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Background: Multiple myeloma is a plasma cell neoplasm with acquired genetic abnormalities of clinical and prognostic importance. Multiple myeloma differs from other hematologic malignancies due to a high fraction of low proliferating malignant plasma cells and the paucity of plasma cells in bone marrow aspiration samples, making cytogenetic analysis a challenge. An abnormal karyotype is found in only one-third of patients with multiple myeloma and interphase fluorescence in situ hybridization is the most useful test for studying the chromosomal abnormalities present in almost 90% of cases. However, it is necessary to study the genetic abnormalities in plasma cells after their identification or selection by morphology, immunophenotyping or sorting. Other challenges are the selection of the most informative FISH panel and determining cut-off levels for FISH probes. This study reports the validation of interphase fluorescence in situ hybridization using CD138 positive cells, according to proposed guidelines published by the European Myeloma Network (EMN) in 2012. Method: Bone marrow samples from patients with multiple myeloma were used to standardize a panel of five probes [1q amplification, 13q14 deletion, 17p deletion, t(4;14), and t(14;16)] in CD138+ cells purified by magnetic cell sorting. Results: This test was validated with a low turnaround time and good reproducibility. Five of six samples showed genetic abnormalities. Monosomy/deletion 13 plus t(4;14) were found in two cases. Conclusion: This technique together with magnetic cell sorting is effective and can be used in the routine laboratory practice. In addition, magnetic cell sorting provides a pure plasma cell population that allows other molecular and genomic studies. [ABSTRACT FROM AUTHOR]

Chemotaxonomic metabolite profiling of 62 indigenous Korean plant species was performed by ultrahigh performance liquid chromatography (UHPLC)-linear trap quadrupole-ion trap (LTQ-IT) mass spectrometry/mass spectrometry (MS/MS) combined with multivariate statistical analysis. In partial least squares discriminant analysis (PLS-DA), the 62 species clustered depending on their phylogenetic family, in particular, Aceraceae, Betulaceae, and Fagaceae were distinguished from Rosaceae, Fabaceae, and Asteraceae. Quinic acid, gallic acid, quercetin, quercetin derivatives, kaempferol, and kaempferol derivatives were identified as family-specific metabolites, and were found in relatively high concentrations in Aceraceae, Betulaceae, and Fagaceae. Fagaceae and Asteraceae were selected based on results of PLS-DA and bioactivities to determine the correlation between metabolic differences among plant families and bioactivities. Quinic acid, quercetin, kaempferol, quercetin derivatives, and kaempferol derivatives were found in higher concentrations in Fagaceae than in Asteraceae, and were positively correlated with antioxidant and tyrosinase inhibition activities. These results suggest that metabolite profiling was a useful tool for finding the different metabolic states of each plant family and understanding the correlation between metabolites and bioactivities in accordance with plant family. [ABSTRACT FROM AUTHOR]

It has become almost paradigmatic in the coral reef literature that fishing-induced reductions of parrotfish abundance cause benthic phase shifts from coral to macroalgal dominance. This study examined the alternatives of top-down control of the benthos by parrotfish density and bottom-up control of parrotfish density by the benthos at four Philippine islands in a long-term (7.5-30 years) 'natural experiment'. No-take marine reserves (NTMRs) demonstrated that fishing reduced parrotfish density significantly at two islands (Sumilon, Mantigue), but not significantly at two other islands (Apo, Selinog). There was no evidence that cover of hard coral decreased, nor macroalgal cover increased, in fished areas relative to NTMRs, no evidence that parrotfish density affected hard coral cover significantly, and thus no evidence of top-down, fishing-induced benthic phase shifts at all four islands. There was, however, compelling evidence that benthos (cover of dead substrata and hard coral) exerted strong bottom-up control on parrotfish density. This bottom-up control was demonstrated most clearly by major environmental disturbances (e.g. typhoons, coral bleaching) that changed benthic habitat and, subsequently, parrotfish density. As hard coral cover declined (and cover of dead substratum increased), parrotfish density increased and vice versa. This response occurred in both major parrotfish feeding guilds (scrapers and excavators). This long-term study on heavily fished coral reefs suggests that the benthos drives the parrotfish, not the other way around. The paradigm of fishing-induced benthic phase shifts may not apply to all coral reefs at all times. Multiple drivers of benthic change on coral reefs should always be considered. [ABSTRACT FROM AUTHOR]

The article focuses on a study on time-dependent correlation of the microbial community and the metabolomics of barley nuruk starter fermentation. It states that the samples in the study were analyzed by the Polymerase Chain Reaction (PCR)- Denaturing Gradient Gel Electrophoresis (DGGE) and real-time PCR (qPCR) and metabolites were analyzed by Gas chromatography–mass spectrometry (GC-MS). It mentions that the study concludes the predominance of Aspergillus oryzae throughout fermentation.

