Evidence-based target setting informs blue carbon strategies for nationally determined contributions.

The magnitude and pace of global climate change demand ambitious and effective implementation of nationally determined contributions (NDCs). Nature-based solutions present an efficient approach to achieving mitigation, adaptation and resilience goals. Yet few nations have quantified the diverse benefits of nature-based solutions to evaluate and select ecosystem targets for their NDCs. Here we report on Belize's pursuit of innovative, evidence-based target setting by accounting for multiple benefits of blue carbon strategies. Through quantification of carbon storage and sequestration and optimization of co-benefits, we explore time-bound targets and prioritize locations for mangrove protection and restoration. We find increases in carbon benefits with larger mangrove investments, while fisheries, tourism and coastal risk-reduction co-benefits grow initially and then plateau. We identify locations, currently lacking protected status, where prioritizing blue carbon strategies would provide the greatest delivery of co-benefits to communities. These findings informed Belize's updated NDCs to include an additional 12,000 ha of mangrove protection and 4,000 ha of mangrove restoration, respectively, by 2030. Our study serves as an example for the more than 150 other countries that have the opportunity to enhance greenhouse gas sequestration and climate adaptation by incorporating blue carbon strategies that provide multiple societal benefits into their NDCs.

Nectin Family Ligands Trigger Immune Effector Functions in Health and Autoimmunity.

The superfamily of immunoglobulin cell-adhesion molecules (IgCAMs) is a well-known family of cell-adhesion molecules used for immune-cell extravasation and cell-cell interaction. Amongst others, this family includes DNAX accessory molecule 1 (DNAM-1/CD226), class-I-restricted T-cell-associated molecule (CRTAM/CD355), T-cell-activated increased late expression (Tactile/CD96), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), Nectins and Nectin-like molecules (Necls). Besides using these molecules to migrate towards inflammatory sites, their interactions within the immune system can support the immunological synapse with antigen-presenting cells or target cells for cytotoxicity, and trigger diverse effector functions. Although their role is generally described in oncoimmunity, this review emphasizes recent advances in the (dys)function of Nectin-family ligands in health, chronic inflammatory conditions and autoimmune diseases. In addition, this review provides a detailed overview on the expression pattern of Nectins and Necls and their ligands on different immune-cell types by focusing on human cell systems.

Belize Blue Carbon: Establishing a national carbon stock estimate for mangrove ecosystems.

Mangrove ecosystems are among the most economically and ecologically valuable marine environments in the world. Mangroves are effective at long-term carbon storage within their sediments and are estimated to hold 12 billion metric tons of carbon worldwide. These ecosystems are therefore vitally important for carbon sequestration and, by extension, climate change mitigation. As part of the Paris Agreement, participating countries agree to provide plans to reduce their carbon emissions, or nationally determined contributions (NDCs). However, despite mangroves being recognized as important nature-based solutions, many countries still lack national data on carbon stocks and must use global or regional averages, which may not be sufficiently accurate. Here, we present the national carbon stock estimate of mangrove ecosystems for the NDC of Belize, acquired through a collaborative approach involving government agencies and NGOs. We conducted a comprehensive sampling of mangroves across the country, including a range of mangrove ecotypes. The mean total ecosystem carbon stock (TECS) for the nation was 444.1 ± 21.0 Mg C ha-1, with 74.4 ± 6.2 Mg C ha-1 in biomass stocks, and 369.7 ± 17.7 Mg C ha-1 in sediment stocks. Combining these data with a recent mapping effort, we provide the first national comprehensive mangrove carbon stock estimate of 25.7 Tg C. The national mean from this study varies from previous global analyses, which can under- or overestimate TECS by as much as 0.6 Tg C and 16.5 Tg C, respectively, depending on the study. These data supported the NDC update of Belize, and can be used to inform the country's mangrove protection and restoration commitments. The collaborative approach of this work should serve as a blueprint for other countries seeking to conserve natural blue carbon sinks as a strategy to achieve their climate targets.

