In May of 2011, NASA selected the
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rigins,
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pectral
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nterpretation,
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esource
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dentification, and
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ecurity–
R
egolith
Ex
plorer (OSIRIS-REx) asteroid sample return mission as the third mission ...in the New Frontiers program. The other two New Frontiers missions are
New Horizons
, which explored Pluto during a flyby in July 2015 and is on its way for a flyby of Kuiper Belt object 2014 MU69 on January 1, 2019, and
Juno
, an orbiting mission that is studying the origin, evolution, and internal structure of Jupiter. The spacecraft departed for near-Earth asteroid (101955) Bennu aboard an United Launch Alliance Atlas V 411 evolved expendable launch vehicle at 7:05 p.m. EDT on September 8, 2016, on a seven-year journey to return samples from Bennu. The spacecraft is on an outbound-cruise trajectory that will result in a rendezvous with Bennu in November 2018. The science instruments on the spacecraft will survey Bennu to measure its physical, geological, and chemical properties, and the team will use these data to select a site on the surface to collect at least 60 g of asteroid regolith. The team will also analyze the remote-sensing data to perform a detailed study of the sample site for context, assess Bennu’s resource potential, refine estimates of its impact probability with Earth, and provide ground-truth data for the extensive astronomical data set collected on this asteroid. The spacecraft will leave Bennu in 2021 and return the sample to the Utah Test and Training Range (UTTR) on September 24, 2023.
A major unanswered question in neuroscience is whether there exists genomic variability between individual neurons of the brain, contributing to functional diversity or to an unexplained burden of ...neurological disease. To address this question, we developed a method to amplify genomes of single neurons from human brains. Because recent reports suggest frequent LINE-1 (L1) retrotransposition in human brains, we performed genome-wide L1 insertion profiling of 300 single neurons from cerebral cortex and caudate nucleus of three normal individuals, recovering >80% of germline insertions from single neurons. While we find somatic L1 insertions, we estimate <0.6 unique somatic insertions per neuron, and most neurons lack detectable somatic insertions, suggesting that L1 is not a major generator of neuronal diversity in cortex and caudate. We then genotyped single cortical cells to characterize the mosaicism of a somatic AKT3 mutation identified in a child with hemimegalencephaly. Single-neuron sequencing allows systematic assessment of genomic diversity in the human brain.
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▸ Whole-genome amplification and sequencing of single neurons from human brains ▸ Single-neuron genome-wide analysis of somatic L1 retrotransposition ▸ Somatic L1 insertions are infrequent in cerebral cortex and caudate nucleus ▸ Single-cell analysis of a somatic mutation causing malformation of the brain
Whole-genome sequencing of individual neurons from human brain shows that retrotransposition of the L1 element is infrequent. L1 insertions may thus generate some somatic mutations but are unlikely to account for neuronal diversity.
Rubble Pile Asteroids Walsh, Kevin J
Annual review of astronomy and astrophysics,
09/2018, Letnik:
56, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The moniker rubble pile is typically applied to all Solar System bodies >200 m and <∼10 km in diameter; in this size range, there is an abundance of evidence that nearly every object is bound ...primarily by self-gravity, with significant void space or bulk porosity between irregularly shaped constituent particles. The understanding of this population is derived from wide-ranging population studies of derived shape and spin, decades of observational studies in numerous wavelengths, evidence left behind from impacts on planets and moons, and the in situ study of a few objects via spacecraft flyby or rendezvous. The internal structure, however, which is responsible for the name rubble pile, is never directly observed but belies a violent history. Many or most of the asteroids on near-Earth orbits and those most accessible for rendezvous and in situ study are likely by-products of the continued collisional evolution of the main asteroid belt.
Background. Invasive fungal diseases are important causes of morbidity and mortality. Clarity and uniformity in defining these infections are important factors in improving the quality of clinical ...studies. A standard set of definitions strengthens the consistency and reproducibility of such studies. Methods. After the introduction of the original European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group definitions, advances in diagnostic technology and the recognition of areas in need of improvement led to a revision of this document. The revision process started with a meeting of participants in 2003, to decide on the process and to draft the proposal. This was followed by several rounds of consultation until a final draft was approved in 2005. This was made available for 6 months to allow public comment, and then the manuscript was prepared and approved. Results. The revised definitions retain the original classifications of “proven,” “probable,” and “possible” invasive fungal disease, but the definition of “probable” has been expanded, whereas the scope of the category “possible” has been diminished. The category of proven invasive fungal disease can apply to any patient, regardless of whether the patient is immunocompromised, whereas the probable and possible categories are proposed for immunocompromised patients only. Conclusions. These revised definitions of invasive fungal disease are intended to advance clinical and epidemiological research and may serve as a useful model for defining other infections in high-risk patients.
