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ATP-hydrolysis-coupled actin polymerization is a fundamental mechanism of cellular force generation1-3. In turn, force4,5 and actin filament (F-actin) nucleotide state6 regulate actin dynamics by tuning F-actin's engagement of actin-binding proteins through mechanisms that are unclear. Here we show that the nucleotide state of actin modulates F-actin structural transitions evoked by bending forces. Cryo-electron microscopy structures of ADP-F-actin and ADP-Pi-F-actin with sufficient resolution to visualize bound solvent reveal intersubunit interfaces bridged by water molecules that could mediate filament lattice flexibility. Despite extensive ordered solvent differences in the nucleotide cleft, these structures feature nearly identical lattices and essentially indistinguishable protein backbone conformations that are unlikely to be discriminable by actin-binding proteins. We next introduce a machine-learning-enabled pipeline for reconstructing bent filaments, enabling us to visualize both continuous structural variability and side-chain-level detail. Bent F-actin structures reveal rearrangements at intersubunit interfaces characterized by substantial alterations of helical twist and deformations in individual protomers, transitions that are distinct in ADP-F-actin and ADP-Pi-F-actin. This suggests that phosphate rigidifies actin subunits to alter the bending structural landscape of F-actin. As bending forces evoke nucleotide-state dependent conformational transitions of sufficient magnitude to be detected by actin-binding proteins, we propose that actin nucleotide state can serve as a co-regulator of F-actin mechanical regulation.
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Citoesqueleto de Actina , Actinas , Adenosina Difosfato , Microscopía por Crioelectrón , Citoesqueleto de Actina/química , Citoesqueleto de Actina/metabolismo , Citoesqueleto de Actina/ultraestructura , Actinas/química , Actinas/metabolismo , Actinas/ultraestructura , Adenosina Difosfato/química , Adenosina Difosfato/metabolismo , Proteínas de Microfilamentos/metabolismo , Solventes , Aprendizaje Automático , Conformación ProteicaRESUMEN
Sustainable HIV remission after antiretroviral therapy (ART) withdrawal, or post-treatment control (PTC), remains a top priority for HIV treatment. We observed surprising PTC in an MHC-haplomatched cohort of MHC-M3+ SIVmac239+ Mauritian cynomolgus macaques (MCMs) initiated on ART at two weeks post-infection (wpi). None of the MCMs possessed MHC haplotypes previously associated with SIV control. For six months after ART withdrawal, we observed undetectable or transient viremia in seven of the eight MCMs, despite detecting replication competent SIV using quantitative viral outgrowth assays. In vivo depletion of CD8α+ cells induced rebound in all animals, indicating the observed PTC was mediated, at least in part, by CD8α+ cells. With intact proviral DNA assays, we found that MCMs had significantly smaller viral reservoirs two wpi than a cohort of identically infected rhesus macaques, a population that rarely develops PTC. We found a similarly small viral reservoir among six additional SIV+ MCMs in which ART was initiated at eight wpi, some of whom exhibited viral rebound. These results suggest that an unusually small viral reservoir is a hallmark among SIV+ MCMs. By evaluating immunological differences between MCMs that did and did not rebound, we identified that PTC was associated with a reduced frequency of CD4+ and CD8+ lymphocyte subsets expressing exhaustion markers. Together, these results suggest a combination of small reservoirs and immune-mediated virus suppression contribute to PTC in MCMs. Further, defining the immunologic mechanisms that engender PTC in this model may identify therapeutic targets for inducing durable HIV remission in humans.