For captive animals, living in barren conditions leads to stereotypic behaviour that is hard to alleviate using environmental enrichment. This resistance to enrichment is often explained via mechanisms that decouple abnormal behaviour from current welfare, such as ‘establishment’: a hypothetical process whereby repetition increases behaviour’s predictability and resistance to change. If such hypotheses are correct, then animals with enrichment-resistant stereotypic behaviour should still find enrichments rewarding. Alternatively, this behaviour could reflect a failure to improve welfare: plausible because age and chronic stress increase neophobia and anhedonia. If this hypothesis is correct, animals with enrichment-resistant stereotypic behaviour should value enrichments less than conspecifics. We tested these hypotheses using C57BL/6 mice, Mus musculus, aged 10–11 and 6–7 months, raised in barren laboratory cages. We observed their behaviour in both these and large enriched cages. Enrichment was more effective on the younger animals. However, contrary to ideas about establishment, the spontaneous predictability of stereotypic behaviour did not increase with age; nor was enrichment less effective on more predictable or time-consuming forms. We assessed the reward value of enriched cages by allowing access via progressively weighted doors (maximum weight pushed corresponding to peak motivation). In older mice, those individuals whose stereotypic behaviour was least reduced by enrichment were also the least motivated to gain access to enrichment. This suggests that the welfare of middle-aged-animals, as well as their stereotypic behaviour, is harder to improve using environmental enrichment. [ABSTRACT FROM AUTHOR]

Abstract: Contrafreeloading is the phenomenon that animals prefer to “work” for food even though “free” food is available nearby. In this study, we investigated whether pigs express contrafreeloading in a test situation where the searching, finding and consuming of food items resembles a natural foraging situation. For that purpose, we investigated whether pigs prefer an environment with straw and hidden food rewards (chocolate raisins) to an environment with straw, but without hidden food rewards and with food rewards “freely” available in a trough. Preference behaviour was investigated in a Conditioned Place Preference task (CPP). Typically, CPP measures the conditioned preference in the absence of reinforcers so that unwanted interference with the reinforcers during testing does not take place. The results show that (a) CPP can be used to establish the preference of pigs for different environments (experiments 1–4); (b) that pigs prefer to forage for food over “freely” available food from a trough (experiment 3) and (c) that anticipating a food reward has reinforcing effects above and beyond the reinforcing effects of acquisition of a food reward alone (experiment 4). The results therefore show that pigs express contrafreeloading when using a natural foraging task and they suggest that the reinforcing effects of anticipation, which occurs during natural foraging in the delays between searching and finding food, may contribute to the observed expression of contrafreeloading in pigs. [Copyright &y& Elsevier]

Kaplan-Meier graphs indicating the probability of primary tumour growth comparing (D) implantation site or (E) mouse strain, where "event" is detection of tumour growth and censored when no tumour was detected at time of necropsy. Tumor grafts derived from women with breast cancer authentically reflect tumor pathology, growth, metastasis and disease outcomes. Post-operative minimal residual disease models to study metastatic relapse in soft-tissue sarcoma patient-derived xenografts (A) Animals were followed until metastasis, or until 12 months post primary tumour resection if no metastases developed, or until 18 months (78 weeks) post tumour implantation if no primary tumour developed. [Extracted from the article]

