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1.
Nat Commun ; 13(1): 1830, 2022 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-35383196

RESUMEN

Leber congenital amaurosis (LCA) is the most common cause of inherited retinal degeneration in children. LCA patients with RPE65 mutations show accelerated cone photoreceptor dysfunction and death, resulting in early visual impairment. It is therefore crucial to develop a robust therapy that not only compensates for lost RPE65 function but also protects photoreceptors from further degeneration. Here, we show that in vivo correction of an Rpe65 mutation by adenine base editor (ABE) prolongs the survival of cones in an LCA mouse model. In vitro screening of ABEs and sgRNAs enables the identification of a variant that enhances in vivo correction efficiency. Subretinal delivery of ABE and sgRNA corrects up to 40% of Rpe65 transcripts, restores cone-mediated visual function, and preserves cones in LCA mice. Single-cell RNA-seq reveals upregulation of genes associated with cone phototransduction and survival. Our findings demonstrate base editing as a potential gene therapy that confers long-lasting retinal protection.


Asunto(s)
Amaurosis Congénita de Leber , Degeneración Retiniana , cis-trans-Isomerasas , Animales , Proteínas del Ojo/genética , Humanos , Amaurosis Congénita de Leber/genética , Amaurosis Congénita de Leber/terapia , Ratones , Ratones Noqueados , Células Fotorreceptoras Retinianas Conos/fisiología , Degeneración Retiniana/complicaciones , Degeneración Retiniana/genética , Degeneración Retiniana/terapia , cis-trans-Isomerasas/genética
2.
Nat Commun ; 13(1): 2085, 2022 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-35440563

RESUMEN

Eighty percent of US oil and natural gas (O&G) production sites are low production well sites, with average site-level production ≤15 barrels of oil equivalent per day and producing only 6% of the nation's O&G output in 2019. Here, we integrate national site-level O&G production data and previously reported site-level CH4 measurement data (n = 240) and find that low production well sites are a disproportionately large source of US O&G well site CH4 emissions, emitting more than 4 (95% confidence interval: 3-6) teragrams, 50% more than the total CH4 emissions from the Permian Basin, one of the world's largest O&G producing regions. We estimate low production well sites represent roughly half (37-75%) of all O&G well site CH4 emissions, and a production-normalized CH4 loss rate of more than 10%-a factor of 6-12 times higher than the mean CH4 loss rate of 1.5% for all O&G well sites in the US. Our work suggests that achieving significant reductions in O&G CH4 emissions will require mitigation of emissions from low production well sites.


Asunto(s)
Contaminantes Atmosféricos , Gas Natural , Contaminantes Atmosféricos/análisis , Metano/análisis , Gas Natural/análisis , Yacimiento de Petróleo y Gas
3.
Plant J ; 2022 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-35411592

RESUMEN

Wild relatives of tomato are a valuable source of natural variation in tomato breeding, as many can be hybridized to the cultivated species (Solanum lycopersicum). Several, including S. lycopersicoides, have been crossed to S. lycopersicum for the development of ordered introgression lines (ILs), facilitating breeding for desirable traits. Despite the utility of these wild relatives and their associated ILs, few finished genome sequences have been produced to aid genetic and genomic studies. Here we report a chromosome-scale genome assembly for S. lycopersicoides LA2951, which contains 37,938 predicted protein-coding genes. With the aid of this genome assembly, we have precisely delimited the boundaries of the S. lycopersicoides introgressions in a set of S. lycopersicum cv. VF36 x LA2951 ILs. We demonstrate the usefulness of the LA2951 genome by identifying several quantitative trait loci (QTLs) for phenolics and carotenoids, including underlying candidate genes, and by investigating the genome organization and immunity-associated function of the clustered Pto gene family. In addition, syntenic analysis of R2R3MYB genes sheds light on the identity of the Aubergine locus underlying anthocyanin production. The genome sequence and IL map provide valuable resources for studying fruit nutrient/quality traits, pathogen resistance, and environmental stress tolerance.

