On the irrationality of moduli spaces of projective hyperk\"ahler manifolds

The aim of this paper is to estimate the irrationality of moduli spaces of hyperk\"ahler manifolds of types K3$^{[n]}$, Kum$_{n}$, OG6, and OG10. We prove that the degrees of irrationality of these moduli spaces are bounded from above by a universal polynomial in the dimension and degree of the manifolds they parametrize. We also give a polynomial bound for the degrees of irrationality of moduli spaces of $(1,d)$-polarized abelian surfaces.Comment: 29 pages. Comments are welcome

On the irrationality of moduli spaces of K3 surfaces

We study how the degrees of irrationality of moduli spaces of polarized K3 surfaces grow with respect to the genus. We prove that the growth is bounded by a polynomial function of degree $14+\varepsilon$ for any $\varepsilon>0$ and, for three sets of infinitely many genera, the bounds can be improved to degree 10. The main ingredients in our proof are the modularity of the generating series of Heegner divisors due to Borcherds and its generalization to higher codimensions due to Kudla, Millson, Zhang, Bruinier, and Westerholt-Raum. For special genera, the proof is also built upon the existence of K3 surfaces associated with certain cubic fourfolds, Gushel-Mukai fourfolds, and hyperkaehler fourfolds.Comment: v2: Results substantially improved. We use Kudla's modularity conjecture to obtain a uniform polynomial bound of the degrees of irrationality for all moduli spaces of polarized K3s. 20 page

Efficient neighborhood evaluations for the vehicle routing problem with multiple time windows

In the vehicle routing problem with multiple time windows (VRPMTW), a single time window must be selected for each customer from the multiple time windows provided. Compared with classical vehicle routing problems with only a single time window per customer, multiple time windows increase the complexity of the routing problem. To minimize the duration of any given route, we present an exact polynomial time algorithm to efficiently determine the optimal start time for servicing each customer. The proposed algorithm has a reduced worst-case and average complexity than existing exact algorithms. Furthermore, the proposed exact algorithm can be used to efficiently evaluate neighborhood operations during a local search resulting in significant acceleration. To examine the benefits of exact neighborhood evaluations and to solve the VRPMTW, the proposed algorithm is embedded in a simple metaheuristic framework generating numerous new best known solutions at competitive computation times

A geospatial approach for mapping the earthquake-induced liquefaction risk at the european scale

none6noopenBozzoni Francesca, Roberta Bonì, Daniele Conca, Claudia Meisina, Carlo G. Lai, Elisa ZuccoloBozzoni, Francesca; Boni', Roberta; Daniele, Conca; Claudia, Meisina; Lai, Carlo G.; Elisa, Zuccol

Impact of remnant vital tissue after locoregional treatment and liver transplant in hepatocellular cancer patients. A multicentre cohort study

The role of pathological findings after locoregional treatments as predictors of hepatocellular cancer recurrence after liver transplantation has been poorly addressed. The aim of the study was to identify the role of remnant vital tissue (RVT) of the target lesion in predicting hepatocellular cancer recurrence. Two hundred and seventy-six patients firstly undergoing locoregional treatment and then transplanted between January 2010 and December 2015 in four European Transplant Centres (i.e. Rome Tor Vergata, Birmingham, Brussels and Ancona) were enrolled in the study to investigate the role of pathological response at upfront locoregional treatment. At multivariable Cox regression analysis, RVT ≥2 cm was a strong independent risk factor for post-LT recurrence (HR = 5.6; P < 0.0001). Five-year disease-free survival rates were 60.8%, 80.9% and 95.0% in patients presenting a RVT ≥2 cm vs. 0.1-1.9 vs. no RVT, respectively. When only Milan Criteria-IN patients were analysed, similar results were reported, with 5-year disease-free survival rates of 58.1%, 79.0% and 94.0% in patients presenting a RVT ≥2 cm vs. 0.1-1.9 vs. no RVT, respectively. RVT is an important determinant of tumour recurrence after liver transplantation performed for hepatocellular cancer. Its discriminative power looks to be evident also in a Milan-IN setting, suggesting to more liberally use locoregional treatments also in these patients

Imaging Self-aligned Moir\'e Crystals and Quasicrystals in Magic-angle Bilayer Graphene on hBN Heterostructures

Using scanning-tunneling-microscopy and theoretical modeling on heterostructures of twisted bilayer graphene and hexagonal Boron-Nitride, we show that the emergent super-moire structures display a rich landscape of moire-crystals and quasicrystals. We reveal a phase-diagram comprised of commensurate moire-crystals embedded in swaths of moire quasicrystals. The 1:1 commensurate crystal, expected to be a Chern insulator, should only exist at one point on the phase-diagram, implying that it ought to be practically undetectable. Surprisingly we find that the commensurate crystals exist over a much wider than predicted range, providing evidence of an unexpected self-alignment mechanism that is explained using an elastic-network model. The remainder of the phase-diagram, where we observe tunable quasicrystals, affords a new platform for exploring the unique electronic-properties of these rarely found in nature structures.Comment: 37 pages, 18 figure

Complete Acid Ceramidase ablation prevents cancer-initiating cell formation in melanoma cells

Acid ceramidase (AC) is a lysosomal cysteine hydrolase that catalyzes the conversion of ceramide into fatty acid and sphingosine. This reaction lowers intracellular ceramide levels and concomitantly generates sphingosine used for sphingosine-1-phosphate (S1P) production. Since increases in ceramide and consequent decreases of S1P reduce proliferation of various cancers, AC might offer a new target for anti-tumor therapy. Here we used CrispR-Cas9-mediated gene editing to delete the gene encoding for AC, ASAH1, in human A375 melanoma cells. ASAH1-null clones show significantly greater accumulation of long-chain saturated ceramides that are substrate for AC. As seen with administration of exogenous ceramide, AC ablation blocks cell cycle progression and accelerates senescence. Importantly, ASAH1-null cells also lose the ability to form cancer-initiating cells and to undergo self-renewal, which is suggestive of a key role for AC in maintaining malignancy and self-renewal of invasive melanoma cells. The results suggest that AC inhibitors might find therapeutic use as adjuvant therapy for advanced melanoma

Acid ceramidase controls apoptosis and increases autophagy in human melanoma cells treated with doxorubicin

Acid ceramidase (AC) is a lysosomal hydrolase encoded by the ASAH1 gene, which cleaves ceramides into sphingosine and fatty acid. AC is expressed at high levels in most human melanoma cell lines and may confer resistance against chemotherapeutic agents. One such agent, doxorubicin, was shown to increase ceramide levels in melanoma cells. Ceramides contribute to the regulation of autophagy and apoptosis. Here we investigated the impact of AC ablation via CRISPR-Cas9 gene editing on the response of A375 melanoma cells to doxorubicin. We found that doxorubicin activates the autophagic response in wild-type A375 cells, which effectively resist apoptotic cell death. In striking contrast, doxorubicin fails to stimulate autophagy in A375 AC-null cells, which rapidly undergo apoptosis when exposed to the drug. The present work highlights changes that affect melanoma cells during incubation with doxorubicin, in A375 melanoma cells lacking AC. We found that the remarkable reduction in recovery rate after doxorubicin treatment is strictly associated with the impairment of autophagy, that forces the AC-inhibited cells into apoptotic path