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| Open AccessThe transcriptional landscape of age in human peripheral blood
Ageing increases the risk of many diseases. Here the authors compare blood cell transcriptomes of over 14,000 individuals and identify a set of about 1,500 genes that are differently expressed with age, shedding light on transcriptional programs linked to the ageing process and age-associated diseases.
- Marjolein J. Peters
- , Roby Joehanes
- & Andrew D. Johnson
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| Open AccessCRL4–DCAF1 ubiquitin E3 ligase directs protein phosphatase 2A degradation to control oocyte meiotic maturation
The E3 ubiquitin ligase CRL4 regulates oocyte survival through hydroxymethylation of genomic DNA. Here Yuet al. show that CRL4 is also required for oocytes to complete meiosis I by mediating the poly-ubiquitination and proteasomal degradation of the cell cycle regulator protein phosphatase 2A-A subunit.
- Chao Yu
- , Shu-Yan Ji
- & Heng-Yu Fan
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| Open AccessRegion-specific variation in the properties of skeletal adipocytes reveals regulated and constitutive marrow adipose tissues
Bone marrow contains adipocytes, which have been thought to form one type of marrow adipose tissue (MAT). Here, the authors identify two MAT subpopulations in mice and humans—‘regulated’ and ‘constitute’ MAT—which show distinct phenotypic and cellular traits, and respond differently to cold exposure.
- Erica L. Scheller
- , Casey R. Doucette
- & Ormond A. MacDougald
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| Open AccessSelective enhancement of insulin sensitivity in the mature adipocyte is sufficient for systemic metabolic improvements
Insulin resistance in adipose tissue is a hallmark of obesity. Here, the authors generate inducible adipocyte-specific PTEN knockout mice to demonstrate that enhanced insulin sensitivity in adipose tissue is directly linked to improved systemic metabolic homeostasis, despite an increase in fat mass.
- Thomas S. Morley
- , Jonathan Y. Xia
- & Philipp E. Scherer
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| Open AccessPannexin 1 channels regulate leukocyte emigration through the venous endothelium during acute inflammation
Endothelial cell activation by inflammation requires extracellular ATP release. Here the authors show that TNF-α induces Src-family kinase-dependent ATP release by Pannexin1 channels in endothelial cells, and that Pannexin1 is required for leukocyte adhesion and emigration into the inflamed tissue.
- Alexander W. Lohman
- , Igor L. Leskov
- & Brant E. Isakson
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Article
| Open AccessDrosophila germ granules are structured and contain homotypic mRNA clusters
What regulates mRNAs transcript localization in the germ granules in Drosophila is unclear. Here Trcek et al.identify that germ plasm proteins are homogeneously distributed in germ granules but once localized, individual mRNAs form homotypic clusters, contributing structure to the germ granules.
- Tatjana Trcek
- , Markus Grosch
- & Ruth Lehmann
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Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4
Thrombin is a key proinflammatory protease regulating leukocyte trafficking at sites of vascular injury. Here the authors show that balanced thrombin interactions with platelet proteins PAR4, GPIbα and fibrin plays a major role in regulating this process.
- Zane S. Kaplan
- , Alessandro Zarpellon
- & Shaun P. Jackson
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| Open AccessA three-step MTOC fragmentation mechanism facilitates bipolar spindle assembly in mouse oocytes
Mitotic spindles assemble from two centrosomes, but oocytes lack centrosomes so how their spindles assemble is unclear. Here Clift and Schuh show that multiple acentriolar microtubule-organizing centres fragment in a three-step process to facilitate bipolar spindle assembly in mouse oocytes.
- Dean Clift
- & Melina Schuh
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Article
| Open AccessCerebral complexity preceded enlarged brain size and reduced olfactory bulbs in Old World monkeys
The evolution of the brain in Old World monkeys (cercopithecoids) is poorly understood. Here the authors describe a complete endocast of Victoriapithecus, a 15 Myr old cercopithecoid, which shows that the brain size was much smaller and the olfactory bulbs much larger than in any extant catarrhine primate.
- Lauren A. Gonzales
- , Brenda R. Benefit
- & Fred Spoor
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| Open AccessBivalent separation into univalents precedes age-related meiosis I errors in oocytes
As oocytes age the frequency of chromosome segregation errors during meiosis I increases. Here the authors use live imaging of oocytes from naturally aged mice to provide direct evidence that bivalent separation into univalents is the primary defect responsible for age-related aneuploidy.
