A novel SOD1 splice site mutation associated with familial ALS revealed by SOD activity analysis

More than 145 mutations have been found in the gene CuZn-Superoxide dismutase (SOD1) in patients with amyotrophic lateral sclerosis (ALS). The vast majority are easily detected nucleotide mutations in the coding region. In a patient from a Swiss ALS family with half-normal erythrocyte SOD1 activity, exon flanking sequence analysis revealed a novel thymine to guanine mutation 7 bp upstream of exon 4 (c.240-7T>G). The results of splicing algorithm analyses were ambiguous, but five out of seven analysis tools suggested a potential novel splice site that would add six new base pairs to the mRNA. If translated, this mRNA would insert Ser and Ile between Glu78 and Arg79 in the SOD1 protein. In fibroblasts from the patient, the predicted mutant transcript and the mutant protein were both highly expressed, and despite the location of the insertion into the metal ion-binding loop IV, the SOD1 activity appeared high. In erythrocytes, which lack protein synthesis and are old compared with cultured fibroblasts, both SOD1 protein and enzymic activity was 50% of controls. Thus, the usage of the novel splice site is near 100%, and the mutant SOD1 shows the reduced stability typical of ALS-associated mutant SOD1s. The findings suggests that this novel intronic mutation is causing the disease and highlights the importance of wide exon-flanking sequencing and transcript analysis combined with erythrocyte SOD1 activity analysis in comprehensive search for SOD1 mutations in ALS. We find that there are potentially more SOD1 mutations than previously reporte

Long-term age-dependent behavioral changes following a single episode of fetal N-methyl-D-Aspartate (NMDA) receptor blockade

BACKGROUND: Administration of the N-methyl-D-aspartate (NMDA) antagonist ketamine during the perinatal period can produce a variety of behavioral and neuroanatomical changes. Our laboratory has reported reliable changes in learning and memory following a single dose of ketamine administered late in gestation. However, the nature of the drug-induced changes depends on the point during embryonic development when ketamine is administered. Embryonic day 18 (E18) rat fetuses pre-treated with ketamine (100 mg/kg, i.p. through the maternal circulation) and taught a conditioned taste aversion (CTA) learn and remember the CTA, whereas E19 fetuses do not. The current study sought to determine if long-term behavioral effects could be detected in animals that received ketamine or a saline control injection on either E18 or E19. Rat behavior was evaluated on two different measures: spontaneous locomotion and water maze learning. Measurements were collected during 2 periods: Juvenile test period [pre-pubertal locomotor test: Postnatal Day 11 (P11); pre-pubertal water maze test: P18] or Young-adult test period [post-pubertal locomotor test: P60; post-pubertal water maze test: P81]. RESULTS: Water maze performance of ketamine-treated rats was similar to that of controls when tested on P18. Likewise, the age of the animal at the time of ketamine/saline treatment did not influence learning of the maze. However, the young-adult water maze test (P81) revealed reliable benefits of prenatal ketamine exposure – especially during the initial re-training trial. On the first trial of the young adult test, rats treated with ketamine on E18 reached the hidden platform faster than any other group – including rats treated with ketamine on E19. Swim speeds of experimental and control rats were not significantly different. Spontaneous horizontal locomotion measured during juvenile testing indicated that ketamine-treated rats were less active than controls. However, later in development, rats treated with ketamine on E18 were more active than rats that received the drug on E19. CONCLUSION: These data suggest that both the day in fetal development when ketamine is administered and the timing of post-natal behavioral testing interact to influence behavioral outcomes. The data also indicate that the paradoxical age-dependent effects of early ketamine treatment on learning, previously described in fetuses and neonates, may also be detected later in young adult rats

