154 research outputs found
An Integrated Approach to Studying Rare Neuromuscular Diseases Using Animal and Human Cell-Based Models.
As sequencing technology improves, the identification of new disease-associated genes and new alleles of known genes is rapidly increasing our understanding of the genetic underpinnings of rare diseases, including neuromuscular diseases. However, precisely because these disorders are rare and often heterogeneous, they are difficult to study in patient populations. In parallel, our ability to engineer the genomes of model organisms, such as mice or rats, has gotten increasingly efficient through techniques such as CRISPR/Cas9 genome editing, allowing the creation of precision human disease models. Suc
Probing for Exoplanets Hiding in Dusty Debris Disks: Disk Imaging, Characterization, and Exploration with HST/STIS Multi-Roll Coronagraphy
Spatially resolved scattered-light images of circumstellar (CS) debris in
exoplanetary systems constrain the physical properties and orbits of the dust
particles in these systems. They also inform on co-orbiting (but unseen)
planets, systemic architectures, and forces perturbing starlight-scattering CS
material. Using HST/STIS optical coronagraphy, we have completed the
observational phase of a program to study the spatial distribution of dust in
ten CS debris systems, and one "mature" protoplanetrary disk all with HST
pedigree, using PSF-subtracted multi-roll coronagraphy. These observations
probe stellocentric distances > 5 AU for the nearest stars, and simultaneously
resolve disk substructures well beyond, corresponding to the giant planet and
Kuiper belt regions in our Solar System. They also disclose diffuse very
low-surface brightness dust at larger stellocentric distances. We present new
results inclusive of fainter disks such as HD92945 confirming, and better
revealing, the existence of a narrow inner debris ring within a larger diffuse
dust disk. Other disks with ring-like sub-structures, significant asymmetries
and complex morphologies include: HD181327 with a posited spray of ejecta from
a recent massive collision in an exo-Kuiper belt; HD61005 suggested interacting
with the local ISM; HD15115 & HD32297, discussed also in the context of
environmental interactions. These disks, and HD15745, suggest debris system
evolution cannot be treated in isolation. For AU Mic's edge-on disk,
out-of-plane surface brightness asymmetries at > 5 AU may implicate one or more
planetary perturbers. Time resolved images of the MP Mus proto-planetary disk
provide spatially resolved temporal variability in the disk illumination. These
and other new images from our program enable direct inter-comparison of the
architectures of these exoplanetary debris systems in the context of our own
Solar System.Comment: 109 pages, 43 figures, accepted for publication in the Astronomical
Journa
A Novel ENU-Induced
The fission and fusion of mitochondria are important processes for maintaining mitochondrial health. One of the proteins responsible for mediating mitochondrial fusion, mitofusin 2 (MFN2), has over 100 known mutations that cause CharcotâMarieâTooth disease type 2A (CMT2A). This disease causes the nerves that control your muscles to degenerate, leading to muscle atrophy and weakness, problems walking, and other related symptoms. In this paper, we describe a mouse line with a recessive mutation in the Mfn2 gene (Leu643Pro) that causes a similar set of symptoms, including abnormal gait, weight loss, and decreased muscular endurance. However, further analysis of these mice revealed signs of skeletal muscle dysfunction (including smaller mitochondria) and bone abnormalities, with little evidence of axon degeneration typical of CMT2A. While this makes these mice a poor model for CMT2A, they are the first reported mouse line with a mutation in the transmembrane domain, a region critical for MFN2âČs role in mitochondrial fusion. For this reason, we believe these mice will be a valuable tool for scientists interested in studying the biological functions of MFN2
Alcohol consumption and lifetime change in cognitive ability:a gene Ă environment interaction study
Studies of the effect of alcohol consumption on cognitive ability are often confounded. One approach to avoid confounding is the Mendelian randomization design. Here, we used such a design to test the hypothesis that a genetic score for alcohol processing capacity moderates the association between alcohol consumption and lifetime change in cognitive ability. Members of the Lothian Birth Cohort 1936 completed the same test of intelligence at age 11 and 70Â years. They were assessed for recent alcohol consumption in later life and genotyped for a set of four single-nucleotide polymorphisms in three alcohol dehydrogenase genes. These variants were unrelated to late-life cognition or to socioeconomic status. We found a significant gene Ă alcohol consumption interaction on lifetime cognitive change (pâ=â0.007). Individuals with higher genetic ability to process alcohol showed relative improvements in cognitive ability with more consumption, whereas those with low processing capacity showed a negative relationship between cognitive change and alcohol consumption with more consumption. The effect of alcohol consumption on cognitive change may thus depend on genetic differences in the ability to metabolize alcohol
Novel Eurasian Highly Pathogenic Avian Influenza A H5 Viruses in Wild Birds, Washington, USA, 2014
