text:
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DOI: 10.1126/scitranslmed.3002917
, 102mr3 (2011);
3 Sci Transl Med
, et al. Martien J. Kas
Between Mouse and Man
Translational Neuroscience of Schizophrenia: Seeking a Meeting of Minds
Editor's Summary
for schizophrenia; a summary and the conclusions are presented.
A meeting held 9 June 2011 in Helsinki, Finland, discussed the requirements for creating useful mouse models
Editor's Summary
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Translational Neuroscience of Schizophrenia:
Seeking a Meeting of Minds Between Mouse and Man
Martien J. Kas,1* René S. Kahn,2David A. Collier,3John L. Waddington,4Jesper Ekelund,5
David J. Porteous,6Klaus Schughart,7Iiris Hovatta8,9
Understanding the etiology of developmental brain disorders such as schizophrenia is critical for achieving
advances in treatment and requires new research strategies that control for individual variation in genetic
background, environmental challenges, and expression of phenotype. SYSGENET, a European systems genetics
network for the study of complex genetic human diseases with mouse genetic reference populations, brought
together in Helsinki a cross-disciplinary group of clinical and basic scientists and mouse geneticists to debate,
formulate, and prioritize a strategy for future research based on mouse models. The main conclusions of this
meeting are summarized here.
Schizophrenia is a psychotic disorder characterized by positive and neg-
ative symptoms, including reality distortion (delusions and halluci-
nations), psychomotor poverty (poverty of speech, social withdrawal,
and blunting of affect), and disorganization (inappropriate affect and
thought disorder), together with cognitive deficits; negative symptoms
and cognitive deficits are the primary determinants of poor functional
outcome. Lifetime risk for schizophrenia is about 1%, and because of
its onset in early adulthood and severity, it causes considerable disabil-
ity to patients and high socioeconomic costs to society. Schizophrenia
is a complex disease influenced by both genetic and environmental fac-
tors, with heritability estimated at about 80%. In recent years, several
susceptibility genes have been identified in human cohorts, leading to
new insights into pathogenetic mechanisms of this neurodevelopmen-
tal disorder (1–3). However, current medications for schizophrenia are
only partially effective; for example, although they reduce psychotic
symptoms, current drugs are minimally effective in improving cogni-
tion (4) and induce a range of potentially life-threatening long-term
side effects. Therefore, there is a need for better treatment practices
for schizophrenia that target positive and negative symptoms and im-
prove cognitive deficits. Increased understanding of the neurobiological
mechanisms underlying schizophrenia should facilitate this task.
Merging knowledge from genetics, genomics, epidemiology, phys-
iology, and pharmacology, including both preclinical and clinical
studies, is needed to resolve core aspects of schizophrenia. In this
regard, studies using animal models can contribute considerably to
a better understanding of the biological processes that underlie dis-
ease risk and development. Experimental animal models will also be
required for the development of new, etiology-directed medication.
The mouse is well placed to address most of these requirements, by
virtue of its advanced genetics, understanding of developmental and
behavioral biology, short generation time, and low cost (5). In par-
ticular, the effects of targeted, experimental, and natural genetic var-
iations and their phenotypic consequences can be studied in mouse
populations or in genetically engineered lines, such as mouse gene
knockout lines (6, 7). However, to provide real insight and to be of
meaningful translational value, it is first essential to identify the core
biological phenotypes and mechanisms that underpin schizophrenia.
This challenge was the focus of the targeted workshop of SYSGENET
on cross-species studies of schizophrenia.
Compromised function of the nervous system in schizophrenia is ev-
ident, on a population basis, as early as the first year of life when pa-
tients show slightly delayed developmental milestones such as walking
(8). Manifestations become more evident during early adolescence
(ages 11 to 16 years) and are characterized by cognitive decline and
social withdrawal. During late adolescence/young adulthood (16 to
25 years), the first symptoms of psychosis appear, most typically hal-
lucinations and delusions. Thus, the first material signs of the illness
are not the more obvious psychotic symptoms but, rather, the slow
but steady decline in cognitive functioning that precedes the onset of
psychosis by an average of 9 years (9, 10) and may continue to pro-
gress thereafter (11). Indeed, cognitive dysfunction constitutes not
only one of the core features of the illness (10) but also one of the
most intractable to treat (4). Although the words "dementia praecox,"
as Kraepelin named the disease he delineated in 1895, may not carry
a hopeful message, the "dementia," that is, the cognitive decline, re-
flects a core process in the illness we currently call schizophrenia.
Not only does cognition worsen during the early course of schizo-
phrenia, there is accompanying loss of cerebral gray matter in excess
of what is seen with normal aging. Brain imaging studies in healthy
humans have revealed that the developing and aging human brain
1Department of Neuroscience and Pharmacology, University Medical Center Utrecht,
3584CG Utrecht, Netherlands.2Department of Psychiatry, Rudolf Magnus Institute of
Neuroscience, University Medical Center Utrecht, 3584CX Utrecht, Netherlands.3Social
Genetic and Developmental Psychiatry Centre, Kings College London, Institute of
Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.4Molecular and
Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.5Depart-
ment of Psychiatry, University of Helsinki, Vaasa Hospital District and Mental Health
and Substance Abuse Services, National Institute of Health and Welfare, 00251 Helsinki,
Finland.6Medical Genetics Section, University of Edinburgh Centre for Molecular Medicine,
Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road,
Edinburgh EH4 2XU, UK.7Department of Infection Genetics, Helmholtz Centre for In-
fection Research and University of Veterinary Medicine Hannover, 38124 Braunschweig,
Germany.8Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki and
Haartman Institute, Department of Medical Genetics, University of Helsinki, 00290 Helsinki,
Finland.9Mental Health and Substance Abuse Services, National Institute for Health and
Welfare, 00300 Helsinki, Finland.
*To whom correspondence should be addressed. E-mail: email@example.com
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undergoes dynamic changes in volume over time. Specifically, abso-
lute brain volume increases up to early puberty and, thereafter, de-
clines before the age of 20 (11). Then, there is a short episode with
slight growth followed by a decline, until a stable brain volume is
achieved around the ages of 25 to 40 years. In contrast, at illness onset,
brain volume in schizophrenic patients is already reduced relative to
matched healthy controls; subsequently, such patients exhibit an ac-
celerated decrease in brain volume, especially in frontal and temporal
cortical brain areas (11). This progressive reduction in cortical volume
in schizophrenia can occur independent of medication (12), is herita-
ble (13), and is correlated with poor prognosis and psychosis severity
(14). Cannabis use, the strongest known environmental risk factor for
schizophrenia identified thus far, worsens gray matter brain volume
loss in schizophrenia (15, 16).
A recent study aimed to reduce phenotypic heterogeneity in a large
sample of psychosis patients, their relatives, and community controls
by using latent class analysis to analyze variation in Comprehensive
Assessment of Symptoms and History (CASH) lifetime-rated symp-
toms (17). This study revealed that variation in five continuous di-
mensions (disorganization, positive, negative, mania, and depression)
was accounted for by the presence of seven homogeneous classes
(Kraepelinian schizophrenia, affective psychosis, manic depression,
deficit nonpsychosis, depression, healthy, and no symptoms). This
analysis showed that almost all (85%) of these schizophrenic patients
were assigned to the Kraepelinian schizophrenia class, whereas the
remaining patients were assigned to the affective psychosis class. Analy-
ses of symptom variation revealed that the difference between schizo-
phrenia and affective psychosis within the patient sample is based on
the distinction between low and high levels of disorganization and
negative symptoms, rather than on the level of positive, psychotic
symptoms. Levels of disorganization and negative symptoms are also
associated with diminished cognitive performance and poor outcome,
suggesting that these may be relevant dimensions to model in mice.
Together, these findings indicate that schizophrenia is a complex
neurodevelopmental disease of cognitive decline associated with pro-
gressive brain loss, negative symptoms, and the emergence of psychotic
symptoms that lead to diagnosis. The presence of measurable physio-
logical parameters should make it possible to study well-defined pheno-
types in mouse populations and mutants and to determine the genetic
basis for premature, disease-related brain loss.
Although the heritability of schizophrenia is high, at about 80% (18), it
has been challenging to identify predisposing variants for schizo-
phrenia in humans. Early studies using linkage mapping, cytogenetic
analysis, and candidate gene studies identified several putative suscep-
tibility genes, including the dopamine receptor 2 (DRD2), neuregulin 1
(NRG1) (19), dysbindin (DTNBP1) (20), and disrupted in schizo-
phrenia 1 (DISC1) (21).The recent common variant–common disease
hypothesis has stimulated a number of genome-wide association studies
(GWAS) and resulted in the identification of variants with weaker
effects, including ZNF804A (22). Several international consortia, in-
cluding SGENE, the ISC (International Schizophrenia Consortium),
and the MGS (Molecular Genetics of Schizophrenia Collaboration),
detected their strongest association signals in the major histocom-
patibility complex (MHC) region, which seem to come from two par-
tially independent signals: one in the large histone gene cluster on
chromosome 6, near the MHC class I region, and another one near
the NOTCH4 gene, which also tags classical human leukocyte antigen
(HLA) alleles DRB1 and HLA-B (23–25). They also identified other
loci, including TCF4 and Neurogranin (23). Follow-up analyses, includ-
ing studies by the Psychiatric Genetics Consortium, and other groups
(26, 27) are gradually identifying further GWAS-significant loci.
Several rare, de novo copy number variants (CNVs) have also been
recently associated with schizophrenia, including deletions at 15q13.3,
1q21.1, neurexin (28), and 17p12 (29) and duplications at 16p11.2,
16p13.1 (30, 31), and VIPR2 (32–34). CNVs at some of these loci as-
sociate also with other phenotypes, including bipolar disorder, autism
spectrum disorders [for example, (29)], cardiovascular diseases such as
aortic dissection and teratology of Fallot (35), and obesity (36); these
findings have important implications with regard to potential DNA
diagnostics, understanding disease etiology across disorders, and treat-
ment development. Even though important disease pathways are be-
ginning to emerge, more than 90% of the heritability of schizophrenia
remains to be explained and larger samples and sequencing-based
approaches are expected to shed light on this issue. It is interesting
that the occurrence of de novo CNVs and recent rare point mutations
may explain why psychiatric diseases with a reduced fecundity, such
as schizophrenia and autism, remain common in the human popula-
tion (37).
The contribution, not only of common risk variants but also of deleted
or duplicated de novo CNV regions in schizophrenia, suggests that
transgenic animals, such as knockouts or knock-ins for these specific
gene regions, may allow determination of genetic causality for schizo-
phrenia. Most mutants studied thus far do not model schizophrenia
per se; rather, they assess the functional roles of genes associated with
risk for schizophrenia (for example, DISC1, DTNBP1, and NRG1) or
putative endophenotypes (for example, Comt deletion in relation to
cognitive phenotypes). Furthermore, studying the "mental health" of
mice is challenging. There may be an unappreciated role for etholog-
ical, species-specific behaviors that become apparent in more natural-
istic settings, including components of the mouse ethogram such as
nest building. Current approaches (38, 39) have more commonly in-
volved trans-species models of positive symptoms (for example, pre-
pulse inhibition), negative symptoms (for example, social behavior),
and cognitive dysfunction (for example, working memory). In the case
of N-ethyl-N-nitrosourea–induced, amino acid substitution Disc1
mouse models, the behavioral phenotypes and pharmacological rescue
are allele-dependent (40). Certain features of schizophrenia, such as
poverty of speech, may be uniquely human. However, anhedonia,
asociality, and avolition are at least theoretically accessible in both hu-
mans and animals and can be studied in relation to genetic risk factors
for schizophrenia (41). For example, Nrg1 mutant mice have selective
disruption of the normal preference for social novelty (42). However,
the uncertainty regarding the clinical concept of schizophrenia means
that the predictive validity for such mutant phenotypes and their
pathobiology is similarly uncertain. Studies with cross-sectional mag-
netic resonance imaging have shown that, in contrast to patients with
schizophrenia, Nrg1 mutant mice have slightly smaller total ventricu-
lar volume and cerebellum when compared to wild-type controls (43).
