The atypical iron-coordination geometry of cytochrome f remains unchanged upon binding to plastocyanin, as inferred by XAS

The transient complex between cytochrome f and plastocyanin from the cyanobacterium Nostoc sp. PCC 7119 has been analysed by X-ray Absorption Spectroscopy in solution, using both proteins in their oxidized and reduced states. Fe K-edge data mainly shows that the atypical metal coordination geometry of cytochrome f, in which the N-terminal amino acid acts as an axial ligand of the heme group, remains unaltered upon binding to its redox partner, plastocyanin. This fact suggests that cytochrome f provides a stable binding site for plastocyanin and minimizes the reorganization energy required in the transient complex formation, which could facilitate the electron transfer between the two redox partners

The Interstellar Medium In Galaxies Seen A Billion Years After The Big Bang

Evolution in the measured rest frame ultraviolet spectral slope and ultraviolet to optical flux ratios indicate a rapid evolution in the dust obscuration of galaxies during the first 3 billion years of cosmic time (z>4). This evolution implies a change in the average interstellar medium properties, but the measurements are systematically uncertain due to untested assumptions, and the inability to measure heavily obscured regions of the galaxies. Previous attempts to directly measure the interstellar medium in normal galaxies at these redshifts have failed for a number of reasons with one notable exception. Here we report measurements of the [CII] gas and dust emission in 9 typical (~1-4L*) star-forming galaxies ~1 billon years after the big bang (z~5-6). We find these galaxies have >12x less thermal emission compared with similar systems ~2 billion years later, and enhanced [CII] emission relative to the far-infrared continuum, confirming a strong evolution in the interstellar medium properties in the early universe. The gas is distributed over scales of 1-8 kpc, and shows diverse dynamics within the sample. These results are consistent with early galaxies having significantly less dust than typical galaxies seen at z<3 and being comparable to local low-metallicity systems.Comment: Submitted to Nature, under review after referee report. 22 pages, 4 figures, 4 Extended Data Figures, 5 Extended Data table

Rimeporide as a first- in-class NHE-1 inhibitor: Results of a phase Ib trial in young patients with Duchenne Muscular Dystrophy

Rimeporide, a first-in-class sodium/proton exchanger Type 1 inhibitor (NHE-1 inhibitor) is repositioned by EspeRare for patients with Duchenne Muscular Dystrophy (DMD). Historically, NHE-1 inhibitors were developed for cardiac therapeutic interventions. There is considerable overlap in the pathophysiological mechanisms in Congestive Heart Failure (CHF) and in cardiomyopathy in DMD, therefore NHE-1 inhibition could be a promising pharmacological approach to the cardiac dysfunctions observed in DMD. Extensive preclinical data was collected in various animal models including dystrophin-deficient (mdx) mice to characterise Rimeporide’s anti-fibrotic and anti-inflammatory properties and there is evidence that NHE-1 inhibitors could play a significant role in modifying DMD cardiac and also skeletal pathologies, as the NHE-1 isoform is ubiquitous. We report here the first study with Rimeporide in DMD patients. This 4-week treatment, open label phase Ib, multiple oral ascending dose study, enrolled 20 ambulant boys with DMD (6–11 years), with outcomes including safety, pharmacokinetic (PK) and pharmacodynamic (PD) biomarkers. Rimeporide was safe and well-tolerated at all doses. PK evaluations showed that Rimeporide was well absorbed orally reaching pharmacological concentrations from the lowest dose, with exposure increasing linearly with dose and with no evidence of accumulation upon repeated dosing. Exploratory PD biomarkers showed positive effect upon a 4-week treatment, supporting its therapeutic potential in patients with DMD, primarily as a cardioprotective treatment, and provide rationale for further efficacy studies

Demonstration of the event identification capabilities of the NEXT-White detector

In experiments searching for neutrinoless double-beta decay, the possibility of identifying the two emitted electrons is a powerful tool in rejecting background events and therefore improving the overall sensitivity of the experiment. In this paper we present the first measurement of the efficiency of a cut based on the different event signatures of double and single electron tracks, using the data of the NEXT-White detector, the first detector of the NEXT experiment operating underground. Using a 228Th calibration source to produce signal-like and background-like events with energies near 1.6 MeV, a signal efficiency of 71.6 ± 1.5 stat± 0.3 sys% for a background acceptance of 20.6 ± 0.4 stat± 0.3 sys% is found, in good agreement with Monte Carlo simulations. An extrapolation to the energy region of the neutrinoless double beta decay by means of Monte Carlo simulations is also carried out, and the results obtained show an improvement in background rejection over those obtained at lower energies. [Figure not available: see fulltext.

