BET inhibitors exhibit broad activity in cancer models, making predictive biomarkers challenging to define. Here we investigate the biomarkers of activity of the clinical BET inhibitor GSK525762 (I-BET; I-BET762) across cancer cell lines and demonstrate that KRAS mutations are novel resistance biomarkers. This finding led us to combine BET with RAS pathway inhibition using MEK inhibitors to overcome resistance, which resulted in synergistic effects on growth and survival in RAS pathway mutant models as well as a subset of cell lines lacking RAS pathway mutations. GSK525762 treatment up-regulated p-ERK1/2 levels in both RAS pathway wild-type and mutant cell lines, suggesting that MEK/ERK pathway activation may also be a mechanism of adaptive BET inhibitor resistance. Importantly, gene expression studies demonstrated that the BET/MEK combination uniquely sustains down-regulation of genes associated with mitosis, leading to prolonged growth arrest that is not observed with either single agent therapy. These studies highlight a potential to enhance the clinical benefit of BET and MEK inhibitors and provide a strong rationale for clinical evaluation of BET/MEK combination therapies in cancer.

As a circadian organ, liver executes diverse functions in different phase of the circadian clock. This process is believed to be driven by a transcription program. Here, we present a transcription factor (TF) DNA-binding activity-centered multi-dimensional proteomics landscape of the mouse liver, which includes DNA-binding profiles of different TFs, phosphorylation, and ubiquitylation patterns, the nuclear sub-proteome, the whole proteome as well as the transcriptome, to portray the hierarchical circadian clock network of this tissue. The TF DNA-binding activity indicates diurnal oscillation in four major pathways, namely the immune response, glucose metabolism, fatty acid metabolism, and the cell cycle. We also isolate the mouse liver Kupffer cells and measure their proteomes during the circadian cycle to reveal a cell-type resolved circadian clock. These comprehensive data sets provide a rich data resource for the understanding of mouse hepatic physiology around the circadian clock.

Transforming growth factor-β1 (TGF-β1) induces phenotypic changes in fibroblasts to become myofibroblasts with increased production of extracellular matrix (ECM) components and cytokines. It is also known that excessive activation of myofibroblasts accelerates cardiac fibrosis, remodeling, and thus cardiac dysfunction. However, no effective therapy has been established to prevent this process although recent clinical studies have demonstrated the effectiveness of hyperthermia in cardiac dysfunction. The aim of this study was to examine the molecular mechanism of hyperthermia on TGF-β1-mediated phenotypic changes in cardiac fibroblasts. TGF-β1 increased the expression of IL-6, α-smooth muscle actin (α-SMA), and collagen in human cardiac fibroblasts (HCFs). Hyperthermia (42 °C) significantly prevented these changes, i.e., increases in IL-6, α-SMA, and collagen, as induced by TGF-β1 in a time-dependent manner. Immunoblotting showed that hyperthermia decreased Akt/S6K signaling, but did not affect Smad2 and Smad3 signaling. Pharmacological inhibition of Akt signaling mimicked these effects of hyperthermia. Furthermore, hyperthermia treatment prevented cardiac fibrosis in Ang II infusion mice model. Putting together, our findings suggest that hyperthermia directly inhibits TGF-β-mediated activation of HCFs via suppressing Akt/S6K signaling.

Two major phospholipase D (PLD) isozymes in mammals, PLD1 and PLD2, hydrolyze the membrane phospholipid phosphatidylcholine to choline and the lipid messenger phosphatidic acid. Although their roles in cancer cells have been well studied, their functions in tumor microenvironment have not yet been clarified. Here, we demonstrate that PLD2 in cytotoxic CD8+ T cells plays a crucial role in anti-tumor immunity by regulating their cell proliferation. We found that growth of tumors formed by subcutaneously transplanted cancer cells is enhanced in Pld2-knockout mice. Interestingly, this phenotype was found to be at least in part attributable to the ablation of Pld2 from bone marrow cells. The number of CD8+ T cells, which induce cancer cell death, significantly decreased in the tumor produced in Pld2-knockout mice. In addition, CD3/CD28-stimulated proliferation of primary cultured splenic CD8+ T cells is markedly suppressed by Pld2 ablation. Finally, CD3/CD28-dependent activation of Erk1/2 and Ras is inhibited in Pld2-deleted CD8+ T cells. Collectively, these results indicate that PLD2 in CD8+ T cells plays a key role in their proliferation through activation of the Ras/Erk signaling pathway, thereby regulating anti-tumor immunity.

