Atlantic Meridional Overturning Circulation

• The AMOC is key to maintaining the mild climate of the UK. • The AMOC is predicted to decline in the 21st century in response to a changing climate. • Past abrupt changes in the AMOC have had dramatic climate consequences. • There is growing evidence that the AMOC has been declining for at least a decade, pushing the Atlantic Multidecadal Variability into a cool phase. • Short term fluctuations in the AMOC have proved to have unexpected impacts, including being linked with severe winters and abrupt sea-level rise

Larval behaviour, dispersal and population connectivity in the deep sea

Ecosystem connectivity is an essential consideration for marine spatial planning of competing interests in the deep sea. Immobile, adult communities are connected through freely floating larvae, depending on new recruits for their health and to adapt to external pressures. We hypothesize that the vertical swimming ability of deep-sea larvae, before they permanently settle at the bottom, is one way larvae can control dispersal. We test this hypothesis with more than 3x108 simulated particles with a range of active swimming behaviours embedded within the currents of a high-resolution ocean model. Despite much stronger horizontal ocean currents, vertical swimming of simulated larvae can have an order of magnitude impact on dispersal. These strong relationships between larval dispersal, pathways, and active swimming demonstrate that lack of data on larval behaviour traits is a serious impediment to modelling deep-sea ecosystem connectivity; this uncertainty greatly limits our ability to develop ecologically coherent marine protected area networks

Large-scale forcing of the European Slope Current and associated inflows to the North Sea

Drifters drogued at 50?m in the European Slope Current at the Hebridean shelf break follow a wide range of pathways, indicating highly variable Atlantic inflow to the North Sea. Slope Current pathways, timescales and transports over 1988–2007 are further quantified in an eddy-resolving ocean model hindcast. Particle trajectories calculated with model currents indicate that Slope Current water is largely ''recruited'' from the eastern subpolar North Atlantic. Observations of absolute dynamic topography and climatological density support theoretical expectations that Slope Current transport is to first order associated with meridional density gradients in the eastern subpolar gyre, which support a geostrophic inflow towards the slope. In the model hindcast, Slope Current transport variability is dominated by abrupt 25–50?% reductions of these density gradients over 1996–1998. Concurrent changes in wind forcing, expressed in terms of density gradients, act in the same sense to reduce Slope Current transport. This indicates that coordinated regional changes of buoyancy and wind forcing acted together to reduce Slope Current transport during the 1990s. Particle trajectories further show that 10–40?% of Slope Current water is destined for the northern North Sea within 6 months of passing to the west of Scotland, with a clear decline in this Atlantic inflow over 1988–2007. The influence of variable Slope Current transport on the northern North Sea is also expressed in salinity, which declines through the hindcast period, and there is evidence for a similar freshening trend in observational records. A proxy for Atlantic inflow may be found in sea level records. Variability of Slope Current transport is implicit in mean sea level differences between Lerwick (Shetland) and Torshavn (Faeroes), in both tide gauge records and a longer model hindcast spanning 1958–2013. Potential impacts of this variability on North Sea biogeochemistry and ecosystems, via associated changes in seasonal stratification and nutrient fluxes, are discussed

Large-scale forcing of the European Slope Current and associated inflows to the North Sea