Radiogenic backgrounds in the NEXT double beta decay experiment

Natural radioactivity represents one of the main backgrounds in the search for neutrinoless double beta decay. Within the NEXT physics program, the radioactivity- induced backgrounds are measured with the NEXT-White detector. Data from 37.9 days of low-background operations at the Laboratorio Subterráneo de Canfranc with xenon depleted in 136Xe are analyzed to derive a total background rate of (0.84±0.02) mHz above 1000 keV. The comparison of data samples with and without the use of the radon abatement system demonstrates that the contribution of airborne-Rn is negligible. A radiogenic background model is built upon the extensive radiopurity screening campaign conducted by the NEXT collaboration. A spectral fit to this model yields the specific contributions of 60Co, 40K, 214Bi and 208Tl to the total background rate, as well as their location in the detector volumes. The results are used to evaluate the impact of the radiogenic backgrounds in the double beta decay analyses, after the application of topological cuts that reduce the total rate to (0.25±0.01) mHz. Based on the best-fit background model, the NEXT-White median sensitivity to the two-neutrino double beta decay is found to be 3.5σ after 1 year of data taking. The background measurement in a Qββ±100 keV energy window validates the best-fit background model also for the neutrinoless double beta decay search with NEXT-100. Only one event is found, while the model expectation is (0.75±0.12) events. [Figure not available: see fulltext.]

Energy calibration of the NEXT-White detector with 1% resolution near Q ββ of 136Xe

Excellent energy resolution is one of the primary advantages of electroluminescent high-pressure xenon TPCs. These detectors are promising tools in searching for rare physics events, such as neutrinoless double-beta decay (ββ0ν), which require precise energy measurements. Using the NEXT-White detector, developed by the NEXT (Neutrino Experiment with a Xenon TPC) collaboration, we show for the first time that an energy resolution of 1% FWHM can be achieved at 2.6 MeV, establishing the present technology as the one with the best energy resolution of all xenon detectors for ββ0ν searches. [Figure not available: see fulltext.

