The role of family history in predicting germline pathogenic variant carriers who develop pancreatic cancer: Results of a multicenter collaboration.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) surveillance is recommended for some individuals with a pathogenic or likely pathogenic variant (PV/LPV) in a PDAC susceptibility gene; the recommendation is often dependent on family history of PDAC. This study aimed to describe PDAC family history in individuals with PDAC who underwent genetic testing to determine the appropriateness of including a family history requirement in these recommendations. METHODS: Individuals with PDAC with a germline heterozygous PV/LPV in ATM, BRCA1, BRCA2, EPCAM, MLH1, MSH2, MSH6, PALB2, or PMS2 (PV/LPV carriers) were assessed for family history of PDAC in first-degree relatives (FDRs) or second-degree relatives (SDRs) from nine institutions. A control group of individuals with PDAC without a germline PV/LPV was also assessed. RESULTS: The study included 196 PV/LPV carriers and 1184 controls. In the PV/LPV carriers, 25.5% had an affected FDR and/or SDR compared to 16.9% in the control group (p = .004). PV/LPV carriers were more likely to have an affected FDR compared to the controls (p = .003) but there was no statistical difference when assessing only affected SDRs (p = .344). CONCLUSIONS: Most PV/LPV carriers who developed PDAC did not have a close family history of PDAC and would not have met most current professional societies' recommendations for consideration of PDAC surveillance before diagnosis. However, PV/LPV carriers were significantly more likely to have a family history of PDAC, particularly an affected FDR. These findings support family history as a risk modifier in PV/LPV carriers, and highlight the need to identify other risk factors.

Is our understanding of aquatic ecosystems sufficient to quantify ecologically driven climate feedbacks?

The Earth functions as an integrated system-its current habitability to complex life is an emergent property dependent on interactions among biological, chemical, and physical components. As global warming affects ecosystem structure and function, so too will the biosphere affect climate by altering atmospheric gas composition and planetary albedo. Constraining these ecosystem-climate feedbacks is essential to accurately predict future change and develop mitigation strategies; however, the interplay among ecosystem processes complicates the assessment of their impact. Here, we explore the state-of-knowledge on how ecological and biological processes (e.g., competition, trophic interactions, metabolism, and adaptation) affect the directionality and magnitude of feedbacks between ecosystems and climate, using illustrative examples from the aquatic sphere. We argue that, despite ample evidence for the likely significance of many, our present understanding of the combinatorial effects of ecosystem dynamics precludes the robust quantification of most ecologically driven climate feedbacks. Constraining these effects must be prioritized within the ecological sciences for only by studying the biosphere as both subject and arbiter of global climate can we develop a sufficiently holistic view of the Earth system to accurately predict Earth's future and unravel its past.

La Terre fonctionne comme un système intégré­son habitabilité pour une vie complexe est une propriété émergente qui dépend des interactions entre les composantes biologiques, chimiques et physiques. Le réchauffement climatique affecte la structure et la fonction des écosystèmes, et en retour, la biosphère affecte également le climat en modifiant la composition des gaz atmosphériques et l'albédo planétaire. Il est essentiel de quantifier ces rétroactions entre les écosystèmes et le climat afin de prédire avec précision les changements futurs et élaborer des stratégies d'atténuation; cependant, l'interaction entre les processus écologiques complique l'évaluation de leurs impacts. Dans cet article, nous examinons l'état des connaissances sur la façon dont les processus écologiques et biologiques (par exemple, la concurrence, les interactions trophiques, le métabolisme, l'adaptation) affectent la directionnalité et l'ampleur des rétroactions entre les écosystèmes et le climat à l'aide d'exemples issus du monde aquatique. Nous soutenons que, malgré les nombreuses preuves de l'importance de plusieurs de ces rétroactions, notre compréhension limitée des effets additifs des processus écosystémiques empêche de faire une quantification robuste de la plupart des rétroactions climatiques d'origine écologique. Circonscrire ces effets doit être une priorité pour les sciences aquatiques, car ce n'est qu'en étudiant la biosphère en tant que sujet et arbitre du climat planétaire que nous pourrons développer une vision suffisamment holistique du système terrestre pour prédire avec précision l'avenir de la Terre et élucider son passé.

