Bromodomain and extra-terminal protein mimic JQ1 decreases inflammation in human vascular endothelial cells: Implications for pulmonary arterial hypertension

Background and objective Nuclear factor kappa B (NF-kB)-mediated inflammatory gene expression and vascular endothelial cell proliferation/remodelling are implicated in the pathophysiology of the fatal disease, pulmonary arterial hypertension (PAH). Bromodomain and extra-terminal (BET) proteins are essential for the expression of a subset of NF-kB-induced inflammatory genes. BET mimics including JQ1+ prevent binding of BETs to acetylated histones and down-regulate the expression of selected genes. Methods The effects of JQ1+ on the proliferation of primary human pulmonary microvascular endothelial cells (HPMECs) from healthy subjects were measured by bromodeoxyuridine (BrdU) incorporation. Cell cycle progression was assessed by flow cytometry; mRNA and protein levels of cyclin-dependent kinases (CDKs), inhibitors and cytokines were determined by reverse transcription-quantitative PCR (RT-qPCR), Western blotting or ELISA. Histone acetyltransferase (HAT) and deacetylase (HDAC) activities were determined in nuclear extracts from whole lung of PAH and control patients. Results JQ1+ significantly inhibited IL6 and IL8 (IL6 and CXCL8) mRNA and protein in HPMECs compared with its inactive enantiomer JQ1−. JQ1+ decreased NF-kB p65 recruitment to native IL6 and IL8 promoters. JQ1+ showed a concentration-dependent decrease in HPMEC proliferation compared with JQ1−-treated cells. JQ1+ induced G1 cell cycle arrest by increasing the expression of the CDK inhibitors (CDKN) 1A (p21cip) and CDKN2D (p19INK4D ) and decreasing that of CDK2, CDK4 and CDK6. JQ1+ also inhibited serum-stimulated migration of HPMECs. Finally, HAT activity was significantly increased in the lung of PAH patients. Conclusion Inhibition of BETs in primary HPMECs decreases inflammation and remodelling. BET proteins could be a target for future therapies for PAH

Motif Minang Kaluak Paku Kacang Balimbiang pada Busana Kasual

Minangkabau sebagai salah satu suku bangsa yang mengisi kekhasan budaya Indonesia memiliki warisan budaya yang terpencar dalam berbagai aspek kehidupannya. Salah satu warisan budaya adalah seni ukir. Seni ukir yang dikembangkan dengan mengambil ide dari alam memiliki makna-makna filosofi bagi kehidupan masyarakat Minangkabau. Semua jenis ukiran yang dipahatkan di Rumah Gadang menunjukkan unsur penting pembentuk budaya Minangkabau bercerminkan kepada apa yang ada di alam. Salah satu ukiran pada rumah gadang yaitu kaluak paku. Kaluak paku adalah nama salah satu motif ukiran dalam adat Minangkabau. Berasal dari motif gulungan (kelukan/kaluak) pada ujung tanaman pakis (paku) yang masih muda. Ukiran kaluak paku rumah gadang melambangkan tanggung jawab seorang lelaki dalam adat Minangkabau kepada generasi penerus, sebagai ayah dari anak-anaknya dan sebagai mamak dari kemenakan (keponakan). Ukiran rumah gadang kaluak paku minangkabau inilah yang menjadi sumber ide penciptaan busana pada tugas akhir ini. Pada Penciptaan karya ini menggunakan beberapa metode, yaitu metode pendekatan estetis dan ergonomis, metode pengumpulan data dengan studi pustaka, dan motode penciptaan dengan teori Gustami Sp 3 tahap 6 Langkah. Dalam proses pembuatan karya dibutuhkan beberapa data, cara pengumpulan data acuan berdasarkan pengumpulan data pustaka yaitu berupa buku, jurnal pada media sosial, serta aplikasi pada smartphone seperti pinterest. Data yang dikumpulkan yang paling utama adalah gambar bentuk visual dari ukiran tanaman kaluak paku minangkabau dan busana kasual. Penciptaan karya yang dihasilkan yaitu berupa 8 busana kasual. Siluet pada kesuluruhan hasil karya yaitu memiliki siluet A yang mengembang pada bagian bawah. Pada penciptaan karya ini menggunakan bahan utama primisima. Perpaduan warna yang diterapkan menggunakan warna khas minangkabau yang diambil dari warna bendera adatnya “marawa” yaitu merah, hitam, dan kuning. Karya- karya yang dihasilkan dengan penggunaan warna tersebut sangat sesuai dengan tema yang mengangkat ukiran rumah gadang kaluak paku minangkabau. Kata Kunci : Minang, Kaluak Paku Kacang Balimbiang, Kasua