Skeletal muscle serves an important role in the utilization of glucose during insulin‑stimulated conditions. Excessive saturated fatty acids are considered to be a major contributing factor to insulin resistance in skeletal muscle cells. The present study investigated the effects of hispidin on palmitate‑induced insulin resistance in C2C12 skeletal muscle myotubes via an MTT assay, glucose uptake assay, Oil‑Red‑O staining and western blot analysis. Hispidin reversed the palmitate‑induced inhibition of glucose uptake, and inhibited palmitate‑induced intracellular lipid accumulation. Hispidin suppressed insulin receptor substrate‑1 Ser307 phosphorylation, and significantly promoted the activation of phosphatidylinositol‑3‑kinase and Akt, via inhibition of protein kinase C theta. Furthermore, hispidin treatment of C2C12 muscle cells increased glucose uptake via activation of adenosine monophosphate‑activated protein kinase. These findings indicated that hispidin may improve palmitate‑induced insulin resistance in skeletal muscle myotubes, and therefore hispidin treatment may be beneficial for patients with diabetes. [ABSTRACT FROM AUTHOR]

Context: Pinus densiflora Siebold & Zucc. (Pinaceae) needle extracts ameliorate oxidative stress, but research into their anti-inflammatory effects is limited. Objective: To investigate antioxidant and anti-inflammatory effects of a Pinus densiflora needles (PINE) ethanol extract in vitro and in vivo. Materials and methods: We measured levels of reactive oxygen species (ROS), superoxide dismutase (SOD) and inflammatory mediators in lipopolysaccharide (LPS)-stimulated RAW264.7 cells at various PINE concentrations (25, 50 and 100 lg/mL; but 6.25, 12.5 and 25 lg/mL for interleukin-1b and prostaglandin E2 (PGE2)). Thirty ICR mice were randomized to six groups: vehicle, control, PINE pre-treatment (0.1, 0.3 and 1 mg/left ear for 10 min followed by arachidonic acid treatment for 30 min) and dexamethasone. The posttreatment ear thickness and myeloperoxidase (MPO) activity were measured. Results: PINE 100 lg/mL significantly decreased ROS (IC50, 70.93 lg/mL, p<0.01), SOD (IC50, 30.99 lg/mL, p<0.05), malondialdehyde (p<0.01), nitric oxide (NO) (IC50, 27.44 lg/mL, p<0.01) and tumour necrosis factor-alpha (p<0.05) levels. Interleukin-1b (p<0.05) and PGE2 (p<0.01) release decreased significantly with 25 lg/mL PINE. PINE 1mg/ear inhibited LPS-stimulated expression of cyclooxygenase-2 and inducible NO synthase in RAW264.7 macrophages and significantly inhibited ear oedema (36.73-15.04% compared to the control, p<0.01) and MPO activity (167.94-105.59%, p<0.05). Discussion and conclusions: PINE exerts antioxidant and anti-inflammatory effects by inhibiting the production of inflammatory mediators. Identified flavonoids such as taxifolin and quercetin glucoside can be attributed to effect of PINE. [ABSTRACT FROM AUTHOR]

A number of polysaccharides exhibit pharmacological activities. Polysaccharides derived from Inonotus obliquus (PLIO) appear to have various potential pharmacological properties, including anti-tumor activity. However, the molecular mechanisms underlying these properties remain to be elucidated. The present study investigated the anti-metastatic potential of PLIO and the underlying signaling pathways in B16-F10 murine melanoma cells using the MTT colorimetric assay, in vitro migration and invasion assays, and flow cytometric and western blot analyses. PLIO inhibited the invasion of B16-F10 cells and suppressed the expression of matrix metalloproteinases. PLIO treatment inhibited nuclear factor-κB (NF-κB) nuclear translocation in B16-F10 cells. In addition, PLIO treatment inhibited the phosphorylation of c-Jun N-terminal kinases and AKT. These results suggest that PLIO may suppress the invasion of highly metastatic melanoma cells via inhibition of the AKT/NF-κB signaling pathways. [ABSTRACT FROM AUTHOR]

