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1.
Cell ; 179(1): 251-267.e24, 2019 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-31539496

RESUMEN

In situ transgenesis methods such as viruses and electroporation can rapidly create somatic transgenic mice but lack control over copy number, zygosity, and locus specificity. Here we establish mosaic analysis by dual recombinase-mediated cassette exchange (MADR), which permits stable labeling of mutant cells expressing transgenic elements from precisely defined chromosomal loci. We provide a toolkit of MADR elements for combination labeling, inducible and reversible transgene manipulation, VCre recombinase expression, and transgenesis of human cells. Further, we demonstrate the versatility of MADR by creating glioma models with mixed reporter-identified zygosity or with "personalized" driver mutations from pediatric glioma. MADR is extensible to thousands of existing mouse lines, providing a flexible platform to democratize the generation of somatic mosaic mice. VIDEO ABSTRACT.


Asunto(s)
Neoplasias Encefálicas/genética , Modelos Animales de Enfermedad , Marcación de Gen/métodos , Sitios Genéticos/genética , Glioma/genética , Mutagénesis Insercional/métodos , Transgenes/genética , Animales , Línea Celular Tumoral , Femenino , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Células-Madre Neurales/metabolismo , Recombinasas/metabolismo , Transfección
2.
Nature ; 626(7998): 327-334, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38109939

RESUMEN

The pulp and paper industry is an important contributor to global greenhouse gas emissions1,2. Country-specific strategies are essential for the industry to achieve net-zero emissions by 2050, given its vast heterogeneities across countries3,4. Here we develop a comprehensive bottom-up assessment of net greenhouse gas emissions of the domestic paper-related sectors for 30 major countries from 1961 to 2019-about 3.2% of global anthropogenic greenhouse gas emissions from the same period5-and explore mitigation strategies through 2,160 scenarios covering key factors. Our results show substantial differences across countries in terms of historical emissions evolution trends and structure. All countries can achieve net-zero emissions for their pulp and paper industry by 2050, with a single measure for most developed countries and several measures for most developing countries. Except for energy-efficiency improvement and energy-system decarbonization, tropical developing countries with abundant forest resources should give priority to sustainable forest management, whereas other developing countries should pay more attention to enhancing methane capture rate and reducing recycling. These insights are crucial for developing net-zero strategies tailored to each country and achieving net-zero emissions by 2050 for the pulp and paper industry.


Asunto(s)
Agricultura Forestal , Efecto Invernadero , Gases de Efecto Invernadero , Industrias , Internacionalidad , Papel , Desarrollo Sostenible , Madera , Efecto Invernadero/prevención & control , Efecto Invernadero/estadística & datos numéricos , Gases de Efecto Invernadero/análisis , Gases de Efecto Invernadero/aislamiento & purificación , Industrias/legislación & jurisprudencia , Industrias/estadística & datos numéricos , Metano/análisis , Metano/aislamiento & purificación , Reciclaje/estadística & datos numéricos , Reciclaje/tendencias , Países Desarrollados , Países en Desarrollo , Bosques , Agricultura Forestal/métodos , Agricultura Forestal/tendencias , Desarrollo Sostenible/tendencias , Clima Tropical
3.
Nature ; 613(7945): 676-681, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36379225

RESUMEN

The open-circuit voltage (VOC) deficit in perovskite solar cells is greater in wide-bandgap (over 1.7 eV) cells than in perovskites of roughly 1.5 eV (refs. 1,2). Quasi-Fermi-level-splitting measurements show VOC-limiting recombination at the electron-transport-layer contact3-5. This, we find, stems from inhomogeneous surface potential and poor perovskite-electron transport layer energetic alignment. Common monoammonium surface treatments fail to address this; as an alternative, we introduce diammonium molecules to modify perovskite surface states and achieve a more uniform spatial distribution of surface potential. Using 1,3-propane diammonium, quasi-Fermi-level splitting increases by 90 meV, enabling 1.79 eV perovskite solar cells with a certified 1.33 V VOC and over 19% power conversion efficiency (PCE). Incorporating this layer into a monolithic all-perovskite tandem, we report a record VOC of 2.19 V (89% of the detailed balance VOC limit) and over 27% PCE (26.3% certified quasi-steady state). These tandems retained more than 86% of their initial PCE after 500 h of operation.