Empirical Models of Transitions between Coral Reef States: Effects of Region, Protection, and Environmental Change

There has been substantial recent change in coral reef communities. To date, most analyses have focussed on static patterns or changes in single variables such as coral cover. However, little is known about how community-level changes occur at large spatial scales. Here, we develop Markov models of annual changes in coral and macroalgal cover in the Caribbean and Great Barrier Reef (GBR) regions

Stress Hormones Receptors in the Amygdala Mediate the Effects of Stress on the Consolidation, but Not the Retrieval, of a Non Aversive Spatial Task

This study examined the effects of the arousal level of the rat and exposure to a behavioral stressor on acquisition, consolidation and retrieval of a non-aversive hippocampal-dependent learning paradigm, the object location task. Learning was tested under two arousal conditions: no previous habituation to the experimental context (high novelty stress/arousal level) or extensive prior habituation (reduced novelty stress/arousal level). Results indicated that in the habituated rats, exposure to an out-of-context stressor (i.e, elevated platform stress) impaired consolidation and retrieval, but not acquisition, of the task. Non-habituated animals under both stressed and control conditions did not show retention of the task. In habituated rats, RU-486 (10 ng/side), a glucocorticoid receptor (GR) antagonist, or propranolol (0.75 µg/side), a beta-adrenergic antagonist, injected into the basolateral amygdala (BLA), prevented the impairing effects of the stressor on consolidation, but not on retrieval. The CB1/CB2 receptor agonist WIN55,212-2 (WIN, 5 µg/side) microinjected into the BLA did not prevent the effects of stress on either consolidation or retrieval. Taken together the results suggest that: (i) GR and β-adrenergic receptors in the BLA mediate the impairing effects of stress on the consolidation, but not the retrieval, of a neutral, non-aversive hippocampal-dependent task, (ii) the impairing effects of stress on hippocampal consolidation and retrieval are mediated by different neural mechanisms (i.e., different neurotransmitters or different brain areas), and (iii) the effects of stress on memory depend on the interaction between several main factors such as the stage of memory processing under investigation, the animal's level of arousal and the nature of the task (neutral or aversive)

The bisphosphonate zoledronic acid impairs membrane localisation and induces cytochrome c release in breast cancer cells

Bisphosphonates are well established in the management of cancer-induced bone disease. Recent studies have indicated that these compounds have direct inhibitory effects on cultured human breast cancer cells. Nitrogen-containing bisphosphonates including zoledronic acid have been shown to induce apoptosis associated with PARP cleavage and DNA fragmentation. The aim of this study was to identify the signalling pathways involved. Forced expression of the anti-apoptotic protein bcl-2 attenuated bisphosphonate-induced loss of cell viability and induction of DNA fragmentation in MDA-MB-231 cells. Zoledronic acid-mediated apoptosis was associated with a time and dose-related release of mitochondrial cytochrome c into the cytosol in two cell lines. Rescue of cells by preincubation with a caspase-3 selective inhibitor and demonstration of pro-caspase-3 cleavage products by immunoblotting suggests that at least one of the caspases activated in response to zoledronic acid treatment is caspase-3. In both MDA-MB-231 and MCF-7 breast cancer cells, zoledronic acid impaired membrane localisation of Ras indicating reduced prenylation of this protein. These observations demonstrate that zoledronic acid-mediated apoptosis is associated with cytochrome c release and consequent caspase activation. This process may be initiated by inhibition of the enzymes in the mevalonate pathway leading to impaired prenylation of key intracellular proteins including Ras

