Autoregulation of Connexin43 Gap Junction Formation by Internally Translated Isoforms

SummaryDuring each heartbeat, intercellular electrical coupling via connexin43 (Cx43) gap junctions enables synchronous cardiac contraction. In failing hearts, impaired Cx43 trafficking reduces gap junction coupling, resulting in arrhythmias. Here we report that internal translation within Cx43 (GJA1) mRNA occurs, resulting in truncated isoforms that autoregulate Cx43 trafficking. We find that at least four truncated Cx43 isoforms occur in the human heart, with a 20 kDa isoform predominating. In-frame AUG codons within GJA1 mRNA are the translation initiation sites and their ablation arrests trafficking of full-length Cx43. The 20 kDa isoform is sufficient to rescue this trafficking defect in trans, suggesting it as a trafficking chaperone for Cx43. Limiting cap-dependent translation through inhibition of mTOR enhances truncated isoform expression, increasing Cx43 gap junction size. The results suggest that internal translation is a mechanism of membrane protein autoregulation and a potent target for therapies aimed at restoring normal electrical coupling in diseased hearts

Evaluating Operational AVHRR Sea Surface Temperature Data at the Coastline Using Benthic Temperature Loggers

The nearshore coastal ocean is one of the most dynamic and biologically productive regions on our planet, supporting a wide range of ecosystem services. It is also one of the most vulnerable regions, increasingly exposed to anthropogenic pressure. In the context of climate change, monitoring changes in nearshore coastal waters requires systematic and sustained observations of key essential climate variables (ECV), one of which is sea surface temperature (SST). As temperature influences physical, chemical and biological processes within coastal systems, accurate monitoring is crucial for detecting change. SST is an ECV that can be measured systematically from satellites. Yet, owing to a lack of adequate in situ data, the accuracy and precision of satellite SST at the coastline are not well known. In a prior study, we attempted to address this by taking advantage of in situ SST measurements collected by a group of surfers. Here, we make use of a three year time-series (2014–2017) of in situ water temperature measurements collected using a temperature logger (recording every 30 min) deployed within a kelp forest (∼3 m below chart datum) at a subtidal rocky reef site near Plymouth, UK. We compared the temperature measurements with three other independent in situ SST datasets in the region, from two autonomous buoys located ∼7 km and ∼33 km from the coastline, and from a group of surfers at two beaches near the kelp site. The three datasets showed good agreement, with discrepancies consistent with the spatial separation of the sites. The in situ SST measurements collected from the kelp site and the two autonomous buoys were matched with operational Advanced Very High Resolution Radiometer (AVHRR) EO SST passes, all within 1 h of the in situ data. By extracting data from the closest satellite pixel to the three sites, we observed a significant reduction in the performance of AVHRR at retrieving SST at the coastline, with root mean square differences at the kelp site over twice that observed at the two offshore buoys. Comparing the in situ water temperature data with pixels surrounding the kelp site revealed the performance of the satellite data improves when moving two to three pixels offshore and that this improvement was better when using an SST algorithm that treats each pixel independently in the retrieval process. At the three sites, we related differences between satellite and in situ SST data with a suite of atmospheric variables, collected from a nearby atmospheric observatory, and a high temporal resolution land surface temperature (LST) dataset. We found that differences between satellite and in situ SST at the coastline (kelp site) were well correlated with LST and solar zenith angle; implying contamination of the pixel by land is the principal cause of these larger differences at the coastline, as opposed to issues with atmospheric correction. This contamination could be either from land directly within the pixel, potentially impacted by errors in geo-location, or possibly through thermal adjacency effects. Our results demonstrate the value of using benthic temperature loggers for evaluating satellite SST data in coastal regions, and highlight issues with retrievals at the coastline that may inform future improvements in operational products

Air–Sea Interactions from Westerly Wind Bursts During the November 2011 MJO in the Indian Ocean