The purpose of the present study was to elucidate the cytoprotective effects of polysaccharides isolated from Inonotus obliquus. The polysaccharides were extracted from the fruiting body of I. obliquus (PFIO) and the liquid culture broth of I. obliquus (PLIO). The effects of PFIO and PLIO on hydrogen peroxide (H2O2)-induced oxidative damage of RINm5F pancreatic β-cells were comparatively investigated using an MTT assay, immunofluorescent staining, flow cytometry, and western blot analyses in vitro. The results of the present study demonstrated that treatment with PFIO and PLIO decreased DNA fragmentation and the rate of apoptosis. In addition, pretreatment of cells with PFIO and PLIO prior to H2O2 exposure resulted in increased insulin secretion and scavenging activity for intracellular reactive oxygen species, as compared with treatment with H2O2 alone. The results of the present study suggested that PFIO and PLIO may exert protective effects against H2O2-induced oxidative stress via the regulation of mitogen-activated protein kinases, nuclear factor-κB and apoptotic proteins. Therefore, PFIO and PLIO may have potential merit as a medicinal food for the prevention of diabetes. [ABSTRACT FROM AUTHOR]

Aurora kinase A (AURKA) is a well-established target in neuroblastoma (NB) due to both its catalytic functions during mitosis and its kinase-independent functions, including stabilization of the key oncoprotein MYCN. We present a structure-activity relationship (SAR) study of MK-5108-derived PROTACs against AURKA by exploring different linker lengths and exit vectors on the thalidomide moiety. PROTAC SK2188 induces the most potent AURKA degradation (DC 50,24h 3.9 nM, D max,24h 89%) and shows an excellent binding and degradation selectivity profile. Treatment of NGP neuroblastoma cells with SK2188 induced concomitant MYCN degradation, high replication stress/DNA damage levels and apoptosis. Moreover, SK2188 significantly outperforms the parent inhibitor MK-5108 in a cell proliferation screen and patient-derived organoids. Furthermore, altering the attachment point of the PEG linker to the 5-position of thalidomide allowed us to identify a potent AURKA degrader with a linker as short as 2 PEG units. With this, our SAR-study provides interesting lead structures for further optimization and validation of AURKA degradation as a potential therapeutic strategy in neuroblastoma. [Display omitted] • A SAR-study of MK-5108-based PROTACs was performed in a neuroblastoma context. • PROTAC SK2188 emerged as the most potent AURKA degrader (DC 50 3.9 nM, D max 89%). • SK2188 shows an excellent AURKA binding and degradation selectivity profile. • PROTAC SK2188 outperforms MK-5108 in NB cell lines and patient-derived organoids. • Exit vector switch on thalidomide allows to construct PROTACs with shorter linkers. [ABSTRACT FROM AUTHOR]

The article discusses court cases related to the insurance coverage litigation in the U.S. The legal cases mentioned in the article include, plaintiff Universal Mortgage Corp. versus defendant Wurttembergische Versigherung AG, petitioner Keene Corp. versus respondent Insurance Co. of North America, and plaintiff Laura Butler versus defendant Union Carbide Corp. The judgements taken by the U.S. courts in all these cases have been focused in the article.

The article focuses on the developments in insurance coverage litigation in the U.S. It notes that there have been many developments in the law that governs the resolution of insurance coverage disputes in a countrywide perspective. It identifies emerging case law which may be important to insurance coverage practitioners in the future. It addresses cases and judgments pertaining to insurance coverage disputes. Furthermore, it discusses important developments arising in the insurance industry such as fidelity bonds, commercial general liability (CGL) policies, and directors and officers (D & O) coverage.

In Aspergillus nidulans, mutation of the transcriptional regulator brlA arrests formation of asexual spore-forming structures called conidiophores but does not hinder vegetative hyphal growth. During conidiophore development a 6-fold, brlA-dependent increase in the kinase activities of NIMXcdc2 and NIMA occurs. A similar level of kinase induction was promoted by ectopic expression of brlA. Northern and Western analysis revealed marked induction of nimXcdc2 mRNA after ectopic expression of brlA and increased amounts of NIMXcdc2. Therefore, nimXcdc2 is developmentally regulated by brlA indicating a direct role for brlA in the regulation of cell cycle genes. That correct regulation of nimXcdc2 is important for normal development was further supported by analysis of conidiophore development and septation in cell cycle specific mutants. Most noticeably, the nimXcdc2AF mutation promoted inappropriate septation and hindered the switch from filamentous growth to budding growth seen during conidiophore development. Therefore, in contrast to the situation previously reported for other multicellular eukaryotes, interaction between developmental regulators and cell cycle regulators is essential for normal morphogenesis in A.nidulans. [ABSTRACT FROM AUTHOR]