A massive, quiescent galaxy at redshift of z=3.717

In the early Universe finding massive galaxies that have stopped forming stars present an observational challenge as their rest-frame ultraviolet emission is negligible and they can only be reliably identified by extremely deep near-infrared surveys. These have revealed the presence of massive, quiescent early-type galaxies appearing in the universe as early as z$\sim$2, an epoch 3 Gyr after the Big Bang. Their age and formation processes have now been explained by an improved generation of galaxy formation models where they form rapidly at z$\sim$3-4, consistent with the typical masses and ages derived from their observations. Deeper surveys have now reported evidence for populations of massive, quiescent galaxies at even higher redshifts and earlier times, however the evidence for their existence, and redshift, has relied entirely on coarsely sampled photometry. These early massive, quiescent galaxies are not predicted by the latest generation of theoretical models. Here, we report the spectroscopic confirmation of one of these galaxies at redshift z=3.717 with a stellar mass of 1.7$\times$10$^{11}$ M$_\odot$ whose absorption line spectrum shows no current star-formation and which has a derived age of nearly half the age of the Universe at this redshift. The observations demonstrates that the galaxy must have quickly formed the majority of its stars within the first billion years of cosmic history in an extreme and short starburst. This ancestral event is similar to those starting to be found by sub-mm wavelength surveys pointing to a possible connection between these two populations. Early formation of such massive systems is likely to require significant revisions to our picture of early galaxy assembly.Comment: 6 pages, 7 figures. This is the final preprint corresponding closely to the published version. Uploaded 6 months after publication in accordance with Nature polic

Independent evolution of ancestral and novel defenses in a genus of toxic plants (Erysimum, Brassicaceae)

Phytochemical diversity is thought to result from coevolutionary cycles as specialization in herbivores imposes diversifying selection on plant chemical defenses. Plants in the speciose genus Erysimum (Brassicaceae) produce both ancestral glucosinolates and evolutionarily novel cardenolides as defenses. Here we test macroevolutionary hypotheses on co-expression, co-regulation, and diversification of these potentially redundant defenses across this genus. We sequenced and assembled the genome of E. cheiranthoides and foliar transcriptomes of 47 additional Erysimum species to construct a phylogeny from 9868 orthologous genes, revealing several geographic clades but also high levels of gene discordance. Concentrations, inducibility, and diversity of the two defenses varied independently among species, with no evidence for trade-offs. Closely related, geographically co-occurring species shared similar cardenolide traits, but not glucosinolate traits, likely as a result of specific selective pressures acting on each defense. Ancestral and novel chemical defenses in Erysimum thus appear to provide complementary rather than redundant functions.Austrian Science Fund (FWF) PZ00P3-161472National Science Foundation (NSF) 1811965 1645256Triad FoundationGerman Research Foundation (DFG) DFG-PE 2059/3-1Agencia Estatal de Investigacion CGL2017-86626-C2-2-PLOEWE Program Insect Biotechnology and BioresourcesJunta de Andalucía A-RNM505-UGR1

In vivo photopharmacology with light-activated opioid drugs

Traditional methods for site-specific drug delivery in the brain are slow, invasive, and difficult to interface with recordings of neural activity. Here, we demonstrate the feasibility and experimental advantages of in vivo photopharmacology using "caged" opioid drugs that are activated in the brain with light after systemic administration in an inactive form. To enable bidirectional manipulations of endogenous opioid receptors in vivo, we developed photoactivatable oxymorphone (PhOX) and photoactivatable naloxone (PhNX), photoactivatable variants of the mu opioid receptor agonist oxymorphone and the antagonist naloxone. Photoactivation of PhOX in multiple brain areas produced local changes in receptor occupancy, brain metabolic activity, neuronal calcium activity, neurochemical signaling, and multiple pain- and reward-related behaviors. Combining PhOX photoactivation with optical recording of extracellular dopamine revealed adaptations in the opioid sensitivity of mesolimbic dopamine circuitry in response to chronic morphine administration. This work establishes a general experimental framework for using in vivo photopharmacology to study the neural basis of drug action

The effects of kisspeptin on β-cell function, serum metabolites and appetite in humans

Aims: To investigate the effect of kisspeptin on glucose-stimulated insulin secretion and appetite in humans. Materials and methods: In 15 healthy men (age: 25.2 ± 1.1 years; BMI: 22.3 ± 0.5 kg m−2), we compared the effects of 1 nmol kg−1 h−1 kisspeptin versus vehicle administration on glucose-stimulated insulin secretion, metabolites, gut hormones, appetite and food intake. In addition, we assessed the effect of kisspeptin on glucose-stimulated insulin secretion in vitro in human pancreatic islets and a human β-cell line (EndoC-βH1 cells). Results: Kisspeptin administration to healthy men enhanced insulin secretion following an intravenous glucose load, and modulated serum metabolites. In keeping with this, kisspeptin increased glucose-stimulated insulin secretion from human islets and a human pancreatic cell line in vitro. In addition, kisspeptin administration did not alter gut hormones, appetite or food intake in healthy men. Conclusions: Collectively, these data demonstrate for the first time a beneficial role for kisspeptin in insulin secretion in humans in vivo. This has important implications for our understanding of the links between reproduction and metabolism in humans, as well as for the ongoing translational development of kisspeptin-based therapies for reproductive and potentially metabolic conditions