Image processing and enhancement filters can significantly improve the diagnostic value of digital radiographs. Evidence shows that increasing the contrast and filtering improve the diagnostic accuracy for caries detection. This study sought to assess the diagnostic accuracy of original and enhanced digital radiographs for the detection of approximal and occlusal caries.

This study aimed to describe the morphological and morphometric aspects of fused mandibular second molars with radicular shallow grooves using micro-computed tomography (CT).

The purpose of the present study was to identify the variability of blood pressure response to a 10-week resistance training (RT) program in hypertensive and normotensive elderly women.

The aim of this study is to improve the anti-biofilm activity of antibiotics. We hypothesized that the antimicrobial peptide (AMP) complex of the host's immune system can be used for this purpose and examined the assumption on model biofilms.

A new subterranean species of pseudocrangonyctid amphipod, Pseudocrangonyx daejeonensissp. n. is described from the interstitial waters in Daejeon, Korea. Pseudocrangonyx daejeonensissp. n. is distinguished from three morphologically similar congeners, P. coreanus Uéno, 1966, P. febras Sidorov, 2009, and P. gudariensis Tomikawa & Sato, 2016, by the characteristics of antenna 1, antenna 2, mandible, gnathopod 2, pleopods, uropods 1-2, and telson. Molecular phylogenetic analyses based on nuclear 28S rRNA and histone H3, and mitochondrial cytochrome c oxidase subunit I and 16S rRNA genes revealed that P. daejeonensis is a sister species of the unnamed Pseudocrangonyx sp. 3 inhabiting central Japan.

Two new species of the bamboo-feeding genus Bambusiphaga Huang & Ding, 1979, B. yingjiangensissp. n. and B. ventroprocessasp. n., are described and illustrated from Yunnan and Hainan, south China. A key to species of the genus are given. A map showing the geographic distribution of the two new species is also provided.

Two populations of new species are described for Hexapleomera Dudich, 1931 from the southeastern coast and Jeju island of South Korea (north west Pacific). The specimens were collected using a light trap set overnight at the entrance near a pier or harbour. Hexapleomera ulsanasp. n. is clearly differentiated from other species in the genus by the uropod with five articles, a maxillule palp with four distal setae, the maxilliped coxa with three proximal setae, the epignath with short and blunt spiniform seta, the propodus of pereopods 2-3 with three ventral setae, and the maxilla with a rugged shape of the distal margin. Differences of mitochondrial cytochrome c oxidase subunit I (mtCOI) gene observed between two populations of H. ulsana from different regions (Ulsan and Jeju Island) and between H. ulsana and H. urashima (Japan) were 1.1 % and 32.4 %, respectively. Two genetically-close populations differed in the setae on pleopod 3, the proximal setae on the maxilliped coxa, and the ventral setae on pereopods 2-3, which showed that geographical distance affected the morphological divergence. In addition, a comprehensive comparison with previous records of Hexapleomera was conducted and close examinations on the appendages, known to have morphological variations between the individuals of one species and/or between different genders, were carried out based on new species and discussed herein.

A new genus and species of Sisyridae, Stictosisyra pennyigen. et sp. n., is described from the Late Cretaceous (earliest Cenomanian/late Albian) Myanmar amber. It can be easily distinguished from other sisyrids genera by the configuration of wing venation such as forewing with four ra-rp crossveins, M forked distal to the separation of RP1, CuA pectinate and CuP simple; hind wing 1r-m long and sinuous. Besides, the newly documented spongillaflies bore distinct, irregularly distributed spots on the forewings.