Signaling circuits and the apical extracellular matrix in aging: connections identified in the nematode Caenorhabditis elegans.

Numerous conserved signaling pathways play critical roles in aging, including insulin/IGF-1, TGF-ß, and Wnt pathways. Some of these pathways also play prominent roles in the formation and maintenance of the extracellular matrix. The nematode Caenorhabditis elegans has been an enduringly productive system for the identification of conserved mechanisms of biological aging. Recent studies in C. elegans highlight the regulatory circuits between conserved signaling pathways and the extracellular matrix, revealing a bidirectional relationship between these factors and providing a platform to address how regulation of and by the extracellular matrix can impact lifespan and organismal health during aging. These discoveries provide new opportunities for clinical advances and novel therapeutic strategies.

Micronutrient content drives elementome variability amongst the Symbiodiniaceae.

BACKGROUND: Elements are the basis of life on Earth, whereby organisms are essentially evolved chemical substances that dynamically interact with each other and their environment. Determining species elemental quotas (their elementome) is a key indicator for their success across environments with different resource availabilities. Elementomes remain undescribed for functionally diverse dinoflagellates within the family Symbiodiniaceae that includes coral endosymbionts. We used dry combustion and ICP-MS to assess whether Symbiodiniaceae (ten isolates spanning five genera Breviolum, Cladocopium, Durusdinium, Effrenium, Symbiodinium) maintained under long-term nutrient replete conditions have unique elementomes (six key macronutrients and nine micronutrients) that would reflect evolutionarily conserved preferential elemental acquisition. For three isolates we assessed how elevated temperature impacted their elementomes. Further, we tested whether Symbiodiniaceae conform to common stoichiometric hypotheses (e.g., the growth rate hypothesis) documented in other marine algae. This study considers whether Symbiodiniaceae isolates possess unique elementomes reflective of their natural ecologies, evolutionary histories, and resistance to environmental change. RESULTS: Symbiodiniaceae isolates maintained under long-term luxury uptake conditions, all exhibited highly divergent elementomes from one another, driven primarily by differential content of micronutrients. All N:P and C:P ratios were below the Redfield ratio values, whereas C:N was close to the Redfield value. Elevated temperature resulted in a more homogenised elementome across isolates. The Family-level elementome was (C19.8N2.6 P1.0S18.8K0.7Ca0.1) · 1000 (Fe55.7Mn5.6Sr2.3Zn0.8Ni0.5Se0.3Cu0.2Mo0.1V0.04) mmol Phosphorous-1 versus (C25.4N3.1P1.0S23.1K0.9Ca0.4) · 1000 (Fe66.7Mn6.3Sr7.2Zn0.8Ni0.4Se0.2Cu0.2Mo0.2V0.05) mmol Phosphorous -1 at 27.4 ± 0.4 °C and 30.7 ± 0.01 °C, respectively. Symbiodiniaceae isolates tested here conformed to some, but not all, stoichiometric principles. CONCLUSIONS: Elementomes for Symbiodiniaceae diverge from those reported for other marine algae, primarily via lower C:N:P and different micronutrient expressions. Long-term maintenance of Symbiodiniaceae isolates in culture under common nutrient replete conditions suggests isolates have evolutionary conserved preferential uptake for certain elements that allows these unique elementomes to be identified. Micronutrient content (normalised to phosphorous) commonly increased in the Symbiodiniaceae isolates in response to elevated temperature, potentially indicating a common elemental signature to warming.

Genomic variation of an endosymbiotic dinoflagellate (Symbiodinium 'fitti') among closely related coral hosts.