Electroluminescence TPCs at the thermal diffusion limit

[EN] The NEXT experiment aims at searching for the hypothetical neutrinoless double-beta decay from the 136Xe isotope using a high-purity xenon TPC. Efficient discrimination of the events through pattern recognition of the topology of primary ionisation tracks is a major requirement for the experiment. However, it is limited by the diffusion of electrons. It is known that the addition of a small fraction of a molecular gas to xenon reduces electron diffusion. On the other hand, the electroluminescence (EL) yield drops and the achievable energy resolution may be compromised. We have studied the effect of adding several molecular gases to xenon (CO2, CH4 and CF4) on the EL yield and energy resolution obtained in a small prototype of driftless gas proportional scintillation counter. We have compared our results on the scintillation characteristics (EL yield and energy resolution) with a microscopic simulation, obtaining the diffusion coefficients in those conditions as well. Accordingly, electron diffusion may be reduced from about 10 mm/ sqrt(¿) for pure xenon down to 2.5 mm/sqrt(m) using additive concentrations of about 0.05%, 0.2% and 0.02% for CO2, CH4 and CF4, respectively. Our results show that CF4 admixtures present the highest EL yield in those conditions, but very poor energy resolution as a result of huge fluctuations observed in the EL formation. CH4 presents the best energy resolution despite the EL yield being the lowest. The results obtained with xenon admixtures are extrapolated to the operational conditions of the NEXT-100 TPC. CO2 and CH4 show potential as molecular additives in a large xenon TPC. While CO2 has some operational constraints, making it difficult to be used in a large TPC, CH4 shows the best performance and stability as molecular additive to be used in the NEXT-100 TPC, with an extrapolated energy resolution of 0.4% at 2.45 MeV for concentrations below 0.4%, which is only slightly worse than the one obtained for pure xenon. We demonstrate the possibility to have an electroluminescence TPC operating very close to the thermal diffusion limit without jeopardizing the TPC performance, if CO2 or CH4 are chosen as additives.The NEXT Collaboration acknowledges support from the following agencies and institutions: the European Research Council (ERC) under the Advanced Grant 339787-NEXT; the European Union's Framework Programme for Research and Innovation Horizon 2020 (2014-2020) under the Marie Sklodowska-Curie Grant Agreements No. 674896, 690575 and 740055; the Ministerio de Economia y Competitividad of Spain under grants FIS2014-53371-C04, the Severo Ochoa Program SEV-2014-0398 and the Maria de Maetzu Program MDM-2016-0692; the GVA of Spain under grants PROMETEO/2016/120 and SEJI/2017/011; the Portuguese FCT under project PTDC/FIS-NUC/2525/2014, under project UID/FIS/04559/2013 to fund the activities of LIBPhys, and under grants PD/BD/105921/2014, SFRH/BPD/109180/2015 and SFRH/BPD/76842/2011; the U.S. Department of Energy under contracts number DE-AC02-07CH11359 (Fermi National Accelerator Laboratory), DE-AC02-06CH11357 (Argonne National Laboratory), DE-FG02-13ER42020 (Texas A&M) and DE-SC0017721 (University of Texas at Arlington); and the University of Texas at Arlington. DGD acknowledges Ramon y Cajal program (Spain) under contract number RYC-2015-18820. We also warmly acknowledge the Laboratori Nazionali del Gran Sasso (LNGS) and the Dark Side collaboration for their help with TPB coating of various parts of the NEXT-White TPC. Finally, we are grateful to the Laboratorio Subterraneo de Canfranc for hosting and supporting the NEXT experiment.Henriques, CAO.; Monteiro, CMB.; Gonzalez-Diaz, D.; Azevedo, CDR.; Freitas, EDC.; Mano, RDP.; Jorge, MR.... (2019). Electroluminescence TPCs at the thermal diffusion limit. Journal of High Energy Physics (Online). 1:1-20. https://doi.org/10.1007/JHEP01(2019)027S1201NEXT collaboration, J. Martín-Albo et al., Sensitivity of NEXT-100 to neutrinoless double beta decay, JHEP 05 (2016) 159 [ arXiv:1511.09246 ] [ INSPIRE ].T. Brunner et al., An RF-only ion-funnel for extraction from high-pressure gases, Intern. J. Mass Spectrom. 379 (2015) 110 [ INSPIRE ].PANDAX-III collaboration, J. Galan, Microbulk MicrOMEGAs for the search of 0νββ of 136 Xe in the PandaX-III experiment, 2016 JINST 11 P04024 [ arXiv:1512.09034 ] [ INSPIRE ].D. Yu. Akimov, A.A. Burenkov, V.F. Kuzichev, V.L. Morgunov and V.N. Solovev, Low background experiments with high pressure gas scintillation proportional detector, physics/9704021 [ INSPIRE ].Yu. M. Gavrilyuk et al., A technique for searching for the 2K capture in 124 Xe with a copper proportional counter, Phys. Atom. Nucl. 78 (2015) 1563 [ INSPIRE ].D.R. Nygren, Columnar recombination: a tool for nuclear recoil directional sensitivity in a xenon-based direct detection WIMP search, J. Phys. Conf. Ser. 460 (2013) 012006 [ INSPIRE ].XENON collaboration, E. Aprile et al., First Dark Matter Search Results from the XENON1T Experiment, Phys. Rev. Lett. 119 (2017) 181301 [ arXiv:1705.06655 ] [ INSPIRE ].XENON100 collaboration, E. Aprile et al., Dark Matter Results from 225 Live Days of XENON100 Data, Phys. Rev. Lett. 109 (2012) 181301 [ arXiv:1207.5988 ] [ INSPIRE ].LUX collaboration, D.S. Akerib et al., Results from a search for dark matter in the complete LUX exposure, Phys. Rev. Lett. 118 (2017) 021303 [ arXiv:1608.07648 ] [ INSPIRE ].PandaX-II collaboration, X. Cui et al., Dark Matter Results From 54-Ton-Day Exposure of PandaX-II