The stomach bacterium Helicobacter pylori is one of the most prevalent human pathogens. It has dispersed globally with its human host resulting in a distinct phylogeographic pattern that can be used to reconstruct both recent and ancient human migrations. The extant European population of H. pylori is known to be a hybrid between Asian and African bacteria, but there exist different hypotheses about when and where the hybridization took place, reflecting the complex demographic history of Europeans. Here, we present a 5,300-year-old H. pylori genome from a European Copper Age glacier mummy. The “Iceman” H. pylori is a nearly-pure representative of the bacterial population of Asian origin that existed in Europe prior to hybridization, suggesting the African population arrived in Europe within the last few thousand years.
Epithelial-mesenchymal transition (EMT) is a highly con- Epithelial-mesenchymal transition (EMT)1 is a cellular process whereby otherwise sessile epithelial cells undergo a shift in plasticity and acquire the ability to disseminate (1-6). Hallmarks of EMT include diminished expression of cell-cell contact and adhesion components (e.g. E-cadherin), diminished expression of cell-matrix components, decreased expression of components involved in cell polarity, elevated expression of proteins involved in cytoskeleton remodelling (e.g. vimentin), and increased expression of various matrix metalloproteinFrom the ‡Department of Biochemistry,
The Human Proteome Project was launched in September 2010 with the goal of characterizing at least one protein product from each protein-coding gene. Here we assess how much of the proteome has been detected to date via tandem mass spectrometry by analyzing PeptideAtlas, a compendium of human derived LC-MS/MS proteomics data from many laboratories around the world. All datasets are processed with a consistent set of parameters using the Trans-Proteomic Pipeline and subjected to a 1% protein FDR filter before inclusion in PeptideAtlas. Therefore, PeptideAtlas contains only high confidence protein identifications. To increase proteome coverage, we explored new comprehensive public data sources for data likely to add new proteins to the Human PeptideAtlas. We then folded these data into a Human PeptideAtlas 2012 build and mapped it to Swiss-Prot, a protein sequence database curated to contain one entry per human protein coding gene. We find that this latest PeptideAtlas build includes at least one peptide for each of ~12,500 Swiss-Prot entries, leaving ~7500 gene products yet to be confidently cataloged. We characterize these “PA-unseen” proteins in terms of tissue localization, transcript abundance, and Gene Ontology enrichment, and propose reasons for their absence from PeptideAtlas and strategies for detecting them in the future.
The autosomal recessive mouse mutation quivering (qv), which arose spontaneously in 1953, produces progressive ataxia with hind limb paralysis, deafness and tremor. Six additional spontaneous alleles, qvJ, qv2J, qv3J, qv4J, qvlnd and qvlnd2J, have been identified. Ear twitch responses (Preyer's reflex) to sound are absent in homozygous qv/qv mice, although cochlear morphology seems normal and cochlear potentials recorded at the round window are no different from those of control mice. However, responses from brainstem auditory nuclei show abnormal transmission of auditory information, indicating that, in contrast to the many known mutations causing deafness originating in the cochlea, deafness in qv is central in origin. Here we report that quivering mice carry loss-of-function mutations in the mouse beta-spectrin 4 gene (Spnb4) that cause alterations in ion channel localization in myelinated nerves; this provides a rationale for the auditory and motor neuropathies of these mice.
A low voltage-activated potassium current, IKL, is found in auditory neuron types that have low excitability and precisely preserve the temporal pattern of activity present in their presynaptic inputs. The gene Kcna1 codes for Kv1.1 potassium channel subunits, which combine in expression systems to produce channel tetramers with properties similar to those of IKL, including sensitivity to dendrotoxin (DTX). Kv1.1 is strongly expressed in neurons with IKL, including auditory neurons of the medial nucleus of the trapezoid body (MNTB). We therefore decided to investigate how the absence of Kv1.1 affected channel properties and function in MNTB neurons from mice lacking Kcna1. We used the whole cell version of the patch clamp technique to record from MNTB neurons in brainstem slices from Kcna1-null (-/-) mice and their wild-type (+/+) and heterozygous (+/-) littermates. There was an IKL in voltage-clamped -/- MNTB neurons, but it was about half the amplitude of the IKL in +/+ neurons, with otherwise similar properties. Consistent with this, -/- MNTB neurons were more excitable than their +/+ counterparts; they fired more than twice as many action potentials (APs) during current steps, and the threshold current amplitude required to generate an AP was roughly halved. +/- MNTB neurons had excitability and IKL amplitudes identical to the +/+ neurons. The IKL remaining in -/- neurons was blocked by DTX, suggesting the underlying channels contained subunits Kv1.2 and/or Kv1.6 (also DTX-sensitive). DTX increased excitability further in the already hyperexcitable -/- MNTB neurons, suggesting that -/- IKL limited excitability despite its reduced amplitude in the absence of Kv1.1 subunits.