4.
Nature ; 624(7991): 289-294, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37871614

RESUMEN

Inverted perovskite solar cells (PSCs) promise enhanced operating stability compared to their normal-structure counterparts1-3. To improve efficiency further, it is crucial to combine effective light management with low interfacial losses4,5. Here we develop a conformal self-assembled monolayer (SAM) as the hole-selective contact on light-managing textured substrates. Molecular dynamics simulations indicate that cluster formation during phosphonic acid adsorption leads to incomplete SAM coverage. We devise a co-adsorbent strategy that disassembles high-order clusters, thus homogenizing the distribution of phosphonic acid molecules, and thereby minimizing interfacial recombination and improving electronic structures. We report a laboratory-measured power conversion efficiency (PCE) of 25.3% and a certified quasi-steady-state PCE of 24.8% for inverted PSCs, with a photocurrent approaching 95% of the Shockley-Queisser maximum. An encapsulated device having a PCE of 24.6% at room temperature retains 95% of its peak performance when stressed at 65 °C and 50% relative humidity following more than 1,000 h of maximum power point tracking under 1 sun illumination. This represents one of the most stable PSCs subjected to accelerated ageing: achieved with a PCE surpassing 24%. The engineering of phosphonic acid adsorption on textured substrates offers a promising avenue for efficient and stable PSCs. It is also anticipated to benefit other optoelectronic devices that require light management.

5.
Nature ; 618(7963): 74-79, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36977463

RESUMEN

The tunable bandgaps and facile fabrication of perovskites make them attractive for multi-junction photovoltaics1,2. However, light-induced phase segregation limits their efficiency and stability3-5: this occurs in wide-bandgap (>1.65 electron volts) iodide/bromide mixed perovskite absorbers, and becomes even more acute in the top cells of triple-junction solar photovoltaics that require a fully 2.0-electron-volt bandgap absorber2,6. Here we report that lattice distortion in iodide/bromide mixed perovskites is correlated with the suppression of phase segregation, generating an increased ion-migration energy barrier arising from the decreased average interatomic distance between the A-site cation and iodide. Using an approximately 2.0-electron-volt rubidium/caesium mixed-cation inorganic perovskite with large lattice distortion in the top subcell, we fabricated all-perovskite triple-junction solar cells and achieved an efficiency of 24.3 per cent (23.3 per cent certified quasi-steady-state efficiency) with an open-circuit voltage of 3.21 volts. This is, to our knowledge, the first reported certified efficiency for perovskite-based triple-junction solar cells. The triple-junction devices retain 80 per cent of their initial efficiency following 420 hours of operation at the maximum power point.

6.
Nature ; 606(7915): 674-677, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35676480

RESUMEN

Solar flares, driven by prompt release of free magnetic energy in the solar corona1,2, are known to accelerate a substantial portion (ten per cent or more)3,4 of available electrons to high energies. Hard X-rays, produced by high-energy electrons accelerated in the flare5, require a high ambient density for their detection. This restricts the observed volume to denser regions that do not necessarily sample the entire volume of accelerated electrons6. Here we report evolving spatially resolved distributions of thermal and non-thermal electrons in a solar flare derived from microwave observations that show the true extent of the acceleration region. These distributions show a volume filled with only (or almost only) non-thermal electrons while being depleted of the thermal plasma, implying that all electrons have experienced a prominent acceleration there. This volume is isolated from a surrounding, more typical flare plasma of mainly thermal particles with a smaller proportion of non-thermal electrons. This highly efficient acceleration happens in the same volume in which the free magnetic energy is being released2.