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Infecciones por VIH , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Humanos , Animales , Macaca mulatta , Linfocitos T CD8-positivos , Infecciones por VIH/tratamiento farmacológico , Macaca fascicularis , Carga Viral , Replicación Viral , Antirretrovirales/uso terapéutico , Antirretrovirales/farmacologíaRESUMEN
To orchestrate cell mechanics, trafficking, and motility, cytoskeletal filaments must assemble into higher-order networks whose local subcellular architecture and composition specify their functions. Cross-linking proteins bridge filaments at the nanoscale to control a network's µm-scale geometry, thereby conferring its mechanical properties and functional dynamics. While these interfilament linkages are key determinants of cytoskeletal function, their structural mechanisms remain poorly understood. Plastins/fimbrins are an evolutionarily ancient family of tandem calponin-homology domain (CHD) proteins required to construct multiple classes of actin networks, which feature diverse geometries specialized to power cytokinesis, microvilli and stereocilia biogenesis, and persistent cell migration. Here, we focus on the structural basis of actin network assembly by human T-plastin, a ubiquitously expressed isoform necessary for the maintenance of stable cellular protrusions generated by actin polymerization forces. By implementing a machine-learning-enabled cryo-electron microscopy pipeline for visualizing cross-linkers bridging multiple filaments, we uncover a sequential bundling mechanism enabling T-plastin to bridge pairs of actin filaments in both parallel and antiparallel orientations. T-plastin populates distinct structural landscapes in these two bridging orientations that are selectively compatible with actin networks featuring divergent architectures and functions. Our structural, biochemical, and cell biological data highlight inter-CHD linkers as key structural elements underlying flexible but stable cross-linking that are likely to be disrupted by T-plastin mutations that cause hereditary bone diseases.
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Actinas , Glicoproteínas de Membrana , Proteínas de Microfilamentos , Citoesqueleto de Actina/metabolismo , Actinas/química , Microscopía por Crioelectrón , Humanos , Glicoproteínas de Membrana/química , Proteínas de Microfilamentos/química , PolimerizacionRESUMEN
BACKGROUND: Objective data comparing the diagnostic performance of different ambulatory cardiac monitors (ACMs) are lacking. OBJECTIVES: To assess variation in monitoring strategy, clinical outcomes and healthcare utilization in patients undergoing ambulatory monitoring without a pre-existing arrhythmia diagnosis. METHODS: Using the full sample (100%) of Medicare claims data, we performed a retrospective cohort study of diagnostic-naïve patients who received first-time ACM in 2017 to 2018 and evaluated arrhythmia encounter diagnosis at 3-months, repeat ACM testing at 6 months, all-cause 90-day emergency department (ED) and inpatient utilization, and cost of different strategies: Holter; long-term continuous monitor (LTCM); non-continuous, event-based external ambulatory event monitor (AEM); and mobile cardiac telemetry (MCT). We secondarily performed a device-specific analysis by manufacturer, identified from unique claim modifier codes. RESULTS: ACMs were used in 287,789 patients (AEM = 10.3%; Holter = 53.8%; LTCM = 13.3%; MCT = 22.5%). Device-specific analysis showed that compared to Holter, AEM, MCT, or other LTCM manufacturers, a specific LTCM (Zioâ XT 14-day patch, iRhythm Technologies, San Francisco, CA) had the highest adjusted odds of diagnosis and lowest adjusted odds of ACM retesting. Findings were consistent for specific arrhythmia diagnoses of ventricular tachycardia, atrioventricular block, and paroxysmal atrial fibrillation. As a category, LTCM was associated with the lowest 1-year incremental health care expenditures (mean Δ$10,159), followed by Holter ($10,755), AEM ($11,462), and MCT ($12,532). CONCLUSIONS: There was large variation in diagnostic monitoring strategy. A specific LTCM was associated with the highest adjusted odds of a new arrhythmia diagnosis and lowest adjusted odds of repeat ACM testing. LTCM as a category had the lowest incremental acute care utilization. Different monitoring strategies may produce different results with respect to diagnosis and care.
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Fibrilación Atrial , Electrocardiografía Ambulatoria , Metacrilatos , Estados Unidos , Humanos , Anciano , Estudios Retrospectivos , Medicare , Fibrilación Atrial/diagnóstico , Gastos en Salud , Aceptación de la Atención de SaludRESUMEN
Wheat (Triticum aestivum) is particularly susceptible to water deficit at the jointing stage of its development. Sucrose non-fermenting 1-related protein kinase 2 (SnRK2) acts as a signaling hub in the response to drought stress, but whether SnRK2 helps plants cope with water deficit via other mechanisms is largely unknown. Here, we cloned and characterized TaSnRK2.10, which was induced by multiple abiotic stresses and phytohormones. Ectopic expression of TaSnRK2.10 in rice (Oryza sativa) conferred drought tolerance, manifested by multiple improved physiological indices, including increased water content, cell membrane stability, and survival rates, as well as decreased water loss and accumulation of H2O2 and malonaldehyde. TaSnRK2.10 interacted with and phosphorylated early responsive to dehydration 15 (TaERD15) and enolase 1 (TaENO1) in vivo and in vitro. TaERD15 phosphorylated by TaSnRK2.10 was prone to degradation by the 26S proteasome, thereby mitigating its negative effects on drought tolerance. Phosphorylation of TaENO1 by TaSnRK2.10 may account for the substantially increased levels of phosphoenolpyruvate (PEP), a key metabolite of primary and secondary metabolism, in TaSnRK2.10-overexpressing rice, thereby enhancing its viability under drought stress. Our results demonstrate that TaSnRK2.10 not only regulated stomatal aperture and the expression of drought-responsive genes, but also enhanced PEP supply and promoted the degradation of TaERD15, all of which enhanced drought tolerance.
