The extracellular signal-regulated kinase (ERK) pathway: a potential therapeutic target in hypertension

Hypertension is a risk factor for myocardial infarction, stroke, renal failure, heart failure, and peripheral vascular disease. One feature of hypertension is a hyperresponsiveness to contractile agents, and inhibition of vasoconstriction forms the basis of some of the treatments for hypertension. Hypertension is also associated with an increase in the growth and proliferation of vascular smooth muscle cells, which can lead to a thickening of the smooth muscle layer of the blood vessels and a reduction in lumen diameter. Targeting both the enhanced contractile responses, and the increased vascular smooth muscle cell growth could potentially be an important pharmacological treatment of hypertension. Extracellular signal-regulated kinase (ERK) is a member of the mitogen-activated protein kinase family that is involved in both vasoconstriction and vascular smooth muscle cell growth and this, therefore, makes it an attractive therapeutic target for treatment of hypertension. ERK activity is raised in vascular smooth muscle cells from animal models of hypertension, and inhibition of ERK activation reduces both vascular smooth muscle cell growth and vasoconstriction. This review discusses the potential for targeting ERK activity in the treatment of hypertension

Dust in the reionization era: ALMA observations of a zz=8.38 Galaxy

We report on the detailed analysis of a gravitationally-lensed Y-band dropout, A2744_YD4, selected from deep Hubble Space Telescope imaging in the Frontier Field cluster Abell 2744. Band 7 observations with the Atacama Large Millimeter Array (ALMA) indicate the proximate detection of a significant 1mm continuum flux suggesting the presence of dust for a star-forming galaxy with a photometric redshift of $z\simeq8$. Deep X-SHOOTER spectra confirms the high redshift identity of A2744_YD4 via the detection of Lyman $\alpha$ emission at a redshift $z$=8.38. The association with the ALMA detection is confirmed by the presence of [OIII] 88$\mu$m emission at the same redshift. Although both emission features are only significant at the 4 $\sigma$ level, we argue their joint detection and the positional coincidence with a high redshift dropout in the HST images confirms the physical association. Analysis of the available photometric data and the modest gravitational magnification ($\mu\simeq2$) indicates A2744_YD4 has a stellar mass of $\sim$ 2$\times$10$^9$ M$_{\odot}$, a star formation rate of $\sim20$ M$_{\odot}$/yr and a dust mass of $\sim$6$\times$10$^{6}$ M$_{\odot}$. We discuss the implications of the formation of such a dust mass only $\simeq$200 Myr after the onset of cosmic reionisation.Comment: Accepted for publication in ApJ

Mass spectrometric characterisation of the circulating peptidome following oral glucose ingestion in control and gastrectomised patients.

RATIONALE: Meal ingestion triggers secretion of a variety of gut and endocrine peptides important in diabetes research which are routinely measured by immunoassays. However, similarities between some peptides (glucagon, oxyntomodulin and glicentin) can cause specificity issues with immunoassays. We used a liquid chromatography/tandem mass spectrometry (LC/MS/MS) methodology to unambiguously monitor multiple gut peptides in human plasma. METHODS: A simple acetonitrile-based protein precipitation step, followed by evaporation and solid-phase extraction, removed high-abundance proteins from samples prior to nano-LC/MS/MS analysis on an Orbitrap Q-Exactive Plus mass spectrometer using a data-dependent methodology. Database searching using PEAKS identified multiple gut-derived peptides, including peptides in the mid-pg/mL range. The relative levels of these and previously characterised peptides were assessed in plasma samples from gastrectomised and control subjects during an oral glucose tolerance test. RESULTS: Analysis of plasma extracts revealed significantly elevated levels of a number of peptides following glucose ingestion in subjects who had undergone gastrectomy compared with controls. These included GLP-1(7-36), GLP-1(9-36), glicentin, oxyntomodulin, GIP(1-42), GIP(3-42), PYY(1-36), PYY(3-36), neurotensin, insulin and C-peptide. Motilin levels decreased following glucose ingestion. Results showed good correlation with immunoassay-derived concentrations of some peptides in the same samples. The gastrectomy group also had higher, but non-glucose-dependent, circulating levels of peptides from PIGR and DMBT1. CONCLUSIONS: Overall, the approach showed that a fast, generic and reproducible LC/MS/MS methodology requiring only a small volume of plasma was capable of the multiplexed detection of a variety of diabetes-related peptides.Wellcome Trust and MR

Achieving Specificity in Selected and Wild-Type N Peptide−RNA Complexes: The Importance of Discrimination against Noncognate RNA Targets

