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South Georgia is a heavily glaciated sub-Antarctic island in the Southern Ocean. Cumberland Bay is the largest fjord on the island, split into two arms, each with a large marine-terminating glacier at the head. Although these glaciers have shown markedly different retreat rates over the past century, the underlying drivers of such differential retreat are not yet understood. This study uses observations and a new high-resolution oceanographic model to characterize oceanographic variability in Cumberland Bay and to explore its influence on glacier retreat. While observations indicate a strong seasonal cycle in temperature and salinity, they reveal no clear hydrographic differences that could explain the differential glacier retreat. Model simulations suggest the subglacial outflow plume dynamics and fjord circulation are sensitive to the bathymetry adjacent to the glacier, though this does not provide persuasive reasoning for the asymmetric glacier retreat. The addition of a postulated shallow inner sill in one fjord arm, however, significantly changes the water properties in the resultant inner basin by blocking the intrusion of colder, higher salinity waters at depth. This increase in temperature could significantly increase submarine melting, which is proposed as a possible contribution to the different rates of glacier retreat observed in the two fjord arms. This study represents the first detailed description of the oceanographic variability of a sub-Antarctic island fjord, highlighting the sensitivity of fjord oceanography to bathymetry. Notably, in fjords systems where temperature decreases with depth, the presence of a shallow sill has the potential to accelerate glacier retreat.

Antarctic krill (Euphausia superba) is a key species in the marine ecosystem of the Southern Ocean, but is also the target of a commercial fishery, with an important fishing ground in the South Orkney Islands region. The potential for competition for krill between predators and the fishery requires risk management strategies for the fishery, underpinned by an understanding of the key physical and behavioural drivers of krill movement and retention in target areas. Here, we present the results of a regional modelling study, combining a high-resolution ocean-sea ice model and an individual-based model parameterised for krill, to elucidate the roles of oceanographic variability and krill behaviour on patterns of transport and retention on and around the South Orkney Plateau. Simulations suggest that oceanic transport from sources around the Antarctic Peninsula is restricted by the northward flowing Antarctic Slope Current. Around the South Orkney Plateau, anticyclonic flows associated with the Weddell Front and the shelf edge transport krill rapidly towards the main fishing grounds to the northwest of the plateau. Transport onto the shelf and subsequent retention are influenced by the strength and direction of regional winds; weaker on-shelf transport and shorter retention times are associated with stronger westerly and northerly winds. The incorporation of sea-ice associated behaviour, whereby krill are moved with sea ice when sea ice is present, significantly modifies the patterns from purely oceanic transport; it reduces the influence of strong regional oceanic flows and increases transport of krill to the South Orkneys region from the Antarctic Peninsula. The inclusion of diel vertical migration also modifies predicted patterns from oceanic transport, but to a lesser extent, and moderates the impact of including sea-ice associated behaviour. We highlight the importance of understanding the behaviour of krill, including age-dependent behavioural changes in response

We use United Kingdom Earth System Model simulations from the Coupled Model Intercomparison Project 6 to analyze the Ross Gyre (RG) dynamics during the historical 1850–2014 period and under two contrasting future climate-change scenarios. The modeled RG is relatively stable, with an extent and strength that agree with observations. The projections exhibit an eastward gyre expansion into the Amundsen-Bellingshausen Seas that starts during the 2040s. The associated cyclonic ocean circulation enhances the onshore transport of warm Circumpolar Deep Water into the inner regional shelf, a regime change that increases the local subsurface shelf temperatures by up to 1.2°C and is independent of future forcing scenario. The RG expansion is generated by a regional ocean surface stress curl intensification associated with anthropogenic sea ice loss. If realised in reality, such a warming would strongly influence the future stability of the West Antarctic Ice Sheet.

INTRODUCTION: Community pharmacists and their teams have remained accessible to the public providing essential services despite immense pressures during the COVID-19 pandemic. They have successfully expanded the influenza vaccination programme and are now supporting the delivery of the COVID-19 vaccination roll-out. AIM: This rapid realist review aims to understand how community pharmacy can most effectively deliver essential and advanced services, with a focus on vaccination, during the pandemic and in the future. METHOD: An embryonic programme theory was generated using four diverse and complementary documents along with the expertise of the project team. Academic databases, preprint services and grey literature were searched and screened for documents meeting our inclusion criteria. The data were extracted from 103 documents to develop and refine a programme theory using a realist logic of analysis. Our analysis generated 13 context-mechanism-outcome configurations explaining when, why and how community pharmacy can support public health vaccination campaigns, maintain essential services during pandemics and capitalise on opportunities for expanded, sustainable public health service roles. The views of stakeholders including pharmacy users, pharmacists, pharmacy teams and other healthcare professionals were sought throughout to refine the 13 explanatory configurations. RESULTS: The 13 context-mechanism-outcome configurations are organised according to decision makers, community pharmacy teams and community pharmacy users as key actors. Review findings include: supporting a clear role for community pharmacies in public health; clarifying pharmacists' legal and professional liabilities; involving pharmacy teams in service specification design; providing suitable guidance, adequate compensation and resources; and leveraging accessible, convenient locations of community pharmacy. DISCUSSION: Community pharmacy has been able to offer key services during the pandemic.