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Oryza , Triticum , Triticum/metabolismo , Oryza/genética , Oryza/metabolismo , Resistencia a la Sequía , Proteínas de Plantas/metabolismo , Peróxido de Hidrógeno/metabolismo , Sequías , Agua/metabolismo , Estrés Fisiológico/genética , Plantas Modificadas Genéticamente/metabolismo , Regulación de la Expresión Génica de las PlantasRESUMEN
INTRODUCTION: In hypertrophic cardiomyopathy (HCM), atrial fibrillation (AF) has historically been regarded to have a deleterious impact on clinical course, strongly associated with progressive heart failure (HF) symptoms. However, there is a paucity of information regarding the impact of AF on HCM employing validated quality of life (QoL) surveys. Therefore, we evaluated the impact of AF on QoL utilizing patient reported outcome measures (PROMs). METHODS: 218 consecutive HCM patients with or without AF at the Lahey HCM center in 2022 completed PROMs at their most recent visit evaluating HF (Kansas City Cardiomyopathy Questionnaire [KCCQ]) and AF symptoms (AF Effect on QoL [AFEQT]). RESULTS: Among the 218 patients, 50 (23%) had a history of AF and comprise the primary study cohort. AF was diagnosed at 55 ± 10 years of age, median of 5.5 years before PROM, with 66% of patients treated with a rhythm control strategy with antiarrhythmic drug and/or AF ablation. AFEQT indicated that 52% of patients experienced no or minimal AF-related disability, mild to moderate in 22%, and severe in 26%. There was no substantial difference in HCM phenotype in patients with no or minimal AF disability compared to those with severe disability. HF symptoms for most HCM patients with prior AF history was consistent with no or minimal (59%) or only mild (27%) disability as measured by KCCQ overall summary scores. In addition, with multivariate analysis, AF history was associated with less HF symptoms and improved QoL (OR 0.4, p = 0.02). CONCLUSION: In contrast to prior perceptions, HCM patients with prior AF history were less likely to incur HF symptoms impairing QoL compared to HCM patients without AF. After treatment, prior history of AF did not substantially impact current QoL. These data provide a realistic appraisal for the impact that AF has on HCM patients and also offers a measure of reassurance for this patient subgroup.
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Fibrilación Atrial , Cardiomiopatía Hipertrófica , Enfermedades Vasculares , Humanos , Calidad de Vida , Antiarrítmicos/uso terapéutico , Cardiomiopatía Hipertrófica/complicaciones , Cardiomiopatía Hipertrófica/diagnóstico , Cardiomiopatía Hipertrófica/terapia , Enfermedades Vasculares/complicacionesRESUMEN
The use of plant genetic resources (PGR)-wild relatives, landraces, and isolated breeding gene pools-has had substantial impacts on wheat breeding for resistance to biotic and abiotic stresses, while increasing nutritional value, end-use quality, and grain yield. In the Global South, post-Green Revolution genetic yield gains are generally achieved with minimal additional inputs. As a result, production has increased, and millions of hectares of natural ecosystems have been spared. Without PGR-derived disease resistance, fungicide use would have easily doubled, massively increasing selection pressure for fungicide resistance. It is estimated that in wheat, a billion liters of fungicide application have been avoided just since 2000. This review presents examples of successful use of PGR including the relentless battle against wheat rust epidemics/pandemics, defending against diseases that jump species barriers like blast, biofortification giving nutrient-dense varieties and the use of novel genetic variation for improving polygenic traits like climate resilience. Crop breeding genepools urgently need to be diversified to increase yields across a range of environments (>200 Mha globally), under less predictable weather and biotic stress pressure, while increasing input use efficiency. Given that the ~0.8 m PGR in wheat collections worldwide are relatively untapped and massive impacts of the tiny fraction studied, larger scale screenings and introgression promise solutions to emerging challenges, facilitated by advanced phenomic and genomic tools. The first translocations in wheat to modify rhizosphere microbiome interaction (reducing biological nitrification, reducing greenhouse gases, and increasing nitrogen use efficiency) is a landmark proof of concept. Phenomics and next-generation sequencing have already elucidated exotic haplotypes associated with biotic and complex abiotic traits now mainstreamed in breeding. Big data from decades of global yield trials can elucidate the benefits of PGR across environments. This kind of impact cannot be achieved without widescale sharing of germplasm and other breeding technologies through networks and public-private partnerships in a pre-competitive space.
