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Predators impact preyscapes (3-D distribution of forage species) by consuming prey according to their abilities or by altering prey behavior as they avoid being consumed. We elucidate prey (Antarctic silverfish[Pleuragramma antarctica] and crystal krill[Euphausia chrystallorophias]) responses to predation associated with the marginal ice zone (MIZ) of the McMurdo Sound, Antarctica, polynya. Prey abundance and habitat was sampled across a 30 × 15 km area by remotely-operated vehicle, and included locations that were accessible (ice edge) or inaccessible (solid fast ice) to air-breathing predators. Prey and habitat sampling coincided with bio-logging of Adélie penguins and observations of other air-breathing predators (penguins, seals, and whales), all of which were competing for the same prey. Adélie penguins dived deeper, and more frequently, near the ice edge. Lowered abundance of krill at the ice edge indicated they were depleted or were responding to increased predation and/or higher light levels along the ice edge. Penguin diet shifted increasingly to silverfish from krill during sampling, and was correlated with the arrival of krill-eating whales. Behaviorally-mediated, high trophic transfer characterizes the McMurdo Sound MIZ, and likely other MIZs, warranting more specific consideration in food web models and conservation efforts.

Endosomal sorting maintains cellular homeostasis by recycling transmembrane proteins and associated proteins and lipids (termed “cargoes”) from the endosomal network to multiple subcellular destinations, including retrograde traffic to the trans-Golgi network (TGN). Viral and bacterial pathogens subvert retrograde trafficking machinery to facilitate infectivity. Here, we develop a proteomic screen to identify retrograde cargo proteins of the endosomal SNX-BAR sorting complex promoting exit 1 (ESCPE-1). Using this methodology, we identify Neuropilin-1 (NRP1), a recently characterized host factor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as a cargo directly bound and trafficked by ESCPE-1. ESCPE-1 mediates retrograde trafficking of engineered nanoparticles functionalized with the NRP1-interacting peptide of the SARS-CoV-2 spike (S) protein. CRISPR-Cas9 deletion of ESCPE-1 subunits reduces SARS-CoV-2 infection levels in cell culture. ESCPE-1 sorting of NRP1 may therefore play a role in the intracellular membrane trafficking of NRP1-interacting viruses such as SARS-CoV-2., Proceedings of the National Academy of Sciences of the United States of America, 119 (25), ISSN:0027-8424, ISSN:1091-6490

Given the important role of voltage-gated sodium (NaV) channel-modulating spider toxins in elucidating the function, pharmacology, and mechanism of action of therapeutically relevant NaV channels, we screened the venom from Australian theraphosid species against the human pain target hNaV1.7. Using assay-guided fractionation, we isolated a 33-residue inhibitor cystine knot (ICK) peptide (Ssp1a) belonging to the NaSpTx1 family. Recombinant Ssp1a (rSsp1a) inhibited neuronal hNaV subtypes with a rank order of potency hNaV1.7 > 1.6 > 1.2 > 1.3 > 1.1. rSsp1a inhibited hNaV1.7, hNaV1.2 and hNaV1.3 without significantly altering the voltage-dependence of activation, inactivation, or delay in recovery from inactivation. However, rSsp1a demonstrated voltage-dependent inhibition at hNaV1.7 and rSsp1a-bound hNaV1.7 opened at extreme depolarizations, suggesting rSsp1a likely interacted with voltage-sensing domain II (VSD II) of hNaV1.7 to trap the channel in its resting state. Nuclear magnetic resonance spectroscopy revealed key structural features of Ssp1a, including an amphipathic surface with hydrophobic and charged patches shown by docking studies to comprise the interacting surface. This study provides the basis for future structure-function studies to guide the development of subtype selective inhibitors.