7.
Nature ; 603(7899): 73-78, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35038717

RESUMEN

All-perovskite tandem solar cells hold the promise of surpassing the efficiency limits of single-junction solar cells1-3; however, until now, the best-performing all-perovskite tandem solar cells have exhibited lower certified efficiency than have single-junction perovskite solar cells4,5. A thick mixed Pb-Sn narrow-bandgap subcell is needed to achieve high photocurrent density in tandem solar cells6, yet this is challenging owing to the short carrier diffusion length within Pb-Sn perovskites. Here we develop ammonium-cation-passivated Pb-Sn perovskites with long diffusion lengths, enabling subcells that have an absorber thickness of approximately 1.2 µm. Molecular dynamics simulations indicate that widely used phenethylammonium cations are only partially adsorbed on the surface defective sites at perovskite crystallization temperatures. The passivator adsorption is predicted to be enhanced using 4-trifluoromethyl-phenylammonium (CF3-PA), which exhibits a stronger perovskite surface-passivator interaction than does phenethylammonium. By adding a small amount of CF3-PA into the precursor solution, we increase the carrier diffusion length within Pb-Sn perovskites twofold, to over 5 µm, and increase the efficiency of Pb-Sn perovskite solar cells to over 22%. We report a certified efficiency of 26.4% in all-perovskite tandem solar cells, which exceeds that of the best-performing single-junction perovskite solar cells. Encapsulated tandem devices retain more than 90% of their initial performance after 600 h of operation at the maximum power point under 1 Sun illumination in ambient conditions.

8.
Nature ; 605(7911): 761-766, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35585240

RESUMEN

Diabetes mellitus is prevalent among women of reproductive age, and many women are left undiagnosed or untreated1. Gestational diabetes has profound and enduring effects on the long-term health of the offspring2,3. However, the link between pregestational diabetes and disease risk into adulthood in the next generation has not been sufficiently investigated. Here we show that pregestational hyperglycaemia renders the offspring more vulnerable to glucose intolerance. The expression of TET3 dioxygenase, responsible for 5-methylcytosine oxidation and DNA demethylation in the zygote4, is reduced in oocytes from a mouse model of hyperglycaemia (HG mice) and humans with diabetes. Insufficient demethylation by oocyte TET3 contributes to hypermethylation at the paternal alleles of several insulin secretion genes, including the glucokinase gene (Gck), that persists from zygote to adult, promoting impaired glucose homeostasis largely owing to the defect in glucose-stimulated insulin secretion. Consistent with these findings, mouse progenies derived from the oocytes of maternal heterozygous and homozygous Tet3 deletion display glucose intolerance and epigenetic abnormalities similar to those from the oocytes of HG mice. Moreover, the expression of exogenous Tet3 mRNA in oocytes from HG mice ameliorates the maternal effect in offspring. Thus, our observations suggest an environment-sensitive window in oocyte development that confers predisposition to glucose intolerance in the next generation through TET3 insufficiency rather than through a direct perturbation of the oocyte epigenome. This finding suggests a potential benefit of pre-conception interventions in mothers to protect the health of offspring.


Asunto(s)
Dioxigenasas , Intolerancia a la Glucosa , Hiperglucemia , Oocitos , Adulto , Animales , Dioxigenasas/metabolismo , Femenino , Glucosa/metabolismo , Intolerancia a la Glucosa/genética , Intolerancia a la Glucosa/metabolismo , Humanos , Hiperglucemia/complicaciones , Hiperglucemia/genética , Hiperglucemia/metabolismo , Herencia Materna , Ratones , Oocitos/metabolismo
9.
Plant Cell ; 36(3): 605-625, 2024 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-38079275

