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Despite decades of study, the molecular mechanisms and selectivity of the biomolecular components of honeybee (Apis mellifera) venom as anticancer agents remain largely unknown. Here, we demonstrate that honeybee venom and its major component melittin potently induce cell death, particularly in the aggressive triple-negative and HER2-enriched breast cancer subtypes. Honeybee venom and melittin suppress the activation of EGFR and HER2 by interfering with the phosphorylation of these receptors in the plasma membrane of breast carcinoma cells. Mutational studies reveal that a positively charged C-terminal melittin sequence mediates plasma membrane interaction and anticancer activity. Engineering of an RGD motif further enhances targeting of melittin to malignant cells with minimal toxicity to normal cells. Lastly, administration of melittin enhances the effect of docetaxel in suppressing breast tumor growth in an allograft model. Our work unveils a molecular mechanism underpinning the anticancer selectivity of melittin, and outlines treatment strategies to target aggressive breast cancers.

Geophysical and geological approaches were employed to understand sediment dispersal systems and their response to various forcing functions (i.e., sea level member marine environments were studied; one with high precipitation and sediment discharge (Gulf of Papua, Papua New Guinea) and the other with low precipitation and sediment discharge (Oceanside Littoral Cell). The high-sedimentation rate in the Margins Source-to-Sink (S2S) program, we acquired CHIRP and core data across the GoP continental shelf that complemented onshore and offshore research in the region. CHIRP seismic data imaged three Holocene sedimentary lobes. The older Central lobe is downlapped by two younger lobes to the north and south. Sediment analysis showed that the older Central lobe has an elemental signature similar to the younger Northern lobe with both sourced from the Purari River watershed and lobe migration appears to be climatically controlled. The Southern lobe has elemental signatures more consistent with the Fly River watershed. Our results suggest the northern rivers began depositing sediments on the shelf during the Holocene sea level rise in the central region of the GoP and migrated abruptly north at ~2 kybp. Conversely, during the early Holocene transgression, sediments in the Fly drainage system were sequestered onshore infilling accommodation created in the large low-relief coastal plain during the sea level rise. Upon infilling the onshore accommodation, the Fly River delivered sediment to the ocean and formed the Southern lobe. Such differences in onshore storage capacity may introduce a lag between low-gradient rivers (Type I) with a large coastal plain versus high-gradient river systems (Type II) with small coastal plains.The second study site is in the sediment-starved Oceanside Littoral Cell (OCL) of Southern California. Terrestrial Laser scanning was performed seasonally using Light Detection and Ranging (LiDAR) technology to perform time series modeling of sea cliff erosion. We established a repeatable and reliable protocol for efficiently conducting coastal sea cliff mapping. Changes in geomorphology were quantified to determine the forcing mechanisms controlling erosion. Results from our investigations provide insight into “hot spots” of erosion along the coast and the controlling processes. Subaerialand marine erosion are predominantly controlled by precipitation and wave energy, respectively. Beach elevation, a seasonally dependent variable, is the most important physical factor controlling whether a sea cliff is vulnerable to marine-based or subaerial erosion. Due to the heavy coastal development and important state revenue from beach tourism, it is critical to continue this type of time series research to understand fully these relationships. This study provides a baseline from which future change due to the rapid sea level rise (>3 mm/yr) and climate change can be assessed.

Activation of the type 1 angiotensin II receptor ([AT.sub.1]) triggers proinflammatory signaling through pathways independent of classical Gq signaling that regulate vascular homeostasis. Here, we report that the [AT.sub.1] receptor preformed a heteromeric complex with the receptor for advanced glycation endproducts (RAGE). Activation of the [AT.sub.1] receptor by angiotensin II (Ang II) triggered transactivation of the cytosolic tail of RAGE and NF-[kappa]B-driven proinflammatory gene expression independently of the liberation of RAGE ligands or the ligand-binding ectodomain of RAGE. The importance of this transactivation pathway was demonstrated by our finding that adverse proinflammatory signaling events induced by [AT.sub.1] receptor activation were attenuated when RAGE was deleted or transactivation of its cytosolic tail was inhibited. At the same time, classical homeostatic Gq signaling pathways were unaffected by RAGE deletion or inhibition. These data position RAGE transactivation by the [AT.sub.1] receptor as a target for vasculoprotective interventions. As proof of concept, we showed that treatment with the mutant RAGE peptide S391A-[RAGE.sub.362-404] was able to inhibit transactivation of RAGE and attenuate Ang II-dependent inflammation and atherogenesis. Furthermore, treatment with WT [RAGE.sub.362-404] restored Ang II-dependent atherogenesis in Ager/Apoe-KO mice, without restoring ligand-mediated signaling via RAGE, suggesting that the major effector of RAGE activation was its transactivation., IntroductionBlockade of the renin-angiotensin aldosterone system (RAAS) is one of the most prescribed treatments in all of medicine. The pleiotropic benefits of RAAS blockade on inflammation (1-3), atherogenesis (4, 5), [...]