- Yogo Sakakibara
- , Shu Hashimoto
- & Tomoya S. Kitajima
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Cidea improves the metabolic profile through expansion of adipose tissue
Unlike rodents, humans produce the protein Cidea in white adipose tissue, where it associates with lipid droplets. Here the authors generate mice that express human Cidea in fat tissues to show Cidea exerts beneficial metabolic effects by regulating the expansion of visceral fat in response to a high-fat diet.
- Gustavo Abreu-Vieira
- , Alexander W. Fischer
- & Natasa Petrovic
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Article
| Open AccessGanoderma lucidum reduces obesity in mice by modulating the composition of the gut microbiota
Ganoderma lucidumis a medicinal mushroom used in Traditional Chinese Medicine with putative anti-diabetic properties. Here, the authors show that polysaccharides from a water extract of this mushroom exert beneficial metabolic effects by modulating the composition of the gut microbiota in mice.
- Chih-Jung Chang
- , Chuan-Sheng Lin
- & Hsin-Chih Lai
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Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites
Growing evidence suggests that environmental rather than genetic factors are major contributors to asthma development. Here the authors show that high intake of dietary fibre by pregnant mice increases resistance of their progeny to the development of allergic airways disease.
- Alison N. Thorburn
- , Craig I. McKenzie
- & Charles R. Mackay
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Article
| Open AccessNELL-1 in the treatment of osteoporotic bone loss
The growth factor NELL-1 induces bone formation during development, but its role in osteoporosis is unknown. This study shows that NELL-1 binding to integrin ß1 induces Wnt/ß-catenin signalling in the bone and restores bone mineral density in osteoporotic mice and sheep, suggesting the therapeutic potential of NELL-1 for the treatment of bone loss.
- Aaron W. James
- , Jia Shen
- & Chia Soo
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Opposing calcium-dependent signalling pathways control skeletal muscle differentiation by regulating a chromatin remodelling enzyme
Brg1 is part of the SWI/SNF chromatin remodelling complex that is essential for embryonic development. Here, the authors show that Brg1 is the target of two opposing calcium-regulated molecules involved in myogenesis: calcineurin, which promotes myogenesis, and protein kinase C β (PKCβ), which inhibits it.
- Brian T. Nasipak
- , Teresita Padilla-Benavides
- & Anthony N. Imbalzano
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Pharmacological repression of PPARγ promotes osteogenesis
Central to the lineage commitment of multipotent mesenchymal stem cells is the nuclear receptor PPARγ, the master regulator of adipogenesis. Here the authors use a variety of structural approaches to rationally design PPARγ inverse agonist SR2595, and demonstrate its ability to promote osteogenesis.
- David P. Marciano
- , Dana S. Kuruvilla
- & Patrick R. Griffin
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Article
| Open AccessOptogenetic control of contractile function in skeletal muscle
Nerve damage can lead to skeletal muscle paralysis. The authors show that localized photostimulation of skeletal muscle expressing the light-sensitive channel Channelrhodopsin-2 generates contraction in the absence of neural impulses and prove that this strategy can be used for optogenetic opening of explanted murine vocal cords.
- Tobias Bruegmann
- , Tobias van Bremen
- & Philipp Sasse
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| Open AccessStimulation of soluble guanylyl cyclase protects against obesity by recruiting brown adipose tissue
The enzyme soluble guanylyl cyclase (sGC) regulates differentiation of brown fat. Here, Hoffman et al.show that a small molecule sGC stimulator increases brown fat activity and browning of white fat, thereby inducing energy expenditure, weight loss and partial protection from diet-induced obesity in mice.
- Linda S. Hoffmann
- , Jennifer Etzrodt
- & Alexander Pfeifer
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| Open AccessExposure to a youthful circulation rejuvenates bone repair through modulation of β-catenin
The reparative capacity of tissues decreases with age. Here, Baht et al. perform parabiosis experiments and provide evidence for the existence of a soluble factor produced by young, but not old, haematopoietic cells that is capable of improving fracture repair in old mice.
- Gurpreet S. Baht
- , David Silkstone
- & Benjamin A. Alman
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| Open AccessMicrobe-dependent lymphatic migration of neutrophils modulates lymphocyte proliferation in lymph nodes
Both sterile and microbial injuries lead to rapid neutrophil recruitment to the site of inflammation. Here the authors show that only neutrophils responding to microbial ligands leave inflamed skin and migrate to draining lymph nodes where they stimulate lymphocyte proliferation.