Mutualisms where hosts are coupled metabolically to their symbionts often exhibit high partner fidelity. Most reef-building coral species form obligate symbioses with a specific species of photosymbionts, dinoflagellates in the family Symbiodiniaceae, despite needing to acquire symbionts early in their development from environmental sources. Three Caribbean acroporids (Acropora palmata, A. cervicornis and their F1 hybrid) are sympatric across much of their range, but often occupy different depth and light habitats. Throughout this range, both species and their hybrid associate with the endosymbiotic dinoflagellate Symbiodinium 'fitti'. Because light (and therefore depth) influences the physiology of dinoflagellates, we investigated whether S. 'fitti' populations from each host taxon were differentiated genetically. Single nucleotide polymorphisms (SNPs) among S. 'fitti' strains were identified by aligning shallow metagenomic sequences of acroporid colonies sampled from across the Caribbean to a ~600-Mb draft assembly of the S. 'fitti' genome (from the CFL14120 A. cervicornis metagenome). Phylogenomic and multivariate analyses revealed that genomic variation among S. 'fitti' strains partitioned to each host taxon rather than by biogeographical origin. This is particularly noteworthy because the hybrid has a sparse fossil record and may be of relatively recent origin. A subset (37.6%) of the SNPs putatively under selection were nonsynonymous mutations predicted to alter protein efficiency. Differences in genomic variation of S. 'fitti' strains from each host taxon may reflect the unique selection pressures created by the microenvironments associated with each host. The nonrandom sorting among S. 'fitti' strains to different hosts could be the basis for lineage diversification via disruptive selection, leading to ecological specialization and ultimately speciation.

Iron Availability Modulates the Response of Endosymbiotic Dinoflagellates to Heat Stress.

Warming and nutrient limitation are stressors known to weaken the health of microalgae. In situations of stress, access to energy reserves can minimize physiological damage. Because of its widespread requirements in biochemical processes, iron is an important trace metal, especially for photosynthetic organisms. Lowered iron availability in oceans experiencing rising temperatures may contribute to the thermal sensitivity of reef-building corals, which rely on mutualisms with dinoflagellates to survive. To test the influence of iron concentration on thermal sensitivity, the physiological responses of cultured symbiotic dinoflagellates (genus Breviolum; family Symbiodiniaceae) were evaluated when exposed to increasing temperatures (26 to 30°C) and iron concentrations ranging from replete (500 pM Fe') to limiting (50 pM Fe') under a diurnal light cycle with saturating radiance. Declines in photosynthetic efficiency at elevated temperatures indicated sensitivity to heat stress. Furthermore, five times the amount of iron was needed to reach exponential growth during heat stress (50 pM Fe' at 26-28°C vs. 250 pM Fe' at 30°C). In treatments where exponential growth was reached, Breviolum psygmophilum grew faster than B.minutum, possibly due to greater cellular contents of iron and other trace metals. The metal composition of B.psygmophilum shifted only at the highest temperature (30°C), whereas changes in B.minutum were observed at lower temperatures (28°C). The influence of iron availability in modulating each alga's response to thermal stress suggests the importance of trace metals to the health of coral-algal mutualisms. Ultimately, a greater ability to acquire scarce metals may improve the tolerance of corals to physiological stressors and contribute to the differences in performance associated with hosting one symbiont species over another.

Indigenous and tribal peoples' health (The Lancet-Lowitja Institute Global Collaboration): a population study.

BACKGROUND: International studies of the health of Indigenous and tribal peoples provide important public health insights. Reliable data are required for the development of policy and health services. Previous studies document poorer outcomes for Indigenous peoples compared with benchmark populations, but have been restricted in their coverage of countries or the range of health indicators. Our objective is to describe the health and social status of Indigenous and tribal peoples relative to benchmark populations from a sample of countries. METHODS: Collaborators with expertise in Indigenous health data systems were identified for each country. Data were obtained for population, life expectancy at birth, infant mortality, low and high birthweight, maternal mortality, nutritional status, educational attainment, and economic status. Data sources consisted of governmental data, data from non-governmental organisations such as UNICEF, and other research. Absolute and relative differences were calculated. FINDINGS: Our data (23 countries, 28 populations) provide evidence of poorer health and social outcomes for Indigenous peoples than for non-Indigenous populations. However, this is not uniformly the case, and the size of the rate difference varies. We document poorer outcomes for Indigenous populations for: life expectancy at birth for 16 of 18 populations with a difference greater than 1 year in 15 populations; infant mortality rate for 18 of 19 populations with a rate difference greater than one per 1000 livebirths in 16 populations; maternal mortality in ten populations; low birthweight with the rate difference greater than 2% in three populations; high birthweight with the rate difference greater than 2% in one population; child malnutrition for ten of 16 populations with a difference greater than 10% in five populations; child obesity for eight of 12 populations with a difference greater than 5% in four populations; adult obesity for seven of 13 populations with a difference greater than 10% in four populations; educational attainment for 26 of 27 populations with a difference greater than 1% in 24 populations; and economic status for 15 of 18 populations with a difference greater than 1% in 14 populations. INTERPRETATION: We systematically collated data across a broader sample of countries and indicators than done in previous studies. Taking into account the UN Sustainable Development Goals, we recommend that national governments develop targeted policy responses to Indigenous health, improving access to health services, and Indigenous data within national surveillance systems. FUNDING: The Lowitja Institute.