Manual QT interval measurement with a smartphone-operated single-lead ECG versus 12-lead ECG: a within-patient diagnostic validation study in primary care.

OBJECTIVE: To determine the accuracy of QT measurement in a smartphone-operated, single-lead ECG (1L-ECG) device (AliveCor KardiaMobile 1L). DESIGN: Cross-sectional, within-patient diagnostic validation study. SETTING/PARTICIPANTS: Patients underwent a 12-lead ECG (12L-ECG) for any non-acute indication in primary care, April 2017-July 2018. INTERVENTION: Simultaneous recording of 1L-ECGs and 12L-ECGs with blinded manual QT assessment. OUTCOMES OF INTEREST: (1) Difference in QT interval in milliseconds (ms) between the devices; (2) measurement agreement between the devices (excellent agreement <20 ms and clinically acceptable agreement <40 ms absolute difference); (3) sensitivity and specificity for detection of extreme QTc (short (≤340 ms) or long (≥480 ms)), on 1L-ECGs versus 12L-ECGs as reference standard. In case of significant discrepancy between lead I/II of 12L-ECGs and 1L-ECGs, we developed a correction tool by adding the difference between QT measurements of 12L-ECG and 1L-ECGs. RESULTS: 250 ECGs of 125 patients were included. The mean QTc interval, using Bazett's formula (QTcB), was 393±25 ms (mean±SD) in 1L-ECGs and 392±27 ms in lead I of 12L-ECGs, a mean difference of 1±21 ms, which was not statistically different (paired t-test (p=0.51) and Bland Altman method (p=0.23)). In terms of agreement between 1L-ECGs and lead I, QTcB had excellent agreement in 66.9% and clinically acceptable agreement in 93.4% of observations. The sensitivity and specificity of detecting extreme QTc were 0% and 99.2%, respectively. The comparison of 1L-ECG QTcB with lead II of 12L-ECGs showed a significant difference (p=<0.01), but when using a correction factor (+9 ms) this difference was cancelled (paired t-test (p=0.43) or Bland Altman test (p=0.57)). Moreover, it led to improved rates of excellent (71.3%) and clinically acceptable (94.3%) agreement. CONCLUSION: Smartphone-operated 1L-ECGs can be used to accurately measure the QTc interval compared with simultaneously obtained 12L-ECGs in a primary care population. This may provide an opportunity for monitoring the effects of potential QTc-prolonging medications.

Incorporation of uncertainty to improve projections of tidal wetland elevation and carbon accumulation with sea-level rise.

Understanding the rates and patterns of tidal wetland elevation changes relative to sea-level is essential for understanding the extent of potential wetland loss over the coming years. Using an enhanced and more flexible modeling framework of an ecosystem model (WARMER-2), we explored sea-level rise (SLR) impacts on wetland elevations and carbon sequestration rates through 2100 by considering plant community transitions, salinity effects on productivity, and changes in sediment availability. We incorporated local experimental results for plant productivity relative to inundation and salinity into a species transition model, as well as site-level estimates of organic matter decomposition. The revised modeling framework includes an improved calibration scheme that more accurately reconstructs soil profiles and incorporates parameter uncertainty through Monte Carlo simulations. Using WARMER-2, we evaluated elevation change in three tidal wetlands in the San Francisco Bay Estuary, CA, USA along an estuarine tidal and salinity gradient with varying scenarios of SLR, salinization, and changes in sediment availability. We also tested the sensitivity of marsh elevation and carbon accumulation rates to different plant productivity functions. Wetland elevation at all three sites was sensitive to changes in sediment availability, but sites with greater initial elevations or space for upland transgression persisted longer under higher SLR rates than sites at lower elevations. Using a multi-species wetland vegetation transition model for organic matter contribution to accretion, WARMER-2 projected increased elevations relative to sea levels (resilience) and higher rates of carbon accumulation when compared with projections assuming no future change in vegetation with SLR. A threshold analysis revealed that all three wetland sites were likely to eventually transition to an unvegetated state with SLR rates above 7 mm/yr. Our results show the utility in incorporating additional estuary-specific parameters to bolster confidence in model projections. The new WARMER-2 modeling framework is widely applicable to other tidal wetland ecosystems and can assist in teasing apart important drivers of wetland elevation change under SLR.

