Ecosystem responses to climate change at a Low Arctic and a High Arctic long-term research site

© The Author(s), 2017. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Ambio 46, Supple. 1 (2017): 160-173, doi:10.1007/s13280-016-0870-x.Long-term measurements of ecological effects of warming are often not statistically significant because of annual variability or signal noise. These are reduced in indicators that filter or reduce the noise around the signal and allow effects of climate warming to emerge. In this way, certain indicators act as medium pass filters integrating the signal over years-to-decades. In the Alaskan Arctic, the 25-year record of warming of air temperature revealed no significant trend, yet environmental and ecological changes prove that warming is affecting the ecosystem. The useful indicators are deep permafrost temperatures, vegetation and shrub biomass, satellite measures of canopy reflectance (NDVI), and chemical measures of soil weathering. In contrast, the 18-year record in the Greenland Arctic revealed an extremely high summer air-warming of 1.3°C/decade; the cover of some plant species increased while the cover of others decreased. Useful indicators of change are NDVI and the active layer thickness.The Toolik research was supported in part by NSF Grants DEB 0207150, DEB 1026843, ARC 1107701, and ARC 1504006

Host gene expression signatures to identify infection type and organ dysfunction in children evaluated for sepsis: a multicentre cohort study.

BackgroundSepsis is defined as dysregulated host response to infection that leads to life-threatening organ dysfunction. Biomarkers characterising the dysregulated host response in sepsis are lacking. We aimed to develop host gene expression signatures to predict organ dysfunction in children with bacterial or viral infection.MethodsThis cohort study was done in emergency departments and intensive care units of four hospitals in Queensland, Australia, and recruited children aged 1 month to 17 years who, upon admission, underwent a diagnostic test, including blood cultures, for suspected sepsis. Whole-blood RNA sequencing of blood was performed with Illumina NovaSeq (San Diego, CA, USA). Samples with completed phenotyping, monitoring, and RNA extraction by March 31, 2020, were included in the discovery cohort; samples collected or completed thereafter and by Oct 27, 2021, constituted the Rapid Paediatric Infection Diagnosis in Sepsis (RAPIDS) internal validation cohort. An external validation cohort was assembled from RNA sequencing gene expression count data from the observational European Childhood Life-threatening Infectious Disease Study (EUCLIDS), which recruited children with severe infection in nine European countries between 2012 and 2016. Feature selection approaches were applied to derive novel gene signatures for disease class (bacterial vs viral infection) and disease severity (presence vs absence of organ dysfunction 24 h post-sampling). The primary endpoint was the presence of organ dysfunction 24 h after blood sampling in the presence of confirmed bacterial versus viral infection. Gene signature performance is reported as area under the receiver operating characteristic curves (AUCs) and 95% CI.FindingsBetween Sept 25, 2017, and Oct 27, 2021, 907 patients were enrolled. Blood samples from 595 patients were included in the discovery cohort, and samples from 312 children were included in the RAPIDS validation cohort. We derived a ten-gene disease class signature that achieved an AUC of 94·1% (95% CI 90·6-97·7) in distinguishing bacterial from viral infections in the RAPIDS validation cohort. A ten-gene disease severity signature achieved an AUC of 82·2% (95% CI 76·3-88·1) in predicting organ dysfunction within 24 h of sampling in the RAPIDS validation cohort. Used in tandem, the disease class and disease severity signatures predicted organ dysfunction within 24 h of sampling with an AUC of 90·5% (95% CI 83·3-97·6) for patients with predicted bacterial infection and 94·7% (87·8-100·0) for patients with predicted viral infection. In the external EUCLIDS validation dataset (n=362), the disease class and disease severity predicted organ dysfunction at time of sampling with an AUC of 70·1% (95% CI 44·1-96·2) for patients with predicted bacterial infection and 69·6% (53·1-86·0) for patients with predicted viral infection.InterpretationIn children evaluated for sepsis, novel host transcriptomic signatures specific for bacterial and viral infection can identify dysregulated host response leading to organ dysfunction.FundingAustralian Government Medical Research Future Fund Genomic Health Futures Mission, Children's Hospital Foundation Queensland, Brisbane Diamantina Health Partners, Emergency Medicine Foundation, Gold Coast Hospital Foundation, Far North Queensland Foundation, Townsville Hospital and Health Services SERTA Grant, and Australian Infectious Diseases Research Centre