Experiment, Phys. Rev. Lett. 119 (2017) 181302 [ arXiv:1708.06917 ] [ INSPIRE ].EXO collaboration, J.B. Albert et al., Search for Neutrinoless Double-Beta Decay with the Upgraded EXO-200 Detector, Phys. Rev. Lett. 120 (2018) 072701 [ arXiv:1707.08707 ] [ INSPIRE ].KamLAND-Zen collaboration, A. Gando et al., Search for Majorana Neutrinos near the Inverted Mass Hierarchy Region with KamLAND-Zen, Phys. Rev. Lett. 117 (2016) 082503 [ arXiv:1605.02889 ] [ INSPIRE ].XMASS collaboration, K. Abe et al., Search for two-neutrino double electron capture on 124 Xe with the XMASS-I detector, Phys. Lett. B 759 (2016) 64 [ arXiv:1510.00754 ] [ INSPIRE ].XENON collaboration, E. Aprile et al., Search for two-neutrino double electron capture of 124 Xe with XENON100, Phys. Rev. C 95 (2017) 024605 [ arXiv:1609.03354 ] [ INSPIRE ].R. Lüscher et al., Search for ββ decay in 136 Xe: new results from the Gotthard experiment, Phys. Lett. B 434 (1998) 407 [ INSPIRE ].NEXT collaboration, P. Ferrario et al., First proof of topological signature in the high pressure xenon gas TPC with electroluminescence amplification for the NEXT experiment, JHEP 01 (2016) 104 [ arXiv:1507.05902 ] [ INSPIRE ].NEXT collaboration, D. Lorca et al., Characterisation of NEXT-DEMO using xenon K α X-rays, 2014 JINST 9 P10007 [ arXiv:1407.3966 ] [ INSPIRE ].NEXT collaboration, D. González-Díaz et al., Accurate γ and MeV-electron track reconstruction with an ultra-low diffusion Xenon/TMA TPC at 10 atm, Nucl. Instrum. Meth. A 804 (2015) 8 [ arXiv:1504.03678 ] [ INSPIRE ].C.M.B. Monteiro et al., Secondary Scintillation Yield in Pure Xenon, 2007 JINST 2 P05001 [ physics/0702142 ] [ INSPIRE ].C.M.B. Monteiro, J.A.M. Lopes, J.F. C.A. Veloso and J.M.F. dos Santos, Secondary scintillation yield in pure argon, Phys. Lett. B 668 (2008) 167 [ INSPIRE ].E.D.C. Freitas et al., Secondary scintillation yield in high-pressure xenon gas for neutrinoless double beta decay (0νββ) search, Phys. Lett. B 684 (2010) 205 [ INSPIRE ].C.M.B. Monteiro et al., Secondary scintillation yield from gaseous micropattern electron multipliers in direct dark matter detection, Phys. Lett. B 677 (2009) 133 [ INSPIRE ].C.M.B. Monteiro, L.M.P. Fernandes, J.F. C.A. Veloso, C.A.B. Oliveira and J.M.F. dos Santos, Secondary scintillation yield from GEM and THGEM gaseous electron multipliers for direct dark matter search, Phys. Lett. B 714 (2012) 18 [ INSPIRE ].C. Balan et al., MicrOMEGAs operation in high pressure xenon: Charge and scintillation readout, 2011 JINST 6 P02006 [ arXiv:1009.2960 ] [ INSPIRE ].J.M.F. dos Santos et al., Development of portable gas proportional scintillation counters for x-ray spectrometry, X-Ray Spectrom. 30 (2001) 373.NEXT collaboration, J. Renner et al., Background rejection in NEXT using deep neural networks, 2017 JINST 12 T01004 [ arXiv:1609.06202 ] [ INSPIRE ].T. Himi et al., Emission spectra from Ar-Xe, Ar-Kr, Ar-N2, Ar-CH4, Ar-CO2 and Xe-N2 gas proportional scintillation counters, Nucl. Instrum. Meth. 205 (1983) 591.C.D.R. Azevedo et al., An homeopathic cure to pure Xenon large diffusion, 2016 JINST 11 C02007 [ arXiv:1511.07189 ] [ INSPIRE ].NEXT collaboration, C.A.O. Henriques et al., Secondary scintillation yield of xenon with sub-percent levels of CO 2 additive for rare-event detection, Phys. Lett. B 773 (2017) 663 [ arXiv:1704.01623 ] [ INSPIRE ].P.C.P.S. Simões, J.M.F. dos Santos and C.A.N. Conde, Driftless gas proportional scintillation counter pulse analysis using digital processing techniques, X Ray Spectrom. 30 (2001) 342.P.C.P.S. Simões et al., A new method for pulse analysis of driftless-gas proportional scintillation counters, Nucl. Instrum. Meth. A 505 (2003) 247.C.D.R. Azevedo et al., Microscopic simulation of xenon-based optical TPCs in the presence of molecular additives, Nucl. Instrum. Meth. A 877 (2018) 157 [ arXiv:1705.09481 ] [ INSPIRE ].L.M.P. Fernandes et al., Primary and secondary scintillation measurements in a xenon Gas Proportional Scintillation Counter, 2010 JINST 5 P09006 [Erratum ibid. 5 (2010) A12001] [ arXiv:1009.2719 ] [ INSPIRE ].C.M.B. Monteiro et al., An argon gas proportional scintillation counter with UV avalanche photodiode scintillation readout, IEEE Trans. Nucl. Sci. 48 (2001) 1081.J.A.M. Lopes et al., A xenon gas proportional scintillation counter with a UV-sensitive large-area avalanche photodiode, IEEE Trans. Nucl. Sci. 48 (2001) 312.D.F. Anderson et al., A large area gas scintillation proportional counter, Nucl. Instrum. Meth. 163 (1979) 125.Z. Kowalski et al., Fano factor implications from gas scintillation proportional counter measurements, Nucl. Instrum. Meth. A 279 (1989) 567.S.J.C. do Carmo et al., Experimental study of the ω-values and Fano factors of gaseous xenon and Ar-Xe mixtures for X-rays, IEEE Trans. Nucl. Sci. 55 (2008) 2637.http://magboltz.web.cern.ch/magboltz/ (accessed 14.11.2016).T.H.V.T. Dias et al., Full-energy absorption of x-ray energies near the Xe L- and K-photoionization thresholds in xenon gas detectors: Simulation and experimental results, J. Appl. Phys. 82 (1997) 2742.D. Nygren, High-pressure xenon gas electroluminescent TPC for 0νββ-decay search, Nucl. Instrum. Meth. A 603 (2009) 337 [ INSPIRE ].NEXT collaboration, V. Álvarez et al., The NEXT-100 experiment for neutrinoless double beta decay searches (Conceptual Design Report), arXiv:1106.3630 [ INSPIRE ].NEXT collaboration, V. Álvarez et al., Operation and first results of the NEXT-DEMO prototype using a silicon photomultiplier tracking array, 2013 JINST 8 P09011 [ arXiv:1306.0471 ] [ INSPIRE ]