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Gene × environment (G × E) interactions are evident in mice; for
example, interactions (i) between maternal immune activation and
Nrg1 mutation, (ii) between adolescent social defeat and Nrg1 muta-
tion, and (iii) between adolescent cannabis exposure and Comt mu-
tation regulate subsequent mouse phenotypes such as social behavior
and working memory in young adulthood (44). Such studies suggest
that, in patients, the overall psychosis phenotype may be influenced by
the interaction of risk genes with both biological and psychosocial
environmental adversities operating at critical time points during de-
velopment, but the applicability of these results from mice to patients
is still uncertain.
Genetic information has the potential to aid clinicians in risk predic-
tion and diagnostics. Both of these approaches are routinely carried
out for monogenic diseases. Certain rare genomic lesions have high
predictive value for schizophrenia, such as the t(1;11) disruption of
DISC1 (45), or the velocardiofacial syndrome (VCSF) deletion locus
on chromosome 22q11 (46). Unfortunately, GWAS of schizophrenia
published to date have generated low values for the relative risk
provided by the identified risk alleles. For example, the International
Schizophrenia Consortium (ISC) reported odds ratios of around 1.2
for their most important findings, with the risk-conferring allele being
very prevalent, around 80 to 90% in most cases (25). Translated into a
predictive test, this has very low specificity and no clinical utility. Com-
bining genetic risk factors to create a genetic risk score has been at-
tempted for other complex phenotypes, leading both to negative results
for height (47) and cardiovascular traits (48) and to statistically signif-
icant but not clinically applicable for type 2 diabetes (49) and coronary
heart disease (50). The current genetic findings do not allow clinically
relevant tests to be performed, but such tests may be possible when the
genetic landscape of schizophrenia becomes better characterized.
Nevertheless, clinical studies in schizophrenia can inform selection
of the most relevant phenotypes for studies in mice. When construct-
ing a mouse to model aspects of schizophrenia, it is important to dis-
tinguish whether one seeks to model a rare, severe trait, potentially
with quantitative endophenotypes, or a trait that is present quantita-
tively in the human population. Traditionally, a stress-diathesis model
has prevailed. This model views disease state as dichotomous but the
underlying risk phenotypes as quantitative. There is also evidence to
suggest that the actual phenotype of psychosis is common and quan-
titatively distributed in the population, with no point of rarity. First,
more than 3% of individuals have a diagnosed psychotic disorder (51).
Moreover, brief auditory illusions when falling asleep/waking up are
common and normal; many widowed persons have sensory impres-
sions of their loved ones; experimental sleep deprivation and sensory
deprivation can cause hallucinations in experimental settings. When
susceptibility to psychosis in the population is assessed by a question-
naire (the Perceptual Aberration Scale), less than half of individuals
report no psychotic-like experiences and the number of psychotic-like
experiences in the population follows a Poisson distribution, with no
point of rarity (52). These findings do not support a dichotomous view
of psychosis in itself. The research community seems divided on this
dichotomous/continuous debate, and whichever eventually turns out
to be true, it is something to keep in mind when constructing mouse
models for this disorder.
Another important issue to consider is which human phenotypes
can be modeled in the mouse and which are human-specific (53). Re-
cent cognitive neuropsychiatric models of psychosis emphasize the
role of attention disturbances and inappropriate incentive learning
in the development of disturbances of thought, such as delusions. It
is clear that more proximal phenotypes, such as sensory gating ab-
normalities, would be a better choice for modeling in mouse than
human-specific, distal phenotypes like delusions of reference. The
most critical question is where on this proximal-distal scale to put
traits such as disruption to social behavior and brain imaging abnor-
malities. These considerations suggest that the phenotypes to be
modeled in the mouse should be a reliably detectable, physiological
measure of proximal processes in the etiological chain of events in
This overview of our current knowledge of the neurobiology of schizo-
phrenia signals an urgent need for animal models that also take into
account the genetic complexity of the small effect size genetic variants
that contribute to the development of core features of the disease. One
main conclusion from this workshop was that schizophrenia is a com-
plex neurodevelopmental disease associated with early, progressive
cognitive decline in association with accelerated reduction in brain
volume of cortical areas and, possibly, the cerebellum. Manifestation
of the diagnostic symptoms of psychosis during late adolescence may
result from the effects of moderate- to high-risk mutations such as
CNVs in some individuals and interaction of a large number of low-
risk polymorphisms with several environmental adversities at critical
time points during development. Future studies should aim at devel-
oping specific, standardized phenotypes to be measured longitudinally,
including cortical thickness and other structural phenotypes, cognitive
phenotypes, prepulse inhibition, sociability/social novelty prefer-
ence, and habituation of exploratory behavior in a novel environment.
These phenotypes will need to be assessed in standardized contexts of
G × G and G × E interaction and measured longitudinally to address
both multifactorial and progressive aspects such as reduction in brain
volume and cognitive decline. Here, mouse model systems will be of
great value.
Targeted therapies for schizophrenia are desperately needed, but their
development and effective use require understanding the molecular
mechanisms involved in the etiology of schizophrenia. Genetics offer
an ideal route to the molecular basis of schizophrenia, as any identified
genes can potentially be linked to their functions from the cellular to
the behavioral level. Mouse models can be very informative both in
the identification of susceptibility genes and in understanding their
biological function (5, 38). In addition to revealing the function of
the gene in a defined genetic background (39), single gene knockout
mouse models of candidate genes for schizophrenia allow studies of
G × E interactions (44). Furthermore, the same mice can be used in
detailed analysis of gene expression, proteomic, and neuronal phe-
notypes both in the intact brain and in cellular models to provide
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additional tools for drug development and testing (for example, with
approaches such as connectivity mapping) (54). Some of these models,
such as those that exhibit positive symptoms, can be validated with
existing drugs for schizophrenia to provide some predictive validity
(40). However, others, such as those with negative symptoms and cog-
nitive dysfunction, which respond poorly even to clozapine, cannot be
validated in this way (53).
On the other hand, clinically relevant mouse models of schizo-
phrenia will complement human genetic efforts to identify small effect
susceptibility variants, because human GWAS fail to capture more
than a modest fraction of the measured heritability (55). Quantitative
trait locus (QTL) mapping with mice has been used to identify sus-
ceptibility genes for endophenotypes of schizophrenia, including ven-
tricular size (56) and prepulse inhibition (57–60) in F2animals and
chromosome substitution strains. However, the relatively small num-
ber of highly polymorphic alleles in these strains might not be optimal
in identifying genes for complex diseases such as schizophrenia.
At the core of the SYSGENET network (http://www.helmholtz-hzi.
de/sysgenet/) is the use of mouse genetic reference populations (GRPs).
An important new GRP that will soon become available is the Collab-
orative Cross (CC), comprising a large panel of recombinant inbred
(RI) strains derived from a genetically diverse set of eight founder
strains and designed specifically for complex trait analysis (61, 62).
The CC population also includes wild derived mouse strains and thus
represents a greater degree of genetic variation than do currently avail-
able GRPs. This resource should offer larger phenotypic and behavioral
variations that are relevant to schizophrenia and other neurodevelop-
mental and behavioral disorders. GRPs also have the intrinsic advan-
tages of access to brain tissue at any chosen developmental time point,
before or after behavioral testing and/or environmental or pharmaco-
logical intervention. Polymorphisms within susceptibility genes may
lead to differences in gene function or expression; these differences
can be studied with gene expression, proteomic, and metabolomic
analyses, allowing identification of gene regulatory networks perturbed
in schizophrenia. Therefore, the set of clinically relevant phenotypes
discussed above should be measured in the CC population. Longitu-
dinal quantitative measurements of brain morphology (for example,
cortical thickness), sensory processing, and behavioral phenotypes
(for example, social behavior) in GRPs will allow the systematic
modeling of clinically relevant phenotypes of schizophrenia at differ-
ent developmental stages and under controlled genetic and environ-
mental conditions (Table 1).
All participants of the meeting concluded that there is a real oppor-
tunity and need for knowledge exchange between preclinical and clin-
ical researchers to better understand the etiology of schizophrenia and
related developmental brain disorders. The laboratory mouse can play
a vital role in constructing and testing hypotheses of direct transla-
tional relevance. The CC will provide an important complement to
the established armamentariumofmouse genetic techniquesand tools.
1. A. Buonanno, The neuregulin signaling pathway and schizophrenia: From genes to
synapses and neural circuits. Brain Res. Bull. 83, 122–131 (2010).
2. M. Johnstone, P. A. Thomson, J. Hall, A. M. McIntosh, S. M. Lawrie, D. J. Porteous, DISC1 in
schizophrenia: Genetic mouse models and human genomic imaging. Schizophr. Bull. 37,
14–20 (2011).
3. M. Kvajo, H. McKellar, J. A. Gogos, Molecules, signaling, and schizophrenia. Curr. Top.
Behav. Neurosci. 4, 629–656 (2010).
4. M. Davidson, S. Galderisi, M. Weiser, N. Werbeloff, W. W. Fleischhacker, R. S. Keefe, H. Boter,
I. P. Keet, D. Prelipceanu, J. K. Rybakowski, J. Libiger, M. Hummer, S. Dollfus, J. J. López-Ibor,
L. G. Hranov, W. Gaebel, J. Peuskens, N. Lindefors, A. Riecher-Rössler, R. S. Kahn, Cognitive
effects of antipsychotic drugs in first-episode schizophrenia and schizophreniform
disorder: A randomized, open-label clinical trial (EUFEST). Am. J. Psychiatry 166, 675–682
5. M. J. Kas, V. Krishnan, T. D. Gould, D. A. Collier, B. Olivier, K. P. Lesch, E. Domenici, E. Fuchs,
C. Gross, E. Castrén, Advances in multidisciplinary and cross-species approaches to examine
the neurobiology of psychiatric disorders. Eur. Neuropsychopharmacol. 21, 532–544 (2011).
6. M. J. Kas, C. Gelegen, L. C. Schalkwyk, D. A. Collier, Interspecies comparisons of func-
tional genetic variations and their implications in neuropsychiatry. Am. J. Med. Genet. B
Neuropsychiatr. Genet. 150B, 309–317 (2009).
7. M. J. Kas, C. Fernandes, L. C. Schalkwyk, D. A. Collier, Genetics of behavioural domains
across the neuropsychiatric spectrum; of mice and men. Mol. Psychiatry 12, 324–330 (2007).
8. J. van Os, S. Kapur, Schizophrenia. Lancet 374, 635–645 (2009).
9. C. J. van Oel, M. M. Sitskoorn, M. P. Cremer, R. S. Kahn, School performance as a premorbid
marker for schizophrenia: A twin study. Schizophr. Bull. 28, 401–414 (2002).
10. A. Reichenberg, A. Caspi, H. Harrington, R. Houts, R. S. Keefe, R. M. Murray, R. Poulton,
T. E. Moffitt, Static and dynamic cognitive deficits in childhood preceding adult
schizophrenia: A 30-year study. Am. J. Psychiatry 167, 160–169 (2010).