Drifters drogued at 50?m in the European Slope Current at the Hebridean shelf break follow a wide range of pathways, indicating highly variable Atlantic inflow to the North Sea. Slope Current pathways, timescales and transports over 1988–2007 are further quantified in an eddy-resolving ocean model hindcast. Particle trajectories calculated with model currents indicate that Slope Current water is largely ''recruited'' from the eastern subpolar North Atlantic. Observations of absolute dynamic topography and climatological density support theoretical expectations that Slope Current transport is to first order associated with meridional density gradients in the eastern subpolar gyre, which support a geostrophic inflow towards the slope. In the model hindcast, Slope Current transport variability is dominated by abrupt 25–50?% reductions of these density gradients over 1996–1998. Concurrent changes in wind forcing, expressed in terms of density gradients, act in the same sense to reduce Slope Current transport. This indicates that coordinated regional changes of buoyancy and wind forcing acted together to reduce Slope Current transport during the 1990s. Particle trajectories further show that 10–40?% of Slope Current water is destined for the northern North Sea within 6 months of passing to the west of Scotland, with a clear decline in this Atlantic inflow over 1988–2007. The influence of variable Slope Current transport on the northern North Sea is also expressed in salinity, which declines through the hindcast period, and there is evidence for a similar freshening trend in observational records. A proxy for Atlantic inflow may be found in sea level records. Variability of Slope Current transport is implicit in mean sea level differences between Lerwick (Shetland) and Torshavn (Faeroes), in both tide gauge records and a longer model hindcast spanning 1958–2013. Potential impacts of this variability on North Sea biogeochemistry and ecosystems, via associated changes in seasonal stratification and nutrient fluxes, are discussed

Linking adaptation science to action to build food secure Pacific Island communities

Climate change is a major threat to food security in Pacific Island countries, with declines in food production and increasing variability in food supplies already evident across the region. Such impacts have already led to observed consequences for human health, safety and economic prosperity. Enhancing the adaptive capacity of Pacific Island communities is one way to reduce vulnerability and is underpinned by the extent to which people can access, understand and use new knowledge to inform their decision-making processes. However, effective engagement of Pacific Island communities in climate adaption remains variable and is an ongoing and significant challenge. Here, we use a qualitative research approach to identify the impediments to engaging Pacific Island communities in the adaptations needed to safeguard food security. The main barriers include cultural differences between western science and cultural knowledge, a lack of trust among local communities and external scientists, inappropriate governance structures, and a lack of political and technical support. We identify the importance of adaptation science, local social networks, key actors (i.e., influential and trusted individuals), and relevant forms of knowledge exchange as being critical to overcoming these barriers. We also identify the importance of co-ordination with existing on-ground activities to effectively leverage, as opposed to duplicating, capacity

The Leishmania donovani LD1 locus gene ORFG encodes a biopterin transporter (BT1)

We have previously described two genes, ORFF and ORFG, from the LD1 locus near one telomere of chromosome 35, which are frequently amplified in Leishmania isolates. In Leishmania donovani LSB-51.1, gene conversion of the rRNA gene locus on chromosome 27 with these two genes resulted in their over-expression, because of their transcription by the RNA polymerase I-mediated rRNA promoter. The predicted ORFG protein has substantial sequence homology to the ESAG10 gene product from the Trypanosoma brucei VSG expression site and both are putative membrane proteins. Using successive rounds of gene replacement of the three ORFG genes in L. donovani LSB-51.1, ORFG null mutants were obtained. These mutant cell lines show a direct relationship between ORFG mRNA, protein expression levels and active transport of biopterin into the cells. Transformation of the null mutant with a plasmid containing ORFG restores biopterin transport activity. In addition, the null mutants are unable to grow in the absence of supplemental biopterin. Thus, ORFG encodes a biopterin transporter and has been renamed BT1

Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee.

We report the updated classification of Inborn Errors of Immunity/Primary Immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 430 inborn errors of immunity, including 64 gene defects that have either been discovered in the past 2 years since the previous update (published January 2018) or were characterized earlier but have since been confirmed or expanded upon in subsequent studies. The application of next-generation sequencing continues to expedite the rapid identification of novel gene defects, rare or common; broaden the immunological and clinical phenotypes of conditions arising from known gene defects and even known variants; and implement gene-specific therapies. These advances are contributing to greater understanding of the molecular, cellular, and immunological mechanisms of disease, thereby enhancing immunological knowledge while improving the management of patients and their families. This report serves as a valuable resource for the molecular diagnosis of individuals with heritable immunological disorders and also for the scientific dissection of cellular and molecular mechanisms underlying inborn errors of immunity and related human diseases