The life cycles of three Madden–Julian oscillation (MJO) events were observed over the Indian Ocean as part of the Dynamics of the MJO (DYNAMO) experiment. During November 2011 near 0°, 80°E, the site of the research vessel Roger Revelle, the authors observed intense multiscale interactions within an MJO convective envelope, including exchanges between synoptic, meso, convective, and turbulence scales in both atmosphere and ocean and complicated by a developing tropical cyclone. Embedded within the MJO event, two bursts of sustained westerly wind (>10 m s−1; 0–8-km height) and enhanced precipitation passed over the ship, each propagating eastward as convectively coupled Kelvin waves at an average speed of 8.6 m s−1. The ocean response was rapid, energetic, and complex. The Yoshida–Wyrtki jet at the equator accelerated from less than 0.5 m s−1 to more than 1.5 m s−1 in 2 days. This doubled the eastward transport along the ocean's equatorial waveguide. Oceanic (subsurface) turbulent heat fluxes were comparable to atmospheric surface fluxes, thus playing a comparable role in cooling the sea surface. The sustained eastward surface jet continued to energize shear-driven entrainment at its base (near 100-m depth) after the MJO wind bursts subsided, thereby further modifying sea surface temperature for a period of several weeks after the storms had passed

Calcification-driven CO2emissions exceed blue Carbon sequestration in a carbonate seagrass meadow

Long-term Blue Carbon burial in seagrass meadows is complicated by other carbon and alkalinity exchanges that shape net carbon sequestration. We measured a suite of such processes, including denitrification, sulfur, and inorganic carbon cycling, and assessed their impact on air-water CO2 exchange in a typical seagrass meadow underlain by carbonate sediments. Eddy covariance measurements reveal a consistent source of CO2 to the atmosphere at an average rate of 610 ± 990 μmol m-2 hour-1 during our study and 700 ± 660 μmol m-2 hour-1 (6.1 mol m-2 year-1) over an annual cycle. Net alkalinity consumption by ecosystem calcification explains \u3e95% of the observed CO2 emissions, far exceeding organic carbon burial and anaerobic alkalinity generation. We argue that the net carbon sequestration potential of seagrass meadows may be overestimated if calcification-induced CO2 emissions are not accounted for, especially in regions where calcification rates exceed net primary production and burial

Rendering an Account: An Open-State Archive in Postgraduate Supervision

The paper begins with a brief account of the transformation of research degree studies under the pressures of global capitalism and neo-liberal governmentality. A parallel transformation is occurring in the conduct of research through the use of information and communication technologies. Yet the potential of ICTs to shape practices of surveillance or to produce new student-supervisor relations and enhance the processes of developing the dissertation has received almost no critical attention. As doctoral supervisor and student, we then describe the features and uses of a web-based open state archive of the student's work-in-progress, developed by the student and accessible to his supervisor. Our intention was to encourage more open conversations between data and theorising, student and supervisor, and ultimately between the student and professional community. However, we recognise that relations of accountability, as these have developed within a contemporary "audit revolution" (Power, 1994, 1997) in universities, create particular "lines of visibility" (Munro, 1996). Thus while the open-state archive may help to redefine in less managerial terms notions of quality, transparency, flexibility and accountability, it might also make possible greater supervisory surveillance. How should we think about the panoptical potential of this archive? We argue that the diverse kinds of interactional patterns and pedagogical intervention it encourages help to create shifting subjectivities. Moreover, the archive itself is multiple, in bringing together an array of diverse materials that can be read in various ways, by following multiple paths. It therefore constitutes a collage, which we identify as a mode of cognition and of accounting distinct from but related to argument and narrative. As a more "open" text (Iser, 1978) it has an indeterminacy which may render it less open to abuse for the technologies of managerial accountability

Cellular expression, trafficking, and function of two isoforms of human ULBP5/RAET1G

