A comparison of quasar emission reconstruction techniques for z ≥ 5.0 Lyman α and Lyman β transmission

Reconstruction techniques for intrinsic quasar continua are crucial for the precision study of Lyman-$\alpha$ (Ly-$\alpha$) and Lyman-$\beta$ (Ly-$\beta$) transmission at $z>5.0$, where the $\lambda5.7$ with IR X-Shooter spectroscopy, obtaining well-characterised measurements for the mean flux transmission at $4.7<z<6.3$. Our results demonstrate the importance of testing and, when relevant, training, continuum reconstruction techniques in a systematic way

The ducky^{2J} Mutation in Cacna2d2 Results in Reduced Spontaneous Purkinje Cell Activity and Altered Gene Expression

The mouse mutant ducky and its allele ducky^{2J} represent a model for absence epilepsy characterized by spike-wave seizures and cerebellar ataxia. These mice have mutations in Cacna2d2, which encodes the α₂δ-2 calcium channel subunit. Of relevance to the ataxic phenotype, α₂δ-2 mRNA is strongly expressed in cerebellar Purkinje cells (PCs). The Cacna2d2du2J mutation results in a 2 bp deletion in the coding region and a complete loss of α₂δ-2 protein. Here we show that du^{2J}/du^{2J} mice have a 30% reduction in somatic calcium current and a marked fall in the spontaneous PC firing rate at 22°C, accompanied by a decrease in firing regularity, which is not affected by blocking synaptic input to PCs. At 34°C, du^{2J}/du^{2J} PCs show no spontaneous intrinsic activity. DU^{2J}/du^{2J} mice also have alterations in the cerebellar expression of several genes related to PC function. At postnatal day 21, there is an elevation of tyrosine hydroxylase mRNA and a reduction in tenascin-C gene expression. Although du^{2J}/+ mice have a marked reduction in α₂δ-2 protein, they show no fall in PC somatic calcium currents or increase in cerebellar tryrosine hydroxylase gene expression. However, du^{2J}/+ PCs do exhibit a significant reduction in firing rate, correlating with the reduction in α₂δ-2. A hypothesis for future study is that effects on gene expression occur as a result of a reduction in somatic calcium currents, whereas effects on PC firing occur as a long-term result of loss of α₂δ-2 and/or a reduction in calcium currents and calcium-dependent processes in regions other than the soma

LUBAC synthesizes linear ubiquitin chains via a thioester intermediate

The linear ubiquitin chain assembly complex (LUBAC) is a RING E3 ligase that regulates immune and inflammatory signalling pathways. Unlike classical RING E3 ligases, LUBAC determines the type of ubiquitin chain being formed, an activity normally associated with the E2 enzyme. We show that the RING-in-between-RING (RBR)-containing region of HOIP—the catalytic subunit of LUBAC—is sufficient to generate linear ubiquitin chains. However, this activity is inhibited by the N-terminal portion of the molecule, an inhibition that is released upon complex formation with HOIL-1L or SHARPIN. Furthermore, we demonstrate that HOIP transfers ubiquitin to the substrate through a thioester intermediate formed by a conserved cysteine in the RING2 domain, supporting the notion that RBR ligases act as RING/HECT hybrids

Elevated arousal at time of decision-making is not the arbiter of risk avoidance in chickens

The somatic marker hypothesis proposes that humans recall previously experienced physiological responses to aid decision-making under uncertainty. However, little is known about the mechanisms used by non-human animals to integrate risk perception with predicted gains and losses. We monitored the behaviour and physiology of chickens when the choice between a high-gain (large food quantity), high-risk (1 in 4 probability of receiving an air-puff) option (HGRAP) or a low-gain (small food quantity), no-risk (of an air-puff) (LGNAP) option. We assessed when arousal increased by considering different stages of the decision-making process (baseline, viewing, anticipation, reward periods) and investigated whether autonomic responses influenced choice outcome both immediately and in the subsequent trial. Chickens were faster to choose and their heart-rate significantly increased between the viewing and anticipation (post-decision, pre-outcome) periods when selecting the HGRAP option. This suggests that they responded physiologically to the impending risk. Additionally, arousal was greater following a HGRAP choice that resulted in an air-puff, but this did not deter chickens from subsequently choosing HGRAP. In contrast to human studies, we did not find evidence that somatic markers were activated during the viewing period, suggesting that arousal is not a good measure of avoidance in non-human animals

On the massive gluon propagator, the PT-BFM scheme and the low-momentum behaviour of decoupling and scaling DSE solutions