Quantifying the level of population connectivity within and between geographically separated single-species deep-water fisheries stocks will be vital for designing effective management plans to preserve such populations. Despite this, stock structure in many fisheries is still poorly described and, at best, subject to precautionary management. Here we use rapidly evolving mitochondrial genes and microsatellite markers to investigate population connectivity patterns in commercially targeted Hyperoglyphe antarctica populations between four seamounts within the Tristan da Cunha Exclusive Economic Zone (EEZ). We find little evidence of population genetic structure between fished populations, with both mtDNA and microsatellite markers showing that there is low genetic population diversity (reflecting substantial gene flow) across the four seamounts. We also find little genetic differentiation between H. antarctica across the wider Southern Hemisphere. Such results support the role for coordinated management of all four populations across the seamounts, and potentially including stocks associated with Australia and New Zealand, with expansion of the fishery clearly having the potential to substantially impact the source of recruits and therefore wider population sustainability.

Seamounts have long been recognised as hotspots for pelagic productivity and diversity in the world’s open ocean habitats. Recent studies have suggested that productivity may vary greatly between different seamounts, depending on complex interactions between the bathymetric features and local oceanography. These processes may enhance local primary production which support elevated biomass at higher trophic levels. In addition to enhancing local biomass, seamounts may also act as aggregative features, attracting pelagic species from the surrounding waters. Such characteristics make seamounts attractive targets for fisheries. However, as these unique habitats are localised and relatively small, they are vulnerable to overexploitation, which may have detrimental impact on the wider region. Mapping and quantitative assessments of the fish biomass at different seamounts are crucial prerequisites to identifying vulnerable seamounts and will aid toward understanding the dynamics of these important ecosystems and their vulnerability to fishing pressures. We used fisheries acoustics during two expeditions in 2018 and 2019, to investigate the distribution and abundance of fish and micronekton on and around five little studied seamounts of Tristan da Cunha, a remote archipelago in the South Atlantic Ocean. The results confirmed increased productivity at the seamounts, compared to the surrounding open ocean with higher acoustic backscatter values, a proxy for biomass, particularly at the shallower (~200 m depth) seamounts. Fish largely dominated the backscatter on most of the seamounts especially over the plateau areas where large densities of prey fish, primarily the mesopelagic Maurolicus inventionis, were detected. Very large aggregations, thought to consist of bentho-pelagic fish, were also observed over the slope of McNish Seamount that resulted in very high biomass estimates. Aggregations of this size and magnitude, have, to our knowledge, never been mapped or quantified

While there is now strong evidence that many factors can shape dispersal, the mechanisms influencing connectivity patterns are species‐specific and remain largely unknown for many species with a high dispersal potential. The rock lobsters Jasus tristani and Jasus paulensis have a long pelagic larval duration (up to 20 months) and inhabit seamounts and islands in the southern Atlantic and Indian Oceans, respectively. We used a multidisciplinary approach to assess the genetic relationships between J. tristani and J. paulensis, investigate historic and contemporary gene flow, and inform fisheries management. Using 17,256 neutral single nucleotide polymorphisms we found low but significant genetic differentiation. We show that patterns of connectivity changed over time in accordance with climatic fluctuations. Historic migration estimates showed stronger connectivity from the Indian to the Atlantic Ocean (influenced by the Agulhas Leakage). In contrast, the individual‐based model coupled with contemporary migration estimates inferred from genetic data showed stronger inter‐ocean connectivity in the opposite direction from the Atlantic to the Indian Ocean driven by the Subtropical Front. We suggest that the J. tristani and J. paulensis historical distribution might have extended further north (when water temperatures were lower) resulting in larval dispersal between the ocean basis being more influenced by the Agulhas Leakage than the Subtropical Front. As water temperatures in the region increase in accordance with anthropogenic climate change, a southern shift in the distribution range of J. tristani and J. paulensis could further reduce larval transport from the Indian to the Atlantic Ocean, adding complexity to fisheries management.

Chronic lymphocytic leukemia (CLL) patients with differential somatic hypermutation status of the immunoglobulin heavy variable genes, namely mutated or unmutated, display fundamental clinico-biological differences. Considering this, we assessed prognosis separately within mutated (M-CLL) and unmutated (U-CLL) CLL in 3015 patients, hypothesizing that the relative significance of relevant indicators may differ between these two categories. Within Binet A M-CLL patients, besides TP53 abnormalities, trisomy 12 and stereotyped subset #2 membership were equivalently associated with the shortest time-to first -treatment and a treatment probability at Five and ten years after diagnosis of 40% and 55%, respectively; the remaining cases exhibited 5-year and 10-year treatment probability of 12% and 25%, respectively. Within Binet A U-CLL patients, besides TP53 abnormalities, del(11q) and/or ST3B1 mutations were associated with the shortest time-to-First treatment (5- and 10-year treatment probability: 78% and 98%, respectively); in the remaining cases, males had a significantly worse prognosis than females. In conclusion, the relative weight of indicators that can accurately risk stratify early-stage CLL patients differs depending on the somatic hypermutation status of the immunoglobulin heavy variable genes of each patient. This finding highlights the fact that compartmentalized approaches based on immunogenetic features are necessary to refine and tailor prognostication in CLL.