The boxB RNA pentaloops from the P22 and λ phages each adopt a GNRA tetraloop fold upon binding their cognate arginine-rich N peptides. The third loop base in P22 boxB (3-out) and the fourth in λ boxB (4-out) are excluded to accommodate this structure. Previously, we selected a pool of λ N sequences with random amino acids at loop contacting positions 13−22 for binding to either of these two GNRA-folded pentaloops or a canonical GNRA tetraloop and isolated a class of peptides with a new conserved arginine (R15). Here, we characterize the binding of λ N and these R15 peptides using fluorescent titrations with 2-aminopurine labeled versions of the three GNRA-folded loops and circular dichroism spectrometry. All peptides preferentially bind the λ boxB RNA loop. λ N and R15 peptide specificity against the P22 loop arises from the cost of rearranging its loop into the 4-out GNRA structure. Modeling indicates that the interaction of R8 with an additional loop phosphate in the 4-out GNRA pentaloop selectively stabilizes this complex relative to the tetraloop. R15 peptides gain additional discrimination against the tetraloop because their arginine also preferentially interacts with the 4-out GNRA pentaloop phosphate backbone, whereas K14 and W18 of λ N contribute equal affinity when binding the tetraloop. Nonspecific electrostatic interactions by basic residues near the C-termini of these peptides create significantly steeper salt dependencies in association constants for noncognate loops, aiding discrimination at high salt concentrations. Our results emphasize the importance of considering specificity against noncognate as well as nonspecific targets in the combinatorial and rational design of biopolymers capable of macromolecular recognition

Achieving Specificity in Selected and Wild-Type N Peptide−RNA Complexes: The Importance of Discrimination against Noncognate RNA Targets

The boxB RNA pentaloops from the P22 and λ phages each adopt a GNRA tetraloop fold upon binding their cognate arginine-rich N peptides. The third loop base in P22 boxB (3-out) and the fourth in λ boxB (4-out) are excluded to accommodate this structure. Previously, we selected a pool of λ N sequences with random amino acids at loop contacting positions 13−22 for binding to either of these two GNRA-folded pentaloops or a canonical GNRA tetraloop and isolated a class of peptides with a new conserved arginine (R15). Here, we characterize the binding of λ N and these R15 peptides using fluorescent titrations with 2-aminopurine labeled versions of the three GNRA-folded loops and circular dichroism spectrometry. All peptides preferentially bind the λ boxB RNA loop. λ N and R15 peptide specificity against the P22 loop arises from the cost of rearranging its loop into the 4-out GNRA structure. Modeling indicates that the interaction of R8 with an additional loop phosphate in the 4-out GNRA pentaloop selectively stabilizes this complex relative to the tetraloop. R15 peptides gain additional discrimination against the tetraloop because their arginine also preferentially interacts with the 4-out GNRA pentaloop phosphate backbone, whereas K14 and W18 of λ N contribute equal affinity when binding the tetraloop. Nonspecific electrostatic interactions by basic residues near the C-termini of these peptides create significantly steeper salt dependencies in association constants for noncognate loops, aiding discrimination at high salt concentrations. Our results emphasize the importance of considering specificity against noncognate as well as nonspecific targets in the combinatorial and rational design of biopolymers capable of macromolecular recognition

Characterization of Volume F Trash from Four Recent STS Missions: Microbial Occurrence, Numbers, and Identifications

The fate of space-generated solid wastes, including trash, for future missions is under consideration by NASA. Several potential treatment options are under active technology development. Potential fates for space-generated solid wastes: Storage without treatment; storage after treatment(s) including volume reduction, water recovery, sterilization, and recovery plus recycling of waste materials. For this study, a microbial characterization was made on trash returned from four recent STS missions. The material analyzed were 'Volume F' trash and other bags of accompanying trash. This is the second of two submitted papers on these wastes. This first one covered trash content, weight and water content. Upon receipt, usually within 2 days of landing, trash contents were catalogued and placed into categories: drink containers, food waste, personal hygiene items, and packaging materials, i.e., plastic film and duct tape. Microbial counts were obtained with cultivatable counts on agar media and direct counts using Acridine Orange fluorescent stain (AODC). Trash bag surfaces, 25 square cm , were also sampled. Direct counts were approximately 1 x 10(exp 6) microbes/square cm and cultivatable counts ranged from 1 x 10 to 1 X 10(exp 4) microbes/ square cm-2. Aerobic microbes, aerobic sporeformers, and yeasts plus molds were common for all four missions. Waste items from each category were placed into sterile ziplock bags and 1.5 L sterile DI water added. These were then dispersed by hand shaking for 2 min. prior to inoculation of count media or determining AODC. In general, cultivatable microbes were found in drinks, food wastes, and personal hygiene items. Direct counts were usually higher than cultivatable counts. Some pathogens were found: Staphylococcus auerus, Escherichia coli (fecal wastes). Count ranges: drink pouches - AODC 2 x 10(exp 6) to 1 X 10(exp 8) g(sub fw) (exp -1); cultivatable counts variable between missions; food wastes: Direct counts were close to aerobic plate counts. Counts ranged from 10(exp 6) to 10(exp 9) per g(sub fw). Identities of isolates from cultivation media were obtained using a Biolog Microbial ID System or microSEQ molecular ID methodology using an ABI3130 gene analyzer