BMP signaling to pharyngeal muscle in the C. elegans response to a bacterial pathogen regulates anti-microbial peptide expression and pharyngeal pumping.

Host response to pathogens recruits multiple tissues in part through conserved cell signaling pathways. In C. elegans, the bone morphogenetic protein (BMP) like DBL-1 signaling pathway has a role in the response to infection in addition to other roles in development and post-developmental functions. In the regulation of body size, the DBL-1 pathway acts through cell autonomous signal activation in the epidermis (hypodermis). We have now elucidated the tissues that respond to DBL-1 signaling upon exposure to two bacterial pathogens. The receptors and Smad signal transducers for DBL-1 are expressed in pharyngeal muscle, intestine, and epidermis. We demonstrate that expression of receptor-regulated Smad (R-Smad) gene sma-3 in the pharynx is sufficient to improve the impaired survival phenotype of sma-3 mutants and that expression of sma-3 in the intestine has no effect when exposing worms to bacterial infection of the intestine. We also show that two antimicrobial peptide genes - abf-2 and cnc-2 - are regulated by DBL-1 signaling through R-Smad SMA-3 activity in the pharynx. Finally, we show that pharyngeal pumping activity is reduced in sma-3 mutants and that other pharynx-defective mutants also have reduced survival on a bacterial pathogen. Our results identify the pharynx as a tissue that responds to BMP signaling to coordinate a systemic response to bacterial pathogens.

BMP signaling to pharyngeal muscle in the C. elegans response to a bacterial pathogen regulates anti-microbial peptide expression and pharyngeal pumping.

Host response to pathogens recruits multiple tissues in part through conserved cell signaling pathways. In Caenorhabditis elegans, the bone morphogenetic protein (BMP) like DBL-1 signaling pathway has a role in the response to infection in addition to other roles in development and postdevelopmental functions. In the regulation of body size, the DBL-1 pathway acts through cell autonomous signal activation in the epidermis (hypodermis). We have now elucidated the tissues that respond to DBL-1 signaling upon exposure to two bacterial pathogens. The receptors and Smad signal transducers for DBL-1 are expressed in pharyngeal muscle, intestine, and epidermis. We demonstrate that expression of receptor-regulated Smad (R-Smad) gene sma-3 in the pharynx is sufficient to improve the impaired survival phenotype of sma-3 mutants and that expression of sma-3 in the intestine has no effect when exposing worms to bacterial infection of the intestine. We also show that two antimicrobial peptide genes - abf-2 and cnc-2 - are regulated by DBL-1 signaling through R-Smad SMA-3 activity in the pharynx. Finally, we show that pharyngeal pumping activity is reduced in sma-3 mutants and that other pharynx-defective mutants also have reduced survival on a bacterial pathogen. Our results identify the pharynx as a tissue that responds to BMP signaling to coordinate a systemic response to bacterial pathogens.

The trace metal economy of the coral holobiont: supplies, demands and exchanges.