The calcareous brown alga Padina pavonica in southern Britain: population change and tenacity over 300 years

Understanding long-term persistence and variability in species populations can help to predict future survival, growth and distribution; however, sustained observations are exceedingly rare. We examine and interpret a remarkable record of the calcareous brown alga Padina pavonica (Phaeophyceae) at its northern limit on the south coast of England (50°N, 1–3°W) from 1680 to 2014, which is probably the longest compilation and review of any marine algal species. Over this period, which extends from the middle of the Little Ice Age to the present, there has been considerable variability in temperature and storminess. We identified a significant number of site extinctions in the second half of the nineteenth century, which coincided with cooler conditions and stormier weather. To interpret thesechanges, we measured recruitment, growth and production of tetraspores at sheltered and exposed sites in 2012–2014, years which had low and high spring temperatures. Potential spore production was greater at the sheltered site due to a longer growing period and survival of larger fronds. Delayed growth in the cooler spring resulted in smaller fronds and lower potential production of tetraspores by early summer. Yet in the warmer year, rapid initial growth caused higher sensitivity to damage and dislodgement by summer storms, which also limited potential spore production. Antagonistic responses to multiple stressors and disturbances make future predictions of survival and distribution difficult. Fronds of Padina pavonica are sensitive to both temperature and physical disturbances, yet vegetative perennation appears to have enabled population persistence and explained the longevity of remaining populations

Investigating Bacterial Sources of Toxicity as an Environmental Contributor to Dopaminergic Neurodegeneration

Parkinson disease (PD) involves progressive neurodegeneration, including loss of dopamine (DA) neurons from the substantia nigra. Select genes associated with rare familial forms of PD function in cellular pathways, such as the ubiquitin-proteasome system (UPS), involved in protein degradation. The misfolding and accumulation of proteins, such as α-synuclein, into inclusions termed Lewy Bodies represents a clinical hallmark of PD. Given the predominance of sporadic PD among patient populations, environmental toxins may induce the disease, although their nature is largely unknown. Thus, an unmet challenge surrounds the discovery of causal or contributory neurotoxic factors that could account for the prevalence of sporadic PD. Bacteria within the order Actinomycetales are renowned for their robust production of secondary metabolites and might represent unidentified sources of environmental exposures. Among these, the aerobic genera, Streptomyces, produce natural proteasome inhibitors that block protein degradation and may potentially damage DA neurons. Here we demonstrate that a metabolite produced by a common soil bacterium, S. venezuelae, caused DA neurodegeneration in the nematode, Caenorhabditis elegans, which increased as animals aged. This metabolite, which disrupts UPS function, caused gradual degeneration of all neuronal classes examined, however DA neurons were particularly vulnerable to exposure. The presence of DA exacerbated toxicity because neurodegeneration was attenuated in mutant nematodes depleted for tyrosine hydroxylase (TH), the rate-limiting enzyme in DA production. Strikingly, this factor caused dose-dependent death of human SH-SY5Y neuroblastoma cells, a dopaminergic line. Efforts to purify the toxic activity revealed that it is a highly stable, lipophilic, and chemically unique small molecule. Evidence of a robust neurotoxic factor that selectively impacts neuronal survival in a progressive yet moderate manner is consistent with the etiology of age-associated neurodegenerative diseases. Collectively, these data suggest the potential for exposures to the metabolites of specific common soil bacteria to possibly represent a contributory environmental component to PD