Poecilia vivipara, a small euryhaline guppy is reported at the Maceió River micro-basin in the Fernando de Noronha oceanic archipelago, northeast Brazil. However, the origin (human-mediated or natural dispersal) of this insular population is still controversial. The present study investigates how this population is phylogenetically related to the surrounding continental populations using the cytochrome oxidase I mitochondrial gene from eleven river basins in South America. Our phylogenetic reconstruction showed a clear geographical distribution arrangement of P. vivipara lineages. The Fernando de Noronha haplotype fell within the 'north' clade, closely related to a shared haplotype between the Paraíba do Norte and Potengi basins; the geographically closest continental drainages. Our phylogenetic reconstruction also showed highly divergent lineages, suggesting that P. vivipara may represent a species complex along its wide distribution. Regarding to the insular population, P. vivipara may have been intentionally introduced to the archipelago for the purpose of mosquito larvae control during the occupation of a U.S. military base following World War II. However, given the euryhaline capacity of P. vivipara, a potential scenario of natural (passive or active) dispersal cannot be ruled out.

The aphid genus, Takecallis Mastumura, 1917, was reviewed from Korea. Four species, T. alba Y. Lee, sp. n., T. arundicolens (Clarke), T. arundinariae (Essig), and T. taiwana (Takahashi), are recognized in Korea and morphological and molecular evidence are presented. Species descriptions and illustrations are given for the four species. A key to Korean species and the results of COI sequence analyses are also provided.

Recent flight intercept trapping in Gabon provided four female specimens of a new species of Scolytoplatypus Schaufuss with several unusual features. It is the smallest known Afrotropical species found to date (1.6 mm long), it has unusually long antennal clubs, and some characters show resemblance to small Asian species or to the Malagasy genus Remansus Jordal. Genetic data from four genes nevertheless place this species as the sister lineage to all other Afrotropical species where it forms an isolated position corresponding to deviant morphological features.

The taxonomy of Quercus langbianensis and its relatives in Vietnam and Cambodia have been revised based on evidence obtained from field observations, morphological comparison of herbarium specimens and molecular analyses using both classic and next generation DNA markers. Based on Bayesian inference using rbcL, matK and ITS regions and Neighbour-joining tree using genome-wide sequences amplified with multiplexed inter-simple sequence repeat (ISSR) primers (MIG-seq), the authors recognised ten species in the complex in Vietnam and Cambodia, three of which are newly described in this paper: Q. baolamensissp. nov., Q. bidoupensissp. nov. and Q. honbaensissp. nov. These new species are all phenotypically similar to Q. langbianensiss. str. in having lanceolate to oblanceolate leaf shape, upper 4-5/6-serrated leaf margin, acute or acuminate leaf apex and bracts of cupule arranged in 5-9 rings but distinguished both morphologically and phylogenetically. In molecular phylogenetic reconstructions, Q. bidoupensis is not close to any other species. In the Bayesian tree, Q. honbaensis is sister to both Q. blaoensis and Q. camusiae that are found in the same locality but morphologically distinct and those three species are sister to Q. langbianensiss. str., while Quercus baolamensis is not sister to Q. langbianensiss. str. in both the Bayesian tree and MIG-seq tree. In addition, Q. cambodiensis and Q. baniensis previously reduced to Q. langbianensiss. lat. have been recognised as distinct species. Six species were in need of lectotypification and that is undertaken herein.

In 2016, saproxylic Diptera associated with aspen (Populus tremula L.) logs were studied in the Kivach Nature Reserve, Russian Karelia, using trunk emergence traps.