Venoarterial extracorporeal membrane oxygenation may be used for circulatory support in cardiogenic shock as a bridge to recovery, a bridge to a ventricular assist device (VAD), or a bridge to transplant. While the determination of potential exit strategies is essential before cannulation, the final determination of a patient’s options may change, in part, through their in-hospital clinical course. We propose that liberation from venoarterial extracorporeal membrane oxygenation should be conceptualized as a process of discovery in the assessment of a patient’s underlying clinical status and a key driver of further clinical decision-making. A trial of liberation from support should be considered when the goals of the weaning trial are well-defined and, ideally, in the absence of potentially confounding clinical factors. In this review, we will discuss readiness to wean criteria from venoarterial extracorporeal membrane oxygenation, as well as specific clinical, biochemical, and echocardiographic parameters that may prove useful in determining weaning timing and revealing the patient’s underlying hemodynamic status and prognosis. The role of various cannula configurations, support devices, and pharmacological adjuncts will also be discussed. Finally, we highlight current gaps in evidence and suggest areas of future research.

Shear-induced crystallization of dyes in the amorphous state is an effective strategy for generating higher energy emission after mechanical perturbation—a rare phenomenon in mechanoresponsive mate...

The goal of this review is to summarize recent findings on the physiologic alterations posed by maternal obesity and implications for the anesthetic care of mother and infant. Obesity is rising nationally and globally. Many studies show associations between excess weight during pregnancy with increased morbidity and mortality. Parturients with obesity are at a higher risk of endocrine, cardiac, pulmonary, and post-operative complications. A neuraxial catheter is recommended given the higher risk of an operative delivery. Consultation by an obstetric anesthesiologist is helpful for patient education and planning. Maternal mortality is the highest in the USA compared to other high-income countries. Understanding the association between obesity and maternal morbidity and mortality is critically important. The obstetric anesthesiologist can improve care by understanding not only the patient's medical needs, but also anticipating complications and having appropriate equipment available. Multi-disciplinary care optimizes outcomes.

The stone crab, Menippe mercenaria, supported the third most valuable fishery in Florida in 2016. Declining catch per unit effort (CPUE) and a negative trend in landings since 2000 have raised concerns among fishermen, researchers, and fishery managers as to the fishery’s sustainability. The Fish and Wildlife Research Institute of the Florida Fish and Wildlife Conservation Commission estimates that the state’s stone crab fishery has been overexploited since 1997. This stock status determination, however, is based largely on trends in total landings and CPUE and does not account for the life-history parameters that describe stock productivity, such as size at maturity, fecundity, and survivorship. In this study, an age-structured per-recruit model was developed to evaluate how alternative biological parameters and management scenarios might affect reproductive output, calculated as the spawning potential ratio (SPR), of a theoretical stone crab population. The model incorporated new estimates of size at maturity, fecundity, and temperature-dependent release mortalities. Spawning potential ratios increased with decreasing size at sexual maturity and were sensitive to increasing natural mortality. The largest contributor to changes in SPR was mortality associated with the declawing and release of stone crabs. We also assessed various management scenarios including regulations governing minimum claw length, requiring the use of juvenile trap excluder devices, and institution of temperature-dependent season openings. Increasing the minimum claw length and excluding small juveniles from traps provided moderate protection to the spawning stock. The model suggests that adaptive management strategies that allow fishing only when water temperatures are below 24 °C (the temperature at which modeled survival is improved) could greatly reduce mortality and increase SPR. We examined a suite of management scenarios on the effect of SPR, but additional research should be conducted to determine the socioeconomic impact of changes in regulations in this valuable fishery.

Cyclic peptides are widespread throughout the plant kingdom, and display diverse sequences, structures and bioactivities. The potential applications attributed to these peptides and their unusual biosynthesis has captivated the attention of researchers for many years. Several gene sequences for plant cyclic peptides have been discovered over the last two decades but it is only recently that we are beginning to understand the intricacies associated with their biosynthesis. Recent studies have focussed on three main classes of plant derived cyclic peptides, namely orbitides, SFTI related peptides and cyclotides. In this mini-review, we discuss the expansion of the known sequence and structural diversity in these families, insights into the enzymes involved in the biosynthesis, the exciting applications which includes a cyclotide currently in clinical trials for the treatment of multiple sclerosis, and new production methods that are being developed to realise the potential of plant cyclic peptides as pharmaceutical or agricultural agents.

