Diseases

  • Letter
    | Open Access

    Studies of identical twins are widely used to dissect the contributions of genes and the environment to human diseases. In multiple sclerosis, an autoimmune demyelinating disease, identical twins often show differences. This might suggest that environmental effects are most significant in this case, but genetic and epigenetic differences between identical twins have been described. Here, however, studies of identical twins show no evidence for genetic, epigenetic or transcriptome differences that could explain disease discordance.

    • Sergio E. Baranzini
    • , Joann Mudge
    •  & Stephen F. Kingsmore
  • Letter |

    A deletion on human chromosome 22 (22q11.2) is one of the largest genetic risk factors for schizophrenia. Mice with a corresponding deletion have problems with working memory, one feature of schizophrenia. It is now found that these mice also show disruptions in synchronous firing between neurons of the prefrontal cortex and of the hippocampus, an electrophysiological phenomenon that has been linked to learning and memory and which is also thought to be disrupted in schizophrenia patients.

    • Torfi Sigurdsson
    • , Kimberly L. Stark
    •  & Joshua A. Gordon
  • Letter |

    Although several synaptic adhesion proteins have been identified as genetic risk factors in schizophrenia, it is unclear as to what role they play in disease progression. Here, it is shown that two such proteins — neuregulin 1 and its receptor ErbB4 — function to regulate the connectivity of specific cortical circuits. The study not only implicates these proteins in the wiring of inhibitory synapses, about which little is known, but also provides a new perspective on their involvement in schizophrenia.

    • Pietro Fazzari
    • , Ana V. Paternain
    •  & Beatriz Rico
  • Letter |

    During atherosclerosis, crystals of cholesterol accumulate in atherosclerotic plaques. But are they a consequence or a cause of the inflammation associated with the disease? Here it is shown that small cholesterol crystals appear early in the development of atherosclerosis, and that they act as an endogenous danger signal, causing inflammation by activating the NLRP3 inflammasome pathway. Cholesterol crystals thus seem to be an early cause, rather than a late consequence, of inflammation.

    • Peter Duewell
    • , Hajime Kono
    •  & Eicke Latz
  • Article |

    African sleeping sickness, caused by Trypanosoma brucei species, is responsible for some 30,000 human deaths each year. Available treatments are limited by poor efficacy and safety profiles. However, a new molecular target for potential treatments has now been identified. The protein target is T. brucei N-myristoyltransferase. In further experiments, lead compounds have been discovered that inhibit this protein, kill trypanosomes in vitro and in vivo, and can cure trypanosomiasis in mice.

    • Julie A. Frearson
    • , Stephen Brand
    •  & Paul G. Wyatt
  • Letter |

    Cancer 'chemoprevention' uses substances to reverse, suppress or prevent the initial phase of carcinogenesis or the progression of neoplastic cells to cancer cells. Here it is shown that treatment with TRAIL proteins and all-trans-retinyl acetate can cause the death, in vitro and in vivo, of premalignant cells deficient in the adenomatous polyposis coli gene. Normal cells are unaffected. Selectively eliminating premalignant tumour cells in this way is thus an effective method for chemoprevention.

    • Ling Zhang
    • , Xiaoyang Ren
    •  & Xiangwei Wu
  • 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
  • Letter |

    In a mouse model of prostate cancer it is shown that infiltrating B cells promote tumorigenesis by secreting lymphotoxin. Lymphotoxin accelerates the emergence of castration-resistant prostate tumours in this model. Interfering with this pathway may offer therapeutic strategies for androgen-independent prostate cancer.

    • Massimo Ammirante
    • , Jun-Li Luo
    •  & Michael Karin
  • Letter |

    Severe trauma can lead to death and sepsis in the absence of apparent infection. Here evidence shows that mitochondrial debris, released from damaged cells, is present in the circulation of seriously injured trauma patients. Such debris is shown to activate neutrophils via specific formyl peptide receptors, triggering systemic inflammation and end organ injury.

    • Qin Zhang
    • , Mustafa Raoof
    •  & Carl J. Hauser
  • Article |

    Mutations near the ORMDL3 gene have been associated with childhood asthma. Here, in yeast, Orm proteins are shown to function in sphingolipid homeostasis; alterations in this control result in misregulation of sphingolipid production and accumulation of toxic metabolites. This raises the testable hypothesis that misregulation of sphingolipids may directly contribute to the development of asthma.