4.
G3 (Bethesda) ; 2022 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-35385099

RESUMEN

: Modern breeding methods integrate next-generation sequencing (NGS) and phenomics to identify plants with the best characteristics and greatest genetic merit for use as parents in subsequent breeding cycles to ultimately create improved cultivars able to sustain high adoption rates by farmers. This data-driven approach hinges on strong foundations in data management, quality control, and analytics. Of crucial importance is a central database able to 1) track breeding materials, 2) store experimental evaluations, 3) record phenotypic measurements using consistent ontologies, 4) store genotypic information, and 5) implement algorithms for analysis, prediction and selection decisions. Because of the complexity of the breeding process, breeding databases also tend to be complex, difficult, and expensive to implement and maintain. Here, we present a breeding database system, Breedbase (https://breedbase.org/). Originally initiated as Cassavabase (https://cassavabase.org/) with the NextGen Cassava project (https://www.nextgencassava.org/), and later developed into a crop-agnostic system, it is presently used by dozens of different crops and projects. The system is web-based and is available as open source software. It is available on GitHub (https://github.com/solgenomics/) and packaged in a Docker image for deployment (https://dockerhub.com/breedbase/). The Breedbase system enables breeding programs to better manage and leverage their data for decision making within a fully integrated digital ecosystem. AVAILABILITY: https://github.com/solgenomics, https://hub.docker.com/r/breedbase/breedbase.

5.
JCI Insight ; 7(4)2022 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-35015730

RESUMEN

Adiponectin receptor 1 (ADIPOR1) is a lipid and glucose metabolism regulator that possesses intrinsic ceramidase activity. Mutations of the ADIPOR1 gene have been associated with nonsyndromic and syndromic retinitis pigmentosa. Here, we show that the absence of AdipoR1 in mice leads to progressive photoreceptor degeneration, significant reduction of electroretinogram amplitudes, decreased retinoid content in the retina, and reduced cone opsin expression. Single-cell RNA-Seq results indicate that ADIPOR1 encoded the most abundantly expressed ceramidase in mice and one of the 2 most highly expressed ceramidases in the human retina, next to acid ceramidase ASAH1. We discovered an accumulation of ceramides in the AdipoR1-/- retina, likely due to insufficient ceramidase activity for healthy retina function, resulting in photoreceptor death. Combined treatment with desipramine/L-cycloserine (DC) lowered ceramide levels and exerted a protective effect on photoreceptors in AdipoR1-/- mice. Moreover, we observed improvement in cone-mediated retinal function in the DC-treated animals. Lastly, we found that prolonged DC treatment corrected the electrical responses of the primary visual cortex to visual stimuli, approaching near-normal levels for some parameters. These results highlight the importance of ADIPOR1 ceramidase in the retina and show that pharmacological inhibition of ceramide generation can provide a therapeutic strategy for ADIPOR1-related retinopathy.


Asunto(s)
Ceramidasas/antagonistas & inhibidores , ADN/genética , Mutación , Receptores de Adiponectina/genética , Células Fotorreceptoras Retinianas Conos/metabolismo , Enfermedades de la Retina/genética , Animales , Análisis Mutacional de ADN , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Receptores de Adiponectina/metabolismo , Células Fotorreceptoras Retinianas Conos/patología , Enfermedades de la Retina/metabolismo , Enfermedades de la Retina/patología
6.
Commun Biol ; 4(1): 1297, 2021 11 17.
Artículo en Inglés | MEDLINE | ID: mdl-34789835

RESUMEN

Primary sensory areas of the mammalian neocortex have a remarkable degree of plasticity, allowing neural circuits to adapt to dynamic environments. However, little is known about the effects of traumatic brain injury on visual circuit function. Here we used anatomy and in vivo electrophysiological recordings in adult mice to quantify neuron responses to visual stimuli two weeks and three months after mild controlled cortical impact injury to primary visual cortex (V1). We found that, although V1 remained largely intact in brain-injured mice, there was ~35% reduction in the number of neurons that affected inhibitory cells more broadly than excitatory neurons. V1 neurons showed dramatically reduced activity, impaired responses to visual stimuli and weaker size selectivity and orientation tuning in vivo. Our results show a single, mild contusion injury produces profound and long-lasting impairments in the way V1 neurons encode visual input. These findings provide initial insight into cortical circuit dysfunction following central visual system neurotrauma.


