Coupling of D2R Short but not D2R Long receptor isoform to the Rho/ROCK signaling pathway renders striatal neurons vulnerable to mutant huntingtin.

Huntington's disease, an inherited neurodegenerative disorder, results from abnormal polyglutamine extension in the N-terminal region of the huntingtin protein. This mutation causes preferential degeneration of striatal projection neurons. We previously demonstrated, in vitro, that dopaminergic D2 receptor stimulation acted in synergy with expanded huntingtin to increase aggregates formation and striatal death through activation of the Rho/ROCK signaling pathway. In vivo, in a lentiviral-mediated model of expanded huntingtin expression in the rat striatum, we found that the D2 antagonist haloperidol protects striatal neurons against expanded huntingtin-mediated toxicity. Two variant transcripts are generated by alternative splicing of the of D2 receptor gene, the D2R-Long and the D2R-Short, which are thought to play different functional roles. We show herein that overexpression of D2R-Short, but not D2R-Long in cell lines is associated with activation of the RhoA/ROCK signaling pathway. In striatal neurons in culture, the selective D2 agonist Quinpirole triggers phosphorylation of cofilin, a downstream effector of ROCK, which is abrogated by siRNAs that knockdown both D2R-Long and D2R-Short, but not by siRNAs targeting D2R-Long alone. Aggregate formation and neuronal death induced by expanded huntingtin, were potentiated by Quinpirole. This D2 agonist-mediated effect was selectively inhibited by the siRNA targeting both D2R-Long and D2R-Short but not D2R-Long alone. Our data provide evidence for a specific coupling of D2R-Short to the RhoA/ROCK/cofilin pathway, and its involvement in striatal vulnerability to expanded huntingtin. A new route for targeting Rho-ROCK signaling in Huntington's disease is unraveled with our findings

Towards a new generation axion helioscope

We study the feasibility of a new generation axion helioscope, the most ambitious and promising detector of solar axions to date. We show that large improvements in magnetic field volume, x-ray focusing optics and detector backgrounds are possible beyond those achieved in the CERN Axion Solar Telescope (CAST). For hadronic models, a sensitivity to the axion-photon coupling of \gagamma\gtrsim {\rm few} \times 10^{-12} GeV$^{-1}$ is conceivable, 1--1.5 orders of magnitude beyond the CAST sensitivity. If axions also couple to electrons, the Sun produces a larger flux for the same value of the Peccei-Quinn scale, allowing one to probe a broader class of models. Except for the axion dark matter searches, this experiment will be the most sensitive axion search ever, reaching or surpassing the stringent bounds from SN1987A and possibly testing the axion interpretation of anomalous white-dwarf cooling that predicts $m_a$ of a few meV. Beyond axions, this new instrument will probe entirely unexplored ranges of parameters for a large variety of axion-like particles (ALPs) and other novel excitations at the low-energy frontier of elementary particle physics.Comment: 37 pages, 11 figures, accepted for publication in JCA

The International Axion Observatory (IAXO)

The International Axion Observatory (IAXO) is a new generation axion helioscope aiming at a sensitivity to the axion-photon coupling of a few 10$^{12}$ GeV$^{-1}$, i.e. 1 - 1.5 orders of magnitude beyond the one currently achieved by CAST. The project relies on improvements in magnetic field volume together with extensive use of x-ray focusing optics and low background detectors, innovations already successfully tested in CAST. Additional physics cases of IAXO could include the detection of electron-coupled axions invoked to solve the white dwarfs anomaly, relic axions, and a large variety of more generic axion-like particles (ALPs) and other novel excitations at the low-energy frontier of elementary particle physics. This contribution is a summary of our paper [1] to which we refer for further details.Comment: 4 pages, 2 figures. To appear in the proceedings of the 7th Patras Workshop on Axions, WIMPs and WISPs, Mykonos, Greece, 201

CAST constraints on the axion-electron coupling

In non-hadronic axion models, which have a tree-level axion-electron interaction, the Sun produces a strong axion flux by bremsstrahlung, Compton scattering, and axio-recombination, the "BCA processes." Based on a new calculation of this flux, including for the first time axio-recombination, we derive limits on the axion-electron Yukawa coupling g_ae and axion-photon interaction strength g_ag using the CAST phase-I data (vacuum phase). For m_a < 10 meV/c2 we find g_ag x g_ae< 8.1 x 10^-23 GeV^-1 at 95% CL. We stress that a next-generation axion helioscope such as the proposed IAXO could push this sensitivity into a range beyond stellar energy-loss limits and test the hypothesis that white-dwarf cooling is dominated by axion emission

The long-term outcomes of CIS patients in the Barcelona inception cohort: Looking back to recognize aggressive MS