The safety and antifungal efficacy of amphotericin B lipid complex (ABLC) were evaluated in 556 cases of invasive fungal infection treated through an open-label, single-patient, emergency-use study ...of patients who were refractory to or intolerant of conventional antifungal therapy. All 556 treatment episodes were evaluable for safety. During the course of ABLC therapy, serum creatinine levels significantly decreased from baseline (P < .02). Among 162 patients with serum creatinine values ⩾2.5 mg/dL at the start of ABLC therapy (baseline), the mean serum creatinine value decreased significantly from the first week through the sixth week (P < .0003). Among the 291 mycologically confirmed cases evaluable for therapeutic response, there was a complete or partial response to ABLC in 167 (57%), including 42% (55) of 130 cases of aspergillosis, 67% (28) of 42 cases of disseminated candidiasis, 71% (17) of 24 cases of zygomycosis, and 82% (9) of 11 cases of fusariosis. Response rates varied according to the pattern of invasive fungal infection, underlying condition, and reason for enrollment (intolerance versus progressive infection). These findings support the use of ABLC in the treatment of invasive fungal infections in patients who are intolerant of or refractory to conventional antifungal therapy.
Global health care is experiencing an unprecedented surge in the number of critically ill patients who require mechanical ventilation due to the COVID-19 pandemic. The requirement for relatively long ...periods of ventilation in those who survive means that many are considered for tracheostomy to free patients from ventilatory support and maximise scarce resources. COVID-19 provides unique challenges for tracheostomy care: health-care workers need to safely undertake tracheostomy procedures and manage patients afterwards, minimising risks of nosocomial transmission and compromises in the quality of care. Conflicting recommendations exist about case selection, the timing and performance of tracheostomy, and the subsequent management of patients. In response, we convened an international working group of individuals with relevant expertise in tracheostomy. We did a literature and internet search for reports of research pertaining to tracheostomy during the COVID-19 pandemic, supplemented by sources comprising statements and guidance on tracheostomy care. By synthesising early experiences from countries that have managed a surge in patient numbers, emerging virological data, and international, multidisciplinary expert opinion, we aim to provide consensus guidelines and recommendations on the conduct and management of tracheostomy during the COVID-19 pandemic.
Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of γ-aminobutyric acid type A (GABA
) receptors to dampen neuronal activity in the brain
. However, direct ...structural information on the mechanisms of general anaesthetics at their physiological receptor sites is lacking. Here we present cryo-electron microscopy structures of GABA
receptors bound to intravenous anaesthetics, benzodiazepines and inhibitory modulators. These structures were solved in a lipidic environment and are complemented by electrophysiology and molecular dynamics simulations. Structures of GABA
receptors in complex with the anaesthetics phenobarbital, etomidate and propofol reveal both distinct and common transmembrane binding sites, which are shared in part by the benzodiazepine drug diazepam. Structures in which GABA
receptors are bound by benzodiazepine-site ligands identify an additional membrane binding site for diazepam and suggest an allosteric mechanism for anaesthetic reversal by flumazenil. This study provides a foundation for understanding how pharmacologically diverse and clinically essential drugs act through overlapping and distinct mechanisms to potentiate inhibitory signalling in the brain.