Developing a novel therapeutic product for the treatment of type 2 diabetes (T2D) is a long, resource‐intensive process. Novel biomarkers could potentially aid clinical trial design by shortening clinical trials or enabling better prediction of at‐risk populations and/or disease progression. Novel clinical trial designs could lead to reduced costs of development and less burden to patients, due to shorter trial duration, and/or less burdensome assessments., This is a review of the potential use of biomarkers in novel clinical trial design. It also describes the IMI2 RHAPSODY consortium.

International audience; Cone snails are venomous marine predators that rely on fast-acting venom to subdue their prey and defend against aggressors. The conotoxins produced in the venom gland are small disulfide-rich peptides with high affinity and selectivity for their pharmacological targets. A dominant group comprises α-conotoxins, targeting nicotinic acetylcholine receptors. Here, we report on the synthesis, structure determination and biological activity of a novel α-conotoxin, CIC, found in the predatory venom of the piscivorous species Conus catus and its truncated mutant Δ-CIC. CIC is a 4/7 α-conotoxin with an unusual extended N-terminal tail. High-resolution NMR spectroscopy shows a major influence of the N-terminal tail on the apparent rigidity of the three-dimensional structure of CIC compared to the more flexible Δ-CIC. Surprisingly, this effect on the structure does not alter the biological activity, since both peptides selectively inhibit α3β2 and α6/α3β2β3 nAChRs with almost identical sub- to low micromolar inhibition constants. Our results suggest that the N-terminal part of α-conotoxins can accommodate chemical modifications without affecting their pharmacology.

Type 2 diabetes (T2D) is a major health problem and is considered one of the top 10 diseases leading to death globally. T2D has been widely associated with systemic and local inflammatory responses and with alterations in the gut microbiota. Microorganisms, including parasitic worms and gut microbes have exquisitely co-evolved with their hosts to establish an immunological interaction that is essential for the formation and maintenance of a balanced immune system, including suppression of excessive inflammation. Herein we show that both prophylactic and therapeutic infection of mice with the parasitic hookworm-like nematode, Nippostrongylus brasiliensis, significantly reduced fasting blood glucose, oral glucose tolerance and body weight gain in two different diet-induced mouse models of T2D. Helminth infection was associated with elevated type 2 immune responses including increased eosinophil numbers in the mesenteric lymph nodes, liver and adipose tissues, as well as increased expression of IL-4 and alternatively activated macrophage marker genes in adipose tissue, liver and gut. N. brasiliensis infection was also associated with significant compositional changes in the gut microbiota at both the phylum and order levels. Our findings show that N. brasiliensis infection drives changes in local and systemic immune cell populations, and that these changes are associated with a reduction in systemic and local inflammation and compositional changes in the gut microbiota which cumulatively might be responsible for the improved insulin sensitivity observed in infected mice. Our findings indicate that carefully controlled therapeutic hookworm infection in humans could be a novel approach for treating metabolic syndrome and thereby preventing T2D. This work was supported by the National Health and Medical Research Council (NHMRC) through a program grant (1132975) and senior principal research fellowship (1117504) to AL, an AITHM Capacity Building grant to PG, AL, and MF, and an Australian Research Council Special Research Initiative award to the Australian Institute of Tropical Health and Medicine at James Cook University (SRI40200003). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Sí

Prediabetes is a state of glycaemic dysregulation below the diagnostic threshold of type 2 diabetes (T2D). Globally, ~352 million people have prediabetes, of which 35-50% develop full-blown diabetes within five years. T2D and its complications are costly to treat, causing considerable morbidity and early mortality. Whether prediabetes is causally related to diabetes complications is unclear. Here we report a causal inference analysis investigating the effects of prediabetes in coronary artery disease, stroke and chronic kidney disease, complemented by a systematic review of relevant observational studies. Although the observational studies suggest that prediabetes is broadly associated with diabetes complications, the causal inference analysis revealed that prediabetes is only causally related with coronary artery disease, with no evidence of causal effects on other diabetes complications. In conclusion, prediabetes likely causes coronary artery disease and its prevention is likely to be most effective if initiated prior to the onset of diabetes.