Background: The activating immunoreceptor NKG2D is expressed on Natural Killer (NK) cells and subsets of T cells. NKG2D contributes to anti-tumour and anti-viral immune responses in vitro and in vivo. The ligands for NKG2D in humans are diverse proteins of the MIC and ULBP/RAET families that are upregulated on the surface of virally infected cells and tumours. Two splicing variants of ULBP5/RAET1G have been cloned previously, but not extensively characterised. Methodology/Principal Findings: We pursue a number of approaches to characterise the expression, trafficking, and function of the two isoforms of ULBP5/RAET1G. We show that both transcripts are frequently expressed in cell lines derived from epithelial cancers, and in primary breast cancers. The full-length transcript, RAET1G1, is predicted to encode a molecule with transmembrane and cytoplasmic domains that are unique amongst NKG2D ligands. Using specific anti-RAET1G1 antiserum to stain tissue microarrays we show that RAET1G1 expression is highly restricted in normal tissues. RAET1G1 was expressed at a low level in normal gastrointestinal epithelial cells in a similar pattern to MICA. Both RAET1G1 and MICA showed increased expression in the gut of patients with celiac disease. In contrast to healthy tissues the RAET1G1 antiserum stained a wide variety or different primary tumour sections. Both endogenously expressed and transfected RAET1G1 was mainly found inside the cell, with a minority of the protein reaching the cell surface. Conversely the truncated splicing variant of RAET1G2 was shown to encode a soluble molecule that could be secreted from cells. Secreted RAET1G2 was shown to downregulate NKG2D receptor expression on NK cells and hence may represent a novel tumour immune evasion strategy. Conclusions/Significance: We demonstrate that the expression patterns of ULBP5RAET1G are very similar to the well-characterised NKG2D ligand, MICA. However the two isoforms of ULBP5/RAET1G have very different cellular localisations that are likely to reflect unique functionality

Multihospital Outbreak of Clostridium difficile Ribotype 027 Infection: Epidemiology and Analysis of Control Measures

Objective. To report a large outbreak of Clostridium difficile infection (CDI; ribotype 027) between June 2007 and August 2008, describe infection control measures, and evaluate the impact of restricting the use of fluoroquinolones in controlling the outbreak. Design. Outbreak investigation in 3 acute care hospitals of the Northern Health and Social Care Trust in Northern Ireland. Interventions. Implementation of a series of CDI control measures that targeted high-risk antibiotic agents (ie, restriction of fluoroquinolones), infection control practices, and environmental hygiene. Results. A total of 318 cases of CDI were identified during the outbreak, which was the result of the interaction between C. difficile ribotype 027 being introduced into the affected hospitals for the first time and other predisposing risk factors (ranging from host factors to suboptimal compliance with antibiotic guidelines and infection control policies). The 30-day all-cause mortality rate was 24.5%; however, CDI was the attributable cause of death for only 2.5% of the infected patients. Time series analysis showed that restricting the use of fluoroquinolones was associated with a significant reduction in the incidence of CDI (coefficient, —0.054; lag time, 4 months; P = .003). Conclusion. These findings provide additional evidence to support the value of antimicrobial stewardship as an essential element of multifaceted interventions to control CDI outbreaks. The present CDI outbreak was ended following the implementation of an action plan improving communication, antibiotic stewardship, infection control practices, environmental hygiene, and surveillanc

Analysis of SARS-CoV-2 antibody seroprevalence in Northern Ireland during 2020–2021