SK2 channels in cerebellar Purkinje cells contribute to excitability modulation in motor-learning-specific memory traces.

Neurons store information by changing synaptic input weights. In addition, they can adjust their membrane excitability to alter spike output. Here, we demonstrate a role of such "intrinsic plasticity" in behavioral learning in a mouse model that allows us to detect specific consequences of absent excitability modulation. Mice with a Purkinje-cell-specific knockout (KO) of the calcium-activated K+ channel SK2 (L7-SK2) show intact vestibulo-ocular reflex (VOR) gain adaptation but impaired eyeblink conditioning (EBC), which relies on the ability to establish associations between stimuli, with the eyelid closure itself depending on a transient suppression of spike firing. In these mice, the intrinsic plasticity of Purkinje cells is prevented without affecting long-term depression or potentiation at their parallel fiber (PF) input. In contrast to the typical spike pattern of EBC-supporting zebrin-negative Purkinje cells, L7-SK2 neurons show reduced background spiking but enhanced excitability. Thus, SK2 plasticity and excitability modulation are essential for specific forms of motor learning.

Wetland carbon storage controlled by millennial-scale variation in relative sea-level rise.

Coastal wetlands (mangrove, tidal marsh and seagrass) sustain the highest rates of carbon sequestration per unit area of all natural systems1,2, primarily because of their comparatively high productivity and preservation of organic carbon within sedimentary substrates3. Climate change and associated relative sea-level rise (RSLR) have been proposed to increase the rate of organic-carbon burial in coastal wetlands in the first half of the twenty-first century4, but these carbon-climate feedback effects have been modelled to diminish over time as wetlands are increasingly submerged and carbon stores become compromised by erosion4,5. Here we show that tidal marshes on coastlines that experienced rapid RSLR over the past few millennia (in the late Holocene, from about 4,200 years ago to the present) have on average 1.7 to 3.7 times higher soil carbon concentrations within 20 centimetres of the surface than those subject to a long period of sea-level stability. This disparity increases with depth, with soil carbon concentrations reduced by a factor of 4.9 to 9.1 at depths of 50 to 100 centimetres. We analyse the response of a wetland exposed to recent rapid RSLR following subsidence associated with pillar collapse in an underlying mine and demonstrate that the gain in carbon accumulation and elevation is proportional to the accommodation space (that is, the space available for mineral and organic material accumulation) created by RSLR. Our results suggest that coastal wetlands characteristic of tectonically stable coastlines have lower carbon storage owing to a lack of accommodation space and that carbon sequestration increases according to the vertical and lateral accommodation space6 created by RSLR. Such wetlands will provide long-term mitigating feedback effects that are relevant to global climate-carbon modelling.

A systematic review on posterior circumflex humeral artery pathology: sports and professions at risk and associated risk factors.

INTRODUCTION: Posterior circumflex humeral artery (PCHA) aneurysm formation and thrombosis as overuse injury in the dominant shoulder can result in ischemia of the forearm, hand and digits due to arterial embolisms. Increased awareness among physicians is necessary as PCHA pathology (PCHAP) might be underdiagnosed. Knowledge of sports and professions at risk and risk-factors for obtaining PCHAP is essential for the development of future preventive measures. This study aims to identify sports and professions at risk as well as risk factors for PCHAP. EVIDENCE ACQUISITION: The databases of MEDLINE, EMBASE, BIOSIS, CINAHL and SPORTDiscus were systematically searched. EVIDENCE SYNTHESIS: Twenty-seven papers fulfilled the inclusion criteria and described 67 patients with PCHAP involved in seven sports and three professions. The sports (number of cases) were volleyball (41), baseball (13), swimming (1), tennis (3), American football (2), canoeing (1) and yoga (1) (2 unknown). The professions included a baseball coach, a circus trapeze artist and a mechanic. Apart from expert opinions, no studies have identified risk factors for PCHAP. An anatomic variation of the PCHA origin is suggested to be protective for PCHAP. CONCLUSIONS: PCHAP is reported in seven overhead sports and three professions. No risk factors for PCHAP were identified. An anatomic variant of the PCHA origin was found to be a potential protective factor for PCHAP. Physicians should be cautious for distal embolization as a result of PCHAP in athletes and workers, both adult and adolescent, involved in repetitive powerful overhead movements.