11. A. M. Hedman, N. E. van Haren, H. G. Schnack, R. S. Kahn, H. E. Hulshoff Pol, Human brain
changes across the life span: A review of 56 longitudinal magnetic resonance imaging
studies. Hum. Brain Mapp. 10.1002/hbm.21334 (2011).
12. T. B. Ziermans, P. F. Schothorst, H. G. Schnack, P. C. Koolschijn, R. S. Kahn, H. van Engeland,
S. Durston, Progressive structural brain changes during development of psychosis.
Schizophr. Bull. 10.1093/schbul/sbq113 (2010).
13. R. G. Brans, N. E. van Haren, G. C. van Baal, H. G. Schnack, R. S. Kahn, H. E. Hulshoff Pol,
Heritability of changes in brain volume over time in twin pairs discordant for schizophrenia.
Arch. Gen. Psychiatry 65, 1259–1268 (2008).
14. H. E. Hulshoff Pol, R. S. Kahn, What happens after the first episode? A review of progressive
brain changes in chronically ill patients with schizophrenia. Schizophr. Bull. 34, 354–366
15. M. Rais, N. E. van Haren, W. Cahn, H. G. Schnack, C. Lepage, L. Collins, A. C. Evans,
H. E. Hulshoff Pol, R. S. Kahn, Cannabis use and progressive cortical thickness loss in areas
rich in CB1 receptors during the first five years of schizophrenia. Eur. Neuropsychopharmacol.
20, 855–865 (2010).
16. M. Rais, W. Cahn, N. Van Haren, H. Schnack, E. Caspers, H. Hulshoff Pol, R. Kahn, Excessive
brain volume loss over time in cannabis-using first-episode schizophrenia patients.
Am. J. Psychiatry 165, 490–496 (2008).
17. E. M. Derks, J. Allardyce, M. P. Boks, J. K. Vermunt, R. Hijman, R. A. Ophoff; GROUP, Kraepelin
was right: A latent class analysis of symptom dimensions in patients and controls.
Schizophr. Bull. 10.1093/schbul/sbq103 (2010).
Table 1. Core features of schizophrenia for mouse modeling.
Schizophrenia Mouse
Critical developmental stages Age-matched developmental stages
Disease progression Longitudinal phenotypic assessment
Environmental factorsMaternal infection/stressful
events/cannabis use
Candidate genesTargeted and "humanized" genetic models
Genetic background/epistasisCollaborative cross/crossing mutant lines
PhenotypesCognitive decline
Cortical thinning
Sensory processing (for example,
prepulse inhibition)
Social behavior
www.ScienceTranslationalMedicine.org28 September 2011Vol 3 Issue 102 102mr3
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Page 6
18. A. G. Cardno, I. I. Gottesman, Twin studies of schizophrenia: From bow-and-arrow concor-
dances to Star Wars Mx and functional genomics. Am. J. Med. Genet. 97, 12–17 (2000).
19. H. Stefansson, E. Sigurdsson, V. Steinthorsdottir, S. Bjornsdottir, T. Sigmundsson, S. Ghosh,
J. Brynjolfsson, S. Gunnarsdottir, O. Ivarsson, T. T. Chou, O. Hjaltason, B. Birgisdottir,
H. Jonsson, V. G. Gudnadottir, E. Gudmundsdottir, A. Bjornsson, B. Ingvarsson, A. Ingason,
S. Sigfusson, H. Hardardottir, R. P. Harvey, D. Lai, M. Zhou, D. Brunner, V. Mutel, A. Gonzalo,
G. Lemke, J. Sainz, G. Johannesson, T. Andresson, D. Gudbjartsson, A. Manolescu, M. L. Frigge,
M. E. Gurney, A. Kong, J.R. Gulcher, H. Petursson, K. Stefansson, Neuregulin 1 and susceptibility
to schizophrenia. Am. J. Hum. Genet. 71, 877–892 (2002).
20. R. E. Straub, Y. Jiang, C. J. MacLean, Y. Ma, B. T. Webb, M. V. Myakishev, C. Harris-Kerr,
B. Wormley, H. Sadek, B. Kadambi, A. J. Cesare, A. Gibberman, X. Wang, F. A. O'Neill,
D. Walsh, K. S. Kendler, Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog
of the mouse dysbindin gene, is associated with schizophrenia. Am. J. Hum. Genet. 71,
337–348 (2002).
21. J. K. Millar, J. C. Wilson-Annan, S. Anderson, S. Christie, M. S. Taylor, C. A. Semple,
R. S. Devon, D. M. St Clair, W. J. Muir, D. H. Blackwood, D. J. Porteous, Disruption of two
novel genes by a translocation co-segregating with schizophrenia. Hum. Mol. Genet. 9,
1415–1423 (2000).
22. M. C. O'Donovan, N. Craddock, N. Norton, H. Williams, T. Peirce, V. Moskvina, I. Nikolov,
M. Hamshere, L. Carroll, L. Georgieva, S. Dwyer, P. Holmans, J. L. Marchini, C. C. Spencer,
B. Howie, H. T. Leung, A. M. Hartmann, H. J. Möller, D. W. Morris, Y. Shi, G. Feng,
P. Hoffmann, P. Propping, C. Vasilescu, W. Maier, M. Rietschel, S. Zammit, J. Schumacher,
E. M. Quinn, T. G. Schulze, N. M. Williams, I. Giegling, N. Iwata, M. Ikeda, A. Darvasi,
S. Shifman, L. He, J. Duan, A. R. Sanders, D. F. Levinson, P. V. Gejman, S. Cichon,
M. M. Nöthen, M. Gill, A. Corvin, D. Rujescu, G. Kirov, M. J. Owen, N. G. Buccola,
B. J. Mowry, R. Freedman, F. Amin, D. W. Black, J. M. Silverman, W. F. Byerley,
C. R. Cloninger; Molecular Genetics of Schizophrenia Collaboration, Identification of
loci associated with schizophrenia by genome-wide association and follow-up.
Nat. Genet. 40, 1053–1055 (2008).
23. H. Stefansson, R. A. Ophoff, S. Steinberg, O. A. Andreassen, S. Cichon, D. Rujescu, T. Werge,
O. P. Pietiläinen, O. Mors, P. B. Mortensen, E. Sigurdsson, O. Gustafsson, M. Nyegaard,
A. Tuulio-Henriksson, A. Ingason, T. Hansen, J. Suvisaari, J. Lonnqvist, T. Paunio, A. D. Børglum,
A. Hartmann, A. Fink-Jensen, M. Nordentoft, D. Hougaard, B. Norgaard-Pedersen, Y. Böttcher,
J. Olesen, R. Breuer, H. J. Möller, I. Giegling, H. B. Rasmussen, S. Timm, M. Mattheisen, I. Bitter,
J. M. Réthelyi, B. B. Magnusdottir, T. Sigmundsson, P. Olason, G. Masson, J. R. Gulcher,
M. Haraldsson, R. Fossdal, T. E. Thorgeirsson, U. Thorsteinsdottir, M. Ruggeri, S. Tosato,
B. Franke, E. Strengman, L. A. Kiemeney; Genetic Risk and Outcome in Psychosis
(GROUP), I. Melle, S. Djurovic, L. Abramova, V. Kaleda, J. Sanjuan, R. de Frutos, E. Bramon,
E. Vassos, G. Fraser, U. Ettinger, M. Picchioni, N. Walker, T. Toulopoulou, A. C. Need, D. Ge,
J. L. Yoon, K. V. Shianna, N. B. Freimer, R. M. Cantor, R. Murray, A. Kong, V. Golimbet,
A. Carracedo, C. Arango, J. Costas, E. G. Jönsson, L. Terenius, I. Agartz, H. Petursson,
M. M. Nöthen, M. Rietschel, P. M. Matthews, P. Muglia, L. Peltonen, D. St Clair, D. B. Goldstein,
K. Stefansson, D. A. Collier, Common variants conferring risk of schizophrenia. Nature
460, 744–747 (2009).
24. J. Shi, D. F. Levinson, J. Duan, A. R. Sanders, Y. Zheng, I. Pe'er, F. Dudbridge, P. A. Holmans,
A. S. Whittemore, B. J. Mowry, A. Olincy, F. Amin, C. R. Cloninger, J. M. Silverman, N. G. Buccola,
W. F. Byerley, D. W. Black, R. R. Crowe, J. R. Oksenberg, D. B. Mirel, K. S. Kendler, R. Freedman,
P. V. Gejman, Common variants on chromosome 6p22.1 are associated with schizophrenia.
Nature 460, 753–757 (2009).
25. International Schizophrenia Consortium, S. M. Purcell, N. R. Wray, J. L. Stone, P. M. Visscher,
M. C. O'Donovan, P. F. Sullivan, P. Sklar, Common polygenic variation contributes to risk of
schizophrenia and bipolar disorder. Nature 460, 748–752 (2009).
26. T. Hansen, A. Ingason, S. Djurovic, I. Melle, M. Fenger, O. Gustafsson, K. D. Jakobsen,
H. B. Rasmussen, S. Tosato, M. Rietschel, J. Frank, M. Owen, C. Bonetto, J. Suvisaari,
J. H. Thygesen, H. Pétursson, J. Lönnqvist, E. Sigurdsson, I. Giegling, N. Craddock,
M. C. O'Donovan, M. Ruggeri, S. Cichon, R. A. Ophoff, O. Pietiläinen, L. Peltonen,
M. M. Nöthen, D. Rujescu, D. St Clair, D. A. Collier, O. A. Andreassen, T. Werge, At-risk
variant in TCF7L2 for type II diabetes increases risk of schizophrenia. Biol. Psychiatry
70, 59–63 (2011).
27. A. Ingason, I. Giegling, S. Cichon, T. Hansen, H. B. Rasmussen, J. Nielsen, G. Jürgens,
P. Muglia, A. M. Hartmann, E. Strengman, C. Vasilescu, T. W. Mühleisen, S. Djurovic,
I. Melle, B. Lerer, H. J. Möller, C. Francks, O. P. Pietiläinen, J. Lonnqvist, J. Suvisaari,
A. Tuulio-Henriksson, M. Walshe, E. Vassos, M. Di Forti, R. Murray, C. Bonetto, S. Tosato;
GROUP Investigators, R. M. Cantor, M. Rietschel, N. Craddock, M. J. Owen, L. Peltonen,
O. A. Andreassen, M. M. Nöthen, D. St Clair, R. A. Ophoff, M. C. O'Donovan, D. A. Collier,
T. Werge, D. Rujescu, A large replication study and meta-analysis in European samples
provides further support for association of AHI1 markers with schizophrenia. Hum. Mol.
Genet. 19, 1379–1386 (2010).
28. D. Rujescu, A. Ingason, S. Cichon, O. P. Pietiläinen, M. R. Barnes, T. Toulopoulou, M. Picchioni,
E. Vassos, U. Ettinger, E. Bramon, R. Murray, M. Ruggeri, S. Tosato, C. Bonetto, S. Steinberg,
E. Sigurdsson, T. Sigmundsson, H. Petursson, A. Gylfason, P. I. Olason, G. Hardarsson,
G. A. Jonsdottir, O. Gustafsson, R. Fossdal, I. Giegling, H. J. Möller, A. M. Hartmann,
P. Hoffmann, C. Crombie, G. Fraser, N. Walker, J. Lonnqvist, J. Suvisaari, A. Tuulio-Henriksson,
S. Djurovic, I. Melle, O. A. Andreassen, T. Hansen, T. Werge, L. A. Kiemeney, B. Franke,
J. Veltman, J. E. Buizer-Voskamp; GROUP Investigators, C. Sabatti, R. A. Ophoff, M. Rietschel,
M. M. Nöthen, K. Stefansson, L. Peltonen, D. St Clair, H. Stefansson, D. A. Collier, Disruption of
the neurexin 1 gene is associated with schizophrenia. Hum. Mol. Genet. 18, 988–996 (2009).
