91 research outputs found
A deep convolutional neural network for brain tissue segmentation in Neonatal MRI
Brain tissue segmentation is a prerequisite for many subsequent automatic quantitative analysis techniques. As with many medical imaging tasks, a shortage of manually annotated training data is a limiting factor which is not easily overcome, particularly using recent deep-learning technology. We present a deep convolutional neural network (CNN) trained on just 2 publicly available manually annotated volumes, trained to annotate 8 tissue types in neonatal T2 MRI. The network makes use of several recent deep-learning techniques as well as artificial augmentation of the training data, to achieve state-of-the- art results on public challenge data
Cerebellar c9RAN proteins associate with clinical and neuropathological characteristics of C9ORF72 repeat expansion carriers.
Clinical and neuropathological characteristics associated with G4C2 repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, are highly variable. To gain insight on the molecular basis for the heterogeneity among C9ORF72 mutation carriers, we evaluated associations between features of disease and levels of two abundantly expressed "c9RAN proteins" produced by repeat-associated non-ATG (RAN) translation of the expanded repeat. For these studies, we took a departure from traditional immunohistochemical approaches and instead employed immunoassays to quantitatively measure poly(GP) and poly(GA) levels in cerebellum, frontal cortex, motor cortex, and/or hippocampus from 55 C9ORF72 mutation carriers [12 patients with ALS, 24 with frontotemporal lobar degeneration (FTLD) and 19 with FTLD with motor neuron disease (FTLD-MND)]. We additionally investigated associations between levels of poly(GP) or poly(GA) and cognitive impairment in 15 C9ORF72 ALS patients for whom neuropsychological data were available. Among the neuroanatomical regions investigated, poly(GP) levels were highest in the cerebellum. In this same region, associations between poly(GP) and both neuropathological and clinical features were detected. Specifically, cerebellar poly(GP) levels were significantly lower in patients with ALS compared to patients with FTLD or FTLD-MND. Furthermore, cerebellar poly(GP) associated with cognitive score in our cohort of 15 patients. In the cerebellum, poly(GA) levels similarly trended lower in the ALS subgroup compared to FTLD or FTLD-MND subgroups, but no association between cerebellar poly(GA) and cognitive score was detected. Both cerebellar poly(GP) and poly(GA) associated with C9ORF72 variant 3 mRNA expression, but not variant 1 expression, repeat size, disease onset, or survival after onset. Overall, these data indicate that cerebellar abnormalities, as evidenced by poly(GP) accumulation, associate with neuropathological and clinical phenotypes, in particular cognitive impairment, of C9ORF72 mutation carriers
Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis.
The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43-positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the approximately 25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis
TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 × 1
Size and velocity-dispersion evolution of early-type galaxies in a Lambda cold dark matter universe
Early-type galaxies (ETGs) are observed to be more compact at z>2 than in the
local Universe. Remarkably, much of this size evolution appears to take place
in a short (1.8 Gyr) time span between z=2.2 and z=1.3, which poses a serious
challenge to hierarchical galaxy formation models where mergers occurring on a
similar timescale are the main mechanism for galaxy growth. We compute the
merger-driven redshift evolution of stellar mass Mstar\propto(1+z)^aM,
half-mass radius Re\propto(1+z)^aR and velocity-dispersion
sigma0\propto(1+z)^asigma predicted by concordance Lambda cold dark matter for
a typical massive ETG in the redshift range z=1.3-2.2. Neglecting dissipative
processes, and thus maximizing evolution in surface density, we find
-1.5<aM<-0.6, -1.9<aR<-0.7 and 0.06<asigma<0.22, under the assumption that the
accreted satellites are spheroids. It follows that the predicted z=2.2
progenitors of z=1.3 ETGs are significantly less compact (on average a factor
of 2 larger Re at given Mstar) than the quiescent galaxies observed at z>2.