OBJECTIVE: To explore the long-term outcomes of patients with clinically isolated syndromes from the Barcelona cohort. METHODS: We selected patients with a follow-up longer than 10 years to (1) estimate the risks of multiple sclerosis (MS) and disability accumulation according to the baseline number of T2 lesions and to compare treated versus untreated patients and early versus delayed treatment, and (2) to study baseline features of patients with aggressive MS (Expanded Disability Status Scale (EDSS) ⩾6.0 at 10 years). RESULTS: In all, 401 patients were included (mean follow-up of 14.4 (standard deviation of 2.9) years). A higher number of T2 lesions was associated with an earlier MS diagnosis and an earlier risk of irreversible disability. Early treatment was associated with a decreased risk of EDSS of 3.0: adjusted hazard ratio = 0.4, 95% confidence interval = (0.2, 0.7). Patients with aggressive MS differed in their baseline brain magnetic resonance images: The median (interquartile range) number of T2 lesions and contrast-enhancing lesions (CEL) was 71 (28–95) versus 7 (1–19) and 3 (1–24) versus 0 (0–1), respectively. The cut-offs that better classified patients with aggressive MS were 20 for T2 lesions and 2 for CEL. CONCLUSION: Although MS natural history is changing, a high lesion load at onset is helpful to identify patients at risk of presenting an aggressive MS

CAST solar axion search with 3^He buffer gas: Closing the hot dark matter gap

The CERN Axion Solar Telescope (CAST) has finished its search for solar axions with 3^He buffer gas, covering the search range 0.64 eV < m_a <1.17 eV. This closes the gap to the cosmological hot dark matter limit and actually overlaps with it. From the absence of excess X-rays when the magnet was pointing to the Sun we set a typical upper limit on the axion-photon coupling of g_ag < 3.3 x 10^{-10} GeV^{-1} at 95% CL, with the exact value depending on the pressure setting. Future direct solar axion searches will focus on increasing the sensitivity to smaller values of g_a, for example by the currently discussed next generation helioscope IAXO.Comment: 5 pages, 2 figures. Last version uploade

Extreme genomic erosion after recurrent demographic bottlenecks in the highly endangered Iberian lynx

Background: Genomic studies of endangered species provide insights into their evolution and demographic history, reveal patterns of genomic erosion that might limit their viability, and offer tools for their effective conservation. The Iberian lynx (Lynx pardinus) is the most endangered felid and a unique example of a species on the brink of extinction. Results: We generate the first annotated draft of the Iberian lynx genome and carry out genome-based analyses of lynx demography, evolution, and population genetics. We identify a series of severe population bottlenecks in the history of the Iberian lynx that predate its known demographic decline during the 20th century and have greatly impacted its genome evolution. We observe drastically reduced rates of weak-to-strong substitutions associated with GC-biased gene conversion and increased rates of fixation of transposable elements. We also find multiple signatures of genetic erosion in the two remnant Iberian lynx populations, including a high frequency of potentially deleterious variants and substitutions, as well as the lowest genome-wide genetic diversity reported so far in any species. Conclusions: The genomic features observed in the Iberian lynx genome may hamper short- and long-term viability through reduced fitness and adaptive potential. The knowledge and resources developed in this study will boost the research on felid evolution and conservation genomics and will benefit the ongoing conservation and management of this emblematic species

Spinal cord lesions: A modest contributor to diagnosis in clinically isolated syndromes but a relevant prognostic factor

Background: The usefulness of performing a spinal cord (SC) magnetic resonance imaging (MRI) in all clinically isolated syndromes (CIS) is controversial. Objective: To assess the value of SC lesions for predicting multiple sclerosis (MS) diagnosis and disability accrual in CIS. Methods: Concerning SC lesions and MS diagnosis (2010 McDonald), adjusted Cox regression analyses were performed in increasingly specific CIS groups: all cases (n = 207), non-SC CIS (n = 143), non-SC CIS with abnormal brain MRI (n = 90) and non-SC CIS with abnormal brain MRI not fulfilling 2010 MS (n = 67). For the outcome Expanded Disability Status Scale (EDSS) ≥3.0, similar analyses were performed in all cases (n = 207), non-SC CIS (n = 143) and SC CIS (n = 64). Performance at 2 years was assessed for all outcomes. Results: The presence of SC lesions increased MS risk 2.0–2.6 times independently of factors like brain lesions. If considering lesion number, the risk ranged from 1.6 to 2.1 for one lesion to 2.4–3.3 for ≥2. SC lesions increased the short-term disability risk around fivefold, better demonstrated in non-SC CIS. SC lesions were very specific for evolution to MS and showed very high sensitivity for EDSS ≥3.0. Conclusion: SC lesions are independent predictors of MS in all CIS and contribute to short-term disability accrual. SC MRIs in CIS could be useful to estimate their prognosis

The Susceptibility of Trypanosomatid Pathogens to PI3/mTOR Kinase Inhibitors Affords a New Opportunity for Drug Repurposing

In our study we describe the potency of established phosphoinositide-3-kinase (PI3K) and mammalian Target of Rapamycin (mTOR) kinase inhibitors against three trypanosomatid parasites: Trypanosoma brucei, T. cruzi, and Leishmania sp., which are the causative agents for African sleeping sickness, Chagas disease, and leishmaniases, respectively. We noted that these parasites and humans express similar kinase enzymes. Since these similar human targets have been pursued by the drug industry for many years in the discovery of cellular growth and proliferation inhibitors, compounds developed as human anti-cancer agents should also have effect on inhibiting growth and proliferation of the parasites. With that in mind, we selected eight established PI3K and mTOR inhibitors for profiling against these pathogens. Among these inhibitors is an advanced clinical candidate against cancer, NVP-BEZ235, which we demonstrate to be a highly potent trypanocide in parasite cultures, and in a mouse model of T. brucei infection. Additionally, we describe observations of these inhibitors' effects on parasite growth and other cellular characteristics