Gap-induced reductions of evoked potentials in the auditory cortex: a possible objective marker for the presence of tinnitus in animals

Animal models of tinnitus are essential for determining the underlying mechanisms and testing pharmacotherapies. However, there is doubt over the validity of current behavioural methods for detecting tinnitus. Here, we applied a stimulus paradigm widely used in a behavioural test (gap-induced inhibition of the acoustic startle reflex GPIAS) while recording from the auditory cortex, and showed neural response changes that mirror those found in the behavioural tests. We implanted guinea pigs (GPs) with electrocorticographic (ECoG) arrays and recorded baseline auditory cortical responses to a startling stimulus. When a gap was inserted in otherwise continuous background noise prior to the startling stimulus, there was a clear reduction in the subsequent evoked response (termed gap-induced reductions in evoked potentials; GIREP), suggestive of a neural analogue of the GPIAS test. We then unilaterally exposed guinea pigs to narrowband noise (left ear; 8-10 kHz; 1 hour) at one of two different sound levels - either 105 dB SPL or 120 dB SPL – and recorded the same responses seven-to-ten weeks following the noise exposure. Significant deficits in GIREP were observed for all areas of the auditory cortex (AC) in the 120 dB-exposed GPs, but not in the 105 dB-exposed GPs. These deficits could not simply be accounted for by changes in response amplitudes. Furthermore, in the contralateral (right) caudal AC we observed a significant increase in evoked potential amplitudes across narrowband background frequencies in both 105 dB and 120 dB-exposed GPs. Taken in the context of the large body of literature that has used the behavioural test as a demonstration of the presence of tinnitus, these results are suggestive of objective neural correlates of the presence of noise-induced tinnitus and hyperacusis

CMTM6 shapes antitumor T cell response through modulating protein expression of CD58 and PD-L1

The dysregulated expression of immune checkpoint molecules enables cancer cells to evade immune destruction. While blockade of inhibitory immune checkpoints like PD-L1 forms the basis of current cancer immunotherapies, a deficiency in costimulatory signals can render these therapies futile. CD58, a costimulatory ligand, plays a crucial role in antitumor immune responses, but the mechanisms controlling its expression remain unclear. Using two systematic approaches, we reveal that CMTM6 positively regulates CD58 expression. Notably, CMTM6 interacts with both CD58 and PD-L1, maintaining the expression of these two immune checkpoint ligands with opposing functions. Functionally, the presence of CMTM6 and CD58 on tumor cells significantly affects T cell-tumor interactions and response to PD-L1-PD-1 blockade. Collectively, these findings provide fundamental insights into CD58 regulation, uncover a shared regulator of stimulatory and inhibitory immune checkpoints, and highlight the importance of tumor-intrinsic CMTM6 and CD58 expression in antitumor immune responses

HD 213885b: a transiting 1-d-period super-Earth with an Earth-like composition around a bright (V = 7.9) star unveiled by TESS

We report the discovery of the 1.008-d, ultrashort period (USP) super-Earth HD 213885b (TOI-141b) orbiting the bright (V = 7.9) star HD 213885 (TOI-141, TIC 403224672), detected using photometry from the recently launched TESS mission. Using FEROS, HARPS, and CORALIE radial velocities, we measure a precise mass of 8.8 ± 0.6 M⊕ for this 1.74 ± 0.05 R⊕ exoplanet, which provides enough information to constrain its bulk composition – similar to Earth’s but enriched in iron. The radius, mass, and stellar irradiation of HD 213885b are, given our data, very similar to 55 Cancri e, making this exoplanet a good target to perform comparative exoplanetology of short period, highly irradiated super-Earths. Our precise radial velocities reveal an additional 4.78-d signal which we interpret as arising from a second, non-transiting planet in the system, HD 213885c, whose minimum mass of 19.9 ± 1.4 M⊕ makes it consistent with being a Neptune-mass exoplanet. The HD 213885 system is very interesting from the perspective of future atmospheric characterization, being the second brightest star to host an USP transiting super-Earth (with the brightest star being, in fact, 55 Cancri). Prospects for characterization with present and future observatories are discussed

MARE, Microcalorimeter Arrays for a Rhenium Experiment: A detector overview

Abstract We describe and discuss the features of MARE, an experiment based on arrays of rhenium low temperature microcalorimeters that have the potential to bring the sensitivity to the neutrino mass down to 0.2 eV, by studying the beta spectrum of Re 187 ( Q -value = 2.47 keV)