A new class of hybrid biomaterials has recently evolved from the combination of peptides and DNA. In this chapter, we survey the unique systems and properties made possible by merging the bioactivity and mechanical properties of peptides with the programmability and reversibility of DNA. We explore peptide–DNA probes and switches, peptide-decorated DNA scaffolds and DNA-decorated peptide structures. We illustrate the rich variety of architectures made from the interplay of orthogonal peptide and DNA assembly motifs in cooperative assemblies, with examples of peptide-directed or DNA-directed hybrid structures. We present systems with hierarchical organization and dynamic assembly, presenting fascinating emergent properties made possible by peptide–DNA combinations. Finally, we discuss the future possibilities and open challenges presented by this intriguing class of hybrid biomaterials.

Marine organisms produce a diverse range of toxins and bioactive peptides to support predation, competition, and defense. The peptide repertoires of stony corals (order Scleractinia) remain relatively understudied despite the presence of tentacles used for predation and defense that are likely to contain a range of bioactive compounds. Here, we show that a tentacle extract from the mushroom coral

Melanocortin receptors are pharmaceutically important receptors that are involved in complex physiological functions. They have been associated with various diseases including obesity, erectile dysfunction, acne, and skin cancer. It has been challenging to transform nonselective endogenous agonist and antagonist ligands into selective and potent ligands. In this study, we investigated naturally occurring peptides derived from frog skin secretions for selectivity and activity toward melanocortin receptors. Three peptides (ORB, ORB2K and ranacyclin‐T) were found to have selectivity towards the melanocortin receptor 5 (MC5R). ORB and ORB2K had partial binding affinity at nanomolar concentrations, whereas ranacyclin‐T had 57% binding efficiency at 1.6 μM. Backbone cyclization of ORB and ORB2K altered the binding efficiency to melanocortin receptors. Our results suggest that these frog‐skin peptides could be modified for developing melanocortin‐specific ligands and potentially future therapeutics.

Another host factor for SARS-CoV-2 Virus-host interactions determine cellular entry and spreading in tissues. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the earlier SARS-CoV use angiotensin-converting enzyme 2 (ACE2) as a receptor; however, their tissue tropism differs, raising the possibility that additional host factors are involved. The spike protein of SARS-CoV-2 contains a cleavage site for the protease furin that is absent from SARS-CoV (see the Perspective by Kielian). Cantuti-Castelvetri et al. now show that neuropilin-1 (NRP1), which is known to bind furin-cleaved substrates, potentiates SARS-CoV-2 infectivity. NRP1 is abundantly expressed in the respiratory and olfactory epithelium, with highest expression in endothelial and epithelial cells. Daly et al. found that the furin-cleaved S1 fragment of the spike protein binds directly to cell surface NRP1 and blocking this interaction with a small-molecule inhibitor or monoclonal antibodies reduced viral infection in cell culture. Understanding the role of NRP1 in SARS-CoV-2 infection may suggest potential targets for future antiviral therapeutics. Science , this issue p. 856 , p. 861 ; see also p. 765

International audience; Venom peptides are promising drug leads, but their therapeutic use is often limited by stability and bioavailability issues. In this study, we designed cyclic analogues of α-conotoxin CIA, a potent muscle nicotinic acetylcholine receptor (nAChR) blocker with a significantly lower affinity at the neuronal α3β2 subtype. Remarkably, all analogues retained the low nanomolar activity of native CIA toward muscle-type nAChRs but showed greatly improved resistance to degradation in human serum and, surprisingly, displayed up to 52-fold higher potency for the α3β2 neuronal nAChR subtype (IC50 1.3 nM). Comparison of nuclear magnetic resonance-derived structures revealed some differences that might explain the gain of potency at α3β2 nAChRs. All peptides were highly paralytic when injected into adult zebrafish and bath-applied to zebrafish larvae, suggesting barrier-crossing capabilities and efficient uptake. Finally, these cyclic CIA analogues were shown to be unique pharmacological tools to investigate the contribution of the presynaptic α3β2 nAChR subtype to the train-of-four fade.

