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Mouse models of neutropenia reveal progenitor-stage-specific defects 期刊论文
NATURE, 2020
作者:  Lombardo, Umberto;  Iriarte, Jose;  Hilbert, Lautaro;  Ruiz-Perez, Javier;  Capriles, Jose M.;  Veit, Heinz
收藏  |  浏览/下载:32/0  |  提交时间:2020/07/03

Advances in genetics and sequencing have identified a plethora of disease-associated and disease-causing genetic alterations. To determine causality between genetics and disease, accurate models for molecular dissection are required  however, the rapid expansion of transcriptional populations identified through single-cell analyses presents a major challenge for accurate comparisons between mutant and wild-type cells. Here we generate mouse models of human severe congenital neutropenia (SCN) using patient-derived mutations in the GFI1 transcription factor. To determine the effects of SCN mutations, we generated single-cell references for granulopoietic genomic states with linked epitopes(1), aligned mutant cells to their wild-type equivalents and identified differentially expressed genes and epigenetic loci. We find that GFI1-target genes are altered sequentially, as cells go through successive states of differentiation. These insights facilitated the genetic rescue of granulocytic specification but not post-commitment defects in innate immune effector function, and underscore the importance of evaluating the effects of mutations and therapy within each relevant cell state.


Mouse models of severe congenital neutropenia using patient-derived mutations in the GFI1 locus are used to determine the mechanisms by which the disease progresses.


  
Hepatic NADH reductive stress underlies common variation in metabolic traits 期刊论文
NATURE, 2020, 583 (7814) : 122-+
作者:  Skov, Laurits;  Coll Macia, Moises;  Sveinbjoernsson, Gardar;  Mafessoni, Fabrizio;  Lucotte, Elise A.;  Einarsdottir, Margret S.;  Jonsson, Hakon;  Halldorsson, Bjarni;  Gudbjartsson, Daniel F.;  Helgason, Agnar;  Schierup, Mikkel Heide;  Stefansson, Kari
收藏  |  浏览/下载:46/0  |  提交时间:2020/07/03

The cellular NADH/NAD(+) ratio is fundamental to biochemistry, but the extent to which it reflects versus drives metabolic physiology in vivo is poorly understood. Here we report the in vivo application of Lactobacillus brevis (Lb)NOX1, a bacterial water-forming NADH oxidase, to assess the metabolic consequences of directly lowering the hepatic cytosolic NADH/NAD(+) ratio in mice. By combining this genetic tool with metabolomics, we identify circulating alpha-hydroxybutyrate levels as a robust marker of an elevated hepatic cytosolic NADH/NAD(+) ratio, also known as reductive stress. In humans, elevations in circulating alpha-hydroxybutyrate levels have previously been associated with impaired glucose tolerance(2), insulin resistance(3) and mitochondrial disease(4), and are associated with a common genetic variant in GCKR(5), which has previously been associated with many seemingly disparate metabolic traits. Using LbNOX, we demonstrate that NADH reductive stress mediates the effects of GCKR variation on many metabolic traits, including circulating triglyceride levels, glucose tolerance and FGF21 levels. Our work identifies an elevated hepatic NADH/NAD(+) ratio as a latent metabolic parameter that is shaped by human genetic variation and contributes causally to key metabolic traits and diseases. Moreover, it underscores the utility of genetic tools such as LbNOX to empower studies of '  causal metabolism'  .


The authors identify an increased hepatic NADH/NAD(+) ratio as an underlying metabolic parameter that is shaped by human genetic variation and contributes causally to key metabolic traits and diseases.