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In a recent Article, Cristofari et al.1 discuss the impact that movements of the Antarctic Polar Front have had on historical king penguin populations, and make future projections based on potential climate change scenarios. They predict that 70% of the world’s breeding population will be severely impacted as the Polar Front, with its nutrient-rich upwelling and high productivity, moves polewards beyond the foraging range of many penguin colonies. We highlight here, however, that a detailed analysis of the models used does not support the projection of a poleward shift in the Polar Front’s future position, and that recent analyses show no evidence for such a shift having occurred in the last several decades.

As new generations of targeted therapies emerge and tumor genome sequencing discovers increasingly comprehensive mutation repertoires, the functional relationships of mutations to tumor phenotypes remain largely unknown. Here, we measured ex vivo sensitivity of 246 blood cancers to 63 drugs alongside genome, transcriptome, and DNA methylome analysis to understand determinants of drug response. We assembled a primary blood cancer cell encyclopedia data set that revealed disease-specific sensitivities for each cancer. Within chronic lymphocytic leukemia (CLL), responses to 62% of drugs were associated with 2 or more mutations, and linked the B cell receptor (BCR) pathway to trisomy 12, an important driver of CLL. Based on drug responses, the disease could be organized into phenotypic subgroups characterized by exploitable dependencies on BCR, mTOR, or MEK signaling and associated with mutations, gene expression, and DNA methylation. Fourteen percent of CLLs were driven by mTOR signaling in a non-BCR-dependent manner. Multivariate modeling revealed immunoglobulin heavy chain variable gene (IGHV) mutation status and trisomy 12 as the most important modulators of response to kinase inhibitors in CLL. Ex vivo drug responses were associated with outcome. This study overcomes the perception that most mutations do not influence drug response of cancer, and points to an updated approach to understanding tumor biology, with implications for biomarker discovery and cancer care.

In the Southern Ocean, the at‐sea distributions of most predators of Antarctic krill are poorly known, primarily because tracking studies have only been undertaken on a restricted set of species, and then only at a limited number of sites. For chinstrap penguins, one of the most abundant krill predators breeding across the Antarctic Peninsula, we show that habitat models developed utilizing the distance from the colony and the bearing to the shelf‐edge, adjusting for the at‐sea density of Pygoscelis penguins from other colonies, can be used to predict, with a high level of confidence, the at‐sea distribution of chinstrap penguins from untracked colonies during the breeding season. Comparison of predicted penguin distributions with outputs from a high‐resolution oceanographic model shows that chinstrap penguins prefer nearshore habitats, over shallow bathymetry, with slow‐flowing waters, but that they sometimes also travel to areas beyond the edge of the continental shelf where the faster‐flowing waters of the Coastal Current or the fronts of the Antarctic Circumpolar Current occur. In the slow‐moving shelf waters, large penguin colonies may lead to krill depletion during incubation and chick‐rearing periods when penguins are acting as central place foragers. The habitats used by chinstrap penguins are also locations preferentially used by the commercial krill fishery, one of the last under‐developed marine capture fisheries anywhere on the planet. As it develops, this fishery has the potential to compete with chinstrap penguins and other natural krill predators. Scaling our habitat models by chinstrap penguin population data demonstrates where overlap with the fishery is likely to be most important. Our results suggest that a better understanding of krill retention and krill depletion in areas used by natural predators and by the krill fishery are needed, and that risk management strategies for the fishery should include assessment of how krill movement can satisfy

In the marine environment, understanding the biophysical mechanisms that drive variability in larval dispersal and population connectivity is essential for estimating the potential impacts of climate change on the resilience and genetic structure of populations. Species whose populations are small, isolated, and discontinuous in distribution will differ fundamentally in their response and resilience to environmental stress, compared with species that are broadly distributed, abundant, and frequently exchange conspecifics. Here, we use an Individual Based Modelling approach, combined with a population genetics projection model, to consider the impacts of a warming climate on the population connectivity of two contrasting Antarctic fish species, Notothenia rossii and Champsocephalus gunnari. Focussing on the Scotia Sea region, sea surface temperatures are predicted to increase significantly by the end of the 21st century, resulting in reduced planktonic duration and increased egg and larval mortality. With shorter planktonic durations, the results of our study predict reduced dispersal of both species across the Scotia Sea, from Antarctic Peninsula sites to islands in the north and east, and increased dispersal among neighbouring sites, such as around the Antarctic Peninsula. Increased mortality modified the magnitude of population connectivity but had little effect on the overall patterns. Whilst the predicted changes in connectivity had little impact on the projected regional population genetic structure of N. rossii, which remained broadly genetically homogeneous within distances of ~1500 km, the genetic isolation of C. gunnari populations in the northern Scotia Sea was predicted to increase with rising sea temperatures. Our study highlights the potential for increased isolation of island populations in a warming world, with implications for the resilience of populations and their ability to adapt to ongoing environmental change, a matter of high relevance to fishe