RESUMEN

Drought stress limits crop yield, but the molecular modulators and their mechanisms underlying the trade-off between drought resistance and crop growth and development remain elusive. Here, a grain width and weight2 (GW2)-like really interesting new gene finger E3 ligase, TaGW2, was identified as a pivotal regulator of both kernel development and drought responses in wheat (Triticum aestivum). TaGW2 overexpression enhances drought resistance but leads to yield drag under full irrigation conditions. In contrast, TaGW2 knockdown or knockout attenuates drought resistance but remarkably increases kernel size and weight. Furthermore, TaGW2 directly interacts with and ubiquitinates the type-B Arabidopsis response regulator TaARR12, promoting its degradation via the 26S proteasome. Analysis of TaARR12 overexpression and knockdown lines indicated that TaARR12 represses the drought response but does not influence grain yield in wheat. Further DNA affinity purification sequencing combined with transcriptome analysis revealed that TaARR12 downregulates stress-responsive genes, especially group-A basic leucine zipper (bZIP) genes, resulting in impaired drought resistance. Notably, TaARR12 knockdown in the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated nuclease 9 (Cas9)-mediated tagw2 knockout mutant leads to significantly higher drought resistance and grain yield compared to wild-type plants. Collectively, these findings show that the TaGW2-TaARR12 regulatory module is essential for drought responses, providing a strategy for improving stress resistance in high-yield wheat varieties.


Asunto(s)
Semillas , Triticum , Semillas/genética , Triticum/metabolismo , Resistencia a la Sequía , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Grano Comestible/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Sequías , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo
10.
Nature ; 591(7849): 246-251, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33692558

RESUMEN

One challenge for the commercial development of solid oxide fuel cells as efficient energy-conversion devices is thermo-mechanical instability. Large internal-strain gradients caused by the mismatch in thermal expansion behaviour between different fuel cell components are the main cause of this instability, which can lead to cell degradation, delamination or fracture1-4. Here we demonstrate an approach to realizing full thermo-mechanical compatibility between the cathode and other cell components by introducing a thermal-expansion offset. We use reactive sintering to combine a cobalt-based perovskite with high electrochemical activity and large thermal-expansion coefficient with a negative-thermal-expansion material, thus forming a composite electrode with a thermal-expansion behaviour that is well matched to that of the electrolyte. A new interphase is formed because of the limited reaction between the two materials in the composite during the calcination process, which also creates A-site deficiencies in the perovskite. As a result, the composite shows both high activity and excellent stability. The introduction of reactive negative-thermal-expansion components may provide a general strategy for the development of fully compatible and highly active electrodes for solid oxide fuel cells.

11.
Nature ; 599(7886): 594-598, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34819678

RESUMEN

Light-emitting diodes (LEDs) based on perovskite quantum dots have shown external quantum efficiencies (EQEs) of over 23% and narrowband emission, but suffer from limited operating stability1. Reduced-dimensional perovskites (RDPs) consisting of quantum wells (QWs) separated by organic intercalating cations show high exciton binding energies and have the potential to increase the stability and the photoluminescence quantum yield2,3. However, until now, RDP-based LEDs have exhibited lower EQEs and inferior colour purities4-6. We posit that the presence of variably confined QWs may contribute to non-radiative recombination losses and broadened emission. Here we report bright RDPs with a more monodispersed QW thickness distribution, achieved through the use of a bifunctional molecular additive that simultaneously controls the RDP polydispersity while passivating the perovskite QW surfaces. We synthesize a fluorinated triphenylphosphine oxide additive that hydrogen bonds with the organic cations, controlling their diffusion during RDP film deposition and suppressing the formation of low-thickness QWs. The phosphine oxide moiety passivates the perovskite grain boundaries via coordination bonding with unsaturated sites, which suppresses defect formation. This results in compact, smooth and uniform RDP thin films with narrowband emission and high photoluminescence quantum yield. This enables LEDs with an EQE of 25.6% with an average of 22.1 ±1.2% over 40 devices, and an operating half-life of two hours at an initial luminance of 7,200 candela per metre squared, indicating tenfold-enhanced operating stability relative to the best-known perovskite LEDs with an EQE exceeding 20%1,4-6.