Protease-activated receptor 4 variant p.Tyr157Cys reduces platelet functional responses and alters receptor trafficking

OBJECTIVE—: Protease-activated receptor 4 (PAR4) is a key regulator of platelet reactivity and is encoded by F2RL3, which has abundant rare missense variants. We aimed to provide proof of principle that rare F2LR3 variants potentially affect on platelet reactivity and responsiveness to PAR1 antagonist drugs and to explore underlying molecular mechanisms. APPROACH AND RESULTS—: We identified 6 rare F2RL3 missense variants in 236 cardiac patients, of which the variant causing a tyrosine 157 to cysteine substitution (Y157C) was predicted computationally to affect most on PAR4 structure. Y157C platelets from 3 cases showed reduced responses to PAR4-activating peptide and to α-thrombin compared with controls, but no reduction in responses to PAR1-activating peptide. Pretreatment with the PAR1 antagonist vorapaxar caused lower residual α-thrombin responses in Y157C platelets than in controls, indicating greater platelet inhibition. HEK293 cells transfected with a PAR4 Y157C expression construct had reduced PAR4 functional responses, unchanged total PAR4 expression but reduced surface expression. PAR4 Y157C was partially retained in the endoplasmic reticulum and displayed an expression pattern consistent with defective N-glycosylation. Mutagenesis of Y322, which is the putative hydrogen bond partner of Y157, also reduced PAR4 surface expression in HEK293 cells. CONCLUSIONS—: Reduced PAR4 responses associated with Y157C result from aberrant anterograde surface receptor trafficking, in part, because of disrupted intramolecular hydrogen bonding. Characterization of PAR4 Y157C establishes that rare F2RL3 variants have the potential to markedly alter platelet PAR4 reactivity particularly after exposure to therapeutic PAR1 antagonists

Human Inborn Errors of Immunity: 2019 Update of the IUIS Phenotypical Classification.

Since 2013, the International Union of Immunological Societies (IUIS) expert committee (EC) on Inborn Errors of Immunity (IEI) has published an updated phenotypic classification of IEI, which accompanies and complements their genotypic classification into ten tables. This phenotypic classification is user-friendly and serves as a resource for clinicians at the bedside. There are now 430 single-gene IEI underlying phenotypes as diverse as infection, malignancy, allergy, autoimmunity, and autoinflammation. We herein report the 2019 phenotypic classification, including the 65 new conditions. The diagnostic algorithms are based on clinical and laboratory phenotypes for each of the ten broad categories of IEI

Changes in serogroup and genotype prevalence among carried meningococci in the United Kingdom during vaccine implementation.

BACKGROUND: Herd immunity is important in the effectiveness of conjugate polysaccharide vaccines against encapsulated bacteria. A large multicenter study investigated the effect of meningococcal serogroup C conjugate vaccine introduction on the meningococcal population. METHODS: Carried meningococci in individuals aged 15-19 years attending education establishments were investigated before and for 2 years after vaccine introduction. Isolates were characterized by multilocus sequence typing, serogroup, and capsular region genotype and changes in phenotypes and genotypes assessed. RESULTS: A total of 8462 meningococci were isolated from 47 765 participants (17.7%). Serogroup prevalence was similar over the 3 years, except for decreases of 80% for serogroup C and 40% for serogroup 29E. Clonal complexes were associated with particular serogroups and their relative proportions fluctuated, with 12 statistically significant changes (6 up, 6 down). The reduction of ST-11 complex serogroup C meningococci was probably due to vaccine introduction. Reasons for a decrease in serogroup 29E ST-254 meningococci (from 1.8% to 0.7%) and an increase in serogroup B ST-213 complex meningococci (from 6.7% to 10.6%) were less clear. CONCLUSIONS: Natural fluctuations in carried meningococcal genotypes and phenotypes a can be affected by the use of conjugate vaccines, and not all of these changes are anticipatable in advance of vaccine introduction