Chronic lymphocytic leukemia is characterized by impaired immune functions largely due to profound T-cell defects. T-cell functions also depend on co-signaling receptors, inhibitory or stimulatory, known as immune checkpoints, including cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed death-1 (PD-1). Here we analyzed the T-cell phenotype focusing on immune checkpoints and activation markers in chronic lymphocytic leukemia patients (n=80) with different clinical characteristics and compared them to healthy controls. In general, patients had higher absolute numbers of CD3+ cells and the CD8+ subset was particularly expanded in previously treated patients. Progressive patients had higher numbers of CD4+ and CD8+ cells expressing PD-1 compared to healthy controls, which was more pronounced in previously treated patients (P=0.0003 and P=0.001, respectively). A significant increase in antigen-experienced T cells was observed in patients within both the CD4+ and CD8+ subsets, with a significantly higher PD-1 expression. Higher numbers of CD4+ and CD8+ cells with intracellular CTLA-4 were observed in patients, as well as high numbers of proliferating (Ki67+) and activated (CD69+) CD4+ and CD8+ cells, more pronounced in patients with active disease. The numbers of Th1, Th2, Th17 and regulatory T cells were substantially increased in patients compared to controls (P<0.05), albeit decreasing to low levels in pre-treated patients. In conclusion, chronic lymphocytic leukemia T cells display increased expression of immune checkpoints, abnormal subset distribution, and a higher proportion of proliferating cells compared to healthy T cells. Disease activity and previous treatment shape the T-cell profile of chronic lymphocytic leukemia patients in different ways.

In recent years, the genetic landscape of B-cell derived lymphoid malignancies, including chronic lymphocytic leukemia (CLL), has been rapidly unraveled, identifying recurrent genetic mutations with potential clinical impact. Interestingly, ~30% of all CLL patients can be assigned to more homogeneous subsets based on the expression of a similar or “stereotyped” B-cell receptor (BcR). Considering that biased distribution of genetic mutations was recently indicated in specific stereotyped subsets, in paper I, we screened 565 subset cases, preferentially assigned to clinically aggressive subsets, and confirm the SF3B1 mutational bias in subset #2 (45%), but also report on similarly marked enrichment in subset #3 (46%). In contrast, NOTCH1 mutations were predominantly detected in subsets #1, #8, #59 and #99 (22-34%). This data further highlights a subset-biased acquisition of genetic mutations in the pathogenesis of at least certain subsets. Aberrant NF-κB signaling due to a deletion within the NFKBIE gene previously reported in CLL warranted extended investigation in other lymphoid malignancies. Therefore, in paper II, we screened 1460 patients with various lymphoid malignancies for NFKBIE deletions and reported enrichment in classical Hodgkin lymphoma (27%) and primary mediastinal B-cell lymphoma (PMBL) (23%). NFKBIE-deleted PMBL cases had higher rates of chemorefractoriness and inferior overall survival (OS). NFKBIE-deletion status remained an independent prognostic marker in multivariate analysis. EGR2 mutations were recently reported in advanced stage CLL patients; thus, in paper III we screened 2403 CLL patients for mutations in EGR2. An overall mutational frequency of 3.8% was reported and EGR2 mutations were associated with younger age, advanced stage and del(11q). EGR2 mutational status remained an independent marker of poor outcome in multivariate analysis, both in the screening and validation cohorts. Whole-genome sequencing (WGS) of 70 CLL cases, assigned to

Recurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n = 1283) and two validation cohorts (UK CLL4 trial patients, n = 366; CLL Research Consortium (CRC) patients, n = 490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2- mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%) and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome., E.Y. and D.N. contributed equally to this study as joint first authors.R.R. and F.D. contributed equally as joint senior authors.

As new generations of targeted therapies emerge and tumor genome sequencing discovers increasingly comprehensive mutation repertoires, the functional relationships of mutations to tumor phenotypes remain largely unknown. Here, we measured ex vivo sensitivity of 246 blood cancers to 63 drugs alongside genome, transcriptome, and DNA methylome analysis to understand determinants of drug response. We assembled a primary blood cancer cell encyclopedia data set that revealed disease-specific sensitivities for each cancer. Within chronic lymphocytic leukemia (CLL), responses to 62% of drugs were associated with 2 or more mutations, and linked the B cell receptor (BCR) pathway to trisomy 12, an important driver of CLL. Based on drug responses, the disease could be organized into phenotypic subgroups characterized by exploitable dependencies on BCR, mTOR, or MEK signaling and associated with mutations, gene expression, and DNA methylation. Fourteen percent of CLLs were driven by mTOR signaling in a non–BCR-dependent manner. Multivariate modeling revealed immunoglobulin heavy chain variable gene (IGHV) mutation status and trisomy 12 as the most important modulators of response to kinase inhibitors in CLL. Ex vivo drug responses were associated with outcome. This study overcomes the perception that most mutations do not influence drug response of cancer, and points to an updated approach to understanding tumor biology, with implications for biomarker discovery and cancer care.

