hour glucose. Univariate and multivariate analyses were performed to assess the association of glucose homeostasis and anthropometric traits with site-specific BMD. RESULTS: Two-hour glucose was negatively associated with arm BMD in women, which remained significant in multivariate analysis (ß = -.15, P = .0015). Positive correlations between fasting insulin and BMD at weight-bearing sites, including pelvis (ß = .22, P < .0001) and legs (ß = .17, P = .001) in women and pelvis (ß = .33, P < .0001) in men, lost significance after multivariate adjustment. Lean mass exhibited strong independent positive associations with BMD at multiple sites in both sexes. CONCLUSION: Our findings suggest that (i) anabolic effects of insulin might work via mechanical loading from lean mass; (ii) a direct negative effect of increasing glucose might be more prominent at cortical-bone-rich sites in women; and (iii) lean mass is a strong positive predictor of bone mass.

Repurposing of bisphosphonates for the prevention and therapy of nonsmall cell lung and breast cancer.

A variety of human cancers, including nonsmall cell lung (NSCLC), breast, and colon cancers, are driven by the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases. Having shown that bisphosphonates, a class of drugs used widely for the therapy of osteoporosis and metastatic bone disease, reduce cancer cell viability by targeting HER1, we explored their potential utility in the prevention and therapy of HER-driven cancers. We show that bisphosphonates inhibit colony formation by HER1(ΔE746-A750)-driven HCC827 NSCLCs and HER1(wt)-expressing MB231 triple negative breast cancers, but not by HER(low)-SW620 colon cancers. In parallel, oral gavage with bisphosphonates of mice xenografted with HCC827 or MB231 cells led to a significant reduction in tumor volume in both treatment and prevention protocols. This result was not seen with mice harboring HER(low) SW620 xenografts. We next explored whether bisphosphonates can serve as adjunctive therapies to tyrosine kinase inhibitors (TKIs), namely gefitinib and erlotinib, and whether the drugs can target TKI-resistant NSCLCs. In silico docking, together with molecular dynamics and anisotropic network modeling, showed that bisphosphonates bind to TKIs within the HER1 kinase domain. As predicted from this combinatorial binding, bisphosphonates enhanced the effects of TKIs in reducing cell viability and driving tumor regression in mice. Impressively, the drugs also overcame erlotinib resistance acquired through the gatekeeper mutation T790M, thus offering an option for TKI-resistant NSCLCs. We suggest that bisphosphonates can potentially be repurposed for the prevention and adjunctive therapy of HER1-driven cancers.

Bisphosphonates inactivate human EGFRs to exert antitumor actions.

Bisphosphonates are the most commonly prescribed medicines for osteoporosis and skeletal metastases. The drugs have also been shown to reduce cancer progression, but only in certain patient subgroups, suggesting that there is a molecular entity that mediates bisphosphonate action on tumor cells. Using connectivity mapping, we identified human epidermal growth factor receptors (human EGFR or HER) as a potential new molecular entity for bisphosphonate action. Protein thermal shift and cell-free kinase assays, together with computational modeling, demonstrated that N-containing bisphosphonates directly bind to the kinase domain of HER1/2 to cause a global reduction in downstream signaling. By doing so, the drugs kill lung, breast, and colon cancer cells that are driven by activating mutations or overexpression of HER1. Knocking down HER isoforms thus abrogates cell killing by bisphosphonates, establishing complete HER dependence and ruling out a significant role for other receptor tyrosine kinases or the enzyme farnesyl pyrophosphate synthase. Consistent with this finding, colon cancer cells expressing low levels of HER do not respond to bisphosphonates. The results suggest that bisphosphonates can potentially be repurposed for the prevention and therapy of HER family-driven cancers.

The effect of chlormadinone acetate on odontogenic differentiation of human dental pulp cells: in vitro study.

BACKGROUND: Chlormadinone acetate (CMA) is a derivative of progesterone and is used as an oral contraceptive. The aim of this study was to investigate the effects of CMA on odontogenic differentiation and mineralization of human dental pulp cells (hDPCs) and related signaling pathways. METHODS: Cell viability was determined by the water-soluble tetrazolium (WST)-1 assay. Odontogenic differentiation of hDPCs was evaluated by real-time polymerase chain reaction using odontogenic marker genes, such as alkaline phosphatase (ALP), osteocalcin (OCN), dentin sialophosphoprotein (DSPP), and dentin matrix protein-1 (DMP-1). Mineralization of hDPCs was evaluated by ALP staining and alizarin red staining. The extracellular signal-regulated kinase (ERK) pathway was examined by Western blot analysis. RESULTS: There was no statistically significant difference in cell viability between the control and CMA-treated groups. Our analysis of odontogenic marker genes indicated that CMA enhanced the expression of those genes. CMA-treated hDPCs showed increased ALP activity and formation of mineralized nodules, compared with control-treated cells. In addition, CMA stimulation resulted in phosphorylation of ERK and resulted in inhibition of downstream molecules by the ERK inhibitor U0126. CONCLUSIONS: These findings suggest that CMA improves odontogenic differentiation and mineralization of hDPCs through the ERK signaling pathway.

Reduction of graphene oxide/alginate composite hydrogels for enhanced adsorption of hydrophobic compounds.

Carbon-based materials, consisting of graphene oxide (GO) or reduced GO (rGO), possess unique abilities to interact with various molecules. In particular, rGO materials hold great promise for adsorption and delivery applications of hydrophobic molecules. However, conventional production and/or usage of rGO in aqueous solution often causes severe aggregation due to its low water solubility and thus difficulties in handling and applications. In our study, to prevent the severe aggregation of GO during reduction and to achieve a high adsorption capacity with hydrophobic compounds, GO/alginate composite hydrogels were first prepared and then reduced in an aqueous ascorbic acid solution at 37 °C. Adsorption studies with a model hydrophobic substance, rhodamine B, revealed that the reduced composite hydrogels are more highly absorbent than the unreduced hydrogels. In addition, the adsorption properties of the composite hydrogels, which are consequences of hydrophobic and ionic interactions, could be modulated by controlling the degree of reduction for the adsorption of different molecules. The composite hydrogels embedding rGO can be very useful in applications related to drug delivery, waste treatment, and biosensing.

First record of Cosmocephalus obvelatus (Acuariidae) in common gulls (Larus canus) from Gangneung, Korea.

A nematode species belonging to the genus Cosmocephalus was collected from the stomach of 2 common gulls, Larus canus. The common gulls were found dead on the seaside of Gangneung City, the Republic of Korea. The worms were identified and classified by light (LM) and scanning electron microscopy (SEM) on the basis of important taxonomic characters. The nematodes were characterized by a body length 9.1-9.3 mm (males) and 15.5-15.9 mm (females) and cordons recurrent in anterior direction and anastomosing laterally at about the level of anterior quarter of the buccal cavity. The salient bicuspid deirids were located on the posterior to the cordons. Lateral alae were well-developed, extending from the level just posterior of deirids to the level about middle of the body. LM and SEM observations identified the worms as C. obvelatus. This is the first reported case of C. obvelatus infection in common gulls in Korea.