Furthermore, we find that the scatter introduced in the size-mass correlation
by the predicted merger-driven growth is difficult to reconcile with the
tightness of the observed scaling law. We conclude that - barring unknown
systematics or selection biases in the current measurements - minor and major
mergers with spheroids are not sufficient to explain the observed size growth
of ETGs within the standard model.Comment: 20 pages, 14 figures, matching version published in MNRAS. Corrected
plots in Figs 6, 7 and 8 with respect to previous versio
Abnormal Expression Of Homeobox Genes And Transthyretin In C9Orf72 Expansion Carriers
Objective: We performed a genome-wide brain expression study to reveal the underpinnings of diseases linked to a repeat expansion in chromosome 9 open reading frame 72 (C9ORF72). Methods: The genome-wide expression profile was investigated in brain tissue obtained from C9ORF72 expansion carriers (n = 32), patients without this expansion (n = 30), and controls (n = 20). Using quantitative real-time PCR, findings were confirmed in our entire pathologic cohort of expansion carriers (n = 56) as well as nonexpansion carriers (n = 31) and controls (n = 20). Results: Our findings were most profound in the cerebellum, where we identified 40 differentially expressed genes, when comparing expansion carriers to patients without this expansion, including 22 genes that have a homeobox (e.g., HOX genes) and/or are located within the HOX gene cluster (top hit: homeobox A5 [HOXA5]). In addition to the upregulation of multiple homeobox genes that play a vital role in neuronal development, we noticed an upregulation of transthyretin (TTR), an extracellular protein that is thought to be involved in neuroprotection. Pathway analysis aligned with these findings and revealed enrichment for gene ontology processes involved in (anatomic) development (e.g., organ morphogenesis). Additional analyses uncovered that HOXA5 and TTR levels are associated with C9ORF72 variant 2 levels as well as with intron-containing transcript levels, and thus, disease-related changes in those transcripts may have triggered the upregulation of HOXA5 and TTR. Conclusions: In conclusion, our identification of genes involved in developmental processes and neuroprotection sheds light on potential compensatory mechanisms influencing the occurrence, presentation, and/or progression of C9ORF72-related diseases
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Prion-like domain mutations in hnRNPs cause multisystem proteinopathy and ALS
Summary Algorithms designed to identify canonical yeast prions predict that ~250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbor a distinctive prion-like domain (PrLD) enriched in uncharged polar amino acids and glycine. PrLDs in RNA-binding proteins are essential for the assembly of ribonucleoprotein granules. However, the interplay between human PrLD function and disease is not understood. Here, we define pathogenic mutations in PrLDs of hnRNPA2/B1 and hnRNPA1 in families with inherited degeneration affecting muscle, brain, motor neuron and bone, and a case of familial ALS. Wild-type hnRNPA2 and hnRNPA1 display an intrinsic tendency to assemble into self-seeding fibrils, which is exacerbated by the disease mutations. Indeed, the pathogenic mutations strengthen a ‘steric zipper’ motif in the PrLD, which accelerates formation of self-seeding fibrils that cross-seed polymerization of wild-type hnRNP. Importantly, the disease mutations promote excess incorporation of hnRNPA2 and hnRNPA1 into stress granules and drive the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Thus, dysregulated polymerization caused by a potent mutant ‘steric zipper’ motif in a PrLD can initiate degenerative disease. Related proteins with PrLDs must be considered candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone
Pleosporales
One hundred and five generic types of Pleosporales are described and illustrated. A brief introduction and detailed history with short notes on morphology, molecular phylogeny as well as a general conclusion of each genus are provided. For those genera where the type or a representative specimen is unavailable, a brief note is given. Altogether 174 genera of Pleosporales are treated. Phaeotrichaceae as well as Kriegeriella, Zeuctomorpha and Muroia are excluded from Pleosporales. Based on the multigene phylogenetic analysis, the suborder Massarineae is emended to accommodate five families, viz. Lentitheciaceae, Massarinaceae, Montagnulaceae, Morosphaeriaceae and Trematosphaeriaceae
Can Minor Merging Account for the Size Growth of Quiescent Galaxies? New Results from the CANDELS Survey
The presence of extremely compact galaxies at z~2 and their subsequent growth
in physical size has been the cause of much puzzlement. We revisit the question
using deep infrared Wide Field Camera 3 data to probe the rest-frame optical
structure of 935 host galaxies selected with 0.4
10^10.7 Msol using optical and near-infrared photometry in the UKIRT Ultra Deep
Survey and GOODS-South fields of the CANDELS survey. At each redshift, the most
compact sources are those with little or no star formation, and we find that
the mean size of these systems grows by a factor of 3.5 +- 0.3 over this
redshift interval. The new data are sufficiently deep to enable us to identify
companions to these hosts whose stellar masses are ten times smaller, while
still yielding suitably accurate photometric redshifts to define a likely
physical association. By searching for faint companions around 404 quiescent
hosts within a projected physical annulus 10 < R < 30 kpc/h, we estimate the
minor merger rate over the redshift range 0.4 < z < 2. After correcting for
contamination from projected pairs, we find that 13-18% of quiescent hosts have
likely physical companions with stellar mass ratios of 0.1 or greater. Mergers
of these companions will typically increase the host mass by 6+-2% per merger
timescale. We estimate the minimum growth rate necessary to explain the
declining abundance of compact galaxies. Using a simple model of merging
motivated by recent numerical simulations, we then assess whether mergers of
the faint companions with their hosts are sufficient to explain this minimal
rate. We find that mergers with mass ratios > 0.1 may explain most of the size
evolution observed at z >~ 1 if a relatively short merger timescale is assumed,
but the rapid growth seen at higher redshift likely requires additional
physical processes.Comment: Accepted to ApJ. Updated following referee report, with expanded
comparisons to published mass-size and pair fraction measurements (Figs. 4
and 9
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