29. D. Moreno-De-Luca; SGENE Consortium, J. G. Mulle; Simons Simplex Collection Genetics
Consortium, E. B. Kaminsky, S. J. Sanders; GeneSTAR, S. M. Myers, M. P. Adam, A. T. Pakula,
N. J. Eisenhauer, K. Uhas, L. Weik, L. Guy, M. E. Care, C. F. Morel, C. Boni, B. A. Salbert,
A. Chandrareddy, L. A. Demmer, E. W. Chow, U. Surti, S. Aradhya, D. L. Pickering,
D. M. Golden, W. G. Sanger, E. Aston, A. R. Brothman, T. J. Gliem, E. C. Thorland, T. Ackley,
R. Iyer, S. Huang, J. C. Barber, J. A. Crolla, S. T. Warren, C. L. Martin, D. H. Ledbetter,
Deletion 17q12 is a recurrent copy number variant that confers high risk of autism
and schizophrenia. Am. J. Hum. Genet. 87, 618–630 (2010).
30. H. Stefansson, D. Rujescu, S. Cichon, O. P. Pietiläinen, A. Ingason, S. Steinberg, R. Fossdal,
E. Sigurdsson, T. Sigmundsson, J. E. Buizer-Voskamp, T. Hansen, K. D. Jakobsen, P. Muglia,
C. Francks, P. M. Matthews, A. Gylfason, B. V. Halldorsson, D. Gudbjartsson, T. E. Thorgeirsson,
A. Sigurdsson, A. Jonasdottir, A. Jonasdottir, A. Bjornsson, S. Mattiasdottir, T. Blondal,
M. Haraldsson, B. B. Magnusdottir, I. Giegling, H. J. Möller, A. Hartmann, K. V. Shianna, D. Ge,
A. C. Need, C. Crombie, G. Fraser, N. Walker, J. Lonnqvist, J. Suvisaari, A. Tuulio-Henriksson,
T. Paunio, T. Toulopoulou, E. Bramon, M. Di Forti, R. Murray, M. Ruggeri, E. Vassos, S. Tosato,
M. Walshe, T. Li, C. Vasilescu, T. W. Mühleisen, A. G. Wang, H. Ullum, S. Djurovic, I. Melle,
J. Olesen, L. A. Kiemeney, B. Franke; GROUP, C. Sabatti, N. B. Freimer, J. R. Gulcher,
U. Thorsteinsdottir, A. Kong, O. A. Andreassen, R. A. Ophoff, A. Georgi, M. Rietschel, T. Werge,
H. Petursson, D. B. Goldstein, M. M. Nöthen, L. Peltonen, D. A. Collier, D. St Clair, K. Stefansson,
Large recurrent microdeletions associated with schizophrenia. Nature 455, 232–236 (2008).
31. International Schizophrenia Consortium, Rare chromosomal deletions and duplications in-
crease risk of schizophrenia. Nature 455, 237–241 (2008).
32. S. E. McCarthy, V. Makarov, G. Kirov, A. M. Addington, J. McClellan, S. Yoon, D. O. Perkins,
D. E. Dickel, M. Kusenda, O. Krastoshevsky, V. Krause, R. A. Kumar, D. Grozeva, D. Malhotra,
T. Walsh, E. H. Zackai, P. Kaplan, J. Ganesh, I. D. Krantz, N. B. Spinner, P. Roccanova,
A. Bhandari, K. Pavon, B. Lakshmi, A. Leotta, J. Kendall, Y. H. Lee, V. Vacic, S. Gary,
L. M. Iakoucheva, T. J. Crow, S. L. Christian, J. A. Lieberman, T. S. Stroup, T. Lehtimäki,
K. Puura, C. Haldeman-Englert, J. Pearl, M. Goodell, V. L. Willour, P. Derosse, J. Steele,
L. Kassem, J. Wolff, N. Chitkara, F. J. McMahon, A. K. Malhotra, J. B. Potash, T. G. Schulze,
M. M. Nöthen, S. Cichon, M. Rietschel, E. Leibenluft, V. Kustanovich, C. M. Lajonchere,
J. S. Sutcliffe, D. Skuse, M. Gill, L. Gallagher, N. R. Mendell; Wellcome Trust Case Control
Consortium, N. Craddock, M. J. Owen, M. C. O'Donovan, T. H. Shaikh, E. Susser, L. E. Delisi,
P. F. Sullivan, C. K. Deutsch, J. Rapoport, D. L. Levy, M. C. King, J. Sebat, Microduplications
of 16p11.2 are associated with schizophrenia. Nat. Genet. 41, 1223–1227 (2009).
33. V. Vacic, S. McCarthy, D. Malhotra, F. Murray, H. H. Chou, A. Peoples, V. Makarov, S. Yoon,
A. Bhandari, R. Corominas, L. M. Iakoucheva, O. Krastoshevsky, V. Krause, V. Larach-Walters,
D. K. Welsh, D. Craig, J. R. Kelsoe, E. S. Gershon, S. M. Leal, M. Dell Aquila, D. W. Morris, M. Gill,
A. Corvin, P. A. Insel, J. McClellan, M. C. King, M. Karayiorgou, D. L. Levy, L. E. DeLisi, J. Sebat,
Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for
schizophrenia. Nature 471, 499–503 (2011).
34. D. F. Levinson, J. Duan, S. Oh, K. Wang, A. R. Sanders, J. Shi, N. Zhang, B. J. Mowry, A. Olincy,
F. Amin, C. R. Cloninger, J. M. Silverman, N. G. Buccola, W. F. Byerley, D. W. Black, K. S.
Kendler, R. Freedman, F. Dudbridge, I. Pe'er, H. Hakonarson, S. E. Bergen, A. H. Fanous,
P. A. Holmans, P. V. Gejman, Copy number variants in schizophrenia: Confirmation of five
previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. Am.
J. Psychiatry 168, 302–316 (2011).
35. S. Q. Kuang, D. C. Guo, S. K. Prakash, M. L. McDonald, R. J. Johnson, M. Wang, E. S. Regalado,
L. Russell, J. M. Cao, C. Kwartler, K. Fraivillig, J. S. Coselli, H. J. Safi, A. L. Estrera, S. M. Leal,
S. A. Lemaire, J. W. Belmont, D. M. Milewicz; GenTAC Investigators, Recurrent chromosome
16p13.1 duplications are a risk factor for aortic dissections. PLoS Genet. 7, e1002118 (2011).
36. R. Bachmann-Gagescu, H. C. Mefford, C. Cowan, G. M. Glew, A. V. Hing, S. Wallace,
P. I. Bader, A. Hamati, P. J. Reitnauer, R. Smith, D. W. Stockton, H. Muhle, I. Helbig,
E. E. Eichler, B. C. Ballif, J. Rosenfeld, K. D. Tsuchiya, Recurrent 200-kb deletions of
16p11.2 that include the SH2B1 gene are associated with developmental delay and
obesity. Genet. Med. 12, 641–647 (2010).
37. R. Uher, The role of genetic variation in the causation of mental illness: An evolution-
informed framework. Mol. Psychiatry 14, 1072–1082 (2009).
38. L. Desbonnet, J. L. Waddington, C. M. O'Tuathaigh, Mice mutant for genes associated with
schizophrenia: Common phenotype or distinct endophenotypes? Behav. Brain Res. 204,
258–273 (2009).
39. B. P. Kirby, J. L. Waddington, C. M. O'Tuathaigh, Advancing a functional genomics for
schizophrenia: Psychopathological and cognitive phenotypes in mutants with gene
disruption. Brain Res. Bull. 83, 162–176 (2010).
40. S. J. Clapcote, T. V. Lipina, J. K. Millar, S. Mackie, S. Christie, F. Ogawa, J. P. Lerch, K. Trimble,
M. Uchiyama, Y. Sakuraba, H. Kaneda, T. Shiroishi, M. D. Houslay, R. M. Henkelman,
www.ScienceTranslationalMedicine.org28 September 2011Vol 3 Issue 102 102mr3
on September 28, 2011
Downloaded from
Page 7
J. G. Sled, Y. Gondo, D. J. Porteous, J. C. Roder, Behavioral phenotypes of Disc1 missense
mutations in mice. Neuron 54, 387–402 (2007).
41. C. M. O'Tuathaigh, B. P. Kirby, P. M. Moran, J. L. Waddington, Mutant mouse models:
Genotype-phenotype relationships to negative symptoms in schizophrenia. Schizophr. Bull.
36, 271–288 (2010).
42. C. M. O'Tuathaigh, D. Babovic, G. J. O'Sullivan, J. J. Clifford, O. Tighe, D. T. Croke, R. Harvey,
J. L. Waddington, Phenotypic characterization of spatial cognition and social behavior in mice
with 'knockout' of the schizophrenia risk gene neuregulin 1. Neuroscience 147, 18–27 (2007).
43. C. M. O'Tuathaigh, M. Harte, C. O'Leary, G. J. O'Sullivan, C. Blau, D. Lai, R. P. Harvey, O. Tighe,
A. J. Fagan, C. Kerskens, G. P. Reynolds, J. L. Waddington, Schizophrenia-related endopheno-
types in heterozygous neuregulin-1 'knockout' mice. Eur. J. Neurosci. 31, 349–358 (2010).
44. C. M. O'Tuathaigh, M. Hryniewiecka, A. Behan, O. Tighe, C. Coughlan, L. Desbonnet,
M. Cannon, M. Karayiorgou, J. A. Gogos, D. R. Cotter, J. L. Waddington, Chronic adolescent
exposure to D-9-tetrahydrocannabinol in COMT mutant mice: Impact on psychosis-related
and other phenotypes. Neuropsychopharmacology 35, 2262–2273 (2010).
45. D. H. Blackwood, A. Fordyce, M. T. Walker, D. M. St Clair, D. J. Porteous, W. J. Muir,
Schizophrenia and affective disorders—Cosegregation with a translocation at chromosome
1q42 that directly disrupts brain-expressed genes: Clinical and P300 findings in a family.
Am. J. Hum. Genet. 69, 428–433 (2001).
46. M. Karayiorgou, T. J. Simon, J. A. Gogos, 22q11.2 microdeletions: Linking DNA structural
variation to brain dysfunction and schizophrenia. Nat. Rev. Neurosci. 11, 402–416 (2010).
47. Y. S. Aulchenko, M. V. Struchalin, N. M. Belonogova, T. I. Axenovich, M. N. Weedon, A. Hofman,
A. G. Uitterlinden, M. Kayser, B. A. Oostra, C. M. van Duijn, A. C. Janssens, P. M. Borodin,
Predicting human height by Victorian and genomic methods. Eur. J. Hum. Genet. 17,
1070–1075 (2009).
48. N. P. Paynter, D. I. Chasman, G. Paré, J. E. Buring, N. R. Cook, J. P. Miletich, P. M. Ridker,
Association between a literature-based genetic risk score and cardiovascular events in
women. JAMA 303, 631–637 (2010).
49. Q. Lu, Y. Song, X. Wang, S. Won, Y. Cui, R. C. Elston, The effect of multiple genetic variants
in predicting the risk of type 2 diabetes. BMC Proc. 3 (Suppl. 7), S49 (2009).