    • David K. Breslow
    • , Sean R. Collins
    •  & Jonathan S. Weissman
  • Letter |

    Peptide hormones such as oxytocin and vasopressin influence social behaviour in several mammalian species. Here it is shown that a population of interneurons in the rat olfactory bulb releases vasopressin, and that vasopressin signalling is required in the olfactory system for proper social recognition in rats. Although vasopressin may not work in exactly the same way in humans, social recognition mediated by experience-dependent vasopressin release may be common.

    • Vicky A. Tobin
    • , Hirofumi Hashimoto
    •  & Mike Ludwig
  • Letter |

    Worldwide, 170 million people are infected with the hepatitis C virus, which is a significant cause of liver-related illnesses and deaths. Standard treatment combines pegylated interferon alpha and ribavirin (RBV), but has some negative effects, notably RBV-induced haemolytic anaemia. Here, a genome-wide study shows that a deficiency in the enzyme inosine triphosphatase protects against haemolytic anaemia in patients receiving RBV.

    • Jacques Fellay
    • , Alexander J. Thompson
    •  & David B. Goldstein
  • Letter |

    Genomic instability has been implicated in tumour development. Here, a new mouse model of Kras-driven lung tumours has been developed, in which genomic instability is caused by overexpression of the mitotic checkpoint protein Mad2. In this model, inhibiting Kras leads to tumour regression, as shown previously. But tumours recur at a much higher rate.

    • Rocio Sotillo
    • , Juan-Manuel Schvartzman
    •  & Robert Benezra
  • Letter |

    Sequence variations in a 58-kilobase interval on human chromosome 9p21 have been associated with an increased risk of coronary artery disease. However, this interval contains no protein-coding genes and the mechanism underlying the increased risk has been unclear. Here, the corresponding interval has been deleted from mouse chromosome 4, revealing that this part of the chromosome regulates the cardiac expression of two nearby genes, Cdkn2a and Cdkn2b, and the proliferation dynamics of vascular cells.

    • Axel Visel
    • , Yiwen Zhu
    •  & Len A. Pennacchio
  • Article |

    One way of discovering genes with key roles in cancer development is to identify genomic regions that are frequently altered in human cancers. Here, high-resolution analyses of somatic copy-number alterations (SCNAs) in numerous cancer specimens provide an overview of regions of focal SCNA that are altered at significant frequency across several cancer types. An oncogenic function is also found for the anti-apoptosis genes MCL1 and BCL2L1, which reside in amplified genome regions in many cancers.

    • Rameen Beroukhim
    • , Craig H. Mermel
    •  & Matthew Meyerson
  • Article |

    The transcriptome of Helicobacter pylori, an important human pathogen involved in gastric ulcers and cancer, is presented. The approach establishes a model for mapping and annotating the primary transcriptomes of many living species.

    • Cynthia M. Sharma
    • , Steve Hoffmann
    •  & Jörg Vogel
  • Letter |

    Recently, numerous single nucleotide polymorphisms have been identified as being associated with obesity, but these loci together account for only a small fraction of the known heritable component. Here, an association is reported between rare deletions of at least 593 kilobases at 16p11.2 and a highly penetrant form of obesity. The strategy used of combining study of extreme phenotypes with targeted follow-up is promising for identifying missing heritability in obesity.

    • R. G. Walters
    • , S. Jacquemont
    •  & J. S. Beckmann
  • Article |

    Insect vectors of diseases locate their animal hosts through olfaction via largely unknown molecular processes. Here the 'empty neuron' system of genetically engineered Drosophila is used to assign specific odorants to the entire repertoire of olfactory receptors of the malaria vector Anopheles gambiae. The results illuminate ecological and neurobiological differences between mosquitoes and fruitflies and provide new potential molecular targets to boost the struggle against insect–borne diseases.

    • Allison F. Carey
    • , Guirong Wang
    •  & John R. Carlson
  • Letter |

    High mutation rates in the influenza A virus facilitate the generation of viral escape mutants, rendering vaccines and drugs potentially ineffective, but targeting host cell determinants could prevent viral escape. Here, 287 human host cell genes influencing influenza A virus replication are found using a genome-wide RNA interference screen. An independent assay is then used to investigate overlap between genes necessary for different viral strains.

    • Alexander Karlas
    • , Nikolaus Machuy
    •  & Thomas F. Meyer