The juxtaposition of highly productive coral reef ecosystems in oligotrophic waters has spurred substantial interest and progress in our understanding of macronutrient uptake, exchange, and recycling among coral holobiont partners (host coral, dinoflagellate endosymbiont, endolithic algae, fungi, viruses, bacterial communities). By contrast, the contribution of trace metals to the physiological performance of the coral holobiont and, in turn, the functional ecology of reef-building corals remains unclear. The coral holobiont's trace metal economy is a network of supply, demand, and exchanges upheld by cross-kingdom symbiotic partnerships. Each partner has unique trace metal requirements that are central to their biochemical functions and the metabolic stability of the holobiont. Organismal homeostasis and the exchanges among partners determine the ability of the coral holobiont to adjust to fluctuating trace metal supplies in heterogeneous reef environments. This review details the requirements for trace metals in core biological processes and describes how metal exchanges among holobiont partners are key to sustaining complex nutritional symbioses in oligotrophic environments. Specifically, we discuss how trace metals contribute to partner compatibility, ability to cope with stress, and thereby to organismal fitness and distribution. Beyond holobiont trace metal cycling, we outline how the dynamic nature of the availability of environmental trace metal supplies can be influenced by a variability of abiotic factors (e.g. temperature, light, pH, etc.). Climate change will have profound consequences on the availability of trace metals and further intensify the myriad stressors that influence coral survival. Lastly, we suggest future research directions necessary for understanding the impacts of trace metals on the coral holobiont symbioses spanning subcellular to organismal levels, which will inform nutrient cycling in coral ecosystems more broadly. Collectively, this cross-scale elucidation of the role of trace metals for the coral holobiont will allow us to improve forecasts of future coral reef function.

Similarities in biomass and energy reserves among coral colonies from contrasting reef environments.

Coral reefs are declining worldwide, yet some coral populations are better adapted to withstand reductions in pH and the rising frequency of marine heatwaves. The nearshore reef habitats of Palau, Micronesia are a proxy for a future of warmer, more acidic oceans. Coral populations in these habitats can resist, and recover from, episodes of thermal stress better than offshore conspecifics. To explore the physiological basis of this tolerance, we compared tissue biomass (ash-free dry weight cm-2), energy reserves (i.e., protein, total lipid, carbohydrate content), and several important lipid classes in six coral species living in both offshore and nearshore environments. In contrast to expectations, a trend emerged of many nearshore colonies exhibiting lower biomass and energy reserves than colonies from offshore sites, which may be explained by the increased metabolic demand of living in a warmer, acidic, environment. Despite hosting different dinoflagellate symbiont species and having access to contrasting prey abundances, total lipid and lipid class compositions were similar in colonies from each habitat. Ultimately, while the regulation of colony biomass and energy reserves may be influenced by factors, including the identity of the resident symbiont, kind of food consumed, and host genetic attributes, these independent processes converged to a similar homeostatic set point under different environmental conditions.

Building consensus around the assessment and interpretation of Symbiodiniaceae diversity.

Within microeukaryotes, genetic variation and functional variation sometimes accumulate more quickly than morphological differences. To understand the evolutionary history and ecology of such lineages, it is key to examine diversity at multiple levels of organization. In the dinoflagellate family Symbiodiniaceae, which can form endosymbioses with cnidarians (e.g., corals, octocorals, sea anemones, jellyfish), other marine invertebrates (e.g., sponges, molluscs, flatworms), and protists (e.g., foraminifera), molecular data have been used extensively over the past three decades to describe phenotypes and to make evolutionary and ecological inferences. Despite advances in Symbiodiniaceae genomics, a lack of consensus among researchers with respect to interpreting genetic data has slowed progress in the field and acted as a barrier to reconciling observations. Here, we identify key challenges regarding the assessment and interpretation of Symbiodiniaceae genetic diversity across three levels: species, populations, and communities. We summarize areas of agreement and highlight techniques and approaches that are broadly accepted. In areas where debate remains, we identify unresolved issues and discuss technologies and approaches that can help to fill knowledge gaps related to genetic and phenotypic diversity. We also discuss ways to stimulate progress, in particular by fostering a more inclusive and collaborative research community. We hope that this perspective will inspire and accelerate coral reef science by serving as a resource to those designing experiments, publishing research, and applying for funding related to Symbiodiniaceae and their symbiotic partnerships.

The coral symbiont Candidatus Aquarickettsia is variably abundant in threatened Caribbean acroporids and transmitted horizontally.