Prediabetes is a state of glycaemic dysregulation below the diagnostic threshold of type 2 diabetes (T2D). Globally, ~352 million people have prediabetes, of which 35–50% develop full-blown diabetes within five years. T2D and its complications are costly to treat, causing considerable morbidity and early mortality. Whether prediabetes is causally related to diabetes complications is unclear. Here we report a causal inference analysis investigating the effects of prediabetes in coronary artery disease, stroke and chronic kidney disease, complemented by a systematic review of relevant observational studies. Although the observational studies suggest that prediabetes is broadly associated with diabetes complications, the causal inference analysis revealed that prediabetes is only causally related with coronary artery disease, with no evidence of causal effects on other diabetes complications. In conclusion, prediabetes likely causes coronary artery disease and its prevention is likely to be most effective if initiated prior to the onset of diabetes., Prediabetes has been associated with diabetes complications, but these relationships may be confounded. Here the authors show, using genetic data in causal inference analyses, that prediabetes raises risk of coronary heart disease, but not other diabetes complications.

The IgE- and IgGA comparative investigation of patient IgE- and IgGNinety five percent (22/23) patients demonstrated IgE-binding to rLat c 1.01, while fewer patients (10/15 children and 7/8 adults) demonstrated robust IgGOur findings demonstrate two specific IgE epitopes on parvalbumin from Asian seabass, while IgG

We evaluated the resilience of the zooplankton community to the Deepwater Horizon oil spill in the northeast Gulf of Mexico, by assessing abundance, biomass, spatial distribution, species composition, and diversity indices during spring, summer, and winter, May 2010 to August 2014. SEAMAP samples collected between spring and summer 2005-2009 were analyzed as a baseline. Our results did not indicate that there was a long-term impact from the oil spill, but did demonstrate that environmental variability and riverine processes strongly governed zooplankton community dynamics. Zooplankton abundances during the oil spill (spring 2010) were not significantly different from abundances during spring 2011 and 2012. Summer 2010 abundances were the highest observed for the 2005 to 2014 period, due to high river discharge, high chlorophyll, and aggregation in eddies. High densities of the dinoflagellate, Noctiluca, during the oil spill, and the copepod, Centropages velificatus, and larvaceans in all years, suggest that these taxa warrant further investigation. Ecosystem connectivity (zooplankton transport by currents into the oil spill region), high fecundity, relatively short generation times, and refugia in deeper depths are key factors in zooplankton resilience to major perturbations. This study serves as a baseline for assessment of future impacts to this system.

Human retromer, a heterotrimer of VPS26 (VPS26A or VPS26B), VPS35 and VPS29, orchestrates the endosomal retrieval of internalised cargo and promotes their cell surface recycling, a prototypical cargo being the glucose transporter GLUT1 (also known as SLC2A1). The role of retromer in the retrograde sorting of the cation-independent mannose 6-phosphate receptor (CI-MPR, also known as IGF2R) from endosomes back to the trans-Golgi network remains controversial. Here, by applying knocksideways technology, we develop a method for acute retromer inactivation. While retromer knocksideways in HeLa and H4 human neuroglioma cells resulted in time-resolved defects in cell surface sorting of GLUT1, we failed to observe a quantifiable defect in CI-MPR sorting. In contrast, knocksideways of the ESCPE-1 complex – a key regulator of retrograde CI-MPR sorting – revealed time-resolved defects in CI-MPR sorting. Together, these data are consistent with a comparatively limited role for retromer in ESCPE-1-mediated CI-MPR retrograde sorting, and establish a methodology for acute retromer and ESCPE-1 inactivation that will aid the time-resolved dissection of their functional roles in endosomal cargo sorting., Summary: Retromer, a master controller of endosomal cargo sorting, is deregulated in neurodegenerative disease. Here, we develop and apply a retromer knocksideways methodology to quantify endosomal cargo sorting upon acute perturbation.

