Hexagonal Tilings and Locally C6 Graphs

We give a complete classification of hexagonal tilings and locally C6 graphs, by showing that each of them has a natural embedding in the torus or in the Klein bottle. We also show that locally grid graphs are minors of hexagonal tilings (and by duality of locally C6 graphs) by contraction of a perfect matching and deletion of the resulting parallel edges, in a form suitable for the study of their Tutte uniqueness.Comment: 14 figure

Parallel PARKing: Parkinson’s Genes Function in Common Pathway

Parkinson’s disease (PD) is associated with diverse genetic and environmental susceptibilities. Functional connections between PD genes have remained elusive. In this issue of Neuron, MacLeod et al. (2013) link three PD susceptibility genes, LRRK2, PARK16, and VSP35, to a common cellular pathway and show how these deficits contribute to dysfunction

Cell Biology. Clogging information flow in ALS.

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a devastating neurodegenerative disorder that causes a progressive loss of motor neurons, leading to paralysis and death typically within 2 to 5 years of onset. There are no cures and few treatments. ALS shares some genetic and pathological overlap with another neurodegenerative disease, frontotemporal dementia (FTD), which causes changes to personality and language. Mutations in the gene called chromosome 9 open reading frame 72 (C9orf72) are the most common genetic cause of both ALS and FTD. This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science on [Volume 345 on 5 September 2014], DOI: 10.1126/science.1259461

PlexinD1 and Semaphorin Signaling Are Required in Endothelial Cells for Cardiovascular Development

AbstractThe identification of new signaling pathways critical for cardiac morphogenesis will contribute to our understanding of congenital heart disease (CHD), which remains a leading cause of mortality in newborn children worldwide. Signals mediated by semaphorin ligands and plexin receptors contribute to the intricate patterning of axons in the central nervous system. Here, we describe a related signaling pathway involving secreted class 3 semaphorins, neuropilins, and a plexin receptor, PlexinD1, expressed by endothelial cells. Interruption of this pathway in mice results in CHD and vascular patterning defects. The type of CHD caused by inactivation of PlexinD1 has previously been attributed to abnormalities of neural crest. Here, we show that this form of CHD can be caused by cell-autonomous endothelial defects. Thus, molecular programs that mediate axon guidance in the central nervous system also function in endothelial cells to orchestrate critical aspects of cardiac morphogenesis

Stress granules as crucibles of ALS pathogenesis

Amyotrophic lateral sclerosis (ALS) is a fatal human neurodegenerative disease affecting primarily motor neurons. Two RNA-binding proteins, TDP-43 and FUS, aggregate in the degenerating motor neurons of ALS patients, and mutations in the genes encoding these proteins cause some forms of ALS. TDP-43 and FUS and several related RNA-binding proteins harbor aggregation-promoting prion-like domains that allow them to rapidly self-associate. This property is critical for the formation and dynamics of cellular ribonucleoprotein granules, the crucibles of RNA metabolism and homeostasis. Recent work connecting TDP-43 and FUS to stress granules has suggested how this cellular pathway, which involves protein aggregation as part of its normal function, might be coopted during disease pathogenesis

The KO*-rings of BT^m, the Davis-Januszkiewicz Spaces and certain toric manifolds

This paper contains an explicit computation of the KO*-ring structure of an m-fold product of CP^{\infty}, the Davis-Januszkiewicz spaces and toric manifolds which have trivial Sq^2-homology.Comment: 34 page

Efficient Prevention of Neurodegenerative Diseases by Depletion of Starvation Response Factor Ataxin-2

Ataxin-2 (ATXN2) homologs exist in all eukaryotic organisms and may have contributed to their origin. Apart from a role in endocytosis, they are known for global effects on mRNA repair and ribosomal translation. Cell size, protein synthesis, and fat and glycogen storage are repressed by ATXN2 via mTORC1 signaling. However, specific liver mitochondrial matrix enzymes and the mitochondrial repair factor PINK1 require ATXN2 abundance. During periods of starvation, ATXN2 is transcriptionally induced and localized to cytosolic stress granules, where nuclear factors dock to compensate RNA pathology. These physiological actions were now revealed to be crucial for human neurodegenerative diseases, given that ATXN2 depletion is surprisingly efficient in preventing motor neuron and cerebellar atrophy, as demonstrated in mouse models, flies, and yeast

Regularity of squarefree monomial ideals

We survey a number of recent studies of the Castelnuovo-Mumford regularity of squarefree monomial ideals. Our focus is on bounds and exact values for the regularity in terms of combinatorial data from associated simplicial complexes and/or hypergraphs.Comment: 23 pages; survey paper; minor changes in V.

Semaphorin-Plexin Signaling Guides Patterning of the Developing Vasculature

AbstractMajor vessels of the vertebrate circulatory system display evolutionarily conserved and reproducible anatomy, but the cues guiding this stereotypic patterning remain obscure. In the nervous system, axonal pathways are shaped by repulsive cues provided by ligands of the semaphorin family that are sensed by migrating neuronal growth cones through plexin receptors. We show that proper blood vessel pathfinding requires the endothelial receptor PlexinD1 and semaphorin signals, and we identify mutations in plexinD1 in the zebrafish vascular patterning mutant out of bounds. These results reveal the fundamental conservation of repulsive patterning mechanisms between axonal migration in the central nervous system and vascular endothelium during angiogenesis

CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity.

Hexanucleotide-repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). The nucleotide-repeat expansions are translated into dipeptide-repeat (DPR) proteins, which are aggregation prone and may contribute to neurodegeneration. We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells. We validated hits by performing secondary CRISPR-Cas9 screens in primary mouse neurons. We uncovered potent modifiers of DPR toxicity whose gene products function in nucleocytoplasmic transport, the endoplasmic reticulum (ER), proteasome, RNA-processing pathways, and chromatin modification. One modifier, TMX2, modulated the ER-stress signature elicited by C9ORF72 DPRs in neurons and improved survival of human induced motor neurons from patients with C9ORF72 ALS. Together, our results demonstrate the promise of CRISPR-Cas9 screens in defining mechanisms of neurodegenerative diseases