12.
Proc Natl Acad Sci U S A ; 121(26): e2400804121, 2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38900800

RESUMEN

Chirality plays a crucial role in biology, as it is highly conserved and fundamentally important in the developmental process. To better understand the relationship between the chirality of individual cells and that of tissues and organisms, we develop a generalized mechanics model of chiral polarized particles to investigate the swirling dynamics of cell populations on substrates. Our analysis reveals that cells with the same chirality can form distinct chiral patterns on ring-shaped or rectangular substrates. Interestingly, our studies indicate that an excessively strong or weak individual cellular chirality hinders the formation of such chiral patterns. Our studies also indicate that there exists the influence distance of substrate boundaries in chiral patterns. Smaller influence distances are observed when cell-cell interactions are weaker. Conversely, when cell-cell interactions are too strong, multiple cells tend to be stacked together, preventing the formation of chiral patterns on substrates in our analysis. Additionally, we demonstrate that the interaction between cells and substrate boundaries effectively controls the chiral distribution of cellular orientations on ring-shaped substrates. This research highlights the significance of coordinating boundary features, individual cellular chirality, and cell-cell interactions in governing the chiral movement of cell populations and provides valuable mechanics insights into comprehending the intricate connection between the chirality of single cells and that of tissues and organisms.


Asunto(s)
Comunicación Celular , Modelos Biológicos , Comunicación Celular/fisiología , Movimiento Celular/fisiología , Polaridad Celular/fisiología
13.
Proc Natl Acad Sci U S A ; 121(20): e2321711121, 2024 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-38713624

RESUMEN

During development, neural stem cells in the cerebral cortex, also known as radial glial cells (RGCs), generate excitatory neurons, followed by production of cortical macroglia and inhibitory neurons that migrate to the olfactory bulb (OB). Understanding the mechanisms for this lineage switch is fundamental for unraveling how proper numbers of diverse neuronal and glial cell types are controlled. We and others recently showed that Sonic Hedgehog (Shh) signaling promotes the cortical RGC lineage switch to generate cortical oligodendrocytes and OB interneurons. During this process, cortical RGCs generate intermediate progenitor cells that express critical gliogenesis genes Ascl1, Egfr, and Olig2. The increased Ascl1 expression and appearance of Egfr+ and Olig2+ cortical progenitors are concurrent with the switch from excitatory neurogenesis to gliogenesis and OB interneuron neurogenesis in the cortex. While Shh signaling promotes Olig2 expression in the developing spinal cord, the exact mechanism for this transcriptional regulation is not known. Furthermore, the transcriptional regulation of Olig2 and Egfr has not been explored. Here, we show that in cortical progenitor cells, multiple regulatory programs, including Pax6 and Gli3, prevent precocious expression of Olig2, a gene essential for production of cortical oligodendrocytes and astrocytes. We identify multiple enhancers that control Olig2 expression in cortical progenitors and show that the mechanisms for regulating Olig2 expression are conserved between the mouse and human. Our study reveals evolutionarily conserved regulatory logic controlling the lineage switch of cortical neural stem cells.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Corteza Cerebral , Receptores ErbB , Proteínas Hedgehog , Proteínas del Tejido Nervioso , Células-Madre Neurales , Neurogénesis , Factor de Transcripción 2 de los Oligodendrocitos , Factor de Transcripción PAX6 , Animales , Neurogénesis/fisiología , Corteza Cerebral/metabolismo , Corteza Cerebral/citología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Receptores ErbB/metabolismo , Receptores ErbB/genética , Ratones , Factor de Transcripción 2 de los Oligodendrocitos/metabolismo , Factor de Transcripción 2 de los Oligodendrocitos/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/genética , Factor de Transcripción PAX6/metabolismo , Factor de Transcripción PAX6/genética , Células-Madre Neurales/metabolismo , Células-Madre Neurales/citología , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Proteína Gli3 con Dedos de Zinc/metabolismo , Proteína Gli3 con Dedos de Zinc/genética , Proteínas del Ojo/metabolismo , Proteínas del Ojo/genética , Proteínas Represoras/metabolismo , Proteínas Represoras/genética , Factores de Transcripción Paired Box/metabolismo , Factores de Transcripción Paired Box/genética , Neuroglía/metabolismo , Neuroglía/citología , Regulación del Desarrollo de la Expresión Génica , Transducción de Señal , Bulbo Olfatorio/metabolismo , Bulbo Olfatorio/citología , Linaje de la Célula , Humanos
14.
Nature ; 588(7839): 616-619, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33361792