50. S. Ripatti, E. Tikkanen, M. Orho-Melander, A. S. Havulinna, K. Silander, A. Sharma, C. Guiducci,
M. Perola, A. Jula, J. Sinisalo, M. L. Lokki, M. S. Nieminen, O. Melander, V. Salomaa, L. Peltonen,
S. Kathiresan, A multilocus genetic risk score for coronary heart disease: Case-control and
prospective cohort analyses. Lancet 376, 1393–1400 (2010).
51. J. Perälä, J. Suvisaari, S. I. Saarni, K. Kuoppasalmi, E. Isometsä, S. Pirkola, T. Partonen,
A. Tuulio-Henriksson, J. Hintikka, T. Kieseppä, T. Härkänen, S. Koskinen, J. Lönnqvist,
Lifetime prevalence of psychotic and bipolar I disorders in a general population.
Arch. Gen. Psychiatry 64, 19–28 (2007).
52. J. Miettunen, J. Veijola, N. Freimer, D. Lichtermann, L. Peltonen, T. Paunio, M. Isohanni,
M. Joukamaa, J. Ekelund, Data on schizotypy and affective scales are gender and
education dependent—Study in the Northern Finland 1966 Birth Cohort. Psychiatry Res.
178, 408–413 (2010).
53. C. M. O'Tuathaigh, J. L. Waddington, Mutant mouse models: Phenotypic relationships to
domains of psychopathology and pathobiology in schizophrenia. Schizophr. Bull. 36,
243–245 (2010).
54. J. Lamb, E. D. Crawford, D. Peck, J. W. Modell, I. C. Blat, M. J. Wrobel, J. Lerner, J. P. Brunet,
A. Subramanian, K. N. Ross, M. Reich, H. Hieronymus, G. Wei, S. A. Armstrong, S. J. Haggarty,
P. A. Clemons, R. Wei, S. A. Carr, E. S. Lander, T. R. Golub, The Connectivity Map: Using
gene-expression signatures to connect small molecules, genes, and disease. Science
313, 1929–1935 (2006).
55. T. A. Manolio, F. S. Collins, N. J. Cox, D. B. Goldstein, L. A. Hindorff, D. J. Hunter, M. I. McCarthy,
E. M. Ramos, L. R. Cardon, A. Chakravarti, J. H. Cho, A. E. Guttmacher, A. Kong, L. Kruglyak,
E. Mardis, C. N. Rotimi, M. Slatkin, D. Valle, A. S. Whittemore, M. Boehnke, A. G. Clark,
E. E. Eichler, G. Gibson, J. L. Haines, T. F. Mackay, S. A. McCarroll, P. M. Visscher, Finding
the missing heritability of complex diseases. Nature 461, 747–753 (2009).
56. C. C. Zygourakis, G. D. Rosen, Quantitative trait loci modulate ventricular size in the mouse
brain. J. Comp. Neurol. 461, 362–369 (2003).
57. M. P. Leussis, M. L. Frayne, M. Saito, E. M. Berry, K. A. Aldinger, G. N. Rockwell, R. P. Hammer Jr.,
A. E. Baskin-Hill, J. B. Singer, J. H. Nadeau, P. Sklar, T. L. Petryshen, Genomic survey of
prepulse inhibition in mouse chromosome substitution strains. Genes Brain Behav. 8,
806–816 (2009).
58. T. L. Petryshen, A. Kirby, R. P. Hammer Jr., S. Purcell, S. B. O'Leary, J. B. Singer, A. E. Hill,
J. H. Nadeau, M. J. Daly, P. Sklar, Two quantitative trait loci for prepulse inhibition of
startle identified on mouse chromosome 16 using chromosome substitution strains.
Genetics 171, 1895–1904 (2005).
59. A. Watanabe, T. Toyota, Y. Owada, T. Hayashi, Y. Iwayama, M. Matsumata, Y. Ishitsuka,
A. Nakaya, M. Maekawa, T. Ohnishi, R. Arai, K. Sakurai, K. Yamada, H. Kondo, K. Hashimoto,
N. Osumi, T. Yoshikawa, Fabp7 maps to a quantitative trait locus for a schizophrenia
endophenotype. PLoS Biol. 5, e297 (2007).
60. K. E. Samocha, J. E. Lim, R. Cheng, G. Sokoloff, A. A. Palmer, Fine mapping of QTL for
prepulse inhibition in LG/J and SM/J mice using F2and advanced intercross lines.
Genes Brain Behav. 9, 759–767 (2010).
61. D. L. Aylor, W. Valdar, W. Foulds-Mathes, R. J. Buus, R. A. Verdugo, R. S. Baric, M. T. Ferris,
J. A. Frelinger, M. Heise, M. B. Frieman, L. E. Gralinski, T. A. Bell, J. D. Didion, K. Hua,
D. L. Nehrenberg, C. L. Powell, J. Steigerwalt, Y. Xie, S. N. Kelada, F. S. Collins, I. V. Yang,
D. A. Schwartz, L. A. Branstetter, E. J. Chesler, D. R. Miller, J. Spence, E. Y. Liu, L. McMillan,
A. Sarkar, J. Wang, W. Wang, Q. Zhang, K. W. Broman, R. Korstanje, C. Durrant, R. Mott,
F. A. Iraqi, D. Pomp, D. Threadgill, F. P. de Villena, G. A. Churchill, Genetic analysis of
complex traits in the emerging Collaborative Cross. Genome Res. 21, 1213–1222
62. G. A. Churchill, D. C. Airey, H. Allayee, J. M. Angel, A. D. Attie, J. Beatty, W. D. Beavis,
J. K. Belknap, B. Bennett, W. Berrettini, A. Bleich, M. Bogue, K. W. Broman, K. J. Buck,
E. Buckler, M. Burmeister, E. J. Chesler, J. M. Cheverud, S. Clapcote, M. N. Cook, R. D. Cox,
J. C. Crabbe, W. E. Crusio, A. Darvasi, C. F. Deschepper, R. W. Doerge, C. R. Farber, J. Forejt,
D. Gaile, S. J. Garlow, H. Geiger, H. Gershenfeld, T. Gordon, J. Gu, W. Gu, G. de Haan,
N. L. Hayes, C. Heller, H. Himmelbauer, R. Hitzemann, K. Hunter, H. C. Hsu, F. A. Iraqi,
B. Ivandic, H. J. Jacob, R. C. Jansen, K. J. Jepsen, D. K. Johnson, T. E. Johnson, G. Kempermann,
C. Kendziorski, M. Kotb, R. F. Kooy, B. Llamas, F. Lammert, J. M. Lassalle, P. R. Lowenstein, L. Lu,
A. Lusis, K. F. Manly, R. Marcucio, D. Matthews, J. F. Medrano, D. R. Miller, G. Mittleman,
B. A. Mock, J. S. Mogil, X. Montagutelli, G. Morahan, D. G. Morris, R. Mott, J. H. Nadeau,
H. Nagase, R. S. Nowakowski, B. F. O'Hara, A. V. Osadchuk, G. P. Page, B. Paigen, K. Paigen,
A. A. Palmer, H. J. Pan, L. Peltonen-Palotie, J. Peirce, D. Pomp, M. Pravenec, D. R. Prows,
Z. Qi, R. H. Reeves, J. Roder, G. D. Rosen, E. E. Schadt, L. C. Schalkwyk, Z. Seltzer,
K. Shimomura, S. Shou, M. J. Sillanpää, L. D. Siracusa, H. W. Snoeck, J. L. Spearow,
K. Svenson, L. M. Tarantino, D. Threadgill, L. A. Toth, W. Valdar, F. P. de Villena, C. Warden,
S. Whatley, R. W. Williams, T. Wiltshire, N. Yi, D. Zhang, M. Zhang, F. Zou; Complex Trait
Consortium, The Collaborative Cross, a community resource for the genetic analysis of
complex traits. Nat. Genet. 36, 1133–1137 (2004).
63. Acknowledgments: The meeting was supported by the SYSGENET network (http://www.
helmholtz-hzi.de/sysgenet/). SYSGENET represents a network of scientists in Europe who
use the mouse as an experimental model system to identify genetic factors that influence
complex phenotypic traits relevant for human diseases. Funding: SYSGENET is funded
through COST, an intergovernmental framework for European Cooperation in Science
and Technology (http://www.cost.eu/about_cost).
Submitted 14 July 2011
Accepted 6 September 2011
Published 28 September 2011
Citation: M. J. Kas, R. S. Kahn, D. A. Collier, J. L. Waddington, J. Ekelund, D. J. Porteous,
K. Schughart, I. Hovatta, Translational neuroscience of schizophrenia: Seeking a meeting of
minds between mouse and man. Sci. Transl. Med. 3, 102mr3 (2011).
www.ScienceTranslationalMedicine.org 28 September 2011Vol 3 Issue 102 102mr3
on September 28, 2011
Downloaded from


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The gray whale parade
Marine observers witness resurgence of gray whales, cite banner breeding seasons
Every winter and spring, Wayne Perryman and his team of scientists stand watch on rocky outcrops of Central California, counting giants that swim down the Pacific coast.
These researchers with the National Oceanic and Atmospheric Administration's Southwest Fisheries Science Center in La Jolla have tracked the resurgence of gray whales from perilously low numbers during whaling days to a healthy population of about 20,000 today.
They've marked the fluctuating numbers of calves born — up this spring for the third year in a row.
Marine observers spotted 431 pairs of mothers and calves swimming north to the Arctic this year. Using mathematical models to account for the gray whales they didn't see, Perryman estimated last week that there were 1,500 to 1,600 calves born in Baja California lagoons this year, making this a banner year.
The migrations have helped Perryman and his colleagues gain more knowledge of the Arctic because gray whales serve as living laboratories of ice conditions in the northern seas.
Each year, 45-foot-long gray whales make a trek from their feeding waters in the Arctic to calving sites in Baja lagoons.
Expectant mothers come first, pregnant bodies bulging. They're on a mission, hurrying to warmer waters to have their babies.
Other adults follow at a more relaxed pace. Although the animals tend to be solitary in the Arctic — focused singularly on gobbling crustaceans — they spend their vacation months socializing and mating, Perryman said.
Lollygagging in the rear are the juveniles and young adults.
And watching them all — for 12 hours per day, five days a week — are teams of researchers equipped with logbooks and binoculars in a sort of shoreside crow's nest.
Stationed at trailers on the central coast, they rotate in three-hour shifts, aiming to count every whale that passes on the winter journey south and then every mother and calf heading north in spring. It's arduous work, more akin to a census than a whale-watching cruise. But for those who have the attention span and the eye for it, it's also fun.
"We're watching the gray whale parade go up and down the coast," said wildlife biologist Dave Weller, who likens the migration to the mass movement of wildebeest in Africa — one of nature's impressive spectacles.
"For me, it's a really pleasure," he said. "It's a great opportunity to watch something of that magnitude."
Weller grew up in Southern California with a lifetime affinity for the sea and its creatures. He studied whales and dolphins at the University of Hawaii, earned a master's degree at San Diego State University and then completed a doctorate at Texas A&M University.
Some of his work has focused on a struggling population of gray whales off Russia, near the island of Sakhalin.
Eastern Pacific gray whales that range from Alaska to Mexico rebounded from near extinction after an international whaling ban was enacted in 1946. But their relatives across the ocean aren't faring as well. Only about 140 of the Russian whales remain, Weller said, and he's trying to learn why.

subset: commoncrawl


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I'm just a college student - a bum, a writer, an artist and someone constantly hungry... X3
I write an anime blog: www.hellonavianimeblog.blogspot.com
4,199 total episodes
Great username and bio lol I've been there.(^.^)Serial Experiments Lain is one of my favorite anime!