Author Correction: Accuracy and Precision of Tidal Wetland Soil Carbon Mapping in the Conterminous United States.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Accuracy and Precision of Tidal Wetland Soil Carbon Mapping in the Conterminous United States.

Tidal wetlands produce long-term soil organic carbon (C) stocks. Thus for carbon accounting purposes, we need accurate and precise information on the magnitude and spatial distribution of those stocks. We assembled and analyzed an unprecedented soil core dataset, and tested three strategies for mapping carbon stocks: applying the average value from the synthesis to mapped tidal wetlands, applying models fit using empirical data and applied using soil, vegetation and salinity maps, and relying on independently generated soil carbon maps. Soil carbon stocks were far lower on average and varied less spatially and with depth than stocks calculated from available soils maps. Further, variation in carbon density was not well-predicted based on climate, salinity, vegetation, or soil classes. Instead, the assembled dataset showed that carbon density across the conterminous united states (CONUS) was normally distributed, with a predictable range of observations. We identified the simplest strategy, applying mean carbon density (27.0 kg C m-3), as the best performing strategy, and conservatively estimated that the top meter of CONUS tidal wetland soil contains 0.72 petagrams C. This strategy could provide standardization in CONUS tidal carbon accounting until such a time as modeling and mapping advancements can quantitatively improve accuracy and precision.

Coastal wetland management as a contribution to the US National Greenhouse Gas Inventory.

The IPCC 2013 Wetlands Supplement provided new guidance for countries on inclusion of wetlands in their National GHG Inventories. The United States has responded by including managed coastal wetlands for the first time in its 2017 GHG Inventory report along with an updated time series in the most recent 2018 submission and plans to update the time series on an annual basis as part of its yearly submission to the United Nations Framework Convention on Climate Change (UNFCCC). The United States followed IPCC Good Practice Guidance when reporting sources and sinks associated with managed coastal wetlands. Here we show that intact vegetated coastal wetlands are a net sink for GHGs. Despite robust regulation that has protected substantial stocks of carbon, the United States continues to lose coastal wetlands to development and the largest loss of wetlands to open water occurs around the Mississippi Delta due mostly to upstream changes in hydrology and sediment delivery, and oil and gas extraction. These processes create GHG emissions. By applying comprehensive Inventory reporting, scientists in the United States have identified opportunities for reducing GHG emissions through restoration of coastal wetlands that also provide many important societal co-benefits.

Tumor suppressor ras association domain family 5 (RASSF5/NORE1) mediates death receptor ligand-induced apoptosis.

