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

Nitrosative damage to free and zinc-bound cysteine thiols underlies nitric oxide toxicity in wild-type Borrelia burgdorferi

Borrelia burgdorferi encounters potentially harmful reactive nitrogen species (RNS) throughout its infective cycle. In this study, diethylamine NONOate (DEA/NO) was used to characterize the lethal effects of RNS on B. burgdorferi. RNS produce a variety of DNA lesions in a broad spectrum of microbial pathogens; however, levels of the DNA deamination product, deoxyinosine, and the numbers of apurinic/apyrimidinic (AP) sites were identical in DNA isolated from untreated and DEA/NO-treated B. burgdorferi cells. Strains with mutations in the nucleotide excision repair (NER) pathway genes uvrC or uvrB treated with DEA/NO had significantly higher spontaneous mutation frequencies, increased numbers of AP sites in DNA and reduced survival compared with wild-type controls. Polyunsaturated fatty acids in B. burgdorferi cell membranes, which are susceptible to peroxidation by reactive oxygen species (ROS), were not sensitive to RNS-mediated lipid peroxidation. However, treatment of B. burgdorferi cells with DEA/NO resulted in nitrosative damage to several proteins, including the zinc-dependent glycolytic enzyme fructose-1,6-bisphosphate aldolase (BB0445), the Borrelia oxidative stress regulator (BosR) and neutrophil-activating protein (NapA). Collectively, these data suggested that nitrosative damage to proteins harbouring free or zinc-bound cysteine thiols, rather than DNA or membrane lipids underlies RNS toxicity in wild-type B. burgdorferi

The Scientific Study of Positive Psychology, Religion/Spirituality, and Physical Health

Humans have long been interested in relations among religion/spirituality (R/S), positive psychological constructs, and physical health. Furthermore, many religions attempt to influence behavior through health-related prescriptions about food choices, sexual activity, substance use, and resting. Similarly, positive psychological constructs have been discussed in light of their presumed benefits on both mental and physical health (Ryff & Singer, 1998). However, R/S and positive psychological constructs have only recently become objects of scientific investigation of their associations with physical health.https://digitalcommons.chapman.edu/psychology_books/1025/thumbnail.jp

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

Amyotrophic lateral sclerosis–specific quality of life–short form (ALSSQOL‐SF): A brief, reliable, and valid version of the ALSSQOL‐R

Introduction: The Amyotrophic Lateral Sclerosis (ALS)‐Specific Quality of Life instrument and its revised version (ALSSQOL and ALSSQOL‐R) have strong psychometric properties, and have demonstrated research and clinical utility. In this study we aimed to develop a short form (ALSSQOL‐SF) suitable for limited clinic time and patient stamina. Methods: The ALSSQOL‐SF was created using Item Response Theory and confirmatory factor analysis on 389 patients. A cross‐validation sample of 162 patients assessed convergent, divergent, and construct validity of the ALSSQOL‐SF compared with psychosocial and physical functioning measures. Results: The ALSSQOL‐SF consisted of 20 items. Compared with the ALSSQOL‐R, optimal precision was retained, and completion time was reduced from 15–25 minutes to 2–4 minutes. Psychometric properties for the ALSSQOL‐SF and its subscales were strong. Discussion: The ALSSQOL‐SF is a disease‐specific global QOL instrument that has a short administration time suitable for clinical use, and can provide clinically useful, valid information about persons with ALS. Muscle Nerve 58: 646–654, 2018Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146574/1/mus26203_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146574/2/mus26203.pd

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

Strong size evolution of the most massive galaxies since z~2

Using the combined capabilities of the large near-infrared Palomar/DEEP-2 survey, and the superb resolution of the ACS HST camera, we explore the size evolution of 831 very massive galaxies (M*>10^{11}h_{70}^{-2}M_sun) since z~2. We split our sample according to their light concentration using the Sersic index n. At a given stellar mass, both low (n2.5) concentrated objects were much smaller in the past than their local massive counterparts. This evolution is particularly strong for the highly concentrated (spheroid-like) objects. At z~1.5, massive spheroid-like objects were a factor of 4(+-0.4) smaller (i.e. almost two orders of magnitudes denser) than those we see today. These small sized, high mass galaxies do not exist in the nearby Universe, suggesting that this population merged with other galaxies over several billion years to form the largest galaxies we see today.Comment: MNRAS in press, 13 pages, 11 figures. Data Table will be published in its integrity in the MNRAS online versio

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

Discriminating Between the Physical Processes that Drive Spheroid Size Evolution

Massive galaxies at high-z have smaller effective radii than those today, but similar central densities. Their size growth therefore relates primarily to the evolving abundance of low-density material. Various models have been proposed to explain this evolution, which have different implications for galaxy, star, and BH formation. We compile observations of spheroid properties as a function of redshift and use them to test proposed models. Evolution in progenitor gas-richness with redshift gives rise to initial formation of smaller spheroids at high-z. These systems can then evolve in apparent or physical size via several channels: (1) equal-density 'dry' mergers, (2) later major or minor 'dry' mergers with less-dense galaxies, (3) adiabatic expansion, (4) evolution in stellar populations & mass-to-light-ratio gradients, (5) age-dependent bias in stellar mass estimators, (6) observational fitting/selection effects. If any one of these is tuned to explain observed size evolution, they make distinct predictions for evolution in other galaxy properties. Only model (2) is consistent with observations as a dominant effect. It is the only model which allows for an increase in M_BH/M_bulge with redshift. Still, the amount of merging needed is larger than that observed or predicted. We therefore compare cosmologically motivated simulations, in which all these effects occur, & show they are consistent with all the observational constraints. Effect (2), which builds up an extended low-density envelope, does dominate the evolution, but effects 1,3,4, & 6 each contribute ~20% to the size evolution (a net factor ~2). This naturally also predicts evolution in M_BH-sigma similar to that observed.Comment: 19 pages, 7 figures. accepted to MNRAS (matches accepted version