A communal catalogue reveals Earth’s multiscale microbial diversity

Our growing awareness of the microbial world’s importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth’s microbial diversity

A communal catalogue reveals Earth's multiscale microbial diversity

Our growing awareness of the microbial world's importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth's microbial diversity.Peer reviewe

Altered bile acid profile associates with cognitive impairment in Alzheimer's disease—An emerging role for gut microbiome

Introduction Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut‐brain axis in neurodegeneration. Bile acids (BAs), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer's disease (AD). Methods Serum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1464 subjects including 370 cognitively normal older adults, 284 with early mild cognitive impairment, 505 with late mild cognitive impairment, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD‐related genetic variants, adjusting for confounders and multiple testing. Results In AD compared to cognitively normal older adults, we observed significantly lower serum concentrations of a primary BA (cholic acid [CA]) and increased levels of the bacterially produced, secondary BA, deoxycholic acid, and its glycine and taurine conjugated forms. An increased ratio of deoxycholic acid:CA, which reflects 7α‐dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response–related genes implicated in AD showed associations with BA profiles. Discussion We report for the first time an association between altered BA profile, genetic variants implicated in AD, and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut‐liver‐brain axis in the pathogenesis of AD

The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques

Nephrolog

Regulation of the immune system during experimental cutaneous leishmaniasis in gene-deficient mice

The obligate intracellular protozoan parasite Leishmania major is transmitted by sandfly vectors and causes cutaneous leishmaniasis in infected hosts, which results in the development of lesions at the site of infection. In the mouse model, genetically resistant mouse strains, such as C57BL/6, are able to contain the pathogen and spontaneously heal the lesions, while genetically susceptible mice, such as BALB/c, are unable to confine the parasite and heal the lesions, and therefore finally succumb to the disease. This genetically programmed outcome of leishmaniasis is determined primarily by cytokine expression patterns, which have been attributed to CD4⁺ helper T cell subsets. Large amounts of the Th1-type cytokines IL-12 and IFN-γ are associated with a protective immune response, while expression of the Th2-type cytokines IL-4 and IL-13 coincide with host susceptibility. Two further cytokines, IL-10 and TGF-β can modify the immune response to Leishmania by suppressing the immune system, and thus preventing complete eradication of the parasites.\ud \ud Immunosuppression during cutaneous leishmaniasis is important for controlling collateral damage that can occur as a result of overzealous inflammation, as well as limiting the immune response once the parasite is eliminated from the host. However, the degree of immunosuppression needs to be finely balanced, since amplified suppression can lead to chronic disease or death due to uncontrolled parasite growth, while insufficient suppression can lead to excessive inflammation causing collateral damage and host injury. A variety of cells from both the innate and adaptive branches of the immune system can mediate immunosuppression. These cells include alternatively activated macrophages (AAMs) and myeloid-derived suppressor cells (MDSCs), which represent the innate branch of the immune system, as well as Tregs, which are the main regulators within the adaptive branch. Since the maintenance of an appropriate immune response relies on the balance of inflammation and immunoregulation, my hypothesis was that during cutaneous leishmaniasis, dysfunctional regulation of the immune response by immunoregulatory cells contributes to pathogenesis and undesirable clinical outcomes.\ud \ud Two gene-deficient mouse models on the genetically resistant C57BL/6 background were used to analyse regulatory aspects of the immune response to L. major. One of these mouse models is deficient for the pro-inflammatory cytokine tumour necrosis factor (TNF) and succumbs to L. major, while the other model, which is deficient for the chemokine receptor CCR7, develops a chronic infection. The susceptible or partly susceptible disease outcomes of these two mouse models differs from the normally resistant phenotype of the C57BL/6 strain, indicating that there is a lack of induction of immunoregulatory cells resulting in collateral damage or increased immunosuppression during infection leading to parasite dissemination. Therefore, both models are well suited to study the ensuing implications of immunoregulation during cutaneous leishmaniasis.\ud \ud Firstly, in the absence of TNF, mice develop a Th1 response and exhibit a lack of Th2 cytokine production in response to L. major, comparable to control mice, and a possible cause for the death of B6.TNF⁻/⁻ mice has yet to be elucidated. In B6.TNF⁻/⁻ mice, but not in control mice, I observed a large percentage of AAMs in the infected footpad and in the draining lymph node. At the site of infection, these AAMs are defined as F4/80⁺CD206⁺ monocytes/macrophages that express arginase 1 (Arg1). In the draining lymph node, two monocytic populations are present, as defined by Ly6C expression, and in the absence of TNF, the population with low expression of Ly6C accumulates at the peak of disease. Both the CD11b⁺Ly6Clo and CD11b⁺Ly6Chi monocytic populations in B6.TNF⁻/⁻ mice display markers for alternative activation, such as Arg1 and CD206, while B6.WT monocytic populations have minimal expression of the same markers. These results indicate that TNF has an antagonistic role in the development of AAMs, and describe a potential mechanism for the death of B6.TNF⁻/⁻ mice after L. major infection.\ud \ud \ud The second model I used to test my hypothesis was the L. major infection of CCR7-deficient mice. This infection model allowed me to study the expansion of Tregs in response to parasitic infection, and in addition, to address more general questions regarding the role of CCR7, since there is currently a general lack of studies examining L. major-infected B6.CCR7-/- mice. Therefore, both the innate and lymphocytic infiltrates during infection were analysed to provide a foundation for further research. In the absence of CCR7, cells crucial for the clearance of parasites, such as inflammatory iNOS-expressing monocytes, were delayed in their migration to the site of infection. Furthermore, B6.CCR7-/- mice had increased expression of the Th2 cytokines IL-4 and IL-10 within the lymph node, while there were no changes in IFN-γ expression. Additionally, there was an increased percentage of Tregs in the draining lymph node of B6.CCR7⁻/⁻ mice throughout infection. Since CCR7 is required for the migration of antigen-presenting DCs into the lymph node, B6.CCR7⁻/⁻ mice were injected with B6.WT DCs to increase DC migration, promote efficient antigen presentation and support an effective Th1 response. Instead, the addition of B6.WT DCs into B6.CCR7⁻/⁻ mice or B6.CCR7⁻/⁻ DCs into B6.WT mice caused exacerbated disease compared to control host mice. Moreover, the injection of B6.WT DCs further increased the percentage of Tregs in the lymph nodes of B6.CCR7⁻/⁻ mice. Taken together, I show that CCR7 is required for maintaining a pro-inflammatory response to L. major.\ud \ud Overall, increased immunosuppression during cutaneous leishmaniasis is an underlying cause for fatal or chronic disease outcomes. Specifically, I showed that TNF negatively regulates the development of AAMs during L. major infection, providing a plausible explanation for the death of TNF-deficient mice. Furthermore, I provide evidence that CCR7 modulates immunosuppression and is required to elicit a Th1 response, as an additional function to its known role in cell migration. Therefore, as hypothesised, disturbed cellular regulation from both the innate and adaptive branches of the immune system contribute to undesired outcomes of L. major infection