We recently reported a truncating deletion in the NFKBIE gene, which encodes IκBϵ, a negative feedback regulator of NF-κB, in clinically aggressive chronic lymphocytic leukemia (CLL). Preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, hence we screened a large patient cohort (n=1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal-zone lymphoma, and T-cell acute lymphoblastic leukemia (<2%), slightly higher frequencies were seen in diffuse large B-cell lymphoma, mantle cell lymphoma, and primary CNS lymphoma (3-4%). In contrast, a remarkably high frequency of NFKBIE aberrations (46/203 cases, 22.7%) was observed in primary mediastinal B-cell lymphoma (PMBL) and Hodgkin lymphoma (3/11 cases, 27.3%). NFKBIE-deleted PMBL patients were more often therapy-refractory (P=.022) and displayed inferior outcome compared to wildtype patients (5-year survival: 59% vs. 78%; P=.034); however they appeared to benefit from radiotherapy (P=.022) and rituximab-containing regimens (P=.074). NFKBIEaberrations remained an independent factor in multivariate analysis (P=.003), also when restricting to immunochemotherapy-treated patients (P=.008). Whole-exome sequencing and gene expression-profiling verified the importance of NF-κB deregulation in PMBL. In summary, we identify NFKBIE aberrations as a common genetic event across B-cell malignancies and highlight NFKBIE deletions as a novel poor-prognostic marker in PMBL., L.M., D.N., and E.Y. contributed equally to this study as joint first authors.R.R. and F.D. contributed equally as joint senior authors.

Fludarabine, cyclophosphamide and rituximab (FCR) is first-line treatment for medically fit chronic lymphocytic leukemia (CLL) patients, however despite good response rates many patients eventually relapse. Whilst recent high-throughput studies have identified novel recurrent genetic lesions in adverse-prognostic CLL, the mechanisms leading to relapse after FCR therapy are not completely understood. To gain insight into this issue, we performed whole-exome sequencing of sequential samples from 41 CLL patients who were uniformly treated with FCR but relapsed after a median of 2 years. In addition to mutations with known adverse-prognostic impact (TP53, NOTCH1, ATM, SF3B1, NFKBIE, BIRC3) a large proportion of cases (19.5%) harbored mutations in RPS15, a gene encoding a component of the 40S ribosomal subunit. Extended screening, totaling 1119 patients, supported a role for RPS15 mutations in aggressive CLL, with one-third of RPS15-mutant cases also carrying TP53 aberrations. In most cases selection of dominant, relapse-specific subclones was observed over time. However, RPS15 mutations were clonal prior to treatment and remained stable at relapse. Notably, all RPS15 mutations represented somatic missense variants and resided within a 7 amino-acid evolutionarily conserved region. We confirmed the recently postulated direct interaction between RPS15 and MDM2/MDMX and transient expression of mutant RPS15 revealed defective regulation of endogenous p53 compared to wildtype RPS15. In summary, we provide novel insights into the heterogeneous genetic landscape of CLL relapsing after FCR treatment and highlight a novel mechanism underlying clinical aggressiveness involving a mutated ribosomal protein, potentially representing an early genetic lesion in CLL pathobiology., De två första författarna delar förstaförfattarskapet.De två sista författarna delar sistaförfattarskapet.

We report on markedly different frequencies of genetic lesions within subsets of chronic lymphocytic leukemia patients carrying mutated or unmutated stereotyped B-cell receptor immunoglobulins in the largest cohort (n=565) studied for this purpose. By combining data on recurrent gene mutations (BIRC3, MYD88, NOTCH1, SF3B1 and TP53) and cytogenetic aberrations, we reveal a subset-biased acquisition of gene mutations. More specifically, the frequency of NOTCH1 mutations was found to be enriched in subsets expressing unmutated immunoglobulin genes, i.e. #1, #6, #8 and #59 (22-34%), often in association with trisomy 12, and was significantly different (P<0.001) to the frequency observed in subset #2 (4%, aggressive disease, variable somatic hypermutation status) and subset #4 (1%, indolent disease, mutated immunoglobulin genes). Interestingly, subsets harboring a high frequency of NOTCH1 mutations were found to carry few (if any) SF3B1 mutations. This starkly contrasts with subsets #2 and #3 where, despite their immunogenetic differences, SF3B1 mutations occurred in 45% and 46% of cases, respectively. In addition, mutations within TP53, whilst enriched in subset #1 (16%), were rare in subsets# 2 and #8 (both 2%), despite all being clinically aggressive. All subsets were negative for MYD88 mutations, whereas BIRC3 mutations were infrequent. Collectively, this striking bias and skewed distribution of mutations and cytogenetic aberrations within specific chronic lymphocytic leukemia subsets implies that the mechanisms underlying clinical aggressiveness are not uniform, but rather support the existence of distinct genetic pathways of clonal evolution governed by a particular stereotyped B-cell receptor selecting a certain molecular lesion(s).

