• Article |

    This paper shows that gut flora can influence cardiovascular disease, by metabolizing a dietary phospholipid. Using a metabolomics approach it is found that plasma levels of three metabolites of dietary phosphatidylcholine—choline, betaine and TMAO—are associated with increased risk of cardiovascular disease in humans. The gut flora is known to have a role in TMAO formation from choline, and this paper shows that dietary choline supplementation enhances macrophage foam cell formation and lesion formation in atherosclerosis-prone mice, but not if the gut flora are depleted with antibiotics.

    • Zeneng Wang
    • , Elizabeth Klipfell
    •  & Stanley L. Hazen
  • Letter |

    Progesterone stimulates an increase in Ca2+ levels in human sperm, but the underlying signalling mechanism is poorly understood. Two studies now show that progesterone activates the sperm-specific, pH-sensitive CatSper calcium channel, leading to a rapid influx of Ca2+ ions into the spermatozoa. These results should help to define the physiological role of progesterone and CatSper in sperm, and could lead to the development of new classes of non-hormonal contraceptives.

    • Polina V. Lishko
    • , Inna L. Botchkina
    •  & Yuriy Kirichok
  • Article |

    To date, various aspects of connectivity have been inferred from electron microscopy (EM) of synaptic contacts, light microscopy of axonal and dendritic arbors, and correlations in activity. However, until now it has not been possible to relate the complex structural wiring between neurons to the function of individual cells. Using a combination of functional imaging and three-dimensional serial EM reconstruction at unprecedented scale, two papers now describe the connectivity of single cells in the mouse visual system. This study investigates the connectivity of inhibitory interneurons in primary visual cortex.

    • Davi D. Bock
    • , Wei-Chung Allen Lee
    •  & R. Clay Reid
  • Letter |

    This study describes a mechanotransduction pathway that links the body wall with the epidermis in Caenorhabditis elegans. The pathway involves the p21 activated kinase PAK 1, an adaptor GIT 1 and its partner PIX 1. Tension exerted by muscles or external pressure keeps GIT 1 on station at hemidesmosomes — the small rivet like bodies that attach epidermal cells to the underlying musculature — and stimulates PAK 1 through PIX 1 and Rac GTPase. The C. elegans hemidesmosome is more than a passive attachment structure, therefore, but a sensor that responds to tension by triggering signalling processes.

    • Huimin Zhang
    • , Frédéric Landmann
    •  & Michel Labouesse
  • Letter |

    This paper shows that the activity of human beta-defensin 1 is regulated by its redox status, with enhanced antibiotic killing activity under reducing conditions as they are found in the distal colon. This is believed to serve to protect the healthy intestinal epithelium against potentially harmful colonization by commensal bacteria and opportunistic fungi. In vitro evidence implicates thioredoxin as the likely reducing agent.

    • Bjoern O. Schroeder
    • , Zhihong Wu
    •  & Jan Wehkamp
  • Letter |

    During periods of fasting the liver produces ketone bodies, which the peripheral tissues can use as a source of energy. Here it is shown that fasting inhibits multi-component mTOR complex 1 (mTORC1) in the liver. Inhibition of mTORC1 is required for activation of PPARα, a master regulator that switches on genes involved in ketogenesis. Livers from aged mice have increased mTORC1 signalling, reduced PPARα activity, and reduced ketone production. The observation that mTORC1 promotes an ageing phenotype in the liver fits well with the observation that inhibition of this pathway increases lifespan in several organisms.

    • Shomit Sengupta
    • , Timothy R. Peterson
    •  & David M. Sabatini
  • Letter |

    These authors describe a molecular pathway by which endothelial cells sustain liver regeneration after surgical resection. Activation of vascular endothelial growth factor-A receptor-2 in a defined subpopulation of liver endothelial cells leads to the upregulation of the endothelial-specific transcription factor Id1, which in turn induces Wnt2 and hepatocyte growth factor, which are secreted from the endothelial cells and trigger hepatocyte proliferation.

    • Bi-Sen Ding
    • , Daniel J. Nolan
    •  & Shahin Rafii
  • Letter |

    The blood–brain barrier (BBB) is made up of vascular endothelial cells and was thought to have formed postnatally from astrocytes. Two independent studies demonstrate that this barrier forms during embryogenesis, with pericyte/endothelial cell interactions being critical to regulate the BBB during development. A better understanding of the relationship among pericytes, neuroendothelial cells and astrocytes in BBB function will contribute to our understanding of BBB breakdown during central nervous system injury and disease.

    • Richard Daneman
    • , Lu Zhou
    •  & Ben A. Barres
  • Article |

    Salmonella enterica serotype Typhimurium causes acute gut inflammation, which promotes the growth of the pathogen through unknown mechanisms. It is now shown that the reactive oxygen species generated during inflammation react with host-derived sulphur compounds to produce tetrathionate, which the pathogen uses as a terminal electron acceptor to support its growth. The ability to use tetrathionate provides the pathogen with a competitive advantage over bacteria that lack this property.