- Henry R. Hampton
- , Jacqueline Bailey
- & Tatyana Chtanova
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Hepatic insulin signalling is dispensable for suppression of glucose output by insulin in vivo
Insulin and the transcription factor FoxO1 are key regulators of hepatic glucose metabolism. Here, Titchenell et al. provide evidence for the existence of an insulin-dependent extrahepatic pathway that is fully capable of regulating hepatic glucose production in the absence of hepatic FoxO1.
- Paul M. Titchenell
- , Qingwei Chu
- & Morris J. Birnbaum
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Analysis of opo cis-regulatory landscape uncovers Vsx2 requirement in early eye morphogenesis
The transcriptional regulation of morphogenetic effectors during eye development is poorly understood. Here, the authors show that transcription of an endocytosis regulator Opois crucial for the neural retina development in zebrafish and activated by the interaction of the transcription factor Vsx2 and retinal enhancer H6_10137.
- Ines Gago-Rodrigues
- , Ana Fernández-Miñán
- & Juan R. Martinez-Morales
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| Open AccessType I interferons regulate eomesodermin expression and the development of unconventional memory CD8+ T cells
Eomesodermin is the key transcription factor for the development of ‘virtual memory’ T cells that develop in the absence of antigen-driven activation. Here the authors show that type I interferons directly activate eomesodermin and contribute to the homeostasis of virtual memory CD8+T cells.
- Valérie Martinet
- , Sandrine Tonon
- & Stanislas Goriely
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| Open AccessJMJD1A is a signal-sensing scaffold that regulates acute chromatin dynamics via SWI/SNF association for thermogenesis
Demethylase JMJD1A activates thermogenesis-related target genes in response to β-adrenergic hormones. Here, the authors show that phosphorylation of JMJD1A at S265 increases its interaction with the SWI/SNF chromatin remodeler, leading to long-range chromatin interactions and target gene activation.
- Yohei Abe
- , Royhan Rozqie
- & Juro Sakai
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| Open AccessExtracellular MRP8/14 is a regulator of β2 integrin-dependent neutrophil slow rolling and adhesion
MRP8/14 are actively secreted by myeloid cells during inflammation. Here the authors show that MRP8/14 play an important role in leukocyte recruitment to the inflammatory site, triggering an autocrine cascade that promotes neutrophil adhesion to the endothelium.
- Monika Pruenster
- , Angela R. M. Kurz
- & Markus Sperandio
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Article
| Open AccessFTO influences adipogenesis by regulating mitotic clonal expansion
Mutations in the FTO gene have been linked to obesity. Here, Merkestein et al. provide in vitro and in vivo evidence that FTOdirectly regulates adipogenesis in mice at the stage of mitotic clonal expansion, likely by modulating the expression of the transcription factor RUNX1T1.
- Myrte Merkestein
- , Samantha Laber
- & Roger D. Cox
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Article
| Open AccessSphingosine-1-phosphate receptor 3 promotes leukocyte rolling by mobilizing endothelial P-selectin
The lipid sphingosine-1-phosphate (S1P) is known to mediate leukocyte recruitment in inflammation. Here, Nussbaum et al.show that S1P, via its receptor S1P3, also regulates leukocyte rolling on endothelium by promoting the presentation of the adhesion molecule P-selectin on the endothelial surface.
- Claudia Nussbaum
- , Sarah Bannenberg
- & Bodo Levkau
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| Open AccessGlycosylation of immunoglobulin G determines osteoclast differentiation and bone loss
The IgG sugar moiety modulates the binding of immune complexes to their Fcγ receptors resulting in pro- or anti-inflammatory response. This study shows that IgG sialylation also affects osteoclastogenesis and bone mass in mice and humans, identifying a new link between bone and the immune system.
- Ulrike Harre
- , Stefanie C. Lang
- & Georg Schett
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| Open AccessMyeloid cell-derived inducible nitric oxide synthase suppresses M1 macrophage polarization
In response to microbial ligands, IRF5 promotes pro-inflammatory M1 macrophage activation and production of nitrous oxide. Here the authors show that nitrous oxide modifies IRF5 tyrosine residues as a negative feedback, limiting the inflammatory response and protecting from endotoxin shock.