Relationship of Weather Types on the Seasonal and Spatial Variability of Rainfall, Runoff, and Sediment Yield in the Western Mediterranean Basin

Rainfall is the key factor to understand soil erosion processes, mechanisms, and rates. Most research was conducted to determine rainfall characteristics and their relationship with soil erosion (erosivity) but there is little information about how atmospheric patterns control soil losses, and this is important to enable sustainable environmental planning and risk prevention. We investigated the temporal and spatial variability of the relationships of rainfall, runoff, and sediment yield with atmospheric patterns (weather types, WTs) in the western Mediterranean basin. For this purpose, we analyzed a large database of rainfall events collected between 1985 and 2015 in 46 experimental plots and catchments with the aim to: (i) evaluate seasonal differences in the contribution of rainfall, runoff, and sediment yield produced by the WTs; and (ii) to analyze the seasonal efficiency of the different WTs (relation frequency and magnitude) related to rainfall, runoff, and sediment yield. The results indicate two different temporal patterns: the first weather type exhibits (during the cold period: autumn and winter) westerly flows that produce the highest rainfall, runoff, and sediment yield values throughout the territory; the second weather type exhibits easterly flows that predominate during the warm period (spring and summer) and it is located on the Mediterranean coast of the Iberian Peninsula. However, the cyclonic situations present high frequency throughout the whole year with a large influence extended around the western Mediterranean basin. Contrary, the anticyclonic situations, despite of its high frequency, do not contribute significantly to the total rainfall, runoff, and sediment (showing the lowest efficiency) because of atmospheric stability that currently characterize this atmospheric pattern. Our approach helps to better understand the relationship of WTs on the seasonal and spatial variability of rainfall, runoff and sediment yield with a regional scale based on the large dataset and number of soil erosion experimental stations.Spanish Government (Ministry of Economy and Competitiveness, MINECO) and FEDER Projects: CGL2014 52135-C3-3-R, ESP2017-89463-C3-3-R, CGL2014-59946-R, CGL2015-65569-R, CGL2015-64284-C2-2-R, CGL2015-64284-C2-1-R, CGL2016-78075-P, GL2008-02879/BTE, LEDDRA 243857, RECARE-FP7, CGL2017-83866-C3-1-R, and PCIN-2017-061/AEI. Dhais Peña-Angulo received a “Juan de la Cierva” postdoctoral contract (FJCI-2017-33652 Spanish Ministry of Economy and Competitiveness, MEC). Ana Lucia acknowledge the "Brigitte-Schlieben-Lange-Programm". The “Geoenvironmental Processes and Global Change” (E02_17R) was financed by the Aragón Government and the European Social Fund. José Andrés López-Tarazón acknowledges the Secretariat for Universities and Research of the Department of the Economy and Knowledge of the Autonomous Government of Catalonia for supporting the Consolidated Research Group 2014 SGR 645 (RIUS- Fluvial Dynamics Research Group). Artemi Cerdà thank the funding of the OCDE TAD/CRP JA00088807. José Martínez-Fernandez acknowledges the project Unidad de Excelencia CLU-2018-04 co-funded by FEDER and Castilla y León Government. Ane Zabaleta is supported by the Hydro-Environmental Processes consolidated research group (IT1029-16, Basque Government). This paper has the benefit of the Lab and Field Data Pool created within the framework of the COST action CONNECTEUR (ES1306)

Clinical laboratory reference values amongst children aged 4 weeks to 17 months in Kilifi, Kenya: A cross sectional observational study

Reference intervals for clinical laboratory parameters are important for assessing eligibility, toxicity grading and management of adverse events in clinical trials. Nonetheless, haematological and biochemical parameters used for clinical trials in sub-Saharan Africa are typically derived from industrialized countries, or from WHO references that are not region-specific. We set out to establish community reference values for haematological and biochemical parameters amongst children aged 4 weeks to 17 months in Kilifi, Kenya. We conducted a cross sectional study nested within phase II and III trials of RTS, S malaria vaccine candidate. We analysed 10 haematological and 2 biochemical parameters from 1,070 and 423 community children without illness prior to experimental vaccine administration. Statistical analysis followed Clinical and Laboratory Standards Institute EP28-A3c guidelines. 95% reference ranges and their respective 90% confidence intervals were determined using non-parametric methods. Findings were compared with published ranges from Tanzania, Europe and The United States. We determined the reference ranges within the following age partitions: 4 weeks to <6 months, 6 months to less than <12 months, and 12 months to 17 months for the haematological parameters; and 4 weeks to 17 months for the biochemical parameters. There were no gender differences for all haematological and biochemical parameters in all age groups. Hb, MCV and platelets 95% reference ranges in infants largely overlapped with those from United States or Europe, except for the lower limit for Hb, Hct and platelets (lower); and upper limit for platelets (higher) and haematocrit(lower). Community norms for common haematological and biochemical parameters differ from developed countries. This reaffirms the need in clinical trials for locally derived reference values to detect deviation from what is usual in typical children in low and middle income countries