  
C9orf72 suppresses systemic and neural inflammation induced by gut bacteria 期刊论文
NATURE, 2020
作者:  Nikoo, Mohammad Samizadeh;  Jafari, Armin;  Perera, Nirmana;  Zhu, Minghua;  Santoruvo, Giovanni;  Matioli, Elison
收藏  |  浏览/下载:37/0  |  提交时间:2020/07/03

A hexanucleotide-repeat expansion in C9ORF72 is the most common genetic variant that contributes to amyotrophic lateral sclerosis and frontotemporal dementia(1,2). The C9ORF72 mutation acts through gain- and loss-of-function mechanisms to induce pathways that are implicated in neural degeneration(3-9). The expansion is transcribed into a long repetitive RNA, which negatively sequesters RNA-binding proteins(5) before its non-canonical translation into neural-toxic dipeptide proteins(3,4). The failure of RNA polymerase to read through the mutation also reduces the abundance of the endogenous C9ORF72 gene product, which functions in endolysosomal pathways and suppresses systemic and neural inflammation(6-9). Notably, the effects of the repeat expansion act with incomplete penetrance in families with a high prevalence of amyotrophic lateral sclerosis or frontotemporal dementia, indicating that either genetic or environmental factors modify the risk of disease for each individual. Identifying disease modifiers is of considerable translational interest, as it could suggest strategies to diminish the risk of developing amyotrophic lateral sclerosis or frontotemporal dementia, or to slow progression. Here we report that an environment with reduced abundance of immune-stimulating bacteria(10,11) protects C9orf72-mutant mice from premature mortality and significantly ameliorates their underlying systemic inflammation and autoimmunity. Consistent with C9orf72 functioning to prevent microbiota from inducing a pathological inflammatory response, we found that reducing the microbial burden in mutant mice with broad spectrum antibiotics-as well as transplanting gut microflora from a protective environment-attenuated inflammatory phenotypes, even after their onset. Our studies provide further evidence that the microbial composition of our gut has an important role in brain health and can interact in surprising ways with well-known genetic risk factors for disorders of the nervous system.


Reduced abundance of immune-stimulating gut bacteria ameliorated the inflammatory and autoimmune phenotypes of mice with mutations in C9orf72, which in the human orthologue are linked to amyotrophic lateral sclerosis and frontotemporal dementia.


  
APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline 期刊论文
NATURE, 2020, 581 (7806) : 70-+
作者:  Doherty, Tiarnan A. S.;  Winchester, Andrew J.;  Macpherson, Stuart;  Johnstone, Duncan N.;  Pareek, Vivek;  Tennyson, Elizabeth M.;  Kosar, Sofiia;  Kosasih, Felix U.;  Anaya, Miguel;  Abdi-Jalebi, Mojtaba;  Andaji-Garmaroudi, Zahra;  Wong, E. Laine;  Madeo, Julien;  Chiang, Yu-Hsien;  Park, Ji-Sang;  Jung, Young-Kwang;  Petoukhoff, Christopher E.;  Divitini, Giorgio;  Man, Michael K. L.;  Ducati, Caterina;  Walsh, Aron;  Midgley, Paul A.;  Dani, Keshav M.;  Stranks, Samuel D.
收藏  |  浏览/下载:57/0  |  提交时间:2020/07/03

Breakdown of the blood-brain barrier in individuals carrying the epsilon 4 allele of the APOE gene, but not the epsilon 3 allele, increases with and predicts cognitive impairment and is independent of amyloid beta or tau pathology.


Vascular contributions to dementia and Alzheimer'  s disease are increasingly recognized(1-6). Recent studies have suggested that breakdown of the blood-brain barrier (BBB) is an early biomarker of human cognitive dysfunction(7), including the early clinical stages of Alzheimer'  s disease(5,8-10). The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer'  s disease(11-14), leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes(15-19), which maintain BBB integrity(20-22). It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the epsilon 3/epsilon 4 or epsilon 4/epsilon 4 alleles) are distinguished from those without APOE4 (epsilon 3/epsilon 3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-beta or tau pathology measured in cerebrospinal fluid or by positron emission tomography(23). High baseline levels of the BBB pericyte injury biomarker soluble PDGFR beta(7,8) in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-beta and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway(19) in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer'  s disease pathology, and might be a therapeutic target in APOE4 carriers.


