Spatial Working Memory Under Differential and Nondifferential Outcomes I: Effects of Scopolamine

This project examined the effects of drugs associated with working memory on the accuracy of subjects completing tasks under differential outcomes (DO), that utilize a unique outcome after each stimulus and response sequence, or tasks with non-differential outcomes (NDO) where the two available outcomes randomly occur after each stimulus and response. Such drug can indicate neurochemical differences and similarities between these tasks, and insight into working memory. Tasks that administer differential outcomes are linked to prospective memory (foreseeing future events), while tasks with non-differential outcomes and common outcomes are associated with retrospective memory (memory of past events). Scopolamine, an acetylcholine antagonist, is prescribed to treat nausea and motion sickness, and is also a muscarinic cholinergic antagonist. Depending on the effect of scopolamine on memory performance at different doses in tasks that utilize differential and non-differential outcomes will indicate acetylcholine’s role in prospective and retrospective memory. Subjects were required to complete delayed matching to position tasks with specific or randomized outcomes for each stimulus and response. Results suggested that acetylcholine mediated prospective and retrospective memory, with scopolamine effecting tasks that utilized differential outcomes less than tasks that utilized non-differential outcomes. This indicates that acetylcholine is linked to the accuracy in performance of tasks that utilize differential and non-differential outcomes, or prospective and retrospective memory.https://openriver.winona.edu/urc2019/1076/thumbnail.jp

Mechanism of action of VP1-001 in cryAB(R120G)-associated and age-related cataracts

PurposeWe previously identified an oxysterol, VP1-001 (also known as compound 29), that partially restores the transparency of lenses with cataracts. To understand the mechanism of VP1-001, we tested the ability of its enantiomer, ent-VP1-001, to bind and stabilize αB-crystallin (cryAB) in vitro and to produce a similar therapeutic effect in cryAB(R120G) mutant and aged wild-type mice with cataracts. VP1-001 and ent-VP1-001 have identical physicochemical properties. These experiments are designed to critically evaluate whether stereoselective binding to cryAB is required for activity.MethodsWe compared the binding of VP1-001 and ent-VP1-001 to cryAB using in silico docking, differential scanning fluorimetry (DSF), and microscale thermophoresis (MST). Compounds were delivered by six topical administrations to mouse eyes over 2 weeks, and the effects on cataracts and lens refractive measures in vivo were examined. Additionally, lens epithelial and fiber cell morphologies were assessed via transmission electron microscopy.ResultsDocking studies suggested greater binding of VP1-001 into a deep groove in the cryAB dimer compared with ent-VP1-001. Consistent with this prediction, DSF and MST experiments showed that VP1-001 bound cryAB, whereas ent-VP1-001 did not. Accordingly, topical treatment of lenses with ent-VP1-001 had no effect, whereas VP1-001 produced a statistically significant improvement in lens clarity and favorable changes in lens morphology.ConclusionsThe ability of VP1-001 to bind native cryAB dimers is important for its ability to reverse lens opacity in mouse models of cataracts

Absence of neuronal autoantibodies in neuropsychiatric systemic lupus erythematosus

International audienceThis study aimed to characterise both neuronal autoantibodies and levels of interferon α, two proposed causative agents in neuropsychiatric systemic lupus erythematosus (NPSLE). Cerebrospinal fluid (CSF) and plasma from 35 patients with systemic lupus erythematosus (SLE; 15 with NPSLE) showed no antibodies against natively expressed N-methyl-D-aspartate receptors (NMDARs), or the surface of live hippocampal neurons. By comparison to controls (n = 104), patients with SLE had antibodies that bound to a peptide representing the extracellular domain of NMDARs (p < 0.0001), however, binding was retained against both rearranged peptides and no peptide (r = 0.85 and r = 0.79, respectively, p < 0.0001). In summary, neuronal-surface reactive antibodies were not detected in NPSLE. Further, while interferon α levels were higher in SLE (p < 0.0001), they lacked specificity for NPSLE. Our findings mandate a search for novel biomarkers in this condition. ANN NEUROL 2020

Determination of rivaroxaban by different factor Xa specific chromogenic substrate assays: reduction of interassay variability

Rivaroxaban and other oral direct factor Xa inhibitors (ODiXa) are currently developed for prophylaxis and treatment of thromboembolic diseases using fixed doses. Although routine monitoring is not required, assessing the intensity of anticoagulation may be useful under certain clinical conditions. ODiXa prolong coagulation times of several clotting assays and, thus, their concentration may be determined in factor Xa specific chromogenic substrate assays. So far, no standardized and validated assay is commercially available. Here, five methods (A through E) are studied and optimized to reduce interassay variability. Human pooled plasma was spiked by a serial dilution of rivaroxaban (25–900 ng/ml). The release of para-nitroaniline from the chromogenic substrates was measured by the optical density (OD) at 405 nm. Method B was identified to yield the lowest sum of deviations from the mean value of the OD concentration curve calculated from all assays. Spline functions were developed for OD versus concentration curves for all methods. The calculated OD versus concentration curves overlapped for all methods. The coefficient of variation for all assays and concentrations of rivaroxaban decreased from 25.3 ± 11.4% using the original data to 3.8 ± 2.2% using the calculated data (P < 0.0001). The robustness of the chromogenic assay (method B) remains to be corroborated in interlaboratory comparisons

Rare variants of the 3'-5' DNA exonuclease TREX1 in early onset small vessel stroke

