Persistent Wnt/β-catenin signaling determines dorsalization of the postnatal subventricular zone and neural Stem cell specification into oligodendrocytes and glutamatergic neurons

In the postnatal and adult central nervous system (CNS), the subventricular zone (SVZ) of the forebrain is the main source of neural stem cells (NSCs) that generate olfactory neurons and oligodendrocytes (OLs), the myelinating cells of the CNS. Here, we provide evidence of a primary role for canonical Wnt/β-catenin signaling in regulating NSC fate along neuronal and oligodendroglial lineages in the postnatal SVZ. Our findings demonstrate that glutamatergic neuronal precursors (NPs) and oligodendrocyte precursors (OPs) are derived strictly from the dorsal SVZ (dSVZ) microdomain under the control of Wnt/β-catenin, whereas GABAergic NPs are derived mainly from the lateral SVZ (lSVZ) microdomain independent of Wnt/β-catenin. Transcript analysis of microdissected SVZ microdomains revealed that canonical Wnt/β-catenin signaling was more pronounced in the dSVZ microdomain. This was confirmed using the β-catenin-activated Wnt-reporter mouse and by pharmacological stimulation of Wnt/β-catenin by infusion of the specific glycogen synthase kinase 3β inhibitor, AR-A014418, which profoundly increased the generation of cycling cells. In vivo genetic/pharmacological stimulation or inhibition of Wnt/β-catenin, respectively, increased and decreased the differentiation of dSVZ-NSCs into glutamatergic NPs, and had a converse effect on GABAergic NPs. Activation of Wnt/β-catenin dramatically stimulated the generation of OPs, but its inhibition had no effect, indicating other factors act in concert with Wnt/β-catenin to fine tune oligodendrogliogenesis in the postnatal dSVZ. These results demonstrate a role for Wnt/β-catenin signaling within the dorsal microdomain of the postnatal SVZ, in regulating the genesis of glutamatergic neurons and OLs

A highly conserved SOX6 double binding site mediates SOX6 gene downregulation in erythroid cells

The Sox6 transcription factor plays critical roles in various cell types, including erythroid cells. Sox6-deficient mice are anemic due to impaired red cell maturation and show inappropriate globin gene expression in definitive erythrocytes. To identify new Sox6 target genes in erythroid cells, we used the known repressive double Sox6 consensus within the εy-globin promoter to perform a bioinformatic genome-wide search for similar, evolutionarily conserved motifs located within genes whose expression changes during erythropoiesis. We found a highly conserved Sox6 consensus within the Sox6 human gene promoter itself. This sequence is bound by Sox6 in vitro and in vivo, and mediates transcriptional repression in transient transfections in human erythroleukemic K562 cells and in primary erythroblasts. The binding of a lentiviral transduced Sox6FLAG protein to the endogenous Sox6 promoter is accompanied, in erythroid cells, by strong downregulation of the endogenous Sox6 transcript and by decreased in vivo chromatin accessibility of this region to the PstI restriction enzyme. These observations suggest that the negative Sox6 autoregulation, mediated by the double Sox6 binding site within its own promoter, may be relevant to control the Sox6 transcriptional downregulation that we observe in human erythroid cultures and in mouse bone marrow cells in late erythroid maturation

Common genetic variants associated with pancreatic adenocarcinoma may also modify risk of pancreatic neuroendocrine neoplasms (vol 39, pg 360, 2018)

Pancreatic neuroendocrine neoplasms (pNEN) account for less than 5% of all pancreatic neoplasms and genetic association studies on susceptibility to the disease are limited. We sought to identify possible overlap of genetic susceptibility loci between pancreatic ductal adenocarcinoma (PDAC) and pNEN; therefore, PDAC susceptibility variants (n=23) from Caucasian genome-wide association studies (GWAS) were genotyped in 369 pNEN cases and 3,277 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium to evaluate the odds associated with pNEN risk, disease onset and tumor characteristics. Main effect analyses showed four PDAC susceptibility variants – rs9854771, rs1561927, rs9543325 and rs10919791 to be associated with pNEN risk. Subsequently, only associations with rs9543325, rs10919791 and rs1561927 were noteworthy with false positive report probability (FPRP) tests. Stratified analyses considering age at onset (50 year threshold), showed rs2736098, rs16986825 and rs9854771 to be associated with risk of developing pNEN at a younger age. Stratified analyses also showed some SNPs to be associated with different degrees of tumor grade, metastatic potential and functionality. Our results identify known GWAS PDAC susceptibility loci, which may also be involved in sporadic pNEN etiology and suggest that some genetic mechanisms governing pathogenesis of these two entities may be similar, with few of these loci being more influential in younger cases or tumor subtypes

Non-standard neutrino interactions in IceCube

Non-standard neutrino interactions (NSI) may arise in various types of new physics. Their existence would change the potential that atmospheric neutrinos encounter when traversing Earth matter and hence alter their oscillation behavior. This imprint on coherent neutrino forward scattering can be probed using high-statistics neutrino experiments such as IceCube and its low-energy extension, DeepCore. Both provide extensive data samples that include all neutrino flavors, with oscillation baselines between tens of kilometers and the diameter of the Earth. DeepCore event energies reach from a few GeV up to the order of 100 GeV - which marks the lower threshold for higher energy IceCube atmospheric samples, ranging up to 10 TeV. In DeepCore data, the large sample size and energy range allow us to consider not only flavor-violating and flavor-nonuniversal NSI in the μ−τ sector, but also those involving electron flavor. The effective parameterization used in our analyses is independent of the underlying model and the new physics mass scale. In this way, competitive limits on several NSI parameters have been set in the past. The 8 years of data available now result in significantly improved sensitivities. This improvement stems not only from the increase in statistics but also from substantial improvement in the treatment of systematic uncertainties, background rejection and event reconstruction

IceCube Search for Earth-traversing ultra-high energy Neutrinos

The search for ultra-high energy neutrinos is more than half a century old. While the hunt for these neutrinos has led to major leaps in neutrino physics, including the detection of astrophysical neutrinos, neutrinos at the EeV energy scale remain undetected. Proposed strategies for the future have mostly been focused on direct detection of the first neutrino interaction, or the decay shower of the resulting charged particle. Here we present an analysis that uses, for the first time, an indirect detection strategy for EeV neutrinos. We focus on tau neutrinos that have traversed Earth, and show that they reach the IceCube detector, unabsorbed, at energies greater than 100 TeV for most trajectories. This opens up the search for ultra-high energy neutrinos to the entire sky. We use ten years of IceCube data to perform an analysis that looks for secondary neutrinos in the northern sky, and highlight the promise such a strategy can have in the next generation of experiments when combined with direct detection techniques

Posteriori analysis on IceCube double pulse tau neutrino candidates

The IceCube Neutrino Observatory at the South Pole detects Cherenkov light emitted by charged secondary particles created by primary neutrino interactions. Double pulse waveforms can arise from charged current interactions of astrophysical tau neutrinos with nucleons in the ice and the subsequent decay of tau leptons. The previous 8-year tau double pulse analysis found three tau neutrino candidate events. Among them, the most promising one observed in 2014 is located very near the dust layer in the middle of the detector. A posterior analysis on this event will be presented in this paper, using a new ice model treatment with continuously varying nuisance parameters to do the targeted Monte Carlo re-simulation for tau and other background neutrino ensembles. The impact of different ice models on the expected signal and background statistics will also be discussed