Mucus Sugar Content Shapes the Bacterial Community Structure in Thermally Stressed Acropora muricata

It has been proposed that the chemical composition of a coral’s mucus can influence the associated bacterial community. However, information on this topic is rare, and non-existent for corals that are under thermal stress. This study therefore compared the carbohydrate composition of mucus in the coral Acropora muricata when subjected to increasing thermal stress from 26°C to 31°C, and determined whether this composition correlated with any changes in the bacterial community. Results showed that, at lower temperatures, the main components of mucus were N-acetyl glucosamine and C6 sugars, but these constituted a significantly lower proportion of the mucus in thermally-stressed corals. The change in the mucus composition coincided with a shift from a γ-Proteobacteria- to a Verrucomicrobiae- and α-Proteobacteria-dominated community in the coral mucus. Bacteria in the class Cyanobacteria also started to become prominent in the mucus when the coral was thermally stressed. The increase in the relative abundance of the Verrucomicrobiae at higher temperature was strongly associated with a change in the proportion of fucose, glucose and mannose in the mucus. Increase in the relative abundance of α-Proteobacteria were associated with GalNAc and glucose, while the drop in relative abundance of γ-Proteobacteria at high temperature coincided with changes in fucose and mannose. Cyanobacteria were highly associated with arabinose and xylose. Changes in mucus composition and the bacterial community in the mucus layer occurred at 29°C, which were prior to visual signs of coral bleaching at 31°C. A compositional change in the coral mucus, induced by thermal stress could therefore be a key factor leading to a shift in the associated bacterial community. This, in turn, has the potential to impact the physiological function of the coral holobiont

Evidence of Resilience in Reef Islands in Response to Rising Sea Level on Huvadhoo Atoll, Maldives

Reef islands are at the forefront of concern for future accelerating sea-level rise since their low-lying and isolated nature puts them at higher risk of marine inundation compared to continental coastlines. However, the perceived threat of complete submersion as implied by projected future sea-level rise and current island elevations do not consider the morphologically resilient nature of reef island systems. In particular, the role of sediment supply in the resilience of these islands is still relatively poorly studied. This study presents detailed descriptions of the sedimentary characteristics and stratigraphy of two lagoonal platform islands in Huvadhoo Atoll, Maldives, that formed during periods of Holocene sea-level rise. Island subsurface stratigraphy was reconstructed by analysing the skeletal composition and textural properties of 306 sediment samples from 37 cores extracted across the islands. Island sediments were dominated by coral sands with varied proportions of secondary constituents (molluscs, Halimeda, foraminifera, and crustose coralline algae). Downcore variations in composition show that the proportion of coral sands decrease with depth and the proportion of molluscs and Halimeda increase with depth (with the exception of cores that terminated on lagoon infill). The increased proportion of Halimeda and molluscs in these early island deposits may have resulted from the catch-up growth strategy of the reef during the mid-Holocene highstand as both organisms have high turnover rates and directly contribute to sediment production after death. The sedimentological response of increased Halimeda and molluscs highlights the resilient and dynamic nature of reef islands and the ability of reefs to adjust ecologically to changing sea levels

Increased typhoon activity in the Pacific deep tropics driven by Little Ice Age circulation changes