    • Sebastian E. Winter
    • , Parameth Thiennimitr
    •  & Andreas J. Bäumler
  • Letter |

    Cells that make up the liver are known to be polyploid. These authors show that mouse hepatocytes can increase and decrease their ploidy in vivo; increases occur as a result of failed cytokinesis, and decreases occur as a result of multipolar mitosis. The resulting genetic heterogeneity might be advantageous following hepatic injury, allowing the selection of 'genetically robust' cells from a pre-existing pool of diverse genotypes.

    • Andrew W. Duncan
    • , Matthew H. Taylor
    •  & Markus Grompe
  • Letter |

    Cell death by apoptosis is crucial for tissue development and function, and occurs throughout life. Apoptotic cells must be cleared by phagocytic cells, but the mechanisms that regulate cell clearance in vivo remain unclear. Here, a conserved engulfment protein, ELMO1, is shown to be required for the phagocytic clearance of apoptotic germ cells by Sertoli cells in mouse testes. The findings make a compelling case for the relationship between engulfment and tissue homeostasis in vivo.

    • Michael R. Elliott
    • , Shuqiu Zheng
    •  & Kodi S. Ravichandran
  • Letter |

    Human immunodeficiency virus (HIV) fails to induce interferon in the cells that it infects, but the underlying mechanisms are not known. These authors show that the virus can in fact activate the interferon pathway in dendritic cells when the usual block to infection is bypassed. Dendritic cell activation depends on the HIV-1 capsid/cyclophilin A interaction, which is known to have a role in HIV-1 infectivity.

    • Nicolas Manel
    • , Brandon Hogstad
    •  & Dan R. Littman
  • Letter |

    B cells are activated by many different antigens to produce appropriate antibodies. B cells express up to 120,000 B-cell antigen receptor (BCR) complexes on their surface, but how do these complexes remain silent on resting B cells, and how are they activated? It is found here that the BCR on resting cells forms oligomers, and that these may be an autoinhibited form of the receptor. Disruption of the oligomer shifts B cells towards activation.

    • Jianying Yang
    •  & Michael Reth
  • Article |

    Neurons of the peripheral nervous system need survival factors to prevent their death during development. Most in the central nervous system do not. Why are peripheral neurons so needy? Here it is shown that the neurotrophin receptors TrkA and TrkC, expressed at high levels by many peripheral nervous system neurons, behave as dependence receptors: they instruct neurons to die if there is no ligand around. By contrast, TrkB, expressed mainly in the central nervous system, does not signal death in the absence of ligand.

    • Vassiliki Nikoletopoulou
    • , Heiko Lickert
    •  & Yves-Alain Barde
  • Letter |

    Anxious temperament in both humans and monkeys is an important early predictor of psychopathology and is known to be heritable. These authors characterize the neural circuitry associated with this trait and the extent to which its function is heritable. A scan of related monkeys after exposure to mild stress showed that activation in both the amygdala and hippocampus was predictive of anxious temperament, but that heritability of activity in hippocampus was greater than that in amygdala.

    • Jonathan A. Oler
    • , Andrew S. Fox
    •  & Ned H. Kalin
  • Article |

    The appropriate initiation and termination of behavioural action sequences is imperative, but the neural mechanisms underlying the learning and execution of fixed behavioural patterns are poorly understood. Here the authors reveal start/stop neuronal activity in basal ganglia circuits that emerge during task training in mice. Genetically altering these circuits disrupted the activity and impaired performance, providing evidence for a causal relationship between the specific neuronal activity and task learning.

    • Xin Jin
    •  & Rui M. Costa
  • Article |

    The microbial content of the human gut has been the focus of much research interest recently. Now another layer of complexity has been added: the viral content of the gut. Virus-like particles were isolated from faecal samples from four sets of identical twins and their mothers, at three time points over a one-year period. The viromes (metagenomes) of these particles were then sequenced. The results show that there is high interpersonal variation in viromes, but that intrapersonal diversity was very low over this time period.

    • Alejandro Reyes
    • , Matthew Haynes
    •  & Jeffrey I. Gordon
  • Letter |

    Macrophages that populate the lymph nodes are known to clear viruses from the lymph and to initiate antiviral humoral immune responses. It is now shown that these macrophages also have another function: they prevent lymph-borne neurotropic viruses from entering the central nervous system. The mechanism is dependent on the production of type I interferon.