Instrumental Variable Estimation of the Causal Effect of Plasma 25-Hydroxy-Vitamin D on Colorectal Cancer Risk: A Mendelian Randomization Analysis

Vitamin D deficiency has been associated with several common diseases, including cancer and is being investigated as a possible risk factor for these conditions. We reported the striking prevalence of vitamin D deficiency in Scotland. Previous epidemiological studies have reported an association between low dietary vitamin D and colorectal cancer (CRC). Using a case-control study design, we tested the association between plasma 25-hydroxy-vitamin D (25-OHD) and CRC (2,001 cases, 2,237 controls). To determine whether plasma 25-OHD levels are causally linked to CRC risk, we applied the control function instrumental variable (IV) method of the Mendelian randomization (MR) approach using four single nucleotide polymorphisms (rs2282679, rs12785878, rs10741657, rs6013897) previously shown to be associated with plasma 25-OHD. Low plasma 25-OHD levels were associated with CRC risk in the crude model (odds ratio (OR): 0.76, 95% Confidence Interval (CI): 0.71, 0.81, p: 1.4×10−14) and after adjusting for age, sex and other confounding factors. Using an allele score that combined all four SNPs as the IV, the estimated causal effect was OR 1.16 (95% CI 0.60, 2.23), whilst it was 0.94 (95% CI 0.46, 1.91) and 0.93 (0.53, 1.63) when using an upstream (rs12785878, rs10741657) and a downstream allele score (rs2282679, rs6013897), respectively. 25-OHD levels were inversely associated with CRC risk, in agreement with recent meta-analyses. The fact that this finding was not replicated when the MR approach was employed might be due to weak instruments, giving low power to demonstrate an effect (<0.35). The prevalence and degree of vitamin D deficiency amongst individuals living in northerly latitudes is of considerable importance because of its relationship to disease. To elucidate the effect of vitamin D on CRC cancer risk, additional large studies of vitamin D and CRC risk are required and/or the application of alternative methods that are less sensitive to weak instrument restrictions

Habitat associations of juvenile versus adult butterflyfishes

Author Posting. © Springer-Verlag, 2008. This is the author's version of the work. It is posted here by permission of Springer-Verlag for personal use, not for redistribution. The definitive version was published in Coral Reefs 27 (2008): 541-551, doi:10.1007/s00338-008-0357-8.Many coral reef fishes exhibit distinct ontogenetic shifts in habitat use while some species settle directly in adult habitats, but there is not any general explanation to account for these differences in settlement strategies among coral reef fishes. This study compared distribution patterns and habitat associations of juvenile (young of the year) butterflyfishes to those of adult conspecifics. Three species, Chaetodon auriga, Chaetodon melannotus, and Chaetodon vagabundus, all of which have limited reliance on coral for food, exhibited marked differences in habitat association of juvenile versus adult individuals. Juveniles of these species were consistently found in shallow-water habitats, whereas adult conspecifics were widely distributed throughout a range of habitats. Juveniles of seven other species (Chaetodon aureofasciatus, Chaetodon baronessa, Chaetodon citrinellus, Chaetodon lunulatus, Chaetodon plebeius, Chaetodon rainfordi, and Chaetodon trifascialis), all of which feed predominantly on live corals, settled directly into habitat occupied by adult conspecifics. Butterflyfishes with strong reliance on corals appear to be constrained to settle in habitats that provide access to essential prey resources, precluding their use of distinct juvenile habitats. More generalist butterflyfishes, however, appear to utilise distinct juvenile habitats and exhibit marked differences in the distribution of juveniles versus adults.This research was funded by a JCU Program Grant to MSP, while MLB was supported by an NSF (USA) Graduate Research Fellowship