You're welcome! I hope you had a great day! ^^
Intresting Blog by the way, ^^ it gives me a good idea on what to watch next.
happy birthday! :3
Wow your list is pretty picky, but nice top 5.
I like your signature!
If you liked or , you'd like the other because...


text:
New to Typophile? Accounts are free, and easy to set up.
I'm trying to identify the type used in the first printing of William Carlos Williams's Spring and All, published in 1923 by the Contact Press.
Thanks for your help.
The body type looks like Baskerville to me.
No, it's not Baskerville. It's some kind of a Didone face: note the unbracketed serifs, and the tall, angled stem of the t, and the curvy leg of the R.
The capitals are quite wide, while the lower-case is relatively narrow. It looks like a cross between a Bodoni (C with two spurs, R, t) and a Century (splayed serifs at the top of T, J and K [not shown in this sample], y).
You're right Greenpig, I glanced at it too quickly!
The title I believe is set in either Janson 56 Italic, Archetype Italic or Bell MT Italic.
I'll get back to you on that tricky body text.
I think it may be Fridericus Antiqua, still available from some metal type foundries, here is a link to a catalogue; the quality is not that good so I may be mistaken...
Thanks, Atwe. That's a font I've never heard of, but I think you're right. The cut is slightly different -- the capitals in the catalog aren't the extra-wide ones in the book text -- but the general letterforms are right on. Thanks for digging up this obscure face. I'll have to do some research on it.
I'm now pretty sure the body face is "French Round Face," which I found in Rookledge. Undigitized, alas.


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Top of Refrigerator
I keep seeing references to putting seedling/germination trays on top of the refrigerator and just now realized what this is about.
In case there are any other newbies out there like myself - this advice is for those of you who don't have fridges that vent their heat out of the bottom and instead have a warm top.
I never used this method but heard a lot about it. I use the DVR, and since its in an enclosed area of the entertainment center I use the shelf above, it does have ventaliation though its enclosed. I also used the floor heat vents and just placed them right next to the vent and got them to sprout that way. Once I can afford to add heat mats I will get some, maybe in the next year or two. Thanks for sharing the info.
That is really curious. The top of my fridge has zero heat - at the front at the back - the whole surface.
There is heat coming from the vent at the bottom front - not a good place to set a tray - might step on the seedlings while accessing the ice maker!
Lori, ... the heat come up from the condensing coil , normally located on the back side. Otherwise the top itself is well insulated. That is why I mention that the tray should be pushed way back".
This post was edited by seysonn on Wed, Feb 19, 14 at 10:00
I think what is happening is that a fan draws the heat down over the coils and pumps it out the bottom. I got out a step stool and put my hand right to the back and still no heat. There is a cupboard above the fridge so if any heat were present, I would think it would build up there.
Mine is a Kitchenaid Superba -think I'll dig out the manual to see why I don't get a bonus germinator!
Lori, i didn't see any mention of using a thermometer to test.
Maybe try leaving one on the top / back of your fridge for a few minutes, you might find a good 6f to 10f temp difference. If so then it should be enough to sprout seeds.
Good luck either way though,
Exactly....this advice comes from the older generation of 'fridges that were warm on top. I'm sure there are still some out there, but many new models are cool. However, heat does rise, so putting seeds atop the 'fridge isn't a bad place to put them.
All refrigerators have condenser (warm) coils or they wouldn't work. Some have coils in the kick space and reject heat there, some have coils at the rear and reject heat there, some have coils on top and reject heat there.
The only constant is that they all reject heat somewhere.
I have a zero clearance fridge, no condenser coils at the rear.
All you people who can germinate in the house are lucky. I have a couple of cats that get into everything. No matter where I try to germinate, they find the tray.
I have a couple of cats that get into everything.


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We hate to see her go, but we love to watch her walk away.
50 Musts: Fall Essentials
Sometimes, it's the little things that really matter. Case in point: statement bags, vintage finds, and notice-me baubles
Bag: Celine
Bracelet: Linda Lee Johnson
Rings: Fin Girls
Cuff: Her boyfriend's from the Naval Academy


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Nowhere has disruption in the news industry been more pronounced than in how we fund journalism. Our funding mechanisms have undergone profound changes. Brian Steffens spoke with Conrad Jungmann, founding partner of LION Digital Media, about what his group is doing to address this issue.
RJI links, daily curation of the best stories from across the Web to help you navigate our fast-changing industry, RJI collects and assembles some of the top stories from around the Web of interest to journalism innovators and entrepreneurs.
What do BuzzFeed, Upworthy and Refinery29 have in common? Well, for one, they've raised millions in venture capital money, and they're all getting deeper into the digital news business. But it's not all rosy in the land of VC-funded digital publishers.
Nonprofit digital news operations tend to be more mission driven than profit/commerce driven. But lacking traditional advertising/revenue streams, sustainability and growth is no less challenging than for legacy media. Brian Steffens visited with Mary Bruno, editor-in-chief of Crosscut Public Media.
The creative newsroom at Edelman Seattle is still under construction with only a handful of the team hired and in place. Brian Steffens spoke with Cherylynne Crowther, executive producer, on its future.
A world where interconnected devices can sense and respond to our activity and emotions may be closer than you think.
With more news published online, consumer behavior has radically changed. At the same time, it has never been easier to start a "news business," spurring unprecedented competition among content providers.
Don't overlook the home of Microsoft, Amazon, Zillow and other innovative companies large and small when looking for voices in media thought leadership. Brian Steffens visited with Ben Huh, founder of Cheezburger and co-founder of Circa.
Good writers can conjure a vivid image in our minds with just words. But journalists also have long relied on illustrations, photographs and videos to enrich a story.
Many newsrooms in an earlier era had several, seemingly good, reasons to pay little heed to real readers and viewers. So, what's changed? Well, seemingly everything. The audience has almost always been a commodity; that's just a lot harder for journalists to be indifferent about these days.
If you've ever been to Austin, Texas, then you know they like to keep things weird. And things have certainly been weird at this year's SXSW. Marketers have turned to Tinder robots, protests against robots, and feline "tech correspondents" to try to make an impression at the ever-growing festival.
What can other newsrooms learn from nonprofit news organizations about partnerships and engagement?
Justin Ellis at Harvard's Nieman Lab summed up the state of The Texas Tribune more astutely than I could in a piece commemorating our fifth anniversary: "Five years in, with the ledger looking good and the journalism running strong, the big question for the Tribune is: How do they find more readers?"
Trina Chiasson, a 2013-2014 RJI Fellow, will share insights from "Data+Design," an open source e-book about preparing data and building visualizations, during a SXSW session next week in Austin, Texas.
Last month, Google researchers published what might be the next leap forward in search. The new algorithm would assess websites based on how trustworthy they are. This change could help push misinformation and hoaxes into the background. But some are already crying foul, calling into question how the algorithm determines facts.
What if the audience could walk around inside a news event? And could mobile apps become a new form of content?
The Columbia Missourian took a new tack on "in-depth journalism" by offering its readers 3-D images of costumed participants in the True/False Film Fest in Columbia, Missouri.
When it comes to getting paid, who are news organizations competing with, and what can they do about it? First answer: They aren't competing with each other. They are competing with all of the other things consumers spend information-access dollars on.
Ideas. Experiments. Research. Solutions.
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The Case of the Sleepy SpyCan narcolepsy disqualify a CIA agent?
Alan Cumming's 'Celibacy' Video Mocks FDA Blood Donor PolicyThe campaign is part of an effort to get the FDA to reverse what critics call a double standard for gay and bisexual men.
Justice Department to Seek Emergency Stay to Allow Immigration ActionThe emergency stay will allow eligible immigrants to apply for benefits granted under recent executive action.
West Virginia Investigates Massive Train DerailmentThe fires that raged after the accident have stopped burning, but questions remain about oil and rail safety in a region known for toxic spills.
Suspect Arrested in Colorado Springs NAACP BombingThaddeus Murphy, 44, may have been targeting another business.
Terrorism Case Against Palestinian Organizations Goes to JuryAmerican plaintiffs seek damages from the Palestinian Authority and PLO.
U.S.-Turkey Agreement to Arm Syrian Rebels a 'Disaster in the Making'Experts warn of divisions between Washington, Ankara and the Syrian opposition.
Oklahoma Teachers Not Too Pleased About Bill to Ban AP U.S. HistoryThe bill was introduced by a representative who seeks to dismantle the "false wall of separation of church and state."
Obama Rejects Idea That West is at War With IslamObama urged countries to tackle violent Islamist militancy around the world.
AIPAC: Netanyahu's Silent PartnerWhy the pro-Israel lobby has been unusually quiet about the bitter diplomatic row between Washington and Jerusalem.
Giuliani, Cruz Criticize Obama Over Islamic Extremism Remarks"I do not believe the president loves America," Politico quotes Giuliani as saying Wednesday.
Lawyers for Accused Boston Marathon Bomber Appeal Again For Trial to Be MovedAttorneys for Dzhokhar Tsarnaev argue an impartial jury could not be seated so close to the site of the attack.
The UEFA Champions League Is a Cure for Sport's Winter DoldrumsThe tournament features Europe's best players.
The Rise and Fall of Silk Road, the Dark Web's AmazonLibertarian surfer dude Ross Ulbricht built his cyber drug cartel, Silk Road, on a belief in free markets and Internet privacy. Now he's in prison for a very long time.
Key Moments in the Life of Silk Road Creator Ross UlbrichtHow a tech-savvy young man from Austin developed the Amazon of the Dark Web.
Mourning the Man Shot by Police in PascoPolice in Washington state killed Antonio Zambrano-Montes after he threw rocks at them. His wife is seeking $25 million.
The World According to Jeb BushBush offered few answers in his first foreign policy speech of the undeclared presidential campaign.
Jeb Bush and the Revolving Door of Foreign Policy WonksThe ex-Florida governor didn't go far outside his comfort zone for his foreign policy cadre.
U.S. Accuses Israel of Inaccurate Leaks on Iran TalksThe accusation intensified tensions before Israeli Prime Minister Benjamin Netanyahu's contentious March visit to Washington.
Obama Names Interim Chief Joseph Clancy to Lead Secret ServiceClancy, a 27-year Secret Service veteran and trusted insider, takes over a troubled agency as its permanent chief.
The Debate Over an Autism Cure Turns HostileOne activist's search for a cure for his autism is drawing a violent backlash.
More Arctic Temperatures in Store For Eastern U.S.Forecasters warned of the worst cold in two decades from another arctic front this week.
The Fine Line Between Anti-Islamism and IslamophobiaHating minority groups like Muslims is alien to America's culture of tolerance.
Arson Suspect Charged in Houston Islamic Center FireThe suspect, a homeless man, claims the fire was an "accident."
A Texas Judge May Save Republicans From ThemselvesHis ruling means the Homeland Security department may not shut down—for a while.
Federal Judge Blocks Obama's Immigration Deportation PlanThe move adds a new wrinkle to a debate already raging in the new, Republican-led U.S. Congress.
Record-Breaking Cold Grips Eastern United StatesStates of emergency were declared in North Carolina, Virginia, Mississippi, Georgia,Kentucky, as well as in Washington, D.C.
Brian Williams: Bald Lies or False Memories?Research shows the disgraced anchor may genuinely believe his tall tale.
FBI Investigates Vandalization of Islamic SchoolThe Rhode Island school has 160 students ranging from pre-kindergarten to eighth grade.
Congress Should Set Limits on Obama's ISIS WarTo avoid mission creep, war authorization should come with strict conditions.


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Changeable roses drive me crazy
Do you have a rosebush that makes roses all year that you don't like and then suddenly in a stretch of changing weather makes a flower that you utterly adore?