    • Matteo Iannacone
    • , E. Ashley Moseman
    •  & Ulrich H. von Andrian
  • Letter |

    Circadian rhythms control many physiological functions. During periods of feeding, pancreatic islets secrete insulin to maintain glucose homeostasis — a rhythmic process that is disturbed in people with diabetes. These authors show that pancreatic islets contain their own clock: they have self-sustained circadian oscillations of CLOCK and BMAL1 genes and proteins, which are vital for the regulation of circadian rhythms. Without this clock, a cascade of cellular failure and pathology initiates the onset of diabetes mellitus.

    • Biliana Marcheva
    • , Kathryn Moynihan Ramsey
    •  & Joseph Bass
  • Letter |

    Here, artificial proteins are described that mimic the molecular architecture of titin — a protein that helps to govern the passive elastic properties of muscle. The new artificial proteins combine structured and unstructured domains, and can be photochemically crosslinked into a solid biomaterial that is resilient at low strains and extensible and tough at high strains. This provides an example of tailoring the macroscopic properties of a material through engineering at the single-molecule level.

    • Shanshan Lv
    • , Daniel M. Dudek
    •  & Hongbin Li
  • Letter |

    One of the roles of the human gut microbiota is to break down nutrients using bacterial enzymes that are lacking from the human genome. It is now shown that the gut microbiota of Japanese, but not American, individuals contains porphyranases, enzymes that digest sulphated polysaccharides which are present in the marine environment only. These findings indicate that diet can select for gene content of the human microbiota.

    • Jan-Hendrik Hehemann
    • , Gaëlle Correc
    •  & Gurvan Michel
  • Article |

    In the pancreas, insulin-producing β-cells are long-lived and generally replicate seldom. They can do so, however, after increased metabolic demand or after injury. Here, a new transgenic model is developed in which β-cells are nearly completely ablated in mice. If given insulin, these mice survive, and grow new β-cells. Lineage-tracing shows that these new β-cells come from α-cells, revealing a previously disregarded degree of pancreatic cell plasticity.

    • Fabrizio Thorel
    • , Virginie Népote
    •  & Pedro L. Herrera
  • Article |

    Many sensory neurons in the mammalian cortex are tuned to specific stimulus features — for example, some fire only when horizontal bars move from top to bottom in the visual field. But it has been unclear whether such tuning is encoded in a neuron's inputs, or whether the neuron itself computes its response. Here, a new technique for visualizing and mapping sensory inputs to the dendrites of neurons in the mouse visual cortex has shown that each neuron makes its own 'decision' as to the orientation preference of its output.

    • Hongbo Jia
    • , Nathalie L. Rochefort
    •  & Arthur Konnerth
  • Letter |

    Here, a new type of innate effector leukocyte cell — the nuocyte — is described and characterized. It is shown that interleukin (IL)25 and IL33 drive the expansion of the nuocyte population, that these cells secrete IL13, and that they are required for protection against helminth infection.

    • Daniel R. Neill
    • , See Heng Wong
    •  & Andrew N. J. McKenzie
  • Article |

    In the mammalian brain, the subventricular zone (SVZ) produces neural progenitor cells that migrate into the cortex to populate the upper layers. In humans this region is massively expanded, producing an outer SVZ (OSVZ). Here, live-cell imaging of developing human tissue was used to show that the OSVZ has similar characteristics to the SVZ, with progenitor cells proliferating in a way that depends on the Notch protein. The findings have implications for our understanding of how the complex human brain evolved.

    • David V. Hansen
    • , Jan H. Lui
    •  & Arnold R. Kriegstein
  • Letter |

    Zebrafish are able to replace lost heart muscle efficiently, and are used as a model to understand why natural heart regeneration — after a heart attack, for instance — is blocked in mammals. Here, and in an accompanying paper, genetic fate-mapping approaches reveal which cell population contributes prominently to cardiac muscle regeneration after an injury approximating myocardial infarction. The results show that cardiac muscle regenerates through activation and expansion of existing cardiomyocytes, without involving a stem-cell population.

    • Chris Jopling
    • , Eduard Sleep
    •  & Juan Carlos Izpisúa Belmonte
  • Letter |

    Although explored in the rodent, the relationship between single neuron activity, oscillations and behavioural learning is unknown in humans. Here, successful memory formation in humans was predicted by the coordination of spike timing relative to the local theta oscillation. These data provide a direct connection between the behavioural modulation of oscillations and plasticity within specific circuits.

    • Ueli Rutishauser
    • , Ian B. Ross
    •  & Erin M. Schuman
  • Article |

    A new mouse model is developed in which haematopoietic malignancies are caused by genetic changes in the microenvironment of blood cells. Deletion in bone progenitor cells of Dicer1, a gene involved in microRNA processing, leads to a myelodysplastic syndrome-like phenotype which can progress to leukaemia. Deregulation of Sbds, which is mutated in human Schwachman–Bodian–Diamond syndrome, may be involved in this process.

    • Marc H. G. P. Raaijmakers
    • , Siddhartha Mukherjee
    •  & David. T. Scadden