Cdk5/p35 has been implicated in cytoskeletal protein phosphorylation in normal brain and in many human neurodegenerative disorders. Yet, mouse models of cdk5/p35 hyperactivity have not yielded corresponding changes in cytoskeletal protein phosphorylation. To elucidate the relationship between p35, cdk5, and the neuronal cytoskeleton, we deleted the p35 gene in mice having a pure C57BL/6 background. We found that p35 deficiency leads to a 38% reduction of cdk5 activity in adult brain. In addition, loss of p35 causes an anterograde redistribution of cdk5 toward peripheral neuronal processes. The unusual presence of nonphosphorylated neurofilament (NF) in aberrant axon fascicles and the relocation of tau and MAP2B from cell bodies and proximal neuronal processes to more distal sites of the neuropil in p35-/- mouse brain implicate p35 in neuronal trafficking, particularly in dynein-driven retrograde transport. In many axons of normal brain, cdk5 fails to colocalize with phosphorylated cytoskeletal protein epitopes. This observation, together with an unexpected increase of NF, tau, and MAP2B phosphoepitopes accompanying the decreased cdk5 activity in p35-/- mice, supports the idea that cdk5 does not phosphorylate cytoskeletal proteins directly. Rather, in structures where cdk5 does colocalize with phosphorylated cytoskeletal protein epitopes, it may function as a negative regulator of other proline-directed kinases that directly phosphorylate the proteins. Evidence for increased glycogen synthase kinase 3beta (GSK3beta) activity in p35-/- mice suggests that GSK3beta may be one such kinase regulated by cdk5. Our studies illustrate that p35 regulates the subcellular distribution of cdk5 and cytoskeletal proteins in neurons and that cdk5 has a hierarchical role in regulating the phosphorylation and function of cytoskeletal proteins.
A large body of evidence has shown the activation of a cohort of cell cycle regulators and the duplication of DNA in degenerating neurons of Alzheimer's disease (AD) brain. Activation of these regulators and duplication of chromosomes precede neurodegeneration and formation of neurofibrillary tangles (NFTs), one of the diagnostic lesions of AD. These findings, in combination with evidence for cell cycle regulation of amyloid precursor protein and tau, has led to the hypothesis that reentry into the cell cycle underlies AD pathogenesis. To test this hypothesis directly, we have created transgenic mice with forced cell cycle activation in postmitotic neurons via conditional expression of the simian virus 40 large T antigen (TAg) oncogene. We show that TAg mice recapitulate the cell cycle changes seen in AD and display a neurodegenerative phenotype accompanied by tau pathology and NFT-like profiles. Moreover, plaque-like amyloid deposits, similar to those seen in AD, are also observed in the brains of TAg mice. These data provide support for an essential role of ectopic cell cycle activation in the generation of the characteristic pathological hallmarks of AD. Furthermore, our TAg mice are the first model to develop NFTs and amyloid pathology simultaneously and in the absence of any human transgenes. These mice will be useful for further defining the nongenetic mechanisms in AD pathogenesis and for the development of cell cycle-based therapies for AD.
Niemann-Pick type C (NPC) disease is an autosomal recessive, lethal neurodegenerative disorder. Although neurodegeneration of Purkinje cells in the mouse model (Npc1 −/− ) is thought to be autonomous, the basis of neuronal death in other regions of the brain remains elusive. We addressed this issue in vivo by using the glial fibrillary acidic protein (GFAP) promoter to direct astrocyte-specific, replacement expression of Npc1 in Npc1 −/− mice. These mice showed enhanced survival, decreased neuronal storage of cholesterol associated with less accumulation of axonal spheroids, lower numbers of degenerated neurons and reactive astrocytes and restoration of myelin tracts. Their death was not associated with the usual terminal decline in weight, but instead with a loss of Purkinje cells and motor coordination. We conclude that neurodegeneration of Npc1 −/− mice is greatly affected by the loss of fibrillary astrocyte function.
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