The symbiont "Candidatus Aquarickettsia rohweri" infects a diversity of aquatic hosts. In the threatened Caribbean coral, Acropora cervicornis, Aquarickettsia proliferates in response to increased nutrient exposure, resulting in suppressed growth and increased disease susceptibility and mortality of coral. This study evaluated the extent, as well as the ecology and evolution of Aquarickettsia infecting threatened corals, Ac. cervicornis, and Ac. palmata and their hybrid ("Ac. prolifera"). Aquarickettsia was found in all acroporids, with coral host and geographic location impacting the infection magnitude. Phylogenomic and genome-wide single-nucleotide variant analysis of Aquarickettsia found phylogenetic clustering by geographic region, not by coral taxon. Analysis of Aquarickettsia fixation indices suggests multiple sequential infections of the same coral colony are unlikely. Furthermore, relative to other Rickettsiales species, Aquarickettsia is undergoing positive selection, with Florida populations experiencing greater positive selection relative to other Caribbean locations. This may be due in part to Aquarickettsia proliferating in response to greater nutrient stress in Florida, as indicated by greater in situ replication rates in these corals. Aquarickettsia was not found to significantly codiversify with either the coral animal or the coral's algal symbiont (Symbiodinium "fitti"). Quantitative PCR analysis showed that gametes, larvae, recruits, and juveniles from susceptible, captive-reared coral genets were not infected with Aquarickettsia. Thus, horizontal transmission of Aquarickettsia via coral mucocytes or an unidentified host is more likely. The prevalence of Aquarickettsia in Ac. cervicornis and its high abundance in the Florida coral population suggests that coral disease mitigation efforts focus on preventing early infection via horizontal transmission.

Applying model approaches in non-model systems: A review and case study on coral cell culture.

Model systems approaches search for commonality in patterns underlying biological diversity and complexity led by common evolutionary paths. The success of the approach does not rest on the species chosen but on the scalability of the model and methods used to develop the model and engage research. Fine-tuning approaches to improve coral cell cultures will provide a robust platform for studying symbiosis breakdown, the calcification mechanism and its disruption, protein interactions, micronutrient transport/exchange, and the toxicity of nanoparticles, among other key biological aspects, with the added advantage of minimizing the ethical conundrum of repeated testing on ecologically threatened organisms. The work presented here aimed to lay the foundation towards development of effective methods to sort and culture reef-building coral cells with the ultimate goal of obtaining immortal cell lines for the study of bleaching, disease and toxicity at the cellular and polyp levels. To achieve this objective, the team conducted a thorough review and tested the available methods (i.e. cell dissociation, isolation, sorting, attachment and proliferation). The most effective and reproducible techniques were combined to consolidate culture methods and generate uncontaminated coral cell cultures for ~7 days (10 days maximum). The tests were conducted on scleractinian corals Pocillopora acuta of the same genotype to harmonize results and reduce variation linked to genetic diversity. The development of cell separation and identification methods in conjunction with further investigations into coral cell-type specific metabolic requirements will allow us to tailor growth media for optimized monocultures as a tool for studying essential reef-building coral traits such as symbiosis, wound healing and calcification at multiple scales.

Do the shuffle: Changes in Symbiodinium consortia throughout juvenile coral development.

Previous studies of symbiotic associations between scleractinians corals and Symbiodinium have demonstrated that the consortium of symbionts can change in response to environmental conditions. However, less is known about symbiont shuffling during early coral development, particularly in brooding species. This study examined whether Symbiodinium consortia (1) varied in Porites astreoides on shallow (10m) and upper mesophotic (30m) reefs, (2) changed during coral development, and (3) influenced growth of juveniles in different environments. Symbiodinium ITS2 sequences were amplified using universal primers and analyzed using phylotype-specific primers designed for phylotypes A, B, and C. Adults from both depths were found to host only phylotype A, phylotypes A and B, or phylotypes A, B, and C and the frequency of the phylotype composition did not vary with depth. However, phylotype A was the dominant symbiont that was vertically transmitted to the planulae. The presence of phylotypes B and C was detected in the majority of juveniles when transplanted onto the shallow and upper mesophotic reefs whereas only phylotype A was detected in the majority of juveniles reared in outdoor aquaria. In addition, growth of juvenile P. astreoides harboring different combinations of Symbiodinium phylotypes did not vary when transplanted to different reef zones. However, juveniles reared in in situ reef environments grew faster than those reared in ex situ outdoor aquaria. These results show that Symbiodinium consortia change during development of P. astreoides and are influenced by environmental conditions.