Synchronously tuning an electrically small antenna at the symbol rate of a frequency shift keyed (FSK) modulation has been shown to efficiently increase the throughput of the transmitter. A major challenge for realizing synchronous antenna tuners is identifying a tuning element that can both block high voltages and retune quickly. This paper explores using a switched, inductive, parasitic tuning element to quickly tune a medium-power HF transmitter.

SARS-CoV-2 is the causative agent of COVID-19, a coronavirus disease that has infected more than 6.6 million people and caused over 390,000 deaths worldwide1,2. The Spike (S) protein of the virus forms projections on the virion surface responsible for host cell attachment and penetration. This viral glycoprotein is synthesized as a precursor in infected cells and, to be active, must be cleaved to two associated polypeptides: S1 and S2(3,4). For SARS-CoV-2 the cleavage is catalysed by furin, a host cell protease, which cleaves the S protein precursor at a specific sequence motif that generates a polybasic Arg-Arg-Ala-Arg (RRAR) C-terminal sequence on S1. This sequence motif conforms to the C-end rule (CendR), which means that the C-terminal sequence may allow the protein to associate with cell surface neuropilin-1 (NRP1) and neuropilin-2 (NRP2) receptors5. Here we demonstrate using immunoprecipitation, site-specific mutagenesis, structural modelling, and antibody blockade that, in addition to engaging the known receptor ACE2, S1 can bind to NRP1 through the canonical CendR mechanism. This interaction enhances infection by SARS-CoV-2 in cell culture. NRP1 thus serves as a host factor for SARS-CoV-2 infection, and provides a therapeutic target for COVID-19.

SummaryAntimicrobial peptides (AMPs) are key components of the innate immune system that protect against pathogens, regulate the microbiome, and are promising targets for pharmaceutical research. Computational tools based on machine learning have the potential to aid discovery of genes encoding novel AMPs but existing approaches are not designed for genome-wide scans. To facilitate such genome-wide discovery of AMPs we developed a fast and accurate AMP classification framework, ampir. ampir is designed for high throughput, integrates well with existing bioinformatics pipelines, and has much higher classification accuracy than existing methods when applied to whole genome data.Availability and Implementationampir is implemented primarily in R with core feature calculation methods written in C++. Release versions are available via CRAN and work on all major operating systems. The development version is maintained at https://github.com/legana/ampirContactlegana.fingerhut@my.jcu.edu.au; ira.cooke@jcu.edu.auSupplementary informationSupplementary data are available at https://github.com/legana/amp_pub

Inflammatory bowel disease (IBD) is a chronic and life-long disease characterized by gastrointestinal tract inflammation. It is caused by the interplay of the host’s genetic predisposition and immune responses, and various environmental factors. Despite many treatment options, there is no cure for IBD. The increasing incidence and prevalence of IBD and lack of effective long-term treatment options have resulted in a substantial economic burden to the healthcare system worldwide. Biologics targeting inflammatory cytokines initiated a shift from symptomatic control towards objective treatment goals such as mucosal healing. There are seven monoclonal antibody therapies excluding their biosimilars approved by the US Food and Drug Administration for induction and maintenance of clinical remission in IBD. Adverse side effects associated with almost all currently available drugs, especially biologics, is the main challenge in IBD management. Natural products have significant potential as therapeutic agents with an increasing role in health care. Given that natural products display great structural diversity and are relatively easy to modify chemically, they represent ideal scaffolds upon which to generate novel therapeutics. This review focuses on the pathology, currently available treatment options for IBD and associated challenges, and the roles played by natural products in health care. It discusses these natural products within the current biodiscovery research agenda, including the applications of drug discovery techniques and the search for next-generation drugs to treat a plethora of inflammatory diseases, with a major focus on IBD.