Roles of WNT, NOTCH, and Hedgehog signaling in the differentiation and function of innate and innate-like lymphocytes

Innate lymphoid cells (ILCs) and innate-like lymphocytes have important roles in immune responses in the context of infection, cancer, and autoimmunity. The factors involved in driving the differentiation and function of these cell types remain to be clearly defined. There are several cellular signaling pathways involved in embryogenesis, which continue to function in adult tissue. In particular, the WNT, NOTCH, and Hedgehog signaling pathways are emerging as regulators of hematopoietic cell development and differentiation. This review discusses the currently known roles of WNT, NOTCH, and Hedgehog signaling in the differentiation and function of ILCs and innate-like lymphocytes

Different regulatory mechanisms in protozoan parasitic infections

The immune response to the protozoan pathogens, Leishmania spp., Trypanosoma spp. and Plasmodium spp., has been studied extensively with particular focus on regulation of the immune response by immunological mechanisms. More specifically, in diseases caused by parasites, immunosuppression frequently prevents immunopathology that can injure the host. However, this allows a small number of parasites to evade the immune response and remain in the host after a clinical cure. The consequences can be chronic infections, which establish a zoonotic or anthroponotic reservoir. This review will highlight some of the identified regulatory mechanisms of the immune system that govern immune responses to parasitic diseases, in particular leishmaniasis, trypanosomiasis and malaria, and discuss implications for the development of efficient vaccines against these diseases