Background: Monoallelic and biallelic mutations in the exonuclease TREX1 cause monogenic small vessel diseases (SVD). Given recent evidence for genetic and pathophysiological overlap between monogenic and polygenic forms of SVD, evaluation of TREX1 in small vessel stroke is warranted. Methods: We sequenced the TREX1 gene in an exploratory cohort of patients with lacunar stroke (Edinburgh Stroke Study, n=290 lacunar stroke cases). We subsequently performed a fully blinded case-control study of early onset MRI-confirmed small vessel stroke within the UK Young Lacunar Stroke Resource (990 cases, 939 controls). Results: No patients with canonical disease-causing mutations of TREX1 were identified in cases or controls. Analysis of an exploratory cohort identified a potential association between rare variants of TREX1 and patients with lacunar stroke. However, subsequent controlled and blinded evaluation of TREX1 in a larger and MRI-confirmed patient cohort, the UK Young Lacunar Stroke Resource, identified heterozygous rare variants in 2.1% of cases and 2.3% of controls. No association was observed with stroke risk (odds ratio = 0.90; 95% confidence interval, 0.49-1.65 p=0.74). Similarly no association was seen with rare TREX1 variants with predicted deleterious effects on enzyme function (odds ratio = 1.05; 95% confidence interval, 0.43-2.61 p=0.91). Conclusions: No patients with early-onset lacunar stroke had genetic evidence of a TREX1-associated monogenic microangiopathy. These results show no evidence of association between rare variants of TREX1 and early onset lacunar stroke. This includes rare variants that significantly affect protein and enzyme function. Routine sequencing of the TREX1 gene in patients with early onset lacunar stroke is therefore unlikely to be of diagnostic utility, in the absence of syndromic features or family history

Arecibon planetaarisen tutkan Maan lähiasteroidihavainnot: 2017 joulukuu - 2019 joulukuu

We successfully observed 191 near-Earth asteroids using the Arecibo Observatory's S-band planetary radar system from 2017 December through 2019 December. We present radar cross sections for 167 asteroids; circular-polarization ratios for 112 asteroids based on Doppler-echo-power spectra measurements; and radar albedos, constraints on size and spin periods, and surface-feature and shape evaluation for 37 selected asteroids using delay-Doppler radar images with a range resolution of 75 m or finer. Out of 33 asteroids with an estimated effective diameter of at least 200 m and sufficient image quality to give clues of the shape, at least 4 (∼12%) are binary asteroids, including 1 equal-mass binary asteroid, 2017 YE5, and at least 10 (∼30%) are contact-binary asteroids. For 5 out of 112 asteroids with reliable measurements in both circular polarizations, we measured circular-polarization ratios greater than 1.0, which could indicate that they are E-type asteroids, while the mean and the 1σ standard deviation were 0.37 ± 0.23. Further, we find a mean opposite-sense circular-polarization radar albedo of 0.21 ± 0.11 for 41 asteroids (0.19 ± 0.06 for 11 S-complex asteroids). We identified two asteroids, 2011 WN15 and (505657) 2014 SR339, as possible metal-rich objects based on their unusually high radar albedos, and discuss possible evidence of water ice in 2017 YE5.Peer reviewe

TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism.

DNA lesions encountered by replicative polymerases threaten genome stability and cell cycle progression. Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitin ligase, in patients with microcephalic primordial dwarfism. We establish that TRAIP relocalizes to sites of DNA damage, where it is required for optimal phosphorylation of H2AX and RPA2 during S-phase in response to ultraviolet (UV) irradiation, as well as fork progression through UV-induced DNA lesions. TRAIP is necessary for efficient cell cycle progression and mutations in TRAIP therefore limit cellular proliferation, providing a potential mechanism for microcephaly and dwarfism phenotypes. Human genetics thus identifies TRAIP as a component of the DNA damage response to replication-blocking DNA lesions.This work was supported by funding from the Medical Research Council and the European Research Council (ERC, 281847) (A.P.J.), the Lister Institute for Preventative Medicine (A.P.J. and G.S.S.), Medical Research Scotland (L.S.B.), German Federal Ministry of Education and Research (BMBF, 01GM1404) and E-RARE network EuroMicro (B.W), Wellcome Trust (M. Hurles), CMMC (P.N.), Cancer Research UK (C17183/A13030) (G.S.S. and M.R.H), Swiss National Science Foundation (P2ZHP3_158709) (O.M.), AIRC (12710) and ERC/EU FP7 (CIG_303806) (S.S.), Cancer Research UK (C6/A11224) and ERC/EU FP7 (HEALTH-F2- 2010-259893) (A.N.B. and S.P.J.).This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ng.345

Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature

Many drugs have been reported to cause thrombotic microangiopathy (TMA), yet evidence supporting a direct association is often weak. In particular, TMA has been reported in association with recombinant type I interferon (IFN) therapies, with recent concern regarding the use of IFN in multiple sclerosis patients. However, a causal association has yet to be demonstrated. Here, we adopt a combined clinical and experimental approach to provide evidence of such an association between type I IFN and TMA. We show that the clinical phenotype of cases referred to a national center is uniformly consistent with a direct dose-dependent drug-induced TMA. We then show that dose-dependent microvascular disease is seen in a transgenic mouse model of IFN toxicity. This includes specific microvascular pathological changes seen in patient biopsies and is dependent on transcriptional activation of the IFN response through the type I interferon α/β receptor (IFNAR). Together our clinical and experimental findings provide evidence of a causal link between type I IFN and TMA. As such, recombinant type I IFN therapies should be stopped at the earliest stage in patients who develop this complication, with implications for risk mitigation