The Infrared Imaging Spectrograph (IRIS) for TMT: instrument overview

IRIS is a near-infrared (0.84 to 2.4 micron) integral field spectrograph and wide-field imager being developed for first light with the Thirty Meter Telescope (TMT). It mounts to the advanced adaptive optics (AO) system NFIRAOS and has integrated on-instrument wavefront sensors (OIWFS) to achieve diffraction-limited spatial resolution at wavelengths longer than 1 μm. With moderate spectral resolution (R ~ 4000 – 8,000) and large bandpass over a continuous field of view, IRIS will open new opportunities in virtually every area of astrophysical science. It will be able to resolve surface features tens of kilometers across Titan, while also mapping the most distant galaxies at the scale of an individual star forming region. This paper summarizes the entire design and capabilities, and includes the results from the nearly completed preliminary design phase

The XQR-30 Metal Absorber Catalog: 778 Absorption Systems Spanning 2 < z < 6.5

Intervening metal absorption lines in the spectra of z > 6 quasars are fundamental probes of the ionization state and chemical composition of circumgalactic and intergalactic gas near the end of the reionization epoch. Large absorber samples are required to robustly measure typical absorber properties and to refine models of the synthesis, transport, and ionization of metals in the early Universe. The "Ultimate XSHOOTER legacy survey of quasars at z~5.8-6.6" (XQR-30) has obtained high signal-to-noise spectra of 30 luminous quasars, nearly quadrupling the existing sample of 12 high quality z~6 quasar spectra. We use this unprecedented sample to construct a catalog of 778 systems showing absorption in one or more of MgII (360 systems), FeII (184), CII (46), CIV (479), SiIV (127), and NV (13) which span 2 < z < 6.5. This catalog significantly expands on existing samples of z > 5 absorbers, especially for CIV and SiIV which are important probes of the ionizing photon background at high redshift. The sample is 50% (90%) complete for rest-frame equivalent widths W > 0.03AA (0.09AA). We publicly release the absorber catalog along with completeness statistics and a Python script to compute the absorption search path for different ions and redshift ranges. This dataset is a key legacy resource for studies of enriched gas from the era of galaxy assembly to cosmic noon, and paves the way for even higher redshift studies with the James Webb Space Telescope and 30m-class telescopes.Comment: 29 pages and 14 figures including 2 appendices. Accepted for publication in MNRAS. The metal absorber catalogue can be downloaded from https://github.com/XQR-30/Metal-catalogue. Contents unchanged from v1 apart from change to author lis

How puzzles are shaping our understanding of biodiversity: A call for more research into biodiversity representation in educational games

Games as a didactic tool (e. g., puzzles) are gaining recognition in environmental education to promote skill development, but also to develop a specific understanding of the natural world. However, a children’s puzzle containing representations of nature may unwillingly lead to “misconceptions” of biodiversity themes and processes, and an over-simplification of the relationship between people and nature. To solve this problem, positive connotations of biodiversity may prompt a conceptual change to a more nuanced, multifaceted conception of biodiversity

Evaluation of the Temporal Muscle Thickness as an Independent Prognostic Biomarker in Patients with Primary Central Nervous System Lymphoma.

In this study, we assessed the prognostic relevance of temporal muscle thickness (TMT), likely reflecting patient's frailty, in patients with primary central nervous system lymphoma (PCNSL). In 128 newly diagnosed PCNSL patients TMT was analyzed on cranial magnetic resonance images. Predefined sex-specific TMT cutoff values were used to categorize the patient cohort. Survival analyses, using a log-rank test as well as Cox models adjusted for further prognostic parameters, were performed. The risk of death was significantly increased for PCNSL patients with reduced muscle thickness (hazard ratio of 3.189, 95% CI: 2-097-4.848, p < 0.001). Importantly, the results confirmed that TMT could be used as an independent prognostic marker upon multivariate Cox modeling (hazard ratio of 2.504, 95% CI: 1.608-3.911, p < 0.001) adjusting for sex, age at time of diagnosis, deep brain involvement of the PCNSL lesions, Eastern Cooperative Oncology Group (ECOG) performance status, and methotrexate-based chemotherapy. A TMT value below the sex-related cutoff value at the time of diagnosis is an independent adverse marker in patients with PCNSL. Thus, our results suggest the systematic inclusion of TMT in further translational and clinical studies designed to help validate its role as a prognostic biomarker