We study the low-momentum behaviour of Yang-Mills propagators obtained from Landau-gauge Dyson-Schwinger equations (DSE) in the PT-BFM scheme. We compare the ghost propagator numerical results with the analytical ones obtained by analyzing the low-momentum behaviour of the ghost propagator DSE in Landau gauge, assuming for the truncation a constant ghost-gluon vertex and a simple model for a massive gluon propagator. The asymptotic expression obtained for the regular or decoupling ghost dressing function up to the order ${\cal O}(q^2)$ is proven to fit pretty well the numerical PT-BFM results. Furthermore, when the size of the coupling renormalized at some scale approaches some critical value, the numerical PT-BFM propagators tend to behave as the scaling ones. We also show that the scaling solution, implying a diverging ghost dressing function, cannot be a DSE solution in the PT-BFM scheme but an unattainable limiting case.Comment: 16 pages, 2 figs., 2 tabs (updated version to be published in JHEP

Tracing the origin of the AGN fuelling reservoir in MCG–6-30-15

The active galaxy MCG–6-30-15 has a 400 pc diameter stellar kinematically distinct core, counter-rotating with respect to the main body of the galaxy. Our previous high spatial resolution (0.1 arcsec) H-band observations of this galaxy mapped the stellar kinematics and [Fe II] 1.64 μm gas dynamics though mainly restricted to the spatial region of the counter-rotating core. In this work, we probe the stellar kinematics on a larger field of view and determine the ionized and molecular gas dynamics to study the formation of the counter-rotating core and the implications for active galactic nucleus (AGN) fuelling. We present integral field spectroscopy observations with SINFONI in the H and K bands in the central 1.2 kpc and with VIMOS HR-blue in the central 4 kpc of the galaxy. Ionized gas outflows of v_out ∼ 100 km s⁻¹ are traced by the [Ca VIII] 2.32 μm coronal line and extend out to at least a radius of r ∼ 140 pc. The molecular gas, traced by the H₂ 2.12 μm emission, is also counter-rotating with respect to the main body of the galaxy, indicating that the formation of the distinct core was associated with inflow of external gas into the centre of MCG–6-30-15. The molecular gas traces the available gas reservoir for AGN fuelling and is detected as close as r ∼ 50–100 pc. External gas accretion is able to significantly replenish the fuelling reservoir suggesting that the event which formed the counter-rotating core was also the main mechanism providing gas for AGN fuelling.PG acknowledges support from STFC (grant reference ST/J003697/2). This research has made use of the NASA/IPAC Extragalactic Database (NED), which is operated by the Jet Propulsion Laboratory, California Institute of Technology, under contract with the National Aeronautics and Space Administration. In this work, we used data obtained as part of the Two Micron All Sky Survey (2MASS), a joint project of the University of Massachusetts and the Infrared Processing and Analysis Center/California Institute of Technology, funded by the National Aeronautics and Space Administration and the National Science Foundation. This research has made use of NASA’s Astrophysics Data System

Chlamydial Infection, Plasma Peroxidation and Obesity in Tubal Infertility

Background: Genital tract infections and obesity are both sources of oxidative stress. Alterations in immune and antioxidant parameters may arise from this or from an indeterminate autoimmune mechanism.Objective: This study aimed to investigate the association of Chlamydial infection, obesity and oxidative response with tubal infertility in Nigerian women.Methods: It was a case-control study of 40 women with tubal infertility and 32 fertile women, respectively, recruited from the Infertility and Family Planning Clinics respectively, of the University College Hospital, Ibadan, Nigeria. Anthropometric indices were measured in each subject and endocervical swabs were taken to screen for current genital tract infection.Antioxidant, hormonal and immunologic analysis were performed on serum.Results: None of the subjects had current genital tract infections. Chlamydia trachomatis IgG positivity was significantly higher in infertile than in fertile subjects [OR 4.33; 95%CI (0.078-0.681)]. No significant variations were observed in the anthropometric indices, antioxidant parameters and hormones between infertile and the fertile women. Bodymass index correlated positively with oxidative stress in infertile subjects. Waist and hip circumferences correlated negatively with oestradiol in women with tubal infertility.Conclusion: Chlamydial infection is associated with tubal factor infertility, however, obesity seems to increase oxidative stress and reduce fertility potential in women with tubal factor infertility.Key words: Tubal infertility, obesity, oxidative stress, Chlamydi

Dominant-negative calcium channel suppression by truncated constructs involves a kinase implicated in the unfolded protein response