- Geming Lu
- , Ruihua Zhang
- & Huabao Xiong
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| Open AccessThe genome-wide effects of ionizing radiation on mutation induction in the mammalian germline
Ionizing radiation (IR) is an extensively studied mutagenic agent that can lead to the accumulation of extra mutations in the offspring of irradiated parents. Here the authors provide a comprehensive genome-wide survey of the consequences of IR on the mammalian germline.
- Adeolu B. Adewoye
- , Sarah J. Lindsay
- & Matthew E. Hurles
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The class II PI 3-kinase, PI3KC2α, links platelet internal membrane structure to shear-dependent adhesive function
The lipid kinase PI3KC2α is essential for embryogenesis, yet its role in adult homeostasis is unknown. Here, the authors show that PI3KC2α regulates the structure of the internal membrane reserves of murine megakaryocytes and platelets, affecting the platelets’ adhesiveness and prothrombotic function.
- Jessica K. Mountford
- , Claire Petitjean
- & Shaun P. Jackson
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Local endocytosis triggers dendritic thinning and pruning in Drosophila sensory neurons
During development, neurons prune their axons and dendrites to eliminate excessive or inappropriate connections initially formed but the mechanistic details of the pruning process are not completely understood. Here the authors visualize pruning events in dendritic branches in Drosophilaand study the role of calcium transients and endocytosis in this process.
- Takahiro Kanamori
- , Jiro Yoshino
- & Kazuo Emoto
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| Open AccessAdipose tissue NAPE-PLD controls fat mass development by altering the browning process and gut microbiota
Endocannabinoids are bioactive lipid molecules produced in the body. Here, Geurts et al. create mice lacking the endocannabinoid-producing enzyme NAPE-PLD in adipocytes and report defects in adipose-induced browning, which are mediated by alterations in the gut microbiome.
- Lucie Geurts
- , Amandine Everard
- & Patrice D. Cani
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Article
| Open AccessSupramolecular synergy in the boundary lubrication of synovial joints
Interacting cartilage surfaces in synovial joints experience very low levels of friction, allowing unhindered mechanical motion. Here, the authors propose how a synergistic interaction of hyaluronan, lubricin and phospholipids, molecules that are ubiquitous in joints, may lead to this high level of lubrication.
- Jasmine Seror
- , Linyi Zhu
- & Jacob Klein
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| Open AccessPW1/Peg3 expression regulates key properties that determine mesoangioblast stem cell competence
Mesoangioblasts are mesodermal stem cells with a therapeutic potential for treatment of muscular dystrophy due to their ability to differentiate into skeletal muscle. This study shows that the PW1/Peg3 protein is crucial for mesoangioblast myogenic and migratory potency and is a therapeutically relevant biomarker.
- Chiara Bonfanti
- , Giuliana Rossi
- & Graziella Messina
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Pre-B cell receptor binding to galectin-1 modifies galectin-1/carbohydrate affinity to modulate specific galectin-1/glycan lattice interactions
Galectin-1 (GAL1) is a secreted protein that binds to glycans and to the pre-B-cell receptor (pre-BCR). Here Bonzi et al. show that pre-BCR binding to GAL1 causes a conformational change in the GAL1 carbohydrate-binding site to inhibit binding to selected glycans.
- Jeremy Bonzi
- , Olivier Bornet
- & Latifa Elantak
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Primitive macrophages control HSPC mobilization and definitive haematopoiesis
Haematopoietic stem/progenitor cells (HSPCs) transform from aortic endothelium into migratory cells that move through stroma and enter circulation to colonize haematopoietic tissues. Here the authors show that HSPCs' passage is facilitated by primitive macrophages that secrete extracellular matrix-degrading enzymes.
- Jana Travnickova
- , Vanessa Tran Chau
- & Karima Kissa
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| Open AccessSensory integration dynamics in a hierarchical network explains choice probabilities in cortical area MT
The activity of sensory neurons can be correlated with perceptual decisions and this effect may provide insights into how sensory information is processed during perceptual tasks. Here the authors develop a network model of sensory and decision-making areas and propose that the dynamics across the network hierarchy explains the choice probabilities.
- Klaus Wimmer
- , Albert Compte
- & Jaime de la Rocha
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TH2 cells and their cytokines regulate formation and function of lymphatic vessels
Lymphatic vessels remodel in response to inflammatory conditions and T-cell-secreted cytokines. Here, the authors show that T helper type 2 cells inhibit lymphangiogenesis by secreting IL-4 and IL-13, and that blockade of these cytokines can alleviate allergic asthma symptoms by improving the lymphatic function in mice.