Substantial erosion of the unstable seacliffs along the economically important coastline of San Diego County, California, threatens existing developments and public safety. Time-series mapping of the seacliffs and beaches provides valuable information about seasonal and rapid-event erosion. With high resolution terrestrial laser scanning (TLS) georeferenced using real-time-kinematic global positioning systems, it is possible to establish reliable comparisons of time-series surveys for quantitative change analysis of seacliff morphology. This paper introduces new field survey methods for georeferencing TLS surveys collected in dynamic environments where conventional control methods cannot be effectively implemented for large-scale mapping. Specifically, the quality control of scan alignment and the identification of optimal surveying parameters of point separation/density, distance from target, setup spacing, and efficiency are discussed for long cliff sections. These TLS surveys, performed several times along an approximately 17-km segment of seacliffs in San Diego County show an average root-mean-square uncertainty of 7.9 cm between adjacent scans approaching the nominal 7.2 cm accuracy of the survey equipment. DOI: 10.1061/(ASCE)0733-9453(2009)135:4(161) CE Database subject headings: Mapping; Terrain; Topographic surveys; Erosion; Cliffs; Lasers; Parameters.

Rapid climate fluctuations associated with ice-sheet oscillations have resulted in pulses of iceberg discharge that are recorded by iceberg scour marks along continental shelves and ice-rafted debris deposits across the North Atlantic. Iceberg transport is largely controlled by ocean surface currents; therefore, iceberg trajectories can serve as a proxy for paleocirculation studies. Records of iceberg transport from ice-rafted debris (i.e., Heinrich layers) in the North Atlantic suggest that most icebergs released during Quaternary glaciations were entrained in a cyclonic subpolar gyre restricted to polar and mid-latitudes; however, new data suggest that there may have been an additional southerly component of transport along the western Atlantic margin. Here, we present evidence of extensive iceberg scouring across the upper slope offshore of South Carolina, ~1000 km south of the proximal ice margin during Quaternary glacial maximums. The location and orientation of the keel marks suggest that icebergs were entrained in a southwestward-flowing coastal current. At present, warm waters of the rapid, northeastward-flowing Gulf Stream bathe the upper slope off the southeastern United States. An offshore shift in the Gulf Stream axis during sea-level lowstand may have allowed glacially fed coastal currents to penetrate farther south. This may be the first evidence of iceberg rafting to subtropical latitudes in the North Atlantic. Keywords: iceberg scour, paleocirculation, multibeam bathymetry, Florida-Hatteras slope.

The angiotensin type 2 (AT2) receptor and the bradykinin type 2 (B2) receptor are G protein-coupled receptors (GPCRs) that have major roles in the cardiovascular system. The two receptors are known to functionally interact at various levels, and there is some evidence that the observed crosstalk may occur as a result of heteromerization. We investigated evidence for heteromerization of the AT2 receptor and the B2 receptor in HEK293FT cells using various bioluminescence resonance energy transfer (BRET)- proximity based assays, including the Receptor Heteromer Investigation Technology (Receptor-HIT) and the NanoBRET ligand-binding assay. The Receptor-HIT assay showed that Gaq, GRK2 and b-arrestin2 recruitment proximal to AT2 receptors only occurred upon B2 receptor coexpression and activation, all of which is indicative of AT2-B2 receptor heteromerization. Additionally, we also observed specific coupling of the B2 receptor with the Gaz protein, and this was found only in cells coexpressing both receptors and stimulated with bradykinin. The recruitment of Gaz, Gaq, GRK2 and barrestin2 was inhibited by B2 receptor but not AT2 receptor antagonism, indicating the importance of B2 receptor activation within AT2-B2 heteromers. The close proximity between the AT2 receptor and B2 receptor at the cell surface was also demonstrated with the NanoBRET ligand-binding assay. Together, our data demonstrate functional interaction between the AT2 receptor and B2 receptor in HEK293FT cells, resulting in novel pharmacology for both receptors with regard to Gaq/GRK2/b-arrestin2 recruitment (AT2 receptor) and Gaz protein coupling (B2 receptor). Our study has revealed a new mechanism for the enigmatic and poorly characterized AT2 receptor to be functionally active within cells, further illustrating the role of heteromerization in the diversity of GPCR pharmacology and signaling. [ABSTRACT FROM AUTHOR]

Objectives: To explore pharmacists' views and experiences of pharmacist-administered vaccinations, motivators and barriers to pharmacists administering vaccinations and their preferences for expansions to such services. Methods: All practising pharmacist members (n = 3400) of the Pharmaceutical Society of New Zealand were invited to participate in an online survey in 2017. Key findings: A total of 468 pharmacists completed the survey (14%). Most (86%) strongly agreed/agreed that pharmacists should provide vaccinations, primarily citing patient benefit, for example, convenience, potential for increased vaccination uptake, easing general practice burden and better utilisation of the pharmacist. Half had completed vaccinator training, mainly for professional satisfaction, to help public or community health and/or to provide a new service for their community. Trained pharmacists had administered influenza (95%), pertussis (47%), zoster (45%) and/or meningococcal vaccines (13%), with patient cost limiting some vaccination uptake. Cost or workplace constraints were leading reasons for the 17% not planning to undertake vaccinator training. Key barriers for pharmacy owners not offering vaccinations were set-up or other costs, insufficient funding (62%) or staffing/time concerns (27%). Some trained vaccinators (39%) wanted the recipient age lowered below 13 years, and 44% wanted intern pharmacists to be able to administer vaccinations. Conclusion This study found strong support for this service, including benefits for patients, and for customer relationships. Identified barriers including service setup and patient costs could be reduced by expanding the categories (e.g. pharmacy students and technicians) of staff able to vaccinate and having more government funded vaccines available through pharmacies, therefore, improving access for patients. [ABSTRACT FROM AUTHOR]