Asunto(s)
Lesiones Traumáticas del Encéfalo/fisiopatología , Neuronas/fisiología , Visión Ocular/fisiología , Animales , Femenino , Masculino , Ratones
8.
Nat Commun ; 12(1): 4715, 2021 08 05.
Artículo en Inglés | MEDLINE | ID: mdl-34354066

RESUMEN

Methane (CH4) emissions from oil and natural gas (O&NG) systems are an important contributor to greenhouse gas emissions. In the United States, recent synthesis studies of field measurements of CH4 emissions at different spatial scales are ~1.5-2× greater compared to official greenhouse gas inventory (GHGI) estimates, with the production-segment as the dominant contributor to this divergence. Based on an updated synthesis of measurements from component-level field studies, we develop a new inventory-based model for CH4 emissions, for the production-segment only, that agrees within error with recent syntheses of site-level field studies and allows for isolation of equipment-level contributions. We find that unintentional emissions from liquid storage tanks and other equipment leaks are the largest contributors to divergence with the GHGI. If our proposed method were adopted in the United States and other jurisdictions, inventory estimates could better guide CH4 mitigation policy priorities.

9.
Sci Adv ; 7(27)2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-34193415

RESUMEN

Industrial emissions play a major role in the global methane budget. The Permian basin is thought to be responsible for almost half of the methane emissions from all U.S. oil- and gas-producing regions, but little is known about individual contributors, a prerequisite for mitigation. We use a new class of satellite measurements acquired during several days in 2019 and 2020 to perform the first regional-scale and high-resolution survey of methane sources in the Permian. We find an unexpectedly large number of extreme point sources (37 plumes with emission rates >500 kg hour-1), which account for a range between 31 and 53% of the estimated emissions in the sampled area. Our analysis reveals that new facilities are major emitters in the area, often due to inefficient flaring operations (20% of detections). These results put current practices into question and are relevant to guide emission reduction efforts.

10.
Ophthalmic Plast Reconstr Surg ; 37(3S): S140-S141, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-32890121

RESUMEN

This is a case report involving 3 siblings, ages 22, 21, and 3 years old, of consanguineous parents and Syrian descent with a particularly unique clinical phenotype and eyelid/gingival findings that have not been previously characterized. Full-thickness eyelid biopsies for 2 of the siblings were evaluated by ophthalmic pathology showed generalized fibrosis without any active destructive process or amyloid. Three of the 9 siblings were affected by this order with no familial history. Ophthalmic plastic surgeons should be aware of this new entity as genetic localization and further identification may help families affected by this disorder.


Asunto(s)
Hermanos , Fibrosis , Humanos , Fenotipo , Síndrome
11.
J Comp Neurol ; 529(1): 129-140, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32361987

RESUMEN

The extrageniculate visual pathway, which carries visual information from the retina through the superficial layers of the superior colliculus and the pulvinar, is poorly understood. The pulvinar is thought to modulate information flow between cortical areas, and has been implicated in cognitive tasks like directing visually guided actions. In order to better understand the underlying circuitry, we performed retrograde injections of modified rabies virus in the visual cortex and pulvinar of the Long-Evans rat. We found a relatively small population of cells projecting to primary visual cortex (V1), compared to a much larger population projecting to higher visual cortex. Reciprocal corticothalamic projections showed a similar result, implying that pulvinar does not play as big a role in directly modulating rodent V1 activity as previously thought.


Asunto(s)
/anatomía & histología , Pulvinar/anatomía & histología , Vías Visuales/anatomía & histología , Animales , Femenino , Pulvinar/citología , Ratas , Ratas Long-Evans , Corteza Visual/anatomía & histología , Corteza Visual/citología , Vías Visuales/citología
12.
Nat Biomed Eng ; 5(2): 169-178, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33077938

RESUMEN

Cytosine base editors and adenine base editors (ABEs) can correct point mutations predictably and independent of Cas9-induced double-stranded DNA breaks (which causes substantial indel formation) and homology-directed repair (which typically leads to low editing efficiency). Here, we show, in adult mice, that a subretinal injection of a lentivirus expressing an ABE and a single-guide RNA targeting a de novo nonsense mutation in the Rpe65 gene corrects the pathogenic mutation with up to 29% efficiency and with minimal formation of indel and off-target mutations, despite the absence of the canonical NGG sequence as a protospacer-adjacent motif. The ABE-treated mice displayed restored RPE65 expression and retinoid isomerase activity, and near-normal levels of retinal and visual functions. Our findings motivate the further testing of ABEs for the treatment of inherited retinal diseases and for the correction of pathological mutations with non-canonical protospacer-adjacent motifs.