- Kihyuk Shin
- , Raghu P. Kataru
- & Seung-Hyo Lee
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Pharmacological inhibition of Dock5 prevents osteolysis by affecting osteoclast podosome organization while preserving bone formation
Small-molecule C21 inhibits Rac GTPase activation by Dock5, which decreases osteoclast activity in vitro. Using three mouse models where bone loss is caused by hyperactive osteoclasts, Vives et al. show that C21 treatment safely and efficiently prevents osteoporosis while preserving bone formation.
- Virginie Vives
- , Gaëlle Cres
- & Anne Blangy
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A narrow window of cortical tension guides asymmetric spindle positioning in the mouse oocyte
Asymmetric spindle positioning in female mouse meiosis depends on the assembly of actin networks. Here, Chaigne et al. show by theoretical modelling and artificial manipulation of the oocyte cortex that a narrow stiffness regime is required to correctly position the spindle during meiosis I in the mouse oocyte.
- A. Chaigne
- , C. Campillo
- & M. E. Terret
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Article
| Open AccessAntibiotics in ingested human blood affect the mosquito microbiota and capacity to transmit malaria
The gut microbiota of malaria-transmitting mosquitoes contributes to the insects’ resistance to the parasite. Here, Gendrin et al. show that antibiotics in ingested human blood alter the mosquito gut microbiota and increase the insect’s survival, fecundity and susceptibility to the parasites.
- Mathilde Gendrin
- , Faye H. Rodgers
- & George K. Christophides
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Berberine activates thermogenesis in white and brown adipose tissue
Berberine is contained in some plant-derived medicines and is known to have anti-diabetic effects. Here the authors show that berberine activates thermogenesis in white and brown adipose tissues, thereby increasing organismal energy expenditure and limiting weight gain in genetically obese mice.
- Zhiguo Zhang
- , Huizhi Zhang
- & Guang Ning
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Inhibition of osteoclastogenesis and inflammatory bone resorption by targeting BET proteins and epigenetic regulation
Epigenetic changes during the differentiation of bone-resorbing cells have important implications in bone remodelling. Here the authors target this pathway with I-BET151, an inhibitor of bromo and extra-terminal proteins that inhibits expression of the MYC-NFAT axis and suppresses bone loss in multiple mouse models.
- Kyung-Hyun Park-Min
- , Elisha Lim
- & Lionel B Ivashkiv
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NAA10 controls osteoblast differentiation and bone formation as a feedback regulator of Runx2
N-alpha-acetyltransferase 10 (NAA10) regulates cell growth and proliferation. Here the authors show that NAA10 also has a role in osteogenesis, by fine-tuning the activity of the osteogenic transcription factor Runx2.
- Haejin Yoon
- , Hye-Lim Kim
- & Jong-Wan Park
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A sequence variant in human KALRN impairs protein function and coincides with reduced cortical thickness
Mutations of the human KALRN gene are implicated in schizophrenia. Here, Russell et al.identify a genetic variant of this gene in a schizophrenia patient and his sibling diagnosed with major depressive disorder and substance abuse, and find that this is associated with reduced cortical volume and thickness.
- Theron A. Russell
- , Katherine D. Blizinsky
- & Peter Penzes
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Microbial genomic analysis reveals the essential role of inflammation in bacteria-induced colorectal cancer
Abundance of certain gut enterobacteria is correlated with inflammation and cancer development in humans, but the interplay between the three factors is unclear. Here the authors show that gut inflammation is required for bacteria-associated tumour development in mouse models.
- Janelle C. Arthur
- , Raad Z. Gharaibeh
- & Christian Jobin
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Symmetrical and asymmetrical division analysis provides evidence for a hierarchy of prostate epithelial cell lineages
The role of cell division modes of basal and luminal epithelial cells in prostate development and tumorigenesis is unclear. Here, the authors show that while luminal cells contribute to development and tumorigenesis via symmetrical divisions, basal cells do so through asymmetric divisions.
- Jia Wang
- , Helen He Zhu
- & Wei-Qiang Gao
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Cultivation-based multiplex phenotyping of human gut microbiota allows targeted recovery of previously uncultured bacteria
Research on the roles played by gut microbes in human health is hampered by our inability to isolate and study them in pure cultures. Here, the authors describe an approach that allows targeted cultivation and rapid characterization of a significant proportion of human gut bacteria.
- Elizabeth A. Rettedal
- , Heidi Gumpert
- & Morten O.A. Sommer