Structural and functional plasticity of synapses are critical neuronal mechanisms underlying learning and memory. While activity-dependent regulation of synaptic strength has been extensively studied, much less is known about the transcriptional control of synapse maintenance and plasticity. Hippocampal mossy fiber (MF) synapses connect dentate granule cells to CA3 pyramidal neurons and are important for spatial memory formation and consolidation. The transcription factor Bcl11b/Ctip2 is expressed in dentate granule cells and required for postnatal hippocampal development. Ablation of Bcl11b/Ctip2 in the adult hippocampus results in impaired adult neurogenesis and spatial memory. The molecular mechanisms underlying the behavioral impairment remained unclear. Here we show that selective deletion of Bcl11b/Ctip2 in the adult mouse hippocampus leads to a rapid loss of excitatory synapses in CA3 as well as reduced ultrastructural complexity of remaining mossy fiber boutons (MFBs). Moreover, a dramatic decline of long-term potentiation (LTP) of the dentate gyrus-CA3 (DG-CA3) projection is caused by adult loss of Bcl11b/Ctip2. Differential transcriptomics revealed the deregulation of genes associated with synaptic transmission in mutants. Together, our data suggest Bcl11b/Ctip2 to regulate maintenance and function of MF synapses in the adult hippocampus.

Neuropeptide Y (NPY) plays an important role in the regulation of energy homeostasis in the level of central and sympathetic nervous systems (SNSs). Genetic silencing of peripheral Y2-receptors have anti-obesity effects, but it is not known whether pharmacological blocking of peripheral Y2-receptors would similarly benefit energy homeostasis. The effects of a peripherally administered Y2-receptor antagonist were studied in healthy and energy-rich conditions with or without excess NPY. Genetically obese mice overexpressing NPY in brain noradrenergic nerves and SNS (OE-NPYDβH) represented the situation of elevated NPY levels, while wildtype (WT) mice represented the normal NPY levels. Specific Y2-receptor antagonist, BIIE0246, was administered (1.3 mg/kg/day, i.p.) for 2 or 4.5 weeks to OE-NPYDβH and WT mice feeding on chow or Western diet. Treatment with Y2-receptor antagonist increased body weight gain in both genotypes on chow diet and caused metabolic disturbances (e.g., hyperinsulinemia and hypercholesterolemia), especially in WT mice. During energy surplus (i.e., on Western diet), blocking of Y2-receptors induced obesity in WT mice, whereas OE-NPYDβH mice showed reduced fat mass gain, hepatic glycogen and serum cholesterol levels relative to body adiposity. Thus, it can be concluded that with normal NPY levels, peripheral Y2-receptor antagonist has no potential for treating obesity, but oppositely may even induce metabolic disorders. However, when energy-rich diet is combined with elevated NPY levels, e.g., stress combined with an unhealthy diet, Y2-receptor antagonism has beneficial effects on metabolic status.

Background: Muscle wasting is a debilitating phenotype associated with chronic heart failure (CHF). We have previously demonstrated that angiotensin II (AII) directly induces muscle wasting in mice through the activation of NADPH oxidase (Nox). In this study, we tested the hypothesis that deficiency of NADPH oxidase 4 (Nox4), a major source of oxidative stress, ameliorates AII-induced muscle wasting through the regulation of redox balance. Methods and Results: Nox4 knockout (KO) and wild-type (WT) mice were used. At baseline, there were no differences in physical characteristics between the WT and KO mice. Saline (vehicle, V) or AII was infused via osmotic minipumps for 4 weeks, after which, the WT + AII mice showed significant increases in Nox activity and NOX4 protein compared with the WT + V mice, as well as decreases in body weight, gastrocnemius muscle weight, and myocyte cross-sectional area. These changes were significantly attenuated in the KO + AII mice (27 ± 1 vs. 31 ± 1 g, 385 ± 3 vs. 438 ± 13 mg, and 1,330 ± 30 vs. 2281 ± 150 μm2, respectively, all P < 0.05). The expression levels of phospho-Akt decreased, whereas those of muscle RING Finger-1 (MuRF-1) and MAFbx/atrogin-1 significantly increased in the WT + AII mice compared with the WT + V mice. Furthermore, nuclear factor erythroid-derived 2-like 2 (Nrf2) and the expression levels of Nrf2-regulated genes significantly decreased in the WT + AII mice compared with the WT + V mice. These changes were significantly attenuated in the KO + AII mice (P < 0.05). Conclusion: Nox4 deficiency attenuated AII-induced muscle wasting, partially through the regulation of Nrf2. The Nox4-Nrf2 axis may play an important role in the development of AII-induced muscle wasting.