NF-κB is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core complex genes within the NF-κB pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes IκBε, a negative regulator of NF-κB in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift deletion, resulting in a truncated protein. Screening of an additional 377 CLL cases revealed that NFKBIE aberrations predominated in poor-prognostic patients and were associated with inferior outcome. Minor subclones and/or clonal evolution were also observed, thus potentially linking this recurrent event to disease progression. Compared with wild-type patients, NFKBIE-deleted cases showed reduced IκBε protein levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65. Considering the central role of B cell receptor (BcR) signaling in CLL pathobiology, it is notable that IκBε loss was enriched in aggressive cases with distinctive stereotyped BcR, likely contributing to their poor prognosis, and leading to an altered response to BcR inhibitors. Because NFKBIE deletions were observed in several other B cell lymphomas, our findings suggest a novel common mechanism of NF-κB deregulation during lymphomagenesis.

Next- generation sequencing has revealed novel recurrent mutations in chronic lymphocytic leukemia, particularly in patients with aggressive disease. Here, we explored targeted re- sequencing as a novel strategy to assess the mutation status of genes with prognostic potential. To this end, we utilized HaloPlex targeted enrichment technology and designed a panel including nine genes: ATM, BIRC3, MYD88, NOTCH1, SF3B1 and TP53, which have been linked to the prognosis of chronic lymphocytic leukemia, and KLHL6, POT1 and XPO1, which are less characterized but were found to be recurrently mutated in various sequencing studies. A total of 188 chronic lymphocytic leukemia patients with poor prognostic features ( unmutated IGHV, n= 137; IGHV3- 21 subset # 2, n= 51) were sequenced on the HiSeq 2000 and data were analyzed using well- established bioinformatics tools. Using a conservative cutoff of 10% for the mutant allele, we found that 114/ 180 ( 63%) patients carried at least one mutation, with mutations in ATM, BIRC3, NOTCH1, SF3B1 and TP53 accounting for 149/ 177 ( 84%) of all mutations. We selected 155 mutations for Sanger validation ( variant allele frequency, 10- 99%) and 93% ( 144/ 155) of mutations were confirmed; notably, all 11 discordant variants had a variant allele frequency between 11- 27%, hence at the detection limit of conventional Sanger sequencing. Technical precision was assessed by repeating the entire HaloPlex procedure for 63 patients; concordance was found for 77/ 82 ( 94%) mutations. In summary, this study demonstrates that targeted next- generation sequencing is an accurate and reproducible technique potentially suitable for routine screening, eventually as a stand- alone test without the need for confirmation by Sanger sequencing., De två första författarna delar förstaförfattarskapet.

Meeting Abstract: 103

Understanding the key drivers of population connectivity in the marine environment is essential for the effective management of natural resources. Although several different approaches to evaluating connectivity have been used, they are rarely integrated quantitatively. Here, we use a ‘seascape genetics’ approach, by combining oceanographic modelling and microsatellite analyses, to understand the dominant influences on the population genetic structure of two Antarctic fishes with contrasting life histories, Champsocephalus gunnari and Notothenia rossii. The close accord between the model projections and empirical genetic structure demonstrated that passive dispersal during the planktonic early life stages is the dominant influence on patterns and extent of genetic structuring in both species. The shorter planktonic phase of C. gunnari restricts direct transport of larvae between distant populations, leading to stronger regional differentiation. By contrast, geographic distance did not affect differentiation in N. rossii, whose longer larval period promotes long-distance dispersal. Interannual variability in oceanographic flows strongly influenced the projected genetic structure, suggesting that shifts in circulation patterns due to climate change are likely to impact future genetic connectivity and opportunities for local adaptation, resilience and recovery from perturbations. Further development of realistic climate models is required to fully assess such potential impacts.

This study seeks to quantify the influence of South Georgia's orography on regional surface winds. A typical case study characterized by large-scale westerly winds is analysed using a high-resolution setup (3.3 km) of the Weather Research and Forecasting (WRF) regional model. The simulation produces significant fine-scale spatial variability which is in agreement with satellite-derived winds. The model simulation indicates that these orography-driven wind disturbances are responsible for strong wind stress curl and enhanced heat flux over the shelf waters surrounding South Georgia. Such surface forcing is entirely absent from the reanalysis, highlighting the need to use high-resolution forcing in regional ocean model simulations

The waters around South Georgia are among the most productive in the Southern Ocean, with zooplankton populations close to the island, in particular Antarctic krill, supporting vast colonies of higher predators. However, our understanding of the processes governing variability in the supply of these food resources is limited by the poor spatial and temporal resolution of available data. Here, we use a numerical modeling approach to examine the underlying physical processes driving the recruitment and retention of zooplankton to the South Georgia shelf. Variability in the magnitude and spatial distribution of recruitment was dominated by the proximity and orientation of the southern Antarctic Circumpolar Current front to the shelf edge. Shelf retention was highest for source sites on the southwest shelf, with the main transport routes off the shelf to the north and northwest. Retention was lowest in the austral summer and winter; in summer increased glacial melt drives stronger off-shelf near-surface currents, while in winter, stronger winds lead to an increase in off-shelf transport. Of particular note was the prediction of a significant increase in retention for particles released throughout the shelf in April and July 2000. This period coincided with the development of pronounced anticlockwise shelf flows, associated with horizontal density gradients due to reduced wind mixing of shelf waters, and differences between shelf and oceanic waters, which significantly reduced off-shelf transport rates. Such findings are crucial for understanding the influence of variability in physical processes on the ecosystem at South Georgia.