  
A pause in Southern Hemisphere circulation trends due to the Montreal Protocol 期刊论文
NATURE, 2020, 579 (7800) : 544-548
作者:  Imai, Yu;  Meyer, Kirsten J.;  Iinishi, Akira;  Favre-Godal, Quentin;  Green, Robert;  Manuse, Sylvie;  Caboni, Mariaelena;  Mori, Miho;  Niles, Samantha;  Ghiglieri, Meghan;  Honrao, Chandrashekhar;  Ma, Xiaoyu;  Guo, Jason J.;  Makriyannis, Alexandros;  Linares-Otoya, Luis;  Boehringer, Nils;  Wuisan, Zerlina G.;  Kaur, Hundeep;  Wu, Runrun;  Mateus, Andre
收藏  |  浏览/下载:45/0  |  提交时间:2020/05/13

Observations show robust near-surface trends in Southern Hemisphere tropospheric circulation towards the end of the twentieth century, including a poleward shift in the mid-latitude jet(1,2), a positive trend in the Southern Annular Mode(1,3-6) and an expansion of the Hadley cell(7,8). It has been established that these trends were driven by ozone depletion in the Antarctic stratosphere due to emissions of ozone-depleting substances(9-11). Here we show that these widely reported circulation trends paused, or slightly reversed, around the year 2000. Using a pattern-based detection and attribution analysis of atmospheric zonal wind, we show that the pause in circulation trends is forced by human activities, and has not occurred owing only to internal or natural variability of the climate system. Furthermore, we demonstrate that stratospheric ozone recovery, resulting from the Montreal Protocol, is the key driver of the pause. Because pre-2000 circulation trends have affected precipitation(12-14), and potentially ocean circulation and salinity(15-17), we anticipate that a pause in these trends will have wider impacts on the Earth system. Signatures of the effects of the Montreal Protocol and the associated stratospheric ozone recovery might therefore manifest, or have already manifested, in other aspects of the Earth system.


  
Global chemical effects of the microbiome include new bile-acid conjugations 期刊论文
NATURE, 2020, 579 (7797) : 123-+
作者:  Dossin, Francois;  Pinheiro, Ines;  Zylicz, Jan J.;  Roensch, Julia;  Collombet, Samuel;  Le Saux, Agnes;  Chelmicki, Tomasz;  Attia, Mikael;  Kapoor, Varun;  Zhan, Ye;  Dingli, Florent;  Loew, Damarys;  Mercher, Thomas;  Dekker, Job;  Heard, Edith
收藏  |  浏览/下载:56/0  |  提交时间:2020/07/03

Metabolomics data from germ-free and specific-pathogen-free mice reveal effects of the microbiome on host chemistry, identifying conjugations of bile acids that are also enriched in patients with inflammatory bowel disease or cystic fibrosis.


A mosaic of cross-phylum chemical interactions occurs between all metazoans and their microbiomes. A number of molecular families that are known to be produced by the microbiome have a marked effect on the balance between health and disease(1-9). Considering the diversity of the human microbiome (which numbers over 40,000 operational taxonomic units(10)), the effect of the microbiome on the chemistry of an entire animal remains underexplored. Here we use mass spectrometry informatics and data visualization approaches(11-13) to provide an assessment of the effects of the microbiome on the chemistry of an entire mammal by comparing metabolomics data from germ-free and specific-pathogen-free mice. We found that the microbiota affects the chemistry of all organs. This included the amino acid conjugations of host bile acids that were used to produce phenylalanocholic acid, tyrosocholic acid and leucocholic acid, which have not previously been characterized despite extensive research on bile-acid chemistry(14). These bile-acid conjugates were also found in humans, and were enriched in patients with inflammatory bowel disease or cystic fibrosis. These compounds agonized the farnesoid X receptor in vitro, and mice gavaged with the compounds showed reduced expression of bile-acid synthesis genes in vivo. Further studies are required to confirm whether these compounds have a physiological role in the host, and whether they contribute to gut diseases that are associated with microbiome dysbiosis.