RESUMEN

At the interface of classical and quantum physics, the Maxwell and Schrödinger equations describe how optical fields drive and control electronic phenomena to enable lightwave electronics at terahertz or petahertz frequencies and on ultrasmall scales1-5. The electric field of light striking a metal interacts with electrons and generates light-matter quasiparticles, such as excitons6 or plasmons7, on an attosecond timescale. Here we create and image a quasiparticle of topological plasmonic spin texture in a structured silver film. The spin angular momentum components of linearly polarized light interacting with an Archimedean coupling structure with a designed geometric phase generate plasmonic waves with different orbital angular momenta. These plasmonic fields undergo spin-orbit interaction and their superposition generates an array of plasmonic vortices. Three of these vortices can form spin textures that carry non-trivial topological charge8 resembling magnetic meron quasiparticles9. These spin textures are localized within a half-wavelength of light, and exist on the timescale of the plasmonic field. We use ultrafast nonlinear coherent photoelectron microscopy to generate attosecond videos of the spatial evolution of the vortex fields; electromagnetic simulations and analytic theory confirm the presence of plasmonic meron quasiparticles. The quasiparticles form a chiral field, which breaks the time-reversal symmetry on a nanometre spatial scale and a 20-femtosecond timescale (the 'nano-femto scale'). This transient creation of non-trivial spin angular momentum topology pertains to cosmological structure creation and topological phase transitions in quantum matter10-12, and may transduce quantum information on the nano-femto scale13,14.

15.
Nature ; 579(7797): 67-72, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32094661

RESUMEN

The Hall-Petch relationship, according to which the strength of a metal increases as the grain size decreases, has been reported to break down at a critical grain size of around 10 to 15 nanometres1,2. As the grain size decreases beyond this point, the dominant mechanism of deformation switches from a dislocation-mediated process to grain boundary sliding, leading to material softening. In one previous approach, stabilization of grain boundaries through relaxation and molybdenum segregation was used to prevent this softening effect in nickel-molybdenum alloys with grain sizes below 10 nanometres3. Here we track in situ the yield stress and deformation texturing of pure nickel samples of various average grain sizes using a diamond anvil cell coupled with radial X-ray diffraction. Our high-pressure experiments reveal continuous strengthening in samples with grain sizes from 200 nanometres down to 3 nanometres, with the strengthening enhanced (rather than reduced) at grain sizes smaller than 20 nanometres. We achieve a yield strength of approximately 4.2 gigapascals in our 3-nanometre-grain-size samples, ten times stronger than that of a commercial nickel material. A maximum flow stress of 10.2 gigapascals is obtained in nickel of grain size 3 nanometres for the pressure range studied here. We see similar patterns of compression strengthening in gold and palladium samples down to the smallest grain sizes. Simulations and transmission electron microscopy reveal that the high strength observed in nickel of grain size 3 nanometres is caused by the superposition of strengthening mechanisms: both partial and full dislocation hardening plus suppression of grain boundary plasticity. These insights contribute to the ongoing search for ultrastrong metals via materials engineering.