Biomass burning releases trace gases and aerosol particles that significantly affect the composition and chemistry of the atmosphere. Australia contributes approximately 8% of gross global carbon emissions from biomass burning, yet there are few previous measurements of emissions from Australian forest fires available in the literature. This paper describes the results of field measurements of trace gases emitted during hazard reduction burns in Australian temperate forests using open-path Fourier transform infrared spectroscopy. In a companion paper, similar techniques are used to characterise the emissions from hazard reduction burns in the savanna regions of the Northern Territory. Details of the experimental methods are explained, including both the measurement set-up and the analysis techniques employed. The advantages and disadvantages of different ways to estimate whole-fire emission factors are discussed and a measurement uncertainty budget is developed. Emission factors for Australian temperate forest fires are measured locally for the first time for many trace gases. Where ecosystem-relevant data are required, we recommend the following emission factors for Australian temperate forest fires (in grams of gas emitted per kilogram of dry fuel burned) which are our mean measured values: 1620 ± 160 g kg−1 of carbon dioxide; 120 ± 20 g kg−1 of carbon monoxide; 3.6 ± 1.1 g kg−1 of methane; 1.3 ± 0.3 g kg−1 of ethylene; 1.7 ± 0.4 g kg−1 of formaldehyde; 2.4 ± 1.2 g kg−1 of methanol; 3.8 ± 1.3 g kg−1 of acetic acid; 0.4 ± 0.2 g kg−1 of formic acid; 1.6 ± 0.6 g kg−1 of ammonia; 0.15 ± 0.09 g kg−1 of nitrous oxide and 0.5 ± 0.2 g kg−1 of ethane.

Waters around South Georgia are amongst the most productive in the Southern Ocean, and support internationally important fisheries. However, there is significant inter-annual variability in fish stocks, and some species have failed to recover from historical overfishing. Dispersal and retention of the planktonic eggs and larvae of marine fish can play a key role in the maintenance of adult stocks. We use a numerical modelling approach to examine the influence of oceanographic and life-history variability on the dispersal and retention of 2 Antarctic fishes: Champsocephalus gunnari (mackerel icefish) and Notothenia rossii (marbled rockcod). Mean retention of N. rossii larvae was predicted to be 5.3%, considerably lower than that of C. gunnari (31.3%), a difference related to the longer planktonic period of the former. Such apparent loss of larvae from local recruitment grounds may contribute to the failure of the N. rossii population to recover from its collapse in the 1970s. However, retention of both species showed high inter-annual variability. Dispersal and retention of C. gunnari were strongly influenced by location of the spawning site, with the greatest contribution to overall retention from spawning sites on the southwest South Georgia shelf. In addition, a consistent feature in C. gunnari was a lack of larval exchange between the proximate South Georgia and Shag Rocks shelves, regions separated by only 240 km. Our findings provide insights into the demographic dynamics and connectivity of C. gunnari and N. rossii populations at South Georgia in relation to prospects for recovery and ongoing responses to environmental variability and change in the region.

The marine ecosystem on the shelf and open ocean adjacent to South Georgia is extraordinarily rich, with a history of commercial exploitation. Although much progress has been made, attempts at modelling (and hence better understanding) this system have consistently been hampered by the poor representation of key physical processes in global or regional ocean general circulation models. Here we present the development of a high-resolution 3D hydrodynamic model of the South Georgia shelf and the adjacent open ocean, including a novel method for prescribing freshwater fluxes. The ability of the model to reproduce the observed oceanography of the region is quantified by comparisons with data from tide gauges at South Georgia, with satellite-derived sea surface temperatures, and with an extensive CTD dataset collected during January–April 1995. Predicted cotidal charts for the diurnal tides O1 and K1 show a periodic amplification in both the current and elevation fields at the shelf edge, suggesting the presence of a diurnally forced continental shelf wave. This could have important implications for processes such as larval transport and retention. The comparison with CTD data reveals mean and root mean square errors in temperature (salinity) of –0.27 °C (−0.07) and 0.64 °C (0.23), respectively. Vertical profiles of potential temperature and salinity on the shelf agree acceptably well with observations, but there is a tendency for the model to under-predict the density contrast between surface and bottom waters. The main limitation on model accuracy is found to be the large-scale forcing. Releasing a passive tracer into the model, transport and retention pathways are identified, including a prevalence for tracer export from the shelf to the west of South Georgia, and a transport pathway linking South Georgia and Shag Rocks. Significantly, the model suggests this to be a unidirectional link, from South Georgia to Shag Rocks, with possible significance for fisheries manage

The ‘Black Saturday’ fires were a series of devastating forest fires that burned across Victoria, Australia, during February and March of 2009. In this study we have used satellite data made publically available by NASA from the Ozone Monitoring Instrument (OMI) and the Atmospheric InfraRed Sounder (AIRS) to track the smoke plume from the Black Saturday firestorm and explore the chemical aging of the smoke plume in the first days after emission. We also determined emission ratios for formaldehyde and nitrogen dioxide within smoke from fires actively burning across Victoria between 7 and 17 February 2009. The mean emission ratios with respect to carbon monoxide derived for these two tropospheric ozone precursors are (0.016 ± 0.004 mol.mol−1) for formaldehyde and (0.005 ± 0.002 mol.mol−1) for nitrogen dioxide. The mean emission ratio for formaldehyde with respect to CO is in broad agreement with values previously quoted in the literature for temperate forest fires. However, to our knowledge there are no previous measurements of emission ratios for nitrogen dioxide from Australian temperate forest fires.

