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

On the Rational Type 0f Moment Angle Complexes

In this note it is shown that the moment angle complexes Z(K;(D^2,,S^1)) which are rationally elliptic are a product of odd spheres and a diskComment: This version avoids the use of an incorrect result from the literature in the proof of Theorem 1.3. There is some text overlap with arXiv:1410.645

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.

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

Symbolic powers of monomial ideals and Cohen-Macaulay vertex-weighted digraphs

In this paper we study irreducible representations and symbolic Rees algebras of monomial ideals. Then we examine edge ideals associated to vertex-weighted oriented graphs. These are digraphs having no oriented cycles of length two with weights on the vertices. For a monomial ideal with no embedded primes we classify the normality of its symbolic Rees algebra in terms of its primary components. If the primary components of a monomial ideal are normal, we present a simple procedure to compute its symbolic Rees algebra using Hilbert bases, and give necessary and sufficient conditions for the equality between its ordinary and symbolic powers. We give an effective characterization of the Cohen--Macaulay vertex-weighted oriented forests. For edge ideals of transitive weighted oriented graphs we show that Alexander duality holds. It is shown that edge ideals of weighted acyclic tournaments are Cohen--Macaulay and satisfy Alexander dualityComment: Special volume dedicated to Professor Antonio Campillo, Springer, to appea

The yeast P5 type ATPase, Spf1, regulates manganese transport into the endoplasmic reticulum

The endoplasmic reticulum (ER) is a large, multifunctional and essential organelle. Despite intense research, the function of more than a third of ER proteins remains unknown even in the well-studied model organism Saccharomyces cerevisiae. One such protein is Spf1, which is a highly conserved, ER localized, putative P-type ATPase. Deletion of SPF1 causes a wide variety of phenotypes including severe ER stress suggesting that this protein is essential for the normal function of the ER. The closest homologue of Spf1 is the vacuolar P-type ATPase Ypk9 that influences Mn2+ homeostasis. However in vitro reconstitution assays with Spf1 have not yielded insight into its transport specificity. Here we took an in vivo approach to detect the direct and indirect effects of deleting SPF1. We found a specific reduction in the luminal concentration of Mn2+ in ∆spf1 cells and an increase following it’s overexpression. In agreement with the observed loss of luminal Mn2+ we could observe concurrent reduction in many Mn2+-related process in the ER lumen. Conversely, cytosolic Mn2+-dependent processes were increased. Together, these data support a role for Spf1p in Mn2+ transport in the cell. We also demonstrate that the human sequence homologue, ATP13A1, is a functionally conserved orthologue. Since ATP13A1 is highly expressed in developing neuronal tissues and in the brain, this should help in the study of Mn2+-dependent neurological disorders

Cisplatin and Oxaliplatin Toxicity: Importance of Cochlear Kinetics as a Determinant for Ototoxicity

Background Cisplatin is a commonly used platinum anti-cancer drug. Regrettably cisplatin has dose-limiting ototoxic side effects, e.g. the drug can induce an irreversible hearing loss. The ototoxic mechanisms of cisplatin have not been elucidated in the human ear and no clinically useful oto-protectors are yet available. Cisplatin is a necessary part of many treatment regimes. Its beneficial therapeutic effects might be reduced if cisplatin was excluded from the treatment in order to protect the hearing function. In this work the ototoxic effects of cisplatin are studied with the aim to better understand the mechanisms behind the irreversible hearing loss induced by this drug. Oxaliplatin is a second generation platinum-derivative anti-cancer drug, free from ototoxic side effects in clinical practice. The effects of oxaliplatin on the inner ear have been studied in this work and the results are compared with cisplatin treatment. The two drugs differ regarding both anti-cancer effects and side effects, which could be attributed to differences in pharmacokinetic factors, cellular uptake and apoptotic mechanisms. The thioredoxin redox system with the enzyme thioredoxin reductase (TrxR) was studied in cochleae due to a suggested DNA-independent apoptotic mechanism of the hair cells. The cochlear pharmacokinetics of cisplatin was assessed and the transport protein organic cation transporter 2 (OCT2) was studied in relation to the ototoxic effect of cisplatin. Material and methods Cultured human colon carcinoma cells and cell cultures of rat organ of Corti were used for apoptosis studies in vitro following exposure to cisplatin and oxaliplatin. Cisplatin and oxaliplatin were administered i.v. to guinea pigs, followed by in vivo sampling of blood, cerebrospinal fluid (CSF) and scala tympani (ST) perilymph. Liquid chromatography with post-column derivatization was used to determine the concentration of parent drug in the samples. Electrophysiological hearing thresholds and the loss of hair cells were assessed to evaluate their ototoxic effects. Phenformin, a potential blocker of OCT2 was administered and the ototoxic side effect of cisplatin was evaluated. For immunohistochemical studies, cochlea from rat, guinea pig and pig were used, where TrxR and OCT2 were evaluated in the cochlea. TrxR-assays were used to measure the TrxR activity in cochlear tissue, both in vivo and in vitro. Results The results from the in vitro studies showed that addition of either cisplatin or oxaliplatin to the culture medium in organ of Corti cell cultures caused a similar amount of outer hair cell loss and inhibition of TrxR activity. Cisplatin exposure to cultured human colon carcinoma cells also reduced the activity of TrxR. The results from the in vivo studies showed that a considerable concentration of cisplatin was present in ST perilymph as compared with weak concentrations of oxaliplatin after high dose oxaliplatin i.v. Ten minutes after cisplatin administration, its concentration in ST perilymph was 4-fold higher in the basal turn of the cochlea as compared to the apex. Cisplatin could be analysed in ST perilymph for up to 120 min. Phenformin i.v. did not reduce the ototoxic side-effect of cisplatin. Positive immunoreactivity to TrxR was evident in both hair cells and spiral ganglion cells. Futhermore, OCT2 was expressed in the supporting cells of organ of Corti and in the spiral ganglion cells. Conclusion The transport of cisplatin to the vulnerable cells of hearing seems to be of major importance for the ototoxic effects. An early high concentration of cisplatin in the base of the cochlea and delayed elimination of cisplatin from ST perilymph may be related to the cisplatin-induced loss of outer hair cells in the basal turn of the cochlea. Cisplatin and oxaliplatin both cause similar ototoxic effects when the organ of Corti is directly exposed in vitro. The thioredoxin redox system with the TrxR enzyme may well play a critical role in cisplatininduced ototoxicity. The presence of OCT2 in the supporting cells indicates that this transport protein is primarily not involved in the uptake of cisplatin from the systemic circulation but rather from the deeper compartments of the cochlea. The knowledge elicited in this work will hopefully suggest objectives for further studies in order to develop oto-protective treatments to preserve the hearing of cisplatin treated patients