16.
Proc Natl Acad Sci U S A ; 120(10): e2220080120, 2023 03 07.
Artículo en Inglés | MEDLINE | ID: mdl-36848570

RESUMEN

Here, we combine international air travel passenger data with a standard epidemiological model of the initial 3 mo of the COVID-19 pandemic (January through March 2020; toward the end of which the entire world locked down). Using the information available during this initial phase of the pandemic, our model accurately describes the main features of the actual global development of the pandemic demonstrated by the high degree of coherence between the model and global data. The validated model allows for an exploration of alternative policy efficacies (reducing air travel and/or introducing different degrees of compulsory immigration quarantine upon arrival to a country) in delaying the global spread of SARS-CoV-2 and thus is suggestive of similar efficacy in anticipating the spread of future global disease outbreaks. We show that a lesson from the recent pandemic is that reducing air travel globally is more effective in reducing the global spread than adopting immigration quarantine. Reducing air travel out of a source country has the most important effect regarding the spreading of the disease to the rest of the world. Based upon our results, we propose a digital twin as a further developed tool to inform future pandemic decision-making to inform measures intended to control the spread of disease agents of potential future pandemics. We discuss the design criteria for such a digital twin model as well as the feasibility of obtaining access to the necessary online data on international air travel.


Asunto(s)
Viaje en Avión , COVID-19 , Humanos , Pandemias/prevención & control , COVID-19/epidemiología , COVID-19/prevención & control , SARS-CoV-2 , Brotes de Enfermedades
17.
J Biol Chem ; 300(5): 107294, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38636665

RESUMEN

Exenatide, a promising cardioprotective agent, protects against cardiac structural remodeling and diastolic dysfunction. Combined blockade of sodium and potassium channels is valuable for managing atrial fibrillation (AF). Here, we explored whether exenatide displayed anti-AF effects by inhibiting human Kv1.5 and Nav1.5 channels. We used the whole-cell patch-clamp technique to investigate the effects of exenatide on hKv1.5 and hNav1.5 channels expressed in human embryonic kidney 293 cells and studied the effects of exenatide on action potential (AP) and other cardiac ionic currents in rat atrial myocytes. Additionally, an electrical mapping system was used to explore the effects of exenatide on electrical properties and AF activity in isolated rat hearts. Finally, a rat AF model, established using acetylcholine and calcium chloride, was employed to evaluate the anti-AF potential of exenatide in rats. Exenatide reversibly suppressed IKv1.5 with IC50 of 3.08 µM, preferentially blocked the hKv1.5 channel in its closed state, and positively shifted the voltage-dependent activation curve. Exenatide also reversibly inhibited INav1.5 with IC50 of 3.30 µM, negatively shifted the voltage-dependent inactivation curve, and slowed its recovery from inactivation with significant use-dependency at 5 and 10 Hz. Furthermore, exenatide prolonged AP duration and suppressed the sustained K+ current (Iss) and transient outward K+ current (Ito), but without inhibition of L-type Ca2+ current (ICa,L) in rat atrial myocytes. Exenatide prevented AF incidence and duration in rat hearts and rats. These findings demonstrate that exenatide inhibits IKv1.5 and INav1.5in vitro and reduces AF susceptibility in isolated rat hearts and rats.


Asunto(s)
Potenciales de Acción , Fibrilación Atrial , Exenatida , Canal de Potasio Kv1.5 , Miocitos Cardíacos , Canal de Sodio Activado por Voltaje NAV1.5 , Bloqueadores del Canal de Sodio Activado por Voltaje , Animales , Humanos , Masculino , Ratas , Potenciales de Acción/efectos de los fármacos , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/metabolismo , Exenatida/farmacología , Exenatida/uso terapéutico , Células HEK293 , Canal de Potasio Kv1.5/antagonistas & inhibidores , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Canal de Sodio Activado por Voltaje NAV1.5/metabolismo , Canal de Sodio Activado por Voltaje NAV1.5/genética , Ratas Sprague-Dawley , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacología , Bloqueadores del Canal de Sodio Activado por Voltaje/uso terapéutico
18.
Nat Mater ; 23(2): 271-280, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37957270