Asunto(s)
Adenina/metabolismo , Edición Génica/métodos , Enfermedades de la Retina/metabolismo , Visión Ocular/fisiología , Animales , Proteína 9 Asociada a CRISPR/metabolismo , Codón sin Sentido/genética , Vectores Genéticos/fisiología , Lentivirus/fisiología , Ratones Endogámicos C57BL
13.
Nucleic Acids Res ; 49(D1): D605-D612, 2021 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-33237311

RESUMEN

Cellular life depends on a complex web of functional associations between biomolecules. Among these associations, protein-protein interactions are particularly important due to their versatility, specificity and adaptability. The STRING database aims to integrate all known and predicted associations between proteins, including both physical interactions as well as functional associations. To achieve this, STRING collects and scores evidence from a number of sources: (i) automated text mining of the scientific literature, (ii) databases of interaction experiments and annotated complexes/pathways, (iii) computational interaction predictions from co-expression and from conserved genomic context and (iv) systematic transfers of interaction evidence from one organism to another. STRING aims for wide coverage; the upcoming version 11.5 of the resource will contain more than 14 000 organisms. In this update paper, we describe changes to the text-mining system, a new scoring-mode for physical interactions, as well as extensive user interface features for customizing, extending and sharing protein networks. In addition, we describe how to query STRING with genome-wide, experimental data, including the automated detection of enriched functionalities and potential biases in the user's query data. The STRING resource is available online, at https://string-db.org/.


Asunto(s)
Bases de Datos de Proteínas , Mapeo de Interacción de Proteínas , Proteínas/genética , Interfaz Usuario-Computador
14.
Environ Sci Technol ; 55(1): 581-592, 2021 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-33314919

RESUMEN

In this study, a ground-based mobile measurement system was developed to provide rapid and cost-effective emission surveillance of both methane (CH4) and volatile organic compounds (VOCs) from oil and gas (O&G) production sites. After testing in several controlled release experiments, the system was deployed in a field campaign in the Eagle Ford basin, TX. We found fat-tail distributions for both methane and total VOC (C4-C12) emissions (e.g., the top 20% sites ranked according to methane and total VOC (C4-C12) emissions were responsible for ∼60 and ∼80% of total emissions, respectively) and a good correlation between them (Spearman's R = 0.74). This result suggests that emission controls targeting relatively large emitters may help significantly reduce both methane and VOCs in oil and wet gas basins, such as the Eagle Ford. A strong correlation (Spearman's R = 0.84) was found between total VOC (C4-C12) emissions estimated using SUMMA canisters and data reported from a local ambient air monitoring station. This finding suggests that this system has the potential for rapid emission surveillance targeting relatively large emitters, which can help achieve emission reductions for both greenhouse gas (GHG) and air toxics from O&G production well pads in a cost-effective way.


Asunto(s)
Contaminantes Atmosféricos , Compuestos Orgánicos Volátiles , Contaminantes Atmosféricos/análisis , Análisis Costo-Beneficio , Monitoreo del Ambiente , Metano/análisis , Compuestos Orgánicos Volátiles/análisis
15.
Patterns (N Y) ; 1(7): 100105, 2020 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-33205138

RESUMEN

Heterogeneous and multidisciplinary data generated by research on sustainable global agriculture and agrifood systems requires quality data labeling or annotation in order to be interoperable. As recommended by the FAIR principles, data, labels, and metadata must use controlled vocabularies and ontologies that are popular in the knowledge domain and commonly used by the community. Despite the existence of robust ontologies in the Life Sciences, there is currently no comprehensive full set of ontologies recommended for data annotation across agricultural research disciplines. In this paper, we discuss the added value of the Ontologies Community of Practice (CoP) of the CGIAR Platform for Big Data in Agriculture for harnessing relevant expertise in ontology development and identifying innovative solutions that support quality data annotation. The Ontologies CoP stimulates knowledge sharing among stakeholders, such as researchers, data managers, domain experts, experts in ontology design, and platform development teams.