Spatial Analyses of Benthic Habitats to Define Coral Reef Ecosystem Regions and Potential Biogeographic Boundaries along a Latitudinal Gradient

Marine organism diversity typically attenuates latitudinally from tropical to colder climate regimes. Since the distribution of many marine species relates to certain habitats and depth regimes, mapping data provide valuable information in the absence of detailed ecological data that can be used to identify and spatially quantify smaller scale (10 s km) coral reef ecosystem regions and potential physical biogeographic barriers. This study focused on the southeast Florida coast due to a recognized, but understudied, tropical to subtropical biogeographic gradient. GIS spatial analyses were conducted on recent, accurate, shallow-water (0–30 m) benthic habitat maps to identify and quantify specific regions along the coast that were statistically distinct in the number and amount of major benthic habitat types. Habitat type and width were measured for 209 evenly-spaced cross-shelf transects. Evaluation of groupings from a cluster analysis at 75% similarity yielded five distinct regions. The number of benthic habitats and their area, width, distance from shore, distance from each other, and LIDAR depths were calculated in GIS and examined to determine regional statistical differences. The number of benthic habitats decreased with increasing latitude from 9 in the south to 4 in the north and many of the habitat metrics statistically differed between regions. Three potential biogeographic barriers were found at the Boca, Hillsboro, and Biscayne boundaries, where specific shallow-water habitats were absent further north; Middle Reef, Inner Reef, and oceanic seagrass beds respectively. The Bahamas Fault Zone boundary was also noted where changes in coastal morphologies occurred that could relate to subtle ecological changes. The analyses defined regions on a smaller scale more appropriate to regional management decisions, hence strengthening marine conservation planning with an objective, scientific foundation for decision making. They provide a framework for similar regional analyses elsewhere

Spatial Patterns in Herbivory on a Coral Reef Are Influenced by Structural Complexity but Not by Algal Traits

Background: Patterns of herbivory can alter the spatial structure of ecosystems, with important consequences for ecosystem functions and biodiversity. While the factors that drive spatial patterns in herbivory in terrestrial systems are well established, comparatively less is known about what influences the distribution of herbivory in coral reefs. Methodology and Principal Findings: We quantified spatial patterns of macroalgal consumption in a cross-section of Ningaloo Reef (Western Australia). We used a combination of descriptive and experimental approaches to assess the influence of multiple macroalgal traits and structural complexity in establishing the observed spatial patterns in macroalgal herbivory, and to identify potential feedback mechanisms between herbivory and macroalgal nutritional quality. Spatial patterns in macroalgal consumption were best explained by differences in structural complexity among habitats. The biomass of herbivorous fish, and rates of herbivory were always greater in the structurally-complex coral-dominated outer reef and reef flat habitats, which were also characterised by high biomass of herbivorous fish, low cover and biomass of macroalgae and the presence of unpalatable algae species. Macroalgal consumption decreased to undetectable levels within 75 m of structurally-complex reef habitat, and algae were most abundant in the structurally-simple lagoon habitats, which were also characterised by the presence of the most palatable algae species. In contrast to terrestrial ecosystems, herbivory patterns were not influenced by the distribution, productivity or nutritional quality of resources (macroalgae), and we found no evidence of a positive feedback between macroalgal consumption and the nitrogen content of algae. Significance: This study highlights the importance of seascape-scale patterns in structural complexity in determining spatial patterns of macroalgal consumption by fish. Given the importance of herbivory in maintaining the ability of coral reefs to reorganise and retain ecosystem functions following disturbance, structural complexity emerges as a critical feature that is essential for the healthy functioning of these ecosystems