NuSTAR Tests of Sterile-Neutrino Dark Matter: New Galactic Bulge Observations and Combined Impact

We analyze two dedicated NuSTAR observations with exposure ${\sim}190$ ks located ${\sim}10^\circ$ from the Galactic plane, one above and the other below, to search for x-ray lines from the radiative decay of sterile-neutrino dark matter. These fields were chosen to minimize astrophysical x-ray backgrounds while remaining near the densest region of the dark matter halo. We find no evidence of anomalous x-ray lines in the energy range 5--20 keV, corresponding to sterile neutrino masses 10--40 keV. Interpreted in the context of sterile neutrinos produced via neutrino mixing, these observations provide the leading constraints in the mass range 10--12 keV, improving upon previous constraints in this range by a factor ${\sim}2$. We also compare our results to Monte Carlo simulations, showing that the fluctuations in our derived limit are not dominated by systematic effects. An updated model of the instrumental background, which is currently under development, will improve NuSTAR's sensitivity to anomalous x-ray lines, particularly for energies 3--5 keV.Comment: 16 pages, 5 figures. Text updated to match published version in PRD. Conclusions unchange

Putting all the X in one basket: Updated X-ray constraints on sub-GeV Dark Matter

Sub-GeV dark matter particles can annihilate or decay producing e^\pm pairs which upscatter the low-energy photon fields in the Galaxy and generate an X-ray emission (via the Inverse Compton effect). Using X-ray data from Xmm-Newton, Integral, NuStar and Suzaku, we derive new constraints on this class of dark matter (DM). In the annihilation case, our new bounds are the strongest available for DM masses above 180 MeV, reaching < 10^-28 cm^3/s for m_DM ~ 1 GeV. In the decay case, our bounds are the strongest to date over a large fraction of the considered mass range, constraining tau > 10^28 s for m_DM ~ 1 GeV and improving by up to 3 orders of magnitude upon existing limits.Comment: 16 pages, 9 figure

Constraints on Axion-like Particles from a Hard XX-ray Observation of Betelgeuse

We use the first observation of Betelgeuse in hard $X$-rays to perform a novel search for axion-like particles (ALPs). Betelgeuse is not expected to be a standard source of $X$-rays, but light ALPs produced in the stellar core could be converted back into photons in the Galactic magnetic field, producing a detectable flux that peaks in the hard $X$-ray band ($E_\gamma>10\mathrm{\,keV}$). Using a 50 ks observation of Betelgeuse by the $NuSTAR$ satellite telescope, we find no significant excess of events above the expected background. Using models of the regular Galactic magnetic field in the direction of Betelgeuse, we set a 95% C.L. upper limit on the ALP-photon coupling of ${g_{a\gamma}<(0.5-1.8)\times10^{-11}}$ GeV$^{-1}$ (depending on magnetic field model) for ALP masses ${m_{a}<(5.5-3.5) \times10^{-11}}$ eV

Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

SummaryWe report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCCs/PGLs), a rare tumor type. Multi-platform integration revealed that PCCs/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, and NF1). We also discovered fusion genes in PCCs/PGLs, involving MAML3, BRAF, NGFR, and NF1. Integrated analysis classified PCCs/PGLs into four molecularly defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCCs/PGLs included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong

New constraints on sterile neutrino dark matter from NuSTAR M31 observations

© 2019 American Physical Society. We use a combined 1.2 Ms of NuSTAR observations of M31 to search for x-ray lines from sterile neutrino dark matter decay. For the first time in a NuSTAR analysis, we consistently take into account the signal contribution from both the focused and unfocused fields of view. We also reduce the modeling systematic uncertainty by performing spectral fits to each observation individually and statistically combining the results, instead of stacking the spectra. We find no evidence of unknown lines, and thus derive limits on the sterile neutrino parameters. Our results place stringent constraints for dark matter masses 12 keV, which reduces the available parameter space for sterile neutrino dark matter produced via neutrino mixing (e.g., in the νMSM) by approximately one-third. Additional NuSTAR observations, together with improved low-energy background modeling, could probe the remaining parameter space in the future. Lastly, we also report model-independent limits on generic dark matter decay rates and annihilation cross sections

Targeting Pathogenic Lafora Bodies in Lafora Disease Using an Antibody-Enzyme Fusion

Lafora disease (LD) is a fatal childhood epilepsy caused by recessive mutations in either the EPM2A or EPM2B gene. A hallmark of LD is the intracellular accumulation of insoluble polysaccharide deposits known as Lafora bodies (LBs) in the brain and other tissues. In LD mouse models, genetic reduction of glycogen synthesis eliminates LB formation and rescues the neurological phenotype. Therefore, LBs have become a therapeutic target for ameliorating LD. Herein, we demonstrate that human pancreatic α-amylase degrades LBs. We fused this amylase to a cell-penetrating antibody fragment, and this antibody-enzyme fusion (VAL-0417) degrades LBs in vitro and dramatically reduces LB loads in vivo in Epm2a−/− mice. Using metabolomics and multivariate analysis, we demonstrate that VAL-0417 treatment of Epm2a−/− mice reverses the metabolic phenotype to a wild-type profile. VAL-0417 is a promising drug for the treatment of LD and a putative precision therapy platform for intractable epilepsy