I feel this way about my Twilight Zone and Lady Jane Grey. I decided so many times that I would send both to another home. Somebody who loved the smoky purple of Ebb Tide or a soft orangy chiffon. I just got the most amazing TZ. Perfect in shape and rich burgundy magenta with just a hint of plum. The color is so amazing right now. I don't recall any rose ever with this royal clor. It looks like hand dyed silk. The fragrance is rich and sweet ( rose-fruit, my favorite) I wish I didn't have to wait so long for them. All summer long, I've been looking at flowers I don't care for.
Lady Jane is the same way. I wait and wait for the soft pink peach dream roses with the hint of yellow. What I get all year is yellowy orange flowers that I think are just ok. I think all summer that I am going to dig it out and make room for something I really want and then along comes a rose fit for a catalog cover.
Roses. They can't be like other flowers at all. No, they have to be temperamental and full of surprises.
I was just looking at the color of the TZ I picked this morning. I think it has shifted again! The color on the edges are slightly deeper violet and the center remains glowy deep magenta-pink and the rest a burgundy plum combination. Hard to explain the luminous color the center has. Sort of like the glow through stained glass late in the afternoon if that helps. Fragrance is holding as a cut flower. How I wish Patrick was here to describe it in his wonderful way.
I live in Phoenix, AZ. Currently my beloved Olympiad is 5-petaled. It's been that way since before the 4th of July. It looks like most of the other red roses in my garden and is typical of roses in the sustained hot days of my climate. In my opinion, alive is better than dead, which is what happens to roses that can't survive. Fortunately, I'll have some beautiful roses from October thru June. If the rose isn't beautiful during that time frame, it'll be replaced.
Don't go crazy, grab a shovel.
How long have you had Twilight Zone? It's a pretty new rose so it's probably under three years old. I almost always give a rose three solid years, sometimes longer, before I start thinking about removing it. So many of my roses haven't kicked in until their third year--Ebb Tide, TZ's parent took quite a while to establish itself. The size of bloom, number of petals, stability of color, at least in my garden, take some time to come about. My TZ was planted bareroot in March and has grown into a nice plant, but it's bloomed only twice, and they were the dark smoky plum most of us want. I know that burgundy plum combo you're talking about. Ascot produces a lot of blooms that color, especially in the spring. It's gorgeous. Diane
One of the things I love, love, about my old tea roses is that many of them have blooms of different colors, depending on the weather. Of course, these are very old roses, very elegant & graceful bushes, and any color they come up with is beautiful. Pale pinks, pale yellows, buff with brick reverse - that is all one rose - Anna Olivier. When my AO does this, it tends to produce an entire bush of whatever color it is in the mood for. When AO has done this for some other folks, they have told me they think they have the "wrong" rose, because it is 100% yellow, or whatever. I just tell them to wait until the next flush, when it will be another color altogether.
My Duchesse de Brabant is usually a pale pink with very cupped blooms, but in the Fall it gets much darker pink, and the blooms are not cupped. I enjoy and admire this changeability in the old roses - I am always watching to see what they will do next!
One of the things modern hybridizers evidently tried to breed out of roses in the 20th century was this tendency to variability of color (as well as fragrance and health, but that was not intentional).
So, I agree that if you have a brand new modern rose that is doing this, it is probably because it is still immature. I would let it alone until it is at least 5 years old.
moroseaz, my Olympiad did the same as yours for most of the
summer.When i first saw the different blooms, i wondered
"what in the world?". It had to be the terribly hot summer
causing this because all other factors have been the same,
and now it is putting out it,s gorgeous blooms once again.
I think it all depends on why you got the rose in the first place. I always get drawn to the subtle multi colored roses but then these are the ones that are likely to change. The person selling the rose displays the picture they like best. I am buying thinking that that is the flower I will get. Those are the risks you take buying newly released roses.
I like roses that change, but they must not include a stage I didn't want in that spot! It's a huge reason I have a pot ghetto.
The roses I grow tend to be much paler in the summer, and that's fine. It's even nice because it marks the seasons. But none of this getting dark and brassy or a dark, strange orange from a rose that was previously subtle once the temperatures skyrocket. My color schemes can't handle it!
I have a rose whose colors you might enjoy, from what you say you liked about LJG. I think it's Dr. Brownell. It was mis-tagged, so I can't say for sure, but it's a Brownell rose for sure. He's not too yellow, and his yellows are buffs and creams, so it's always lovely with the pinks and apricots he shows.


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Ouch! 1955 Mercedes SLS 300 Smashes Into a 1959 Jaguar
Last Saturday, two iconic cars with a combined value of around £5 million were on a collision course during a qualifying race at the 73rd Goodwood Members' Meeting. The two involved were a 1955 Mercedes SLS 300 "Porter Special" and a 1959 Lister-Jaguar "Knobbly". According to Daily Mail, the 1955 Mercedes SLS 300 had an estimated value of £4 million while the Jaguar was priced at approximately £1 million. Both cars were left in a really bad shape after the incident on the Goodwood track. The source said the Mercedes was owned by Dr. Klaus Lahr, a German car collector. It came from the factory as a Mercedes 300 SL, but it was customized after a very serious car… Continue Reading »


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|By Yeshim Deniz
Article Rating:
|August 20, 2014 10:45 PM EDT
Cisco sponsor logo at Cloud Expo's giant Silicon View billboard on Highway 101 which is viewed by more than 1.3 million motorists per week.
SYS-CON Events, Inc. named Cisco "Gold Sponsor" of upcoming Cloud Expo, co-located with 3rd International Internet of @ThingsExpo, the largest IoT event in the world. 15th International Cloud Expo will take place November 4-6, 2014 at the Santa Clara Convention Center in Santa Clara, California.
IT organizations are struggling to keep pace with changes in cloud computing scale, global reach, and analytics. But they must, in order to extract value from the billions of new connections created by the Internet of Everything. No single cloud can address every workload need.
Cisco's Intercloud — a global cloud of clouds — offer an unmatched portfolio of IT services for customers, providers, and partners. With an Intercloud approach, Cisco partners with its clients to match their organization with the right cloud computing strategy. At Cloud Expo Silicon Valley, learn about the options.
Cisco will present a number of technical sessions, including a general session which will be announced next week.
Data Privacy Perspectives: U.S. vs Europe
It's time to face reality: "Americans are from Mars, Europeans are from Venus," and in today's increasingly connected world, understanding "inter-planetary" alignments and deviations is mission-critical for cloud.
In her session at 15th Cloud Expo, Evelyn de Souza, Data Privacy and Compliance Strategy Leader at Cisco Systems, will discuss cultural expectations of privacy based on new research across these elements:
- Applicable Laws: What constitutes data sovereignty, personal data and data breaches
- Lawful interception: How consumers feel about the means that governments use to obtain data from cloud services
- User Consent: The ability of third parties to gather data from cloud services for the purposes of business, health and even marketing purposes.
Speaker Bio:
Evelyn de Souza is a cloud compliance and data privacy strategy leader at Cisco responsible for championing solutions to address emerging industry trends. She is a strong proponent of building repeatable processes that enable organizations to sustain compliance while optimizing data security posture. Evelyn co-chairs the Cloud Security Alliance Cloud Controls Matrix (CCM), which harmonizes regulations and industry standards to a common framework.
Evolution of Agile Application Deployment
Agility is top of mind for Cloud/Service providers and Enterprises alike. Policy Driven Data Center provides a policy model for application deployment by decoupling application needs from the underlying infrastructure primitives. In his session at 15th Cloud Expo,
David Klebanov, a Technical Solutions Architect with Cisco Systems, to discuss how it differentiates from the software-defined top-down control by offering a declarative approach to allow faster and simpler application deployment.
Speaker Bio:
David Klebanov is a Technical Solutions Architect with Cisco Systems. In his work David influences strategic development of the industry leading Data Center switching platforms, which lay foundation for the next generation cloud fabrics. David also takes great pride in speaking at industry events, releasing publications and working on patents.
The 15th International Cloud Expo has just expanded its conference program, to bring together Cloud Computing, APM, APIs, Security, Big Data, Internet of Things, DevOps and WebRTC at one location.
The show now has three tracks devoted exclusively to the IoT (with WebRTC present in one of the tracks), a full single track focusing on Big Data, and a two-track DevOps Summit, in addition to four tracks devoted exclusively to Cloud Computing in the enterprise.
Cloud Expo is the single show where delegates and technology vendors can meet to experience and discuss the entire world of the cloud.
With Cloud Computing driving a higher percentage of enterprise IT budgets every year, it becomes increasingly important to learn about the latest technology developments and solutions.
Attend Cloud Expo Nov 4-6, at the Santa Clara Convention Center, CA. Craft your own custom experience. Learn the latest from the world's best technologists. Find the vendors you want and put them to the test.
15th Cloud Expo Expanded Conference Program
Cloud Expo
Track 1: Enterprise Cloud Adoption
Track 2: APM, Cloud and Hot Topics
Track 3: Cloud APIs & Business
Track 4: Cloud Security - Mobility
Big Data Expo
Track 5: Big Data/Analytics
Track 6: Consumer IoT
Track 7: Enterprise IoT
Track 8: IoT Developer & WebRTC
DevOps Summit
Track 1: "Dev" Developer Focus
Track 2: "Ops" Operations Focus
More than 150 all-star faculty members will discuss the hottest technology topics in November. In addition to the expanded APM and API coverage, Cloud Expo Silicon Valley will offer a variety of Linux containers and Docker sessions.
DevOps Summit at Cloud Expo also doubled its content from June, in two full simultaneous tracks for three days.
Tracks and topics for DevOps Summit at Cloud Expo will include:
- Application delivery
- ROI and business value
- Site reliability
- Continuous delivery
- Kanban, Scrum, and Agile
- Continuous integration
- Release scalability
- Continuous release
- Service virtualization
- Operational monitoring
- Capacity management
- Load testing
- Quality assurance
- Manager and exec support
- Release automation
- Cultural change
- Breaking down IT silos
- Cloud development
- Cloud platforms
- Test automation
- Teaming
- Application security
- API management
- Identity and access
- Audit and control
- DevOps and ITIL, ISO, Six Sigma, COBIT
- Mobile DevOps
- DevOps for legacy systems
- Software-defined servers
- Network automation
- Server automation
- Configuration automation
- Continuous support
- DevOps anti-patterns
- Enterprise DevOps
- DevOps system architecture
- IT orchestration
- Containerization
- DevOps skills and training
- WebOps, CloudOps, ChatOps, NoOps
- Change management
Tracks and topics for Internet of @ThingsExpo will include:
Consumer IoT & Wearables
- Wearables
- Smart Appliances
- Smart Cars
- Smartphones 2.0
- Smart Travel
- Personal Fitness
- Health Care
- Personalized Marketing
- Customized Shopping
- Personal Finance
- The Digital Divide
- Mobile Cash & Markets
- Games & the IoT
- The Future of Education
- Virtual Reality
Enterprise IoT
- The Business Case for IoT
- Smart Grids
- Smart Cities
- Smart Transportation
- The Smart Home
- Authentication/Security
- Wiring the IoT
- The Internet of Everything
- Digital Transformation of Enterprise IT
- Agriculture
- Transportation
- Manufacturing
- Local & State Government
- Federal Government
IoT Developers
- Eclipse Foundation
- Cloud Foundry
- Linux Containers
- Node-Red
- Open Source Hardware
- AJAX and the IoT
- Leveraging SOA
- Multi-Cloud IoT
- Evolving Standards
- WebSockets
- Security & Privacy Protocols
- GPS & Proximity Services
- Bluetooth/RFID/etc.