We present a new method for deriving total emissions estimates from large vegetation fires using satellite-based measurements of aerosol optical depth. This method is based upon simultaneous measurements of total column amounts of trace gases and aerosol optical depth of the atmosphere through smoke plumes from Australian fires. These measurements were derived from ground-based solar remote sensing spectrometers in the infrared and UV-visible spectral regions and also provide emission ratios that may be used in more conventional bottom-up estimates of total emissions. Measurements of emissions from Australian forest fires are relatively sparse given the significance of this source to the global emissions budget from biomass burning. Additional measurements of emission ratios of a number of trace gases have been made using open-path FTIR measurements through smoke plumes from hazard reduction burns in New South Wales.

The ‘Black Saturday’ fires were a series of devastating bushfires that burned across Victoria, Australia, during February 2009. The smoke plume from Saturday the 7th February, the worst day of the fires, separated from subsequent emissions and persisted for several weeks, providing the opportunity to track the changing composition of the smoke plume as it aged. In this study we have used satellite data from the Ozone Monitoring Instrument (OMI) and the Atmospheric InfraRed Sounder (AIRS) to characterise the emissions of formaldehyde and nitrogen dioxide from the fires. Emission ratios with respect to carbon monoxide are determined for formaldehyde (0.017 ± 0.004 mol.mol-1) and nitrogen dioxide (0.004 ± 0.001 mol.mol-1). Additionally OMI UV Aerosol Index is used to track the smoke plume and infer how the concentration of these gases changes as the smoke ages. Our study suggests that formaldehyde concentrations within the smoke plume increase during the first day before declining to background levels within 2 days after emission. Nitrogen dioxide concentrations show a monotonic decrease reaching background levels about 1 day after emission.

Background: Chronic cough is common, and medical treatment can be ineffective. Mindfulness is a psychological intervention that aims to teach moment-to-moment non-judgemental awareness of thoughts, feelings and sensations. Method: 30 healthy subjects and 30 patients with chronic cough were studied in two sequential trials. For both studies, cough reflex sensitivity to citric acid (C5) was measured on two occasions, with urge to cough rated following each inhalation; between challenges subjects were randomised to (1) no intervention, (2) mindfulness or (3) no intervention but modified cough challenge (subjects suppress coughing). For the healthy volunteers, measures were 1 h apart and mindfulness was practised for 15 min. For the patients with chronic cough measures were 1 week apart and mindfulness was practised daily for 30 min. Results: In healthy volunteers, median change (interquartile range (IQR)) in cough reflex sensitivity (logC5) for no intervention, mindfulness and suppression was +1.0 (0.0 to +1.3), +2.0 (+1.0 to +3.0) and +3.0 (+2.8 to +3.0) doubling concentrations (p = 0.003); there were significant reductions for both mindfulness (p = 0.043) and suppression (p = 0.002) over no intervention. In patients with cough, median change (IQR) in logC5 for no intervention, mindfulness training and voluntary suppression was 0.0 (−1.0 to +1.0), +1.0 (−0.3 to +1.0) and +1.0 (+1.0 to +2.0) doubling concentrations (p = 0.046); there was a significant reduction for suppression (p = 0.02) but not mindfulness (p = 0.35). Urge to cough did not change after mindfulness compared with control in either healthy subjects (p = 0.33) or those with chronic cough (p = 0.47). Conclusion: Compared with control, mindfulness decreased cough reflex sensitivity in healthy volunteers, but did not alter cough threshold in patients with chronic cough. Both groups were able to suppress cough responses to citric acid inhalation.

This review and synthesis of relevant literature considers the nature of boredom and boredom proneness in general terms before focusing on how the academic boredom experienced by undergraduates at university is sufficiently different from other known types to warrant a unique and important field of study. Derived from within the literature itself, academic boredom is commonly presented as a largely negative and deactivating achievement related emotion known to impact usually adversely on student engagement and performance. Tracing traditional as well as contemporary views from within psychology, which has tended to dominate the field, findings that remain largely quantitative and highly statistical in nature are exemplified alongside the more exploratory but mixed-methods and educational work recently conducted in the UK. A comparison of the questionnaire-based self-report instruments frequently used in data collection is also included. Rooted largely within Control-Value Theory, the implications associated with academic boredom are far from trivial, particularly with respect to understanding sites and triggers, how students respond and cope and how the overall quality of the student experience might be improved. Limitations in the work undertaken to date draw attention to opportunities for further educational and interdisciplinary research.