Author Posting. © The Author(s), 2020. This is the author's version of the work. It is posted here by permission of Nature Research for personal use, not for redistribution. The definitive version was published in Bramante, J. F., Ford, M. R., Kench, P. S., Ashton, A. D., Toomey, M. R., Sullivan, R. M., Karnauskas, K. B., Ummenhofer, C. C., & Donnelly, J. P. (2020). Increased typhoon activity in the Pacific deep tropics driven by Little Ice Age circulation changes. Nature Geoscience, 13, 806–811. doi:10.1038/s41561-020-00656-2.The instrumental record reveals that tropical cyclone activity is sensitive to oceanic and atmospheric variability on inter-annual and decadal scales. However, our understanding of the influence of climate on tropical cyclone behaviour is restricted by the short historical record and the sparseness of prehistorical reconstructions, particularly in the western North Pacific, where coastal communities suffer loss of life and livelihood from typhoons annually. Here, to explore past regional typhoon dynamics, we reconstruct three millennia of deep tropical North Pacific cyclogenesis. Combined with existing records, our reconstruction demonstrates that low-baseline typhoon activity prior to 1350 ce was followed by an interval of frequent storms during the Little Ice Age. This pattern, concurrent with hydroclimate proxy variability, suggests a centennial-scale link between Pacific hydroclimate and tropical cyclone climatology. An ensemble of global climate models demonstrates a migration of the Pacific Walker circulation and variability in two Pacific climate modes during the Little Ice Age, which probably contributed to enhanced tropical cyclone activity in the tropical western North Pacific. In the next century, projected changes to the Pacific Walker circulation and expansion of the tropics will invert these Little Ice Age hydroclimate trends, potentially reducing typhoon activity in the deep tropical Pacific.This work was supported by the Strategic Environmental Research and Development Program (SERDP RC-2336). C.C.U. acknowledges support from NSF under AGS-1602455. We thank student intern D. Carter for extensive labwork on core LTD3. We acknowledge the WCRP’s Working Group on Coupled Modelling, which is responsible for CMIP, and we thank the climate modelling groups for producing and making available their model output. CMIP5 model output was provided by the WHOI CMIP5 Community Storage Server via their website: http://cmip5.whoi.edu/. Any use of trade, firm or product names is for descriptive purposes only and does not imply endorsement by the US Government.2021-05-1

ROR1 and ROR2 expression in pancreatic cancer

Background: The Wnt receptors ROR1 and ROR2 are generating increased interest as cancer therapeutic targets but remain understudied in pancreatic ductal adenocarcinoma (PDAC). Compared to canonical Wnt/ β-catenin signalling, the role of noncanonical Wnt signalling in PDAC remains largely unknown. Only one study has investigated the prognostic significance of the noncanonical Wnt signalling receptor, ROR2 in PDAC. No studies have investigated the prognostic role of ROR1 in PDAC. Methods: Here, we performed analysis of ROR1 and ROR2 mRNA expression in three publicly available datasets ICGC-PACA-AU (n = 81), TCGA-PAAD (n = 150) and CPTAC-PDAC (n = 137). ROR1 and ROR2 protein expression from the CPTAC-PDAC discovery cohort were also analysed. Immunohistochemistry (IHC) using the validated anti ROR1 monoclonal antibody (4A5) was performed on the Australian Pancreatic Cancer Genome Initiative (APGI) cohort of PDAC samples (n = 152). Association between ROR1 cytoplasmic staining intensity and clinicopathological parameters including stage, grade and overall survival (OS) was investigated. Results: High ROR1 mRNA expression levels correlated with a favourable OS outcome in all of the ICGC-PACA-AU, TCGA-PAAD and CPTAC-PDAC cohorts. ROR1 protein expression was not associated with stage, grade or OS in the APGI cohort. Conclusion: ROR1 and ROR2 have potential as prognostic markers when measured at the mRNA level in PDAC. Our IHC cohort did not support ROR1 protein expression in predicting OS, and highlighted the discrepancy of prognostic biomarkers when measured by MS, IHC and RNAseq

Integrated genomic characterization of pancreatic ductal adenocarcinoma

We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine

Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors1,2, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Loss of coral reef growth capacity to track future increases in sea level

Water-depths above coral reefs is predicted to increase due to global sea-level rise (SLR). As ecological degradation inhibits the vertical accretion of coral reefs, it is likely that coastal wave exposure will increase but there currently exists a lack of data in projections concerning local rates of reef growth and local SLR. In this study we have aggregated ecological data of more than 200 tropical western Atlantic and Indian Ocean reefs and calculated their vertical growth which we have then compared with recent and projected rates of SLR across different Representative Concentration Pathway (RCP) scenarios. While many reefs currently show vertical growth that would be sufficient to keep-up with recent historic SLR, future projections under scenario RCP4.5 reveal that without substantial ecological recovery many reefs will not have the capacity to track SLR. Under RCP8.5, we predict that mean water depth will increase by over half a metre by 2100 across the majority of reefs. We found that coral cover strongly predicted whether a reef could track SLR, but that the majority of reefs had coral cover significantly lower than that required to prevent reef submergence. To limit reef submergence, and thus the impacts of waves and storms on adjacent coasts, climate mitigation and local impacts that reduce coral cover (e.g., local pollution and physical damage through development land reclamation) will be necessary

DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association

Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts