Fast radio bursts (FRBs) are bright, millisecond-duration radio transients originating from sources at extragalactic distances
, the origin of which is unknown. Some FRB sources emit repeat bursts, ...ruling out cataclysmic origins for those events
. Despite searches for periodicity in repeat burst arrival times on timescales from milliseconds to many days
, these bursts have hitherto been observed to appear sporadically and-although clustered
-without a regular pattern. Here we report observations of a 16.35 ± 0.15 day periodicity (or possibly a higher-frequency alias of that periodicity) from the repeating FRB 180916.J0158+65 detected by the Canadian Hydrogen Intensity Mapping Experiment Fast Radio Burst Project
. In 38 bursts recorded from 16 September 2018 to 4 February 2020 UTC, we find that all bursts arrive in a five-day phase window, and 50 per cent of the bursts arrive in a 0.6-day phase window. Our results suggest a mechanism for periodic modulation either of the burst emission itself or through external amplification or absorption, and disfavour models invoking purely sporadic processes.
The development of clinically viable delivery methods presents one of the greatest challenges in the therapeutic application of CRISPR/Cas9 mediated genome editing. Here, we report the development of ...a lipid nanoparticle (LNP)-mediated delivery system that, with a single administration, enabled significant editing of the mouse transthyretin (Ttr) gene in the liver, with a >97% reduction in serum protein levels that persisted for at least 12 months. These results were achieved with an LNP delivery system that was biodegradable and well tolerated. The LNP delivery system was combined with a sgRNA having a chemical modification pattern that was important for high levels of in vivo activity. The formulation was similarly effective in a rat model. Our work demonstrates that this LNP system can deliver CRISPR/Cas9 components to achieve clinically relevant levels of in vivo genome editing with a concomitant reduction of TTR serum protein, highlighting the potential of this system as an effective genome editing platform.
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•LNP delivery achieves >97% target protein knockdown for at least 12 months•Editing level is cumulative following multiple LNP doses•A sgRNA chemical modification pattern was critical for high levels of in vivo activity•Biodegradable lipid and CRISPR/Cas9 components are transient and well tolerated
Finn et al. describe the development of a transient, biodegradable LNP-based CRISPR/Cas9 delivery system that achieves >97% knockdown of serum TTR levels following a single administration. Editing levels were stable for 12 months, despite the transient nature of the delivery system and the editing components.
Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate. Structural studies have been restricted to the amino-terminal extracellular ...domain, providing little understanding of the membrane-spanning signal transduction domain. Metabotropic glutamate receptor 5 is of considerable interest as a drug target in the treatment of fragile X syndrome, autism, depression, anxiety, addiction and movement disorders. Here we report the crystal structure of the transmembrane domain of the human receptor in complex with the negative allosteric modulator, mavoglurant. The structure provides detailed insight into the architecture of the transmembrane domain of class C receptors including the precise location of the allosteric binding site within the transmembrane domain and key micro-switches which regulate receptor signalling. This structure also provides a model for all class C G-protein-coupled receptors and may aid in the design of new small-molecule drugs for the treatment of brain disorders.
Abstract
Background
Outbreaks of coronavirus disease 2019 (COVID-19) have been reported in nursing homes and assisted living facilities; however, the extent of asymptomatic and presymptomatic severe ...acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in this high-risk population remains unclear.
Methods
We conducted an investigation of the first known outbreak of SARS-CoV-2 at a skilled nursing facility (SNF) in Illinois on 15 March 2020 and followed residents for 30 days. We tested 126/127 residents for SARS-CoV-2 via reverse-transcription polymerase chain reaction and performed symptom assessments. We calculated the point prevalence of SARS-CoV-2 and assessed symptom onset over 30-day follow-up to determine: (1) the proportion of cases who were symptomatic, presymptomatic, and asymptomatic and (2) incidence of symptoms among those who tested negative. We used the Kaplan-Meier method to determine the 30-day probability of death for cases.
Results
Of 126 residents tested, 33 had confirmed SARS-CoV-2 on 15 March. Nineteen (58%) had symptoms at the time of testing, 1 (3%) developed symptoms over follow-up, and 13 (39%) remained asymptomatic. Thirty-five residents who tested negative on 15 March developed symptoms over follow-up; of these, 3 were re-tested and 2 were positive. The 30-day probability of death among cases was 29%.
Conclusions
SNFs are particularly vulnerable to SARS-CoV-2, and residents are at risk of severe outcomes. Attention must be paid to preventing outbreaks in these and other congregate care settings. Widespread testing and infection control are key to help prevent COVID-19 morbidity and mortality in these high-risk populations.
In an investigation of the first known outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a skilled nursing facility in Illinois, we found that 39% of confirmed cases remained asymptomatic, and the 30-day probability of death was 29%.
Transactivation response element RNA-binding protein (TRBP or TARBP2) initially identified to play an important role in human immunodeficiency virus (HIV) replication also has emerged as a regulator ...of microRNA biogenesis. In addition, TRBP functions in signaling pathways by negatively regulating the interferon-induced double-stranded RNA (dsRNA)-activated protein kinase (PKR) during viral infections and cell stress. During cellular stress, PKR is activated and phosphorylates the α subunit of the eukaryotic translation factor eIF2, leading to the cessation of general protein synthesis. TRBP inhibits PKR activity by direct interaction as well as by binding to PKR's two known activators, dsRNA and PACT, thus preventing their interaction with PKR. In this study, we demonstrate for the first time that TRBP is phosphorylated in response to oxidative stress and upon phosphorylation, inhibits PKR more efficiently promoting cell survival. These results establish that PKR regulation through stress-induced TRBP phosphorylation is an important mechanism ensuring cellular recovery and preventing apoptosis due to sustained PKR activation.
Using longitudinal neuroimaging, Cole et al. show that traumatic brain injury (TBI) results in progressive loss of brain tissue that continues for years after an injury. Tissue loss occurs ...predominantly in cerebral white matter and cortical sulci. Neuroimaging may be a feasible method for evaluating neuroprotective therapies after TBI.
Abstract
Traumatic brain injury leads to significant loss of brain volume, which continues into the chronic stage. This can be sensitively measured using volumetric analysis of MRI. Here we: (i) investigated longitudinal patterns of brain atrophy; (ii) tested whether atrophy is greatest in sulcal cortical regions; and (iii) showed how atrophy could be used to power intervention trials aimed at slowing neurodegeneration. In 61 patients with moderate-severe traumatic brain injury (mean age = 41.55 years ± 12.77) and 32 healthy controls (mean age = 34.22 years ± 10.29), cross-sectional and longitudinal (1-year follow-up) brain structure was assessed using voxel-based morphometry on T1-weighted scans. Longitudinal brain volume changes were characterized using a novel neuroimaging analysis pipeline that generates a Jacobian determinant metric, reflecting spatial warping between baseline and follow-up scans. Jacobian determinant values were summarized regionally and compared with clinical and neuropsychological measures. Patients with traumatic brain injury showed lower grey and white matter volume in multiple brain regions compared to controls at baseline. Atrophy over 1 year was pronounced following traumatic brain injury. Patients with traumatic brain injury lost a mean (± standard deviation) of 1.55% ± 2.19 of grey matter volume per year, 1.49% ± 2.20 of white matter volume or 1.51% ± 1.60 of whole brain volume. Healthy controls lost 0.55% ± 1.13 of grey matter volume and gained 0.26% ± 1.11 of white matter volume; equating to a 0.22% ± 0.83 reduction in whole brain volume. Atrophy was greatest in white matter, where the majority (84%) of regions were affected. This effect was independent of and substantially greater than that of ageing. Increased atrophy was also seen in cortical sulci compared to gyri. There was no relationship between atrophy and time since injury or age at baseline. Atrophy rates were related to memory performance at the end of the follow-up period, as well as to changes in memory performance, prior to multiple comparison correction. In conclusion, traumatic brain injury results in progressive loss of brain tissue volume, which continues for many years post-injury. Atrophy is most prominent in the white matter, but is also more pronounced in cortical sulci compared to gyri. These findings suggest the Jacobian determinant provides a method of quantifying brain atrophy following a traumatic brain injury and is informative in determining the long-term neurodegenerative effects after injury. Power calculations indicate that Jacobian determinant images are an efficient surrogate marker in clinical trials of neuroprotective therapeutics.
A repeating fast radio burst Spitler, L G; Scholz, P; Hessels, J W T ...
Nature (London),
03/2016, Letnik:
531, Številka:
7593
Journal Article
Recenzirano
Odprti dostop
Fast radio bursts are millisecond-duration astronomical radio pulses of unknown physical origin that appear to come from extragalactic distances. Previous follow-up observations have failed to find ...additional bursts at the same dispersion measure (that is, the integrated column density of free electrons between source and telescope) and sky position as the original detections. The apparent non-repeating nature of these bursts has led to the suggestion that they originate in cataclysmic events. Here we report observations of ten additional bursts from the direction of the fast radio burst FRB 121102. These bursts have dispersion measures and sky positions consistent with the original burst. This unambiguously identifies FRB 121102 as repeating and demonstrates that its source survives the energetic events that cause the bursts. Additionally, the bursts from FRB 121102 show a wide range of spectral shapes that appear to be predominantly intrinsic to the source and which vary on timescales of minutes or less. Although there may be multiple physical origins for the population of fast radio bursts, these repeat bursts with high dispersion measure and variable spectra specifically seen from the direction of FRB 121102 support an origin in a young, highly magnetized, extragalactic neutron star.
Although considerable evidence suggests that the chemical synapse is a lynchpin underlying affective disorders, how molecular insults differentially affect specific synaptic connections remains ...poorly understood. For instance, Neurexin 1a and 2 (NRXN1 and NRXN2) and CNTNAP2 (also known as CASPR2), all members of the neurexin superfamily of transmembrane molecules, have been implicated in neuropsychiatric disorders. However, their loss leads to deficits that have been best characterized with regard to their effect on excitatory cells. Notably, other disease-associated genes such as BDNF and ERBB4 implicate specific interneuron synapses in psychiatric disorders. Consistent with this, cortical interneuron dysfunction has been linked to epilepsy, schizophrenia and autism. Using a microarray screen that focused upon synapse-associated molecules, we identified Cntnap4 (contactin associated protein-like 4, also known as Caspr4) as highly enriched in developing murine interneurons. In this study we show that Cntnap4 is localized presynaptically and its loss leads to a reduction in the output of cortical parvalbumin (PV)-positive GABAergic (γ-aminobutyric acid producing) basket cells. Paradoxically, the loss of Cntnap4 augments midbrain dopaminergic release in the nucleus accumbens. In Cntnap4 mutant mice, synaptic defects in these disease-relevant neuronal populations are mirrored by sensory-motor gating and grooming endophenotypes; these symptoms could be pharmacologically reversed, providing promise for therapeutic intervention in psychiatric disorders.
Data collected through the National Expert Survey (NES) of the Global Entrepreneurship Monitor (GEM) are widely used to benchmark and assess the quality and impact of national entrepreneurial ...ecosystems. Based on a comprehensive analysis of the publicly available NES data, we show that the construct validity of the survey is not sufficient and that the experts differ so greatly in their evaluations of the entrepreneurial framework conditions (EFCs) in a country that meaningful cross-country and within-country (longitudinal) analyses are precluded. We conclude that the currently available NES data are not suited for motivating policy decisions.
Using the dynamic capabilities and flexible planning framework, we propose a Dynamic strategic planning (DSP) scale. We test for the nomological validity of Dynamic strategic planning using ...operational capabilities (OC) as a mediator. Using a survey of 267 US-based SMEs, we test for the mediation effect of operational capabilities (disaster immunity, innovation, product quality, delivery reliability, process flexibility, and cost leadership) between Dynamic strategic planning scale (clarity of vision, understanding of core capabilities, selecting strategic targets, shared responsibility, and taking action) and financial performance. Supporting the nomological argument that Dynamic strategic planning will be less efficacious directly and would be more effective when it is manifested through operational capabilities, the findings show that Dynamic strategic planning has a negative but non-significant association with financial performance; however, it positively influences financial performance through operational capabilities. Implications of the results are discussed with theoretical contributions and future research directions.
•We propose a dynamic strategic planning (DSP) scale based on dynamic capabilities framework.•DSP has a direct negative association with financial performance.•DSP positively influences financial performance through operational capabilities.•DSP will be less efficacious unless it is manifested through operations capability.
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