Cone snails produce a fast-acting and often paralyzing venom, largely dominated by disulfide-rich conotoxins targeting ion channels. Although disulfide-poor conopeptides are usually minor components of cone snail venoms, their ability to target key membrane receptors such as GPCRs make them highly valuable as drug lead compounds. From the venom gland transcriptome of Conus miliaris, we report here on the discovery and characterization of two conopressins, which are nonapeptide ligands of the vasopressin/oxytocin receptor family. These novel sequence variants show unusual features, including a charge inversion at the critical position 8, with an aspartate instead of a highly conserved lysine or arginine residue. Both the amidated and acid C-terminal analogues were synthesized, followed by pharmacological characterization on human and zebrafish receptors and structural investigation by NMR. Whereas conopressin-M1 showed weak and only partial agonist activity at hV1bR (amidated form only) and ZFV1a1R (both amidated and acid form), both conopressin-M2 analogues acted as full agonists at the ZFV2 receptor with low micromolar affinity. Together with the NMR structures of amidated conopressins-M1, -M2 and -G, this study provides novel structure-activity relationship information that may help in the design of more selective ligands.

Accurate predictions of the transport and fate of oil spilled in the marine environment are essential for response and mitigation efforts. The sedimentation of oil-associated marine snow (MOS) has been shown to be an important pathway by which Deepwater Horizon (DWH) oil was removed from the water column; thus, information is needed on the vertical and lateral dispersion of MOS. Here, we simulated the physical environment in the NE Gulf of Mexico using the Connectivity Modeling System (Paris et al., Environ Model Softw 42:47–54, 2013). Field measurements of marine snow provided initial conditions for the simulations. High Mississippi River (MR) discharge during 2010 and 2013 resulted in strong eastward flowing fronts along the shelf break to the east of the MR, and an anticyclonic eddy at the shelf break retained and aggregated particles, which acted to enhance MOS sedimentation. Forward simulations suggested that particles with high sinking rates (200 m d−1) reached the seafloor within

G proteins are key mediators in the signaling of G protein-coupled receptors and involved in a plethora of important physiological processes. The natural product cyclic depsipeptides YM-254890 and FR900359 are the only known selective inhibitors of the Gq protein subfamily. So far, all reported YM-254890 and FR900359 analogs show no inhibition of other G protein subtypes except the Gq, G11 and G14 proteins. Here we report the rationalization of the high potency of FR900359 and efforts towards understanding the G protein subtype selectivity by synthesis of a collection of structurally and stereochemically diverse analogs of YM-254890 using an efficient synthetic protocol. We performed the first conformational study of YM-254890 in aqueous solution by NMR spectroscopy and replica exchange molecular dynamics, which suggested that the combined contribution of residues with appropriate size, stereochemistry and conformational stability are critical for inhibitory potency. Moreover, in addition to the fit of the binding pocket, more factors should be taken into consideration for the development of compounds targeting other G proteins.

There are three recent developments in the field of therapeutic residential care (TRC) which provide a major leap forward for new policy and practice directions. These developments further promote ...

Background The prevalence of hypertensive disorders of pregnancy (HDP) in Australia's urban Indigenous women is unknown. Aim To explore the risk factors associated with HDP for a cohort of urban Indigenous women in South-Western Sydney, Australia Methods and Materials This study was conducted in partnership with the Tharawal Aboriginal Medical Service (TAMS). Women (18-45 years) were recruited at the clinic and community events. The quantitative questionnaire included obstetric history, personal and family history of hypertension. Anthropometric measurements and blood pressure were conducted. Rates were compared with Australian Bureau of Statistics (ABS) national rates. Results Eighty three participants completed the questionnaire. The rate of ever having HDP in a pregnancy was 36.1%. The overall ABS rate was 9.8% and for Indigenous women, 14%. The mean maternal age at first pregnancy was 20.8 years (S.D. 3.7 years). The mean body mass index (BMI) of the sample population (n=81) was 32.2kg/m2 (S.D. 9.5kg/m2) and BMI was not related to HDP (p = 0.197). Of those questioned, 25.3% had an individual history and 63.9% had a family history of hypertension. The effect of family history of hypertension (p = 0.020) (OR 4.29; 95%CI; 1.42-12.93) and individual history of hypertension (p