New quasar proximity zone size measurements at z∼6z\sim 6 using the enlarged XQR-30 sample

Proximity zones of high-redshift quasars are unique probes of their central supermassive black holes as well as the intergalactic medium in the last stages of reionization. We present 22 new measurements of proximity zones of quasars with redshifts between 5.8 and 6.6, using the enlarged XQR-30 sample of high-resolution, high-SNR quasar spectra. The quasars in our sample have UV magnitudes of $M_{1450}\sim -27$ and black hole masses of $10^9$\unicode{x2013}$10^{10}$ M$_\odot$. Our inferred proximity zone sizes are 2\unicode{x2013}7 physical Mpc, with a typical uncertainty of less than 0.5 physical Mpc, which, for the first time, also includes uncertainty in the quasar continuum. We find that the correlation between proximity zone sizes and the quasar redshift, luminosity, or black hole mass, indicates a large diversity of quasar lifetimes. Two of our proximity zone sizes are exceptionally small. The spectrum of one of these quasars, with $z=6.02$, displays, unusually for this redshift, damping wing absorption without any detectable metal lines, which could potentially originate from the IGM. The other quasar has a high-ionization absorber $\sim$0.5 pMpc from the edge of the proximity zone. This work increases the number of proximity zone measurements available in the last stages of cosmic reionization to 87. This data will lead to better constraints on quasar lifetimes and obscuration fractions at high redshift, which in turn will help probe the seed mass and formation redshift of supermassive black holes.Comment: 16 pages, 9 figures, Accepted in MNRA

Characterization of a Pan-Immunoglobulin Assay Quantifying Antibodies Directed against the Receptor Binding Domain of the SARS-CoV-2 S1-Subunit of the Spike Protein: A Population-Based Study.

Pan-immunoglobulin assays can simultaneously detect IgG, IgM and IgA directed against the receptor binding domain (RBD) of the S1 subunit of the spike protein (S) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 S1-RBD Ig). In this work, we aim to evaluate a quantitative SARS-CoV-2 S1-RBD Ig electrochemiluminescence immunoassay (ECLIA) regarding analytical, diagnostic, operational and clinical characteristics. Our work takes the form of a population-based study in the principality of Liechtenstein, including 125 cases with clinically well-described and laboratory confirmed SARS-CoV-2 infection and 1159 individuals without evidence of coronavirus disease 2019 (COVID-19). SARS-CoV-2 cases were tested for antibodies in sera taken with a median of 48 days (interquartile range, IQR, 43-52) and 139 days (IQR, 129-144) after symptom onset. Sera were also tested with other assays targeting antibodies against non-RBD-S1 and -S1/S2 epitopes. Sensitivity was 97.6% (95% confidence interval, CI, 93.2-99.1), whereas specificity was 99.8% (95% CI, 99.4-99.9). Antibody levels linearly decreased from hospitalized patients to symptomatic outpatients and SARS-CoV-2 infection without symptoms (p < 0.001). Among cases with SARS-CoV-2 infection, smokers had lower antibody levels than non-smokers (p = 0.04), and patients with fever had higher antibody levels than patients without fever (p = 0.001). Pan-SARS-CoV-2 S1-RBD Ig in SARS-CoV-2 infection cases significantly increased from first to second follow-up (p < 0.001). A substantial proportion of individuals without evidence of past SARS-CoV-2 infection displayed non-S1-RBD antibody reactivities (248/1159, i.e., 21.4%, 95% CI, 19.1-23.4). In conclusion, a quantitative SARS-CoV-2 S1-RBD Ig assay offers favorable and sustained assay characteristics allowing the determination of quantitative associations between clinical characteristics (e.g., disease severity, smoking or fever) and antibody levels. The assay could also help to identify individuals with antibodies of non-S1-RBD specificity with potential clinical cross-reactivity to SARS-CoV-2