- Nest Labs
Sponsorship Opportunities
for Cloud Expo® 2014 Silicon Valley
Cloud Expo® 2014 Silicon Valley "show prospectus" has shipped. Sponsorship, exhibit, and keynote opportunities can be obtained from Carmen Gonzalez by email at events (at) sys-con.com, or by phone 201 802-3021.
Early Bird Registration Options
for Cloud Expo® 2014 Silicon Valley
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About SYS-CON Media & Events
SYS-CON Media (www.sys-con.com) has since 1994 been connecting technology companies and customers through a comprehensive content stream at www.sys-con.com - featuring over forty focused subject areas, from Cloud Computing to Web Security - interwoven with market-leading full-scale conferences produced by SYS-CON Events. The company's internationally recognized brands include among others Cloud Expo® (www.CloudComputingExpo.com), Big Data Expo (http://BigDataExpo.net), Virtualization Conference & Expo (www.VirtualizationConference.com), DevOps Summit (http://DevOpsSummit.sys-con.com), Internet of @ThingsExpo (http://www.ThingsExpo.com), SDDC Expo (http://SDDCExpo.sys-con.com), WebRTC Summit (http://WebRTCSummit.net), Government IT Conference & Expo (www.GovITExpo.com), Cloud Computing Bootcamp (www.CloudComputingBootcamp.com), and UlitzerLive! New Media Conference & Expo (http://events.sys-con.com).
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SYS-CON Events announced today that Liaison Technologies, a leading provider of data management and integration cloud services and solutions, has been named "Silver Sponsor" of SYS-CON's 16th International Cloud Expo®, which will take place on June 9-11, 2015, at the Javits Center in New York, NY. Liaison Technologies is a recognized market leader in providing cloud-enabled data integration and data management solutions to break down complex information barriers, enabling enterprises to make smarter decisions, faster.
Mar. 26, 2015 03:00 PM EDT Reads: 3,274
SYS-CON Events announced today that Solgenia will exhibit at SYS-CON's 16th International Cloud Expo®, which will take place on June 9-11, 2015, at the Javits Center in New York City, NY, and the 17th International Cloud Expo®, which will take place on November 3–5, 2015, at the Santa Clara Convention Center in Santa Clara, CA. Solgenia is the global market leader in Cloud Collaboration and Cloud Infrastructure software solutions. Designed to "Bridge the Gap" between Personal and Professional Social, Mobile and Cloud user experiences, our solutions help large and medium-sized organizations dr...
Mar. 26, 2015 03:00 PM EDT Reads: 2,434
Connected devices and the Internet of Things are getting significant momentum in 2014. In his session at Internet of @ThingsExpo, Jim Hunter, Chief Scientist & Technology Evangelist at Greenwave Systems, examined three key elements that together will drive mass adoption of the IoT before the end of 2015. The first element is the recent advent of robust open source protocols (like AllJoyn and WebRTC) that facilitate M2M communication. The second is broad availability of flexible, cost-effective storage designed to handle the massive surge in back-end data in a world where timely analytics is e...
Mar. 26, 2015 02:45 PM EDT Reads: 4,596
SYS-CON Events announced today that Akana, formerly SOA Software, has been named "Bronze Sponsor" of SYS-CON's 16th International Cloud Expo® New York, which will take place June 9-11, 2015, at the Javits Center in New York City, NY. Akana's comprehensive suite of API Management, API Security, Integrated SOA Governance, and Cloud Integration solutions helps businesses accelerate digital transformation by securely extending their reach across multiple channels – mobile, cloud and Internet of Things. Akana enables enterprises to share data as APIs, connect and integrate applications, drive part...
Mar. 26, 2015 02:15 PM EDT Reads: 1,278
SYS-CON Events announced today that CommVault has been named "Bronze Sponsor" of SYS-CON's 16th International Cloud Expo®, which will take place on June 9-11, 2015, at the Javits Center in New York City, NY, and the 17th International Cloud Expo®, which will take place on November 3–5, 2015, at the Santa Clara Convention Center in Santa Clara, CA. A singular vision – a belief in a better way to address current and future data management needs – guides CommVault in the development of Singular Information Management® solutions for high-performance data protection, universal availability and sim...
Mar. 26, 2015 02:00 PM EDT Reads: 1,360
Cloud is not a commodity. And no matter what you call it, computing doesn't come out of the sky. It comes from physical hardware inside brick and mortar facilities connected by hundreds of miles of networking cable. And no two clouds are built the same way. SoftLayer gives you the highest performing cloud infrastructure available. One platform that takes data centers around the world that are full of the widest range of cloud computing options, and then integrates and automates everything. Join SoftLayer on June 9 at 16th Cloud Expo to learn about IBM Cloud's SoftLayer platform, explore se...
Mar. 26, 2015 02:00 PM EDT Reads: 1,439
SYS-CON Media announced today that @ThingsExpo Blog launched with 7,788 original stories. @ThingsExpo Blog offers top articles, news stories, and blog posts from the world's well-known experts and guarantees better exposure for its authors than any other publication. @ThingsExpo Blog can be bookmarked. The Internet of Things (IoT) is the most profound change in personal and enterprise IT since the creation of the Worldwide Web more than 20 years ago.
Mar. 26, 2015 01:45 PM EDT Reads: 2,090
The 3rd International Internet of @ThingsExpo, co-located with the 16th International Cloud Expo - to be held June 9-11, 2015, at the Javits Center in New York City, NY - announces that its Call for Papers is open. The Internet of Things (IoT) is the biggest idea since the creation of the Worldwide Web more than 20 years ago.
Mar. 26, 2015 01:00 PM EDT Reads: 2,819
The WebRTC Summit 2014 New York, to be held June 9-11, 2015, at the Javits Center in New York, NY, announces that its Call for Papers is open. Topics include all aspects of improving IT delivery by eliminating waste through automated business models leveraging cloud technologies. WebRTC Summit is co-located with 16th International Cloud Expo, @ThingsExpo, Big Data Expo, and DevOps Summit.
Mar. 26, 2015 12:45 PM EDT Reads: 918
The Internet of Things promises to transform businesses (and lives), but navigating the business and technical path to success can be difficult to understand. In his session at @ThingsExpo, Sean Lorenz, Technical Product Manager for Xively at LogMeIn, demonstrated how to approach creating broadly successful connected customer solutions using real world business transformation studies including New England BioLabs and more.
Mar. 26, 2015 12:30 PM EDT Reads: 4,637
SYS-CON Media announced today that 9 out of 10 " most read" DevOps articles are published by @DevOpsSummit Blog. Launched in October 2014, @DevOpsSummit Blog offers top articles, news stories, and blog posts from the world's well-known experts and guarantees better exposure for its authors than any other publication. The widespread success of cloud computing is driving the DevOps revolution in enterprise IT. Now as never before, development teams must communicate and collaborate in a dynamic, 24/7/365 environment. There is no time to wait for long development cycles that produce softw...
Mar. 26, 2015 12:15 PM EDT Reads: 2,309
The world's leading Cloud event, Cloud Expo has launched Microservices Journal on the SYS-CON.com portal, featuring over 19,000 original articles, news stories, features, and blog entries. DevOps Journal is focused on this critical enterprise IT topic in the world of cloud computing. Microservices Journal offers top articles, news stories, and blog posts from the world's well-known experts and guarantees better exposure for its authors than any other publication. Follow new article posts on Twitter at @MicroservicesE
Mar. 26, 2015 12:00 PM EDT Reads: 1,180
SYS-CON Events announced today that Site24x7, the cloud infrastructure monitoring service, will exhibit at SYS-CON's 16th International Cloud Expo®, which will take place on June 9-11, 2015, at the Javits Center in New York City, NY. Site24x7 is a cloud infrastructure monitoring service that helps monitor the uptime and performance of websites, online applications, servers, mobile websites and custom APIs. The monitoring is done from 50+ locations across the world and from various wireless carriers, thus providing a global perspective of the end-user experience. Site24x7 supports monitoring H...
Mar. 26, 2015 11:45 AM EDT Reads: 1,497
Wearable technology was dominant at this year's International Consumer Electronics Show (CES) , and MWC was no exception to this trend. New versions of favorites, such as the Samsung Gear (three new products were released: the Gear 2, the Gear 2 Neo and the Gear Fit), shared the limelight with new wearables like Pebble Time Steel (the new premium version of the company's previously released smartwatch) and the LG Watch Urbane. The most dramatic difference at MWC was an emphasis on presenting wearables as fashion accessories and moving away from the original clunky technology associated with t...
Mar. 26, 2015 11:30 AM EDT Reads: 791
SYS-CON Events announced today that SafeLogic has been named "Bag Sponsor" of SYS-CON's 16th International Cloud Expo® New York, which will take place June 9-11, 2015, at the Javits Center in New York City, NY. SafeLogic provides security products for applications in mobile and server/appliance environments. SafeLogic's flagship product CryptoComply is a FIPS 140-2 validated cryptographic engine designed to secure data on servers, workstations, appliances, mobile devices, and in the Cloud.
Mar. 26, 2015 11:00 AM EDT Reads: 1,236
One of the biggest challenges when developing connected devices is identifying user value and delivering it through successful user experiences. In his session at Internet of @ThingsExpo, Mike Kuniavsky, Principal Scientist, Innovation Services at PARC, described an IoT-specific approach to user experience design that combines approaches from interaction design, industrial design and service design to create experiences that go beyond simple connected gadgets to create lasting, multi-device experiences grounded in people's real needs and desires.
Mar. 26, 2015 11:00 AM EDT Reads: 4,537
The list of 'new paradigm' technologies that now surrounds us appears to be at an all time high. From cloud computing and Big Data analytics to Bring Your Own Device (BYOD) and the Internet of Things (IoT), today we have to deal with what the industry likes to call 'paradigm shifts' at every level of IT. This is disruption; of course, we understand that – change is almost always disruptive.
Mar. 26, 2015 10:00 AM EDT Reads: 703
Containers and microservices have become topics of intense interest throughout the cloud developer and enterprise IT communities. Accordingly, attendees at the upcoming 16th Cloud Expo at the Javits Center in New York June 9-11 will find fresh new content in a new track called PaaS | Containers & Microservices Containers are not being considered for the first time by the cloud community, but a current era of re-consideration has pushed them to the top of the cloud agenda. With the launch of Docker's initial release in March of 2013, interest was revved up several notches. Then late last...
Mar. 26, 2015 09:15 AM EDT Reads: 2,017
Can call centers hang up the phones for good? Intuitive Solutions did. WebRTC enabled this contact center provider to eliminate antiquated telephony and desktop phone infrastructure with a pure web-based solution, allowing them to expand beyond brick-and-mortar confines to a home-based agent model. It also ensured scalability and better service for customers, including MUY! Companies, one of the country's largest franchise restaurant companies with 232 Pizza Hut locations. This is one example of WebRTC adoption today, but the potential is limitless when powered by IoT.
Mar. 26, 2015 09:00 AM EDT Reads: 4,703
@ThingsExpo has been named the Top 5 Most Influential M2M Brand by Onalytica in the 'Machine to Machine: Top 100 Influencers and Brands.' Onalytica analyzed the online debate on M2M by looking at over 85,000 tweets to provide the most influential individuals and brands that drive the discussion. According to Onalytica the "analysis showed a very engaged community with a lot of interactive tweets. The M2M discussion seems to be more fragmented and driven by some of the major brands present in the M2M space. This really allows some room for influential individuals to create more high value inter...
Mar. 26, 2015 08:45 AM EDT Reads: 4,502