Fast ice plays important physical and ecological roles: as a barrier to wind, waves and radiation, as both barrier and safe resting place for air-breathing animals, and as substrate for microbial communities. While sea ice has been monitored for decades using satellite imagery, high-resolution imagery sufficient to distinguish fast ice from mobile pack ice extends only back toc.2000. Fast ice trends may differ from previously identified changes in regional sea ice distributions. To investigate effects of climate and human activities on fast ice dynamics in McMurdo Sound, Ross Sea, the sea and fast ice seasonal events (1978–2015), ice thicknesses and temperatures (1986–2014), wind velocities (1973–2015) and dates that an icebreaker annually opens a channel to McMurdo Station (1956–2015) are reported. A significant relationship exists between sea ice concentration and fast ice extent in the Sound. While fast/sea ice retreat dates have not changed, fast/sea ice reaches a minimum later and begins to advance earlier, in partial agreement with changes in Ross Sea regional pack ice dynamics. Fast ice minimum extent within McMurdo Sound is significantly correlated with icebreaker arrival date as well as wind velocity. The potential impacts of changes in fast ice climatology on the local marine ecosystem are discussed.

Persistent mobile ocean observation platforms, supported by arrays of subsea marine vehicle service stations, will enable direct study of oceanographic and geological processes that, due to their transient nature and spatiotemporal variability, are not well understood. These include, but are not limited to, ocean-seafloor interactions and crustal ecosystems, mid-ocean ridge volcanism, coastal circulation and shelf ecosystems, reef health, and arctic sea-ice interaction. Further, certain types of subsea events, such as erupting submarine volcanoes, instabilities in methane hydrate deposits, marine mass-wasting events, turbidite flows, the ecological impacts of major earthquakes, breaking internal waves, the fate of mid-water vortices, and episodes of anoxic upwelling, can be energetic, transient, and unpredictable, often having unverifiable consequences. These cannot be readily detected, characterized, or quantified owing to the difficulty of anticipating the onset of such phenomena. The intractability of launching major sea-going assets with short lead times to capture and document such evanescent system-level processes from beginning to end means that our understanding of these and related processes is not readily expandable with current oceanographic tools.Marine Vehicle Highways (MVHs) will change the way ocean science is conducted by making temporally and spatially distributed data sets more attainable and accessible, opening the door for broader participation in transformative ocean science.

The turripeptide ubi3a was isolated from the venom of the marine gastropod Unedogemmula bisaya, family Turridae, by bioassay-guided purification; both native and synthetic ubi3a elicited prolonged tremors when injected intracranially into mice. The sequence of the peptide, DCCOCOAGAVRCRFACC-NH2 (O = 4-hydroxyproline) follows the framework III pattern for cysteines (CC–C–C–CC) in the M-superfamily of conopeptides. The three-dimensional structure determined by NMR spectroscopy indicated a disulfide connectivity that is not found in conopeptides with the cysteine framework III: C1–C4, C2–C6, C3–C5. The peptide inhibited the activity of the α9α10 nicotinic acetylcholine receptor with relatively low affinity (IC50, 10.2 μM). Initial Constellation Pharmacology data revealed an excitatory activity of ubi3a on a specific subset of mouse dorsal root ganglion neurons.

The optical properties of meta-alkoxy-substituted difluoroboron dibenzoylmethane dyes were investigated in solution and in the solid state. Meta-alkoxy substitution induced strong intramolecular charge transfer (ICT) from the oxygen-donating substituent to the halide and boron acceptors in the excited state, as compared to the π-π* transition that is observed with para-alkoxy substitution. The optical properties of para- and meta-substituted alkoxy boron dyes were evaluated by calculations, in dilute solution, and in solid-state films. When embedded in amorphous matrixes (e.g., PLA, PMMA, PS, cholesterol), all dyes showed fluorescence (F) and phosphorescence (P) emission. In this report, we show that meta-substitution resulted in enhanced solvatochromism and an increased phosphorescence-to-fluorescence ratio in solid-state films compared to analogous para-substituted samples. With enhanced phosphorescence intensity via the heavy-atom effect, iodo-substituted dyes were further studied in PLA-PEG nanoparticles. Oxygen calibrations revealed stronger phosphorescence and a greater oxygen-sensing range for the meta- versus para-alkoxy-substituted dyes, features that are important for oxygen-sensing materials design.