GGGGCC repeat expansions of C9orf72 represent the most common genetic variant of amyotrophic lateral sclerosis and frontotemporal degeneration, but the mechanism of pathogenesis is unclear. Recent ...reports have suggested that the transcribed repeat might form toxic RNA foci that sequester various RNA processing proteins. Consensus as to the identity of the binding partners is missing and whole neuronal proteome investigation is needed. Using RNA fluorescence in situ hybridization we first identified nuclear and cytoplasmic RNA foci in peripheral and central nervous system biosamples from patients with amyotrophic lateral sclerosis with a repeat expansion of C9orf72 (C9orf72+), but not from those patients without a repeat expansion of C9orf72 (C9orf72-) or control subjects. Moreover, in the cases examined, the distribution of foci-positive neurons correlated with the clinical phenotype (t-test P < 0.05). As expected, RNA foci are ablated by RNase treatment. Interestingly, we identified foci in fibroblasts from an asymptomatic C9orf72+ carrier. We next performed pulldown assays, with GGGGCC5, in conjunction with mass spectrometry analysis, to identify candidate binding partners of the GGGGCC repeat expansion. Proteins containing RNA recognition motifs and involved in splicing, messenger RNA nuclear export and/or translation were significantly enriched. Immunohistochemistry in central nervous system tissue from C9orf72+ patients with amyotrophic lateral sclerosis demonstrated co-localization of RNA foci with SRSF2, hnRNP H1/F, ALYREF and hnRNP A1 in cerebellar granule cells and with SRSF2, hnRNP H1/F and ALYREF in motor neurons, the primary target of pathology in amyotrophic lateral sclerosis. Direct binding of proteins to GGGGCC repeat RNA was confirmed in vitro by ultraviolet-crosslinking assays. Co-localization was only detected in a small proportion of RNA foci, suggesting dynamic sequestration rather than irreversible binding. Additional immunohistochemistry demonstrated that neurons with and without RNA foci were equally likely to show nuclear depletion of TDP-43 (χ(2) P = 0.75) or poly-GA dipeptide repeat protein inclusions (χ(2) P = 0.46). Our findings suggest two non-exclusive pathogenic mechanisms: (i) functional depletion of RNA-processing proteins resulting in disruption of messenger RNA splicing; and (ii) licensing of expanded C9orf72 pre-messenger RNA for nuclear export by inappropriate association with messenger RNA export adaptor protein(s) leading to cytoplasmic repeat associated non-ATG translation and formation of potentially toxic dipeptide repeat protein.
The increasing capabilities of exoskeletons and powered prosthetics for walking assistance have paved the way for more sophisticated and individualized control strategies. In response to this ...opportunity, recent work on human-in-the-loop optimization has considered the problem of automatically tuning control parameters based on realtime physiological measurements. However, the common use of metabolic cost as a performance metric creates significant experimental challenges due to its long measurement times and low signal-to-noise ratio. We evaluate the use of Bayesian optimization-a family of sample-efficient, noise-tolerant, and global optimization methods-for quickly identifying near-optimal control parameters. To manage experimental complexity and provide comparisons against related work, we consider the task of minimizing metabolic cost by optimizing walking step frequencies in unaided human subjects. Compared to an existing approach based on gradient descent, Bayesian optimization identified a near-optimal step frequency with a faster time to convergence (12 minutes, p < 0.01), smaller inter-subject variability in convergence time (± 2 minutes, p < 0.01), and lower overall energy expenditure (p < 0.01).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Emerging evidence suggests that maternal folate status can impact cognitive development in childhood. Folate-dependent DNA methylation may provide a biological mechanism to link folate status during ...pregnancy with cognition in the offspring.
The objective was to investigate the effect of continued folic acid (FA) supplementation beyond the first trimester of pregnancy on DNA methylation in cord blood of epigenetically controlled genes related to brain development and function.
Using available cord blood samples (n = 86) from the Folic Acid Supplementation in the Second and Third Trimesters (FASSTT) trial in pregnancy, we applied pyrosequencing techniques to analyze cord blood DNA at 9 candidate loci known to be regulated by methylation, including some previously implicated in observational studies: the widely dispersed retrotransposon long interspersed nuclear element-1 (LINE-1) and 8 single-copy loci (RBM46, PEG3, IGF2, GRB10, BDNF, GRIN3B, OPCML, and APC2).
The newborns of mothers who received ongoing FA (400 µg/d) through the second and third trimesters, compared with placebo, had significantly lower overall DNA methylation levels at LINE-1 (56.3% ± 1.7% compared with 57.2% ± 2.1%; P = 0.024), IFG2 (48.9% ± 4.4% compared with 51.2% ± 5.1%; P = 0.021), and BDNF (2.7% ± 0.7% compared with 3.1% ± 0.8%; P = 0.003). The effect of FA treatment on DNA methylation was significant only in female offspring for IGF2 (P = 0.028) and only in males for BDNF (P = 0.012). For GRB10 and GRIN3B, we detected no effect on overall methylation; however, individual cytosine-phosphate-guanine sites showed significant DNA methylation changes in response to FA.
Continued supplementation with FA through trimesters 2 and 3 of pregnancy results in significant changes in DNA methylation in cord blood of genes related to brain development. The findings offer a potential biological mechanism linking maternal folate status with neurodevelopment of the offspring, but this requires further investigation using a genome-wide approach.
This trial was registered at www.isrctn.com as ISRCTN19917787.
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