BackgroundWith the spread of SARS-CoV-2 impacting upon public health directly and socioeconomically, further information was required to inform policy decisions designed to limit virus spread during the pandemic. This study sought to contribute to serosurveillance work within Northern Ireland to track SARS-CoV-2 progression and guide health strategy.MethodsSera/plasma samples from clinical biochemistry laboratories were analysed for anti-SARS-CoV-2 antibodies. Samples were assessed using an Elecsys anti-SARS-CoV-2 or anti-SARS-CoV-2 S ECLIA (Roche) on an automated cobas e 801 analyser. Samples were also assessed via an anti-SARS-CoV-2 ELISA (Euroimmun). A subset of samples assessed via the Elecsys anti-SARS-CoV-2 ECLIA were subsequently analysed in an ACE2 pseudoneutralisation assay using a V-PLEX SARS-CoV-2 Panel 7 for IgG and ACE2 (Meso Scale Diagnostics).ResultsAcross three testing rounds (June–July 2020, November–December 2020 and June–July 2021 (rounds 1–3 respectively)), 4844 residual sera/plasma specimens were assayed for anti-SARS-CoV-2 antibodies. Seropositivity rates increased across the study, peaking at 11.6 % (95 % CI 10.4%–13.0 %) during round 3. Varying trends in SARS-CoV-2 seropositivity were noted based on demographic factors. For instance, highest rates of seropositivity shifted from older to younger demographics across the study period. In round 3, Alpha (B.1.1.7) variant neutralising antibodies were most frequently detected across age groups, with median concentration of anti-spike protein antibodies elevated in 50–69 year olds and anti-S1 RBD antibodies elevated in 70+ year olds, relative to other age groups.ConclusionsWith seropositivity rates of <15 % across the assessment period, it can be concluded that the significant proportion of the Northern Ireland population had not yet naturally contracted the virus by mid-2021

Stirring by small-scale vortices caused by patchy mixing

Author Posting. © American Meteorological Society, 2005. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 35 (2005): 1245-1262, doi:10.1175/JPO2713.1.Evidence is presented that lateral dispersion on scales of 1–10 km in the stratified waters of the continental shelf may be significantly enhanced by stirring by small-scale geostrophic motions caused by patches of mixed fluid adjusting in the aftermath of diapycnal mixing events. Dye-release experiments conducted during the recent Coastal Mixing and Optics (CMO) experiment provide estimates of diapycnal and lateral dispersion. Microstructure observations made during these experiments showed patchy turbulence on vertical scales of 1–10 m and horizontal scales of a few hundred meters to a few kilometers. Momentum scaling and a simple random walk formulation were used to estimate the effective lateral dispersion caused by motions resulting from lateral adjustment following episodic mixing events. It is predicted that lateral dispersion is largest when the scale of mixed patches is on the order of the internal Rossby radius of deformation, which seems to have been the case for CMO. For parameter values relevant to CMO, lower-bound estimates of the effective lateral diffusivity by this mechanism ranged from 0.1 to 1 m2s−1. Revised estimates after accounting for the possibility of long-lived motions were an order of magnitude larger and ranged from 1 to 10 m2s−1. The predicted dispersion is large enough to explain the observed lateral dispersion in all four CMO dye-release experiments examined.The Coastal Mixing and Optics dye studies were funded by the Office of Naval Research under Grants N00014-95-1-0633 (tracer experiments) and N00014-95-1-1063 (AASERT fellowship). Additional analysis was also performed under ONR Grant N00014-01-1-0984

Air-Sea Interactions from Westerly Wind Bursts During the November 2011 MJO in the Indian Ocean

The life cycles of three Madden–Julian oscillation (MJO) events were observed over the Indian Ocean as part of the Dynamics of the MJO (DYNAMO) experiment. During November 2011 near 0°, 80°E, the site of the research vessel Roger Revelle, the authors observed intense multiscale interactions within an MJO convective envelope, including exchanges between synoptic, meso, convective, and turbulence scales in both atmosphere and ocean and complicated by a developing tropical cyclone. Embedded within the MJO event, two bursts of sustained westerly wind (>10 m s⁻¹; 0–8-km height) and enhanced precipitation passed over the ship, each propagating eastward as convectively coupled Kelvin waves at an average speed of 8.6 m s⁻¹. The ocean response was rapid, energetic, and complex. The Yoshida–Wyrtki jet at the equator accelerated from less than 0.5 m s⁻¹ to more than 1.5 m s⁻¹ in 2 days. This doubled the eastward transport along the ocean's equatorial waveguide. Oceanic (subsurface) turbulent heat fluxes were comparable to atmospheric surface fluxes, thus playing a comparable role in cooling the sea surface. The sustained eastward surface jet continued to energize shear-driven entrainment at its base (near 100-m depth) after the MJO wind bursts subsided, thereby further modifying sea surface temperature for a period of several weeks after the storms had passed