Cervical spine immobilisation is only required in drowning patients at high risk of axial loading of the spine

Objectives: Wave forced impacts are known to result in cervical spine injuries (CSI) and approximately 20% of drownings in Australia occur at the beach. The most common mechanism of injury in studies examining the frequency of CSI in drowning patients is shallow water diving. The aim of the present study was to determine what proportion of CSIs occurring in bodies of water experienced a concomitant drowning injury in a location where wave forced impacts are likely to be an additional risk factor. Methods Electronic medical records at the Sunshine Coast Hospital and Health Service EDs, Queensland Ambulance Service case records and Surf Life Saving Queensland data between 1 January 2015 and 21 April 2021 were manually linked. Outcomes recorded included victim demographics, scene information, hospital course and patient disposition. Results Ninety-one of 574 (15.9%) CSIs occurred in a body of water with risk of drowning. However, only 4 (4.3%) had a simultaneous drowning injury, representing 0.8% (4/483) of drowning presentations. Ten (10.9%) patients reported loss of consciousness, including the four with drowning. The principal mechanism of CSI was a wave forced impact (71/91, 78%). Most injuries occurred at the beach (79/91, 86.8%). Delayed presentation was common (28/91, 31%). A history of axial loading was 100% sensitive when indicating imaging. Conclusions The combination of CSI and drowning is uncommon. Cervical spine precautions are only required in drowning patients with signs or a history, or at high risk of, axial loading of the spine. This paper supports the move away from routine cervical spine precautions even in a high-risk population

Characterization of Volume F Trash from Four Recent STS Missions: Weights, Categorization, Water Content

The fate of space-generated solid wastes, including trash, for future missions is under consideration by NASA. Several potential treatment options are under consideration and active technology development. Potential fates for space-generated solid wastes are: Storage without treatment; storage after treatment(s) including volume reduction, water recovery, sterilization, and recovery plus recycling of waste materials. Recycling might be important for partial or full closure scenarios because of the prohibitive costs associated with resupply of consumable materials. For this study, we determined the composition of trash returned from four recent STS missions. The trash material was 'Volume F' trash and other trash, in large zip-lock bags, that accompanied the Volume F trash. This is the first of two submitted papers on these wastes. This one will cover trash content, weight and water content. The other will report on the microbial Characterization of this trash. STS trash was usually made available within 2 days of landing at KSC. The Volume F bag was weighed, opened and the contents were catalogued and placed into one of the following categories: food waste (and containers), drink containers, personal hygiene items - including EVA maximum absorbent garments (MAGs)and Elbow packs (daily toilet wipes, etc), paper, and packaging materials - plastic firm and duct tape. Trash generation rates for the four STS missions: Total wet trash was 0.602 plus or minus 0.089 kg(sub wet) crew(sup -1) d(sup -1) containing about 25% water at 0.154 plus or minus 0.030 kg(sub water) crew(sup -1) d(sup -1) (avg plus or minus stdev). Cataloguing by category: personal hygiene wastes accounted for 50% of the total trash and 69% of the total water for the four missions; drink items were 16% of total weight and 16% water; food wastes were 22% of total weight and 15% of the water; office waste and plastic film were 2% and 11% of the total waste and did not contain any water. The results can be used by NASA to determine requirements and criteria for Waste Management Systems on future missions

Combined organic biomarker and use-wear analyses of stone artefacts from Liang Bua, Flores, Indonesia

Organic biomarker and lithic use-wear analyses of archaeological implements manufactured and/or used by hominins in the past offers a means of assessing how prehistoric peoples utilised natural resources. Currently, most studies focus on one of these techniques, rather than using both in sequence. This study aims to assess the potential of combining both methods to analyse stone artefacts, using a set of 69 stones excavated from the cave site of Liang Bua (Flores, Indonesia). Prior to chemical analysis, an initial inspection of the artefacts revealed potential use-wear traces but no visible residues. Gas chromatography mass spectrometry (GC-MS) analysis, including the targeting of 86 lipids, terpenes, terpenoids, alkanes and their analogues, found compounds with plant or animal origin on 27 of the 69 stones. The artefacts were subsequently cleaned, and use-wear analysis identified traces of use on 43 artefacts. Use-wear analysis confirmed traces of use on 23 of the 27 artefacts with potential use-residues that were determined by GC-MS. The GC-MS results were broadly consistent with the functional classes identified in the later use-wear analysis. This inclusive approach for stone artefact analysis strengthens the identifications made through multiple lines of enquiry. There remain conflicts and uncertainties in specific cases, suggesting the need for further refinement and analyses of the relationships between use-wear and residues