Expression of the calcium channel Ca(V)2.2 is markedly suppressed by coexpression with truncated constructs of Ca(V)2.2. Furthermore, a two-domain construct of Ca(V)2.1 mimicking an episodic ataxia-2 mutation strongly inhibited Ca(V)2.1 currents. We have now determined the specificity of this effect, identified a potential mechanism, and have shown that such constructs also inhibit endogenous calcium currents when transfected into neuronal cell lines. Suppression of calcium channel expression requires interaction between truncated and full-length channels, because there is inter-subfamily specificity. Although there is marked cross-suppression within the Ca(V)2 calcium channel family, there is no cross-suppression between Ca(V)2 and Ca(V)3 channels. The mechanism involves activation of a component of the unfolded protein response, the endoplasmic reticulum resident RNA-dependent kinase (PERK), because it is inhibited by expression of dominant-negative constructs of this kinase. Activation of PERK has been shown previously to cause translational arrest, which has the potential to result in a generalized effect on protein synthesis. In agreement with this, coexpression of the truncated domain I of Ca(V)2.2, together with full-length Ca(V)2.2, reduced the level not only of Ca(V)2.2 protein but also the coexpressed alpha2delta-2. Thapsigargin, which globally activates the unfolded protein response, very markedly suppressed Ca(V)2.2 currents and also reduced the expression level of both Ca(V)2.2 and alpha2delta-2 protein. We propose that voltage-gated calcium channels represent a class of difficult-to-fold transmembrane proteins, in this case misfolding is induced by interaction with a truncated cognate Ca(V) channel. This may represent a mechanism of pathology in episodic ataxia-2

A new transdisciplinary research model to investigate and improve the health of the public

Transdisciplinary research approaches are being applied to today's complex health problems, including the climate crisis and widening inequalities. Diverse forms of disciplinary and experiential knowledge are required to understand these challenges and develop workable solutions. We aimed to create an updated model reflective of the strengths and challenges of current transdisciplinary health research that can be a guide for future studies. We searched Medline using terms related to transdisciplinary, health and research. We coded data deductively and inductively using thematic analysis to develop a preliminary model of transdisciplinary research. The model was tested and improved through: (i) a workshop with 27 participants at an international conference in Xiamen, China and (ii) online questionnaire feedback from included study authors. Our revised model recommends the following approach: (i) co-learning, an ongoing phase that recognizes the distributed nature of knowledge generation and learning across partners; (ii) (pre-)development, activities that occur before and during project initiation to establish a shared mission and ways of working; (iii) reflection and refinement to evaluate and improve processes and results, responding to emergent information and priorities as an ongoing phase; (iv) conceptualization to develop goals and the study approach by combining diverse knowledge; (v) investigation to conduct the research; (vi) implementation to use new knowledge to solve societal problems. The model includes linear and cyclical processes that may cycle back to project development. Our new model will support transdisciplinary research teams and their partners by detailing the necessary ingredients to conduct such research and achieve health impact

Leber Congenital Amaurosis Associated with Mutations in CEP290, Clinical Phenotype, and Natural History in Preparation for Trials of Novel Therapies

PURPOSE: To investigate and describe in detail the demographics, functional and anatomic characteristics, and clinical course of Leber congenital amaurosis (LCA) associated with mutations in the CEP290 gene (LCA-CEP290) in a large cohort of adults and children. DESIGN: Retrospective case series. PARTICIPANTS: Patients with mutations in CEP290 identified at a single UK referral center. METHODS: Review of case notes and results of retinal imaging (color fundus photography, fundus autofluorescence [FAF] imaging, OCT), electrophysiologic assessment, and molecular genetic testing. MAIN OUTCOME MEASURES: Molecular genetic testing, clinical findings including visual acuity and retinal imaging, and electrophysiologic assessment. RESULTS: Forty patients with LCA-CEP290 were identified. The deep intronic mutation c.2991+1655 A>G was the most common disease-causing variant (23/40 patients) identified in the compound heterozygous state in 20 patients (50%) and homozygous in 2 patients (5%). Visual acuity (VA) varied from 6/9 to no perception of light, and only 2 of 12 patients with longitudinal VA data showed deterioration in VA in their better-seeing eye over time. A normal fundus was found at diagnosis in younger patients (mean age, 1.9 years), with older patients showing white flecks (mean age, 5.9 years) or pigmentary retinopathy (mean age, 21.7 years). Eleven of 12 patients (92%) with OCT imaging had preservation of foveal architecture. Ten of 12 patients (83%) with FAF imaging had a perifoveal hyperautofluorescent ring. Having 2 nonsense CEP290 mutations was associated with worse final VA and the presence of nonocular features. CONCLUSIONS: Detailed analysis of the clinical phenotype of LCA-CEP290 in a large cohort confirms that there is a window of opportunity in childhood for therapeutic intervention based on relative structural preservation in the central cone-rich retina in a significant proportion of patients, with the majority harboring the deep intronic variant potentially tractable to several planned gene editing approaches