Epigenetic silencing of RASSF (Ras association domain family) genes RASSF1 and RASSF5 (also called NORE1) by CpG hypermethylation is found frequently in many cancers. Although the physiological roles of RASSF1 have been studied in some detail, the exact functions of RASSF5 are not well understood. Here, we show that RASSF5 plays an important role in mediating apoptosis in response to death receptor ligands, TNF-α and TNF-related apoptosis-inducing ligand. Depletion of RASSF5 by siRNA significantly reduced TNF-α-mediated apoptosis, likely through its interaction with proapoptotic kinase MST1, a mammalian homolog of Hippo. Consistent with this, siRNA knockdown of MST1 also resulted in resistance to TNF-α-induced apoptosis. To further study the role of Rassf5 in vivo, we generated Rassf5-deficient mouse. Inactivation of Rassf5 in mouse embryonic fibroblasts (MEFs) resulted in resistance to TNF-α- and TNF-related apoptosis-inducing ligand-mediated apoptosis. Importantly, Rassf5-null mice were significantly more resistant to TNF-α-induced apoptosis and failed to activate Mst1. Loss of Rassf5 also resulted in spontaneous immortalization of MEFs at earlier passages than the control MEFs, and Rassf5-null immortalized MEFs, but not the immortalized wild type MEFs, were fully transformed by K-RasG12V. Together, our results demonstrate a direct role for RASSF5 in death receptor ligand-mediated apoptosis and provide further evidence for RASSF5 as a tumor suppressor.

EWS/FLI1 oncogene activates caspase 3 transcription and triggers apoptosis in vivo.

EWS/FLI1 is a fusion gene product generated by a chromosomal translocation t(11;22)(q24;q12) found in Ewing sarcoma. EWS/FLI1 encodes an aberrant transcription factor with oncogenic properties in vitro. Paradoxically, expression of EWS/FLI1 in nontransformed primary cells results in apoptosis, but the exact mechanism remains unclear. In primary mouse embryonic fibroblasts derived from conditional EWS/FLI1 knock-in embryos, expression of EWS/FLI1 resulted in apoptosis with concomitant increase in the endogenous Caspase 3 (Casp3) mRNA. EWS/FLI1 directly bound and activated the CASP3 promoter, whereas small interfering RNA-mediated knockdown of EWS/FLI1 led to a marked decrease in CASP3 transcripts in Ewing sarcoma cell lines. Ectopic expression of EWS/FLI1 resulted in an increased expression of CASP3 protein in heterologous cell lines. Importantly, expression of EWS/FLI1 in the mouse triggered an early onset of apoptosis in kidneys and acute lethality. These findings suggest that EWS/FLI1 induces apoptosis, at least partially, through the activation of CASP3 and show the cell context-dependent roles of EWS/FLI1 in apoptosis and tumorigenesis.

Adenosine transporter ENT4 is a direct target of EWS/WT1 translocation product and is highly expressed in desmoplastic small round cell tumor.

BACKGROUND: Desmoplastic Small Round Cell Tumor (DSRCT) is a highly aggressive malignancy that affects mainly adolescents and young adults. A defining characteristic of DSRCT is a specific chromosomal translocation, t(11;22)(p13;q12), that fuses EWS with WT1, leading to a production of two isoforms of chimeric transcription factor, EWS/WT1(-KTS) and EWS/WT1(+KTS). The chimeric proteins are thought to play critical roles in various stages of oncogenesis through aberrant transcription of different genes, but only a few of these genes have been identified. METHODOLOGY/PRINCIPAL FINDINGS: We report the identification of a new target of EWS/WT1, ENT4 (equilibrative nucleoside transporter 4) which encodes a pH-dependent adenosine transporter. ENT4 is transcriptionally activated by both isoforms of EWS/WT1 as evidenced by promoter-reporter and chromatin immunoprecipitation (ChIP) analyses. Furthermore, ENT4 is highly and specifically expressed in primary tumors of DSRCT as well as in a DSRCT cell line, JN-DSRCT-1. Treatment of JN-DSRCT-1 cells with adenosine analogs, such as 2-chloro-2'-deoxyadenosine (2-CdA), resulted in an increased cytotoxic response in dose- and pH-dependent manner. CONCLUSIONS/SIGNIFICANCE: Our detailed analyses of a novel target of EWS/WT1 in DSRCT reveal an insight into the oncogenic mechanism of EWS-fusion chromosomal translocation gene products and provide a new marker for DSRCT. Furthermore, identification of ENT4 as a highly expressed transcript in DSRCT may represent an attractive pathway for targeting chemotherapeutic drugs into DSRCT.