Retinitis Pigmentosa (RP) is a hereditary retinal disorder that causes the atrophy of photoreceptor rod cells. Since individual defective genes converge on the same disease, we hypothesized that all causal genes of RP belong in a complex network. To explore this hypothesis, we conducted a gene connection analysis using 161 genes attributed to RP, compiled from the Retinal Information Network, RetNet. We then examined the protein interaction network (PIN) of these genes. In line with our hypothesis, using STRING, we directly connected 149 genes out of the recognized 159 genes. To uncover the association between the PIN and the ten unrecalled genes, we developed an algorithm to pinpoint the best candidate genes to connect the uncalled genes to the PIN and identified ten such genes. We propose that mutations within these ten genes may also cause RP; this notion is supported by analyzing and categorizing the known causal genes based on cellular locations and related functions. The successful establishment of the PIN among all documented genes and the discovery of novel genes for RP strongly suggest an interconnectedness that causes the disease on the molecular level. In addition, our computational gene search protocol can help identify the genes and loci responsible for genetic diseases, not limited to RP.

Low-grade gliomas are one of the most common brain tumors in children, where they frequently form within the optic pathway (optic pathway gliomas; OPGs). Since many OPGs occur in the context of the Neurofibromatosis Type 1 (NF1) cancer predisposition syndrome, we have previously employed Nf1 genetically-engineered mouse (GEM) strains to study the pathogenesis of these low-grade glial neoplasms. In the light of the finding that human and mouse low-grade gliomas are composed of Olig2+ cells and that Olig2+ oligodendrocyte precursor cells (OPCs) give rise to murine high-grade gliomas, we sought to determine whether Olig2+ OPCs could be tumor-initiating cells for Nf1 optic glioma. Similar to the GFAP-Cre transgenic strain previously employed to generate Nf1 optic gliomas, Olig2+ cells also give rise to astrocytes in the murine optic nerve in vivo. However, in contrast to the GFAP-Cre strain where somatic Nf1 inactivation in embryonic neural progenitor/stem cells (Nf1flox/mut; GFAP-Cre mice) results in optic gliomas by 3 months of age in vivo, mice with Nf1 gene inactivation in Olig2+ OPCs (Nf1flox/mut; Olig2-Cre mice) do not form optic gliomas until 6 months of age. These distinct patterns of glioma latency do not reflect differences in the timing or brain location of somatic Nf1 loss. Instead, they most likely reflect the cell of origin, as somatic Nf1 loss in CD133+ neural progenitor/stem cells during late embryogenesis results in optic gliomas at 3 months of age. Collectively, these data demonstrate that the cell of origin dictates the time to tumorigenesis in murine optic glioma.

Neurons have recently emerged as essential cellular constituents of the tumour microenvironment, and their activity has been shown to increase the growth of a diverse number of solid tumours¹. Although the role of neurons in tumour progression has previously been demonstrated², the importance of neuronal activity to tumour initiation is less clear-particularly in the setting of cancer predisposition syndromes. Fifteen per cent of individuals with the neurofibromatosis 1 (NF1) cancer predisposition syndrome (in which tumours arise in close association with nerves) develop low-grade neoplasms of the optic pathway (known as optic pathway gliomas (OPGs)) during early childhood^3,4, raising  the possibility that postnatal light-induced activity of the optic nerve drives tumour initiation. Here we use an authenticated mouse model of OPG driven by mutations in the neurofibromatosis 1 tumour suppressor gene (Nf1)⁵ to demonstrate that stimulation of optic nerve activity increases optic glioma growth, and that decreasing visual experience via light deprivation prevents tumour formation and maintenance. We show that the initiation of Nf1-driven OPGs (Nf1-OPGs) depends on visual experience during a developmental period in which Nf1-mutant mice are susceptible to tumorigenesis. Germline Nf1 mutation in retinal neurons results in aberrantly increased shedding of neuroligin 3 (NLGN3) within the optic nerve in response to retinal neuronal activity. Moreover, genetic Nlgn3 loss or pharmacological inhibition of NLGN3 shedding blocks the formation and progression of Nf1-OPGs. Collectively, our studies establish an obligate role for neuronal activity in the development of some types of brain tumours, elucidate a therapeutic strategy to reduce OPG incidence or mitigate tumour progression, and underscore the role of Nf1mutation-mediated dysregulation of neuronal signalling pathways in mouse models of the NF1 cancer predisposition syndrome.

The Cryogenic Underground Observatory for Rare Events (CUORE) is the first bolometric experiment searching for neutrinoless double beta decay that has been able to reach the 1-ton scale. The detector consists of an array of 988 TeO 2 crystals arranged in a cylindrical compact structure of 19 towers, each of them made of 52 crystals. The construction of the experiment was completed in August 2016 and the data taking started in spring 2017 after a period of commissioning and tests. In this work we present the neutrinoless double beta decay results of CUORE from examining a total TeO 2 exposure of 86.3 kg yr, characterized by an effective energy resolution of 7.7 keV FWHM and a background in the region of interest of 0.014 counts/(keV kg yr). In this physics run, CUORE placed a lower limit on the decay half-life of neutrinoless double beta decay of 130 Te ≤ 1.3 · 10 25 yr (90% C.L.). Moreover, an analysis of the background of the experiment is presented as well as the measurement of the 130 Te 2vββ decay with a resulting half-life of T 2v1/2 = [7.9 ± 0.1 (stat.) ± 0.2 (syst.)] x 10 20 yr which is the most precise measurement of the half-life and compatible with previous results.