  
ILC2s amplify PD-1 blockade by activating tissue-specific cancer immunity 期刊论文
NATURE, 2020
作者:  Papai, Gabor;  Frechard, Alexandre;  Kolesnikova, Olga;  Crucifix, Corinne;  Schultz, Patrick;  Ben-Shem, Adam
收藏  |  浏览/下载:21/0  |  提交时间:2020/07/03

Tumour-infiltrating group 2 innate lymphoid cells prime CD8(+) T cells and amplify the anti-tumour effects of PD-1 blockade in pancreatic ductal adenocarcinoma.


Group 2 innate lymphoid cells (ILC2s) regulate inflammation and immunity in mammalian tissues(1,2). Although ILC2s are found in cancers of these tissues(3), their roles in cancer immunity and immunotherapy are unclear. Here we show that ILC2s infiltrate pancreatic ductal adenocarcinomas (PDACs) to activate tissue-specific tumour immunity. Interleukin-33 (IL33) activates tumour ILC2s (TILC2s) and CD8(+) T cells in orthotopic pancreatic tumours but not heterotopic skin tumours in mice to restrict pancreas-specific tumour growth. Resting and activated TILC2s express the inhibitory checkpoint receptor PD-1. Antibody-mediated PD-1 blockade relieves ILC2 cell-intrinsic PD-1 inhibition to expand TILC2s, augment anti-tumour immunity, and enhance tumour control, identifying activated TILC2s as targets of anti-PD-1 immunotherapy. Finally, both PD-1(+) TILC2s and PD-1(+) T cells are present in most human PDACs. Our results identify ILC2s as anti-cancer immune cells for PDAC immunotherapy. More broadly, ILC2s emerge as tissue-specific enhancers of cancer immunity that amplify the efficacy of anti-PD-1 immunotherapy. As ILC2s and T cells co-exist in human cancers and share stimulatory and inhibitory pathways, immunotherapeutic strategies to collectively target anti-cancer ILC2s and T cells may be broadly applicable.


  
Compounding the Disturbance: Family Forest Owner Reactions to Invasive Forest Insects 期刊论文
ECOLOGICAL ECONOMICS, 2020, 167
作者:  Markowski-Lindsay, Marla;  Borsuk, Mark E.;  Butler, Brett J.;  Duveneck, Matthew J.;  Holt, Jonathan;  Kittredge, David B.;  Laflower, Danelle;  MacLean, Meghan Graham;  Orwig, David;  Thompson, Jonathan R.
收藏  |  浏览/下载:14/0  |  提交时间:2020/07/02
Contingent behavior  Coupled natural-human system  Family forest owner  Forest disturbance  Indirect effects  Land use  Timber harvesting  
Urbanization in Arid Central Arizona Watersheds Results in Decreased Stream Flashiness 期刊论文
WATER RESOURCES RESEARCH, 2019
作者:  McPhillips, L. E.;  Earl, S. R.;  Hale, R. L.;  Grimm, N. B.
收藏  |  浏览/下载:22/0  |  提交时间:2020/02/16
anthropogenic effects  human impacts  catchment  streamflow  watershed  
Increased body size along urbanization gradients at both community and intraspecific level in macro-moths 期刊论文
GLOBAL CHANGE BIOLOGY, 2018, 24 (8) : 3837-3848
作者:  Merckx, Thomas;  Kaiser, Aurelien;  Van Dyck, Hans
收藏  |  浏览/下载:19/0  |  提交时间:2019/04/09
bat food webs  body size shifts  cascading effects  human-induced rapid evolutionary change  intraspecific trait variation  light pollution  pollinator networks  urban ecology