16.
Environ Sci Technol ; 54(21): 13926-13934, 2020 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-33058723

RESUMEN

Methane emission fluxes were estimated for 71 oil and gas well pads in the western Permian Basin (Delaware Basin), using a mobile laboratory and an inverse Gaussian dispersion method (OTM 33A). Sites with emissions that were below detection limit (BDL) for OTM 33A were recorded and included in the sample. Average emission rate per site was estimated by bootstrapping and by maximum likelihood best log-normal fit. Sites had to be split into "complex" (sites with liquid storage tanks and/or compressors) and "simple" (sites with only wellheads/pump jacks/separators) categories to achieve acceptable log-normal fits. For complex sites, the log-normal fit depends heavily on the number of BDL sites included. As more BDL sites are included, the log-normal distribution fit to the data is falsely widened, overestimating the mean, highlighting the importance of correctly characterizing low end emissions when using log-normal fits. Basin-wide methane emission rates were estimated for the production sector of the New Mexico portion of the Permian and range from ∼520 000 tons per year, TPY (bootstrapping, 95% CI: 300 000-790 000) to ∼610 000 TPY (log-normal fit method, 95% CI: 330 000-1 000 000). These estimates are a factor of 5.5-9.0 times greater than EPA National Emission Inventory (NEI) estimates for the region.


Asunto(s)
Contaminantes Atmosféricos , Metano , Contaminantes Atmosféricos/análisis , Laboratorios , Metano/análisis , Gas Natural/análisis , New Mexico
17.
Nat Biomed Eng ; 4(11): 1119, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-33122854

RESUMEN

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

18.
Neuroscience ; 441: 117-130, 2020 08 10.
Artículo en Inglés | MEDLINE | ID: mdl-32599121

RESUMEN

The pulvinar is a higher-order thalamic relay and a central component of the extrageniculate visual pathway, with input from the superior colliculus and visual cortex and output to all of visual cortex. Rodent pulvinar, more commonly called the lateral posterior nucleus (LP), consists of three highly-conserved subdivisions, and offers the advantage of simplicity in its study compared to more subdivided primate pulvinar. Little is known about receptive field properties of LP, let alone whether functional differences exist between different LP subdivisions, making it difficult to understand what visual information is relayed and what kinds of computations the pulvinar might support. Here, we characterized single-cell response properties in two V1 recipient subdivisions of rat pulvinar, the rostromedial (LPrm) and lateral (LPl), and found that a fourth of the cells were selective for orientation, compared to half in V1, and that LP tuning widths were significantly broader. Response latencies were also significantly longer and preferred size more than three times larger on average than in V1; the latter suggesting pulvinar as a source of spatial context to V1. Between subdivisons, LPl cells preferred higher temporal frequencies, whereas LPrm showed a greater degree of direction selectivity and pattern motion detection. Taken together with known differences in connectivity patterns, these results suggest two separate visual feature processing channels in the pulvinar, one in LPl related to higher speed processing which likely derives from superior colliculus input, and the other in LPrm for motion processing derived through input from visual cortex. SIGNIFICANCE STATEMENT: The pulvinar has a perplexing role in visual cognition as no clear link has been found between the functional properties of its neurons and behavioral deficits that arise when it is damaged. The pulvinar, called the lateral posterior nucleus (LP) in rats, is a higher order thalamic relay with input from the superior colliculus and visual cortex and output to all of visual cortex. By characterizing single-cell response properties in anatomically distinct subdivisions we found two separate visual feature processing channels in the pulvinar, one in lateral LP related to higher speed processing which likely derives from superior colliculus input, and the other in rostromedial LP for motion processing derived through input from visual cortex.


Asunto(s)
Pulvinar , Corteza Visual , Animales , Núcleos Talámicos Laterales , Estimulación Luminosa , Ratas , Colículos Superiores , Vías Visuales
19.
Sci Adv ; 6(17): eaaz5120, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32494644

RESUMEN

Using new satellite observations and atmospheric inverse modeling, we report methane emissions from the Permian Basin, which is among the world's most prolific oil-producing regions and accounts for >30% of total U.S. oil production. Based on satellite measurements from May 2018 to March 2019, Permian methane emissions from oil and natural gas production are estimated to be 2.7 ± 0.5 Tg a-1, representing the largest methane flux ever reported from a U.S. oil/gas-producing region and are more than two times higher than bottom-up inventory-based estimates. This magnitude of emissions is 3.7% of the gross gas extracted in the Permian, i.e., ~60% higher than the national average leakage rate. The high methane leakage rate is likely contributed by extensive venting and flaring, resulting from insufficient infrastructure to process and transport natural gas. This work demonstrates a high-resolution satellite data-based atmospheric inversion framework, providing a robust top-down analytical tool for quantifying and evaluating subregional methane emissions.

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