The novel Eurasian lineage clade 2.3.4.4 highly pathogenic avian influenza (HPAI) A(H5N8) virus (http://www.who.int/influenza/gisrs_laboratory/h5_nomenclature_clade2344/en/) spread rapidly and globally during 2014, substantially affecting poultry populations. The first outbreaks were reported during January 2014 in chickens and domestic ducks in South Korea and subsequently in China and Japan (1â4), reaching Germany, the Netherlands, and the United Kingdom by November 2014 and Italy in early December 2014 (5). Also in November 2014, a novel HPAI H5N2 virus was reported in outbreaks on chicken and turkey farms in Fraser Valley, British Columbia, Canada (5). This H5N2 influenza virus is a reassortant that contains the Eurasian clade 2.3.4.4 H5 plus 4 other Eurasian genes (polymerase acidic protein subunit, matrix protein, polymerase basic protein subunit [PB] 2, nonstructural protein) and 3 North American wild bird lineage genes (neuraminidase [NA], nucleoprotein, PB1) (5). Taiwan has recently reported novel reassortants of the H5 clade 2.3.4.4 with other Eurasian viruses (H5N2, H5N3)
Early Increase in Extrasynaptic NMDA Receptor Signaling and Expression Contributes to Phenotype Onset in Huntington's Disease Mice
SummaryN-methyl-D-aspartate receptor (NMDAR) excitotoxicity is implicated in the pathogenesis of Huntington's disease (HD), a late-onset neurodegenerative disorder. However, NMDARs are poor therapeutic targets, due to their essential physiological role. Recent studies demonstrate that synaptic NMDAR transmission drives neuroprotective gene transcription, whereas extrasynaptic NMDAR activation promotes cell death. We report specifically increased extrasynaptic NMDAR expression, current, and associated reductions in nuclear CREB activation in HD mouse striatum. The changes are observed in the absence of dendritic morphological alterations, before and after phenotype onset, correlate with mutation severity, and require caspase-6 cleavage of mutant huntingtin. Moreover, pharmacological block of extrasynaptic NMDARs with memantine reversed signaling and motor learning deficits. Our data demonstrate elevated extrasynaptic NMDAR activity in an animal model of neurodegenerative disease. We provide a candidate mechanism linking several pathways previously implicated in HD pathogenesis and demonstrate successful early therapeutic intervention in mice
Feedback from the heart: emotional learning and memory is controlled by cardiac cycle, interoceptive accuracy and personality
Feedback processing is critical to trial-and-error learning. Here, we examined whether interoceptive signals concerning the state of cardiovascular arousal influence the processing of reinforcing feedback during the learning of âemotionalâ face-name pairs, with subsequent effects on retrieval. Participants (N = 29) engaged in a learning task of face-name pairs (fearful, neutral, happy faces). Correct and incorrect learning decisions were reinforced by auditory feedback, which was delivered either at cardiac systole (on the heartbeat, when baroreceptors signal the contraction of the heart to the brain), or at diastole (between heartbeats during baroreceptor quiescence). We discovered a cardiac influence on feedback processing that enhanced the learning of fearful faces in people with heightened interoceptive ability. Individuals with enhanced accuracy on a heartbeat counting task learned fearful face-name pairs better when feedback was given at systole than at diastole. This effect was not present for neutral and happy faces. At retrieval, we also observed related effects of personality: First, individuals scoring higher for extraversion showed poorer retrieval accuracy. These individuals additionally manifested lower resting heart rate and lower state anxiety, suggesting that attenuated levels of cardiovascular arousal in extraverts underlies poorer performance. Second, higher extraversion scores predicted higher emotional intensity ratings of fearful faces reinforced at systole. Third, individuals scoring higher for neuroticism showed higher retrieval confidence for fearful faces reinforced at diastole. Our results show that cardiac signals shape feedback processing to influence learning of fearful faces, an effect underpinned by personality differences linked to psychophysiological arousal
A developmental approach to diversifying neuroscience through effective mentorship practices: perspectives on cross-identity mentorship and a critical call to action.
Many early-career neuroscientists with diverse identities may not have mentors who are more advanced in the neuroscience pipeline and have a congruent identity due to historic biases, laws, and policies impacting access to education. Cross-identity mentoring relationships pose challenges and power imbalances that impact the retention of diverse early career neuroscientists, but also hold the potential for a mutually enriching and collaborative relationship that fosters the mentee\u27s success. Additionally, the barriers faced by diverse mentees and their mentorship needs may evolve with career progression and require developmental considerations. This article provides perspectives on factors that impact cross-identity mentorship from individuals participating in Diversifying the Community of Neuroscience (CNS)-a longitudinal, National Institute of Neurological Disorders and Stroke (NINDS) R25 neuroscience mentorship program developed to increase diversity in the neurosciences. Participants in Diversifying CNS were comprised of 14 graduate students, postdoctoral fellows, and early career faculty who completed an online qualitative survey on cross-identity mentorship practices that impact their experience in neuroscience fields. Qualitative survey data were analyzed using inductive thematic analysis and resulted in four themes across career levels: (1) approach to mentorship and interpersonal dynamics, (2) allyship and management of power imbalance, (3) academic sponsorship, and (4) institutional barriers impacting navigation of academia. These themes, along with identified mentorship needs by developmental stage, provide insights mentors can use to better support the success of their mentees with diverse intersectional identities. As highlighted in our discussion, a mentor\u27s awareness of systemic barriers along with active allyship are foundational for their role
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