RESUMEN

Interfacing molecular machines to inorganic nanoparticles can, in principle, lead to hybrid nanomachines with extended functions. Here we demonstrate a ligand engineering approach to develop atomically precise hybrid nanomachines by interfacing gold nanoclusters with tetraphenylethylene molecular rotors. When gold nanoclusters are irradiated with near-infrared light, the rotation of surface-decorated tetraphenylethylene moieties actively dissipates the absorbed energy to sustain the photothermal nanomachine with an intact structure and steady efficiency. Solid-state nuclear magnetic resonance and femtosecond transient absorption spectroscopy reveal that the photogenerated hot electrons are rapidly cooled down within picoseconds via electron-phonon coupling in the nanomachine. We find that the nanomachine remains structurally and functionally intact in mammalian cells and in vivo. A single dose of near-infrared irradiation can effectively ablate tumours without recurrence in tumour-bearing mice, which shows promise in the development of nanomachine-based theranostics.


Asunto(s)
Nanopartículas , Neoplasias , Estilbenos , Animales , Ratones , Fototerapia/métodos , Nanopartículas/química , Oro/química , Mamíferos
19.
Hepatology ; 2024 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-38825975

RESUMEN

BACKGROUND AND AIMS: Improving the care of decompensated cirrhosis is a significant clinical challenge. The primary aim of this trial was to assess the efficacy of a chronic disease management (CDM) model to reduce liver-related emergency admissions (LREA). The secondary aims were to assess model effects on quality-of-care and patient-reported outcomes. APPROACH AND RESULTS: The study design was a 2-year, multicenter, randomized controlled study with 1:1 allocation of a CDM model versus usual care. The study setting involved both tertiary and community care. Participants were randomly allocated following a decompensated cirrhosis admission. The intervention was a multifaceted CDM model coordinated by a liver nurse. A total of 147 participants (intervention=75, control=71) were recruited with a median Model for End-Stage Liver Disease score of 19. For the primary outcome, there was no difference in the overall LREA rate for the intervention group versus the control group (incident rate ratio 0.89; 95% CI: 0.53-1.50, p=0.666) or in actuarial survival (HR=1.14; 95% CI: 0.66-1.96, p=0.646). However, there was a reduced risk of LREA due to encephalopathy in the intervention versus control group (HR=1.87; 95% CI: 1.18-2.96, p=0.007). Significant improvement in quality-of-care measures was seen for the performance of bone density (p<0.001), vitamin D testing (p<0.001), and HCC surveillance adherence (p=0.050). For assessable participants (44/74 intervention, 32/71 controls) significant improvements in patient-reported outcomes at 3 months were seen in self-management ability and quality of life as assessed by visual analog scale (p=0.044). CONCLUSIONS: This CDM intervention did not reduce overall LREA events and may not be effective in decompensated cirrhosis for this end point.

20.
Plant Cell ; 34(7): 2730-2746, 2022 07 04.
Artículo en Inglés | MEDLINE | ID: mdl-35435232

RESUMEN

Glycogen synthase kinase 3 (GSK3) family members serve as signaling hubs for plant development and stress responses, yet the underlying mechanism of their transcriptional regulation remains a long-standing mystery. Here we show that the transcription of SHAGGY-like kinase 11/12 (SK11/12), two members of the GSK3 gene family, is promoted by the splicing factor SmD1b, which is essential for distributing carbon sources into storage and protective components in Arabidopsis seeds. The chromatin recruitment of SmD1b at the SK11/12 loci promotes their transcription associated with co-transcriptional splicing of the first introns in the 5'-untranslated region of SK11/12. The loss of SmD1b function generates transcripts with unspliced introns that create disruptive R-loops to hamper the transcriptional elongation of SK11/12, in addition to compromising the recruitment of RNA polymerase II to the SK11/12 genomic regions. These effects imposed by SmD1b determine the transcription of SK11/12 to confer a key switch of carbon flow among metabolic pathways in zygotic and maternal tissues in seeds.


Asunto(s)
Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Carbono/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Semillas/genética , Semillas/metabolismo
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