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Seguridad Alimentaria , Fitomejoramiento , Enfermedades de las Plantas , Triticum , Triticum/genética , Triticum/microbiología , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/prevención & control , Resistencia a la Enfermedad/genética , Pandemias , Fungicidas Industriales , AmbienteRESUMEN
Simulators can realize novel phenomena by separating them from the complexities of a full physical implementation. Here, we put forward a scheme that can simulate the exotic statistics of D(S_{3}) non-Abelian anyons with minimal resources. The qudit lattice representation of this planar code supports local encoding of D(S_{3}) anyons. As a proof-of-principle demonstration, we employ a classical photonic simulator to encode a single qutrit and manipulate it to perform the fusion and braiding properties of non-Abelian D(S_{3}) anyons. The photonic technology allows us to perform the required nonunitary operations with much higher fidelity than what can be achieved with current quantum computers. Our approach can be directly generalized to larger systems or to different anyonic models, thus enabling advances in the exploration of quantum error correction and fundamental physics alike.
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INTRODUCTION: The Massachusetts legislature passed An Act Modernizing Tobacco Control in November 2019 to restrict retail sales of flavored commercially manufactured tobacco products including menthol products, increase penalties for violating the law's provisions, and provide health insurance coverage for tobacco treatment. AIMS AND METHODS: This study explores key informants' perceptions of intended and unintended impacts of implementation of the 2019 Massachusetts statewide law through a health equity and racial justice lens. We conducted in-depth interviews with 25 key informants from three key informant groups (public health officials and advocates, clinicians, and school staff) between March 2021 and April 2022. Using deductive codes on unintended impacts of the implementation of the law's policies, we conducted a focused analysis to identify impacts that were perceived and observed by informants from different key informant groups. RESULTS: Perceived or observed impacts of the law were identified across multiple levels by key informants and included concerns related to three broad themes: 1) intended impacts on health equity and racial justice, 2) ongoing availability of restricted products undermining the intended impact of the law, and 3) inequitable targeting by the policies and enforcement among communities of color. CONCLUSIONS: Future evaluation is needed to assess the intended and unintended impacts of implementation of the Massachusetts law to maximize the potential of the policies to reduce tobacco-related health disparities. We discuss implications and recommendations for achieving a national policy and equitable enforcement of flavored tobacco sales restrictions. IMPLICATIONS: This qualitative study among 25 key informants including public health and tobacco control advocates, clinicians, and school staff obtained perspectives of intended and unintended health equity and racial justice impacts of the 2019 Massachusetts An Act Modernizing Tobacco Control. Findings and recommendations from this study can inform monitoring efforts to assess the law's impacts in Massachusetts and the adoption of similar flavored tobacco sales restrictions and other tobacco control policies in other states to maximize the health equity benefits and minimize unintended impacts.
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Equidad en Salud , Productos de Tabaco , Massachusetts , Humanos , Productos de Tabaco/legislación & jurisprudencia , Justicia Social , Salud Pública/legislación & jurisprudencia , Control del TabacoRESUMEN
High temperatures in the field hinder bread wheat high-yield production, mainly because of the adverse effects of heat over photosynthesis. The Yaqui Valley, the main wheat producer region in Mexico, is a zone prone to have temperatures over 30°C. The aim of this work was to test the flag leaf photosynthetic performance in 10 bread wheat genotypes grown under high temperatures in the field. The study took place during two seasons (2019-2020 and 2020-2021). In each season, control seeds were sown in December, while heat-stressed were sown in late January to subject wheat to heat stress (HS) during the grain-filling stage. HS reduced Grain yield from 20 to 58% in the first season. HS did not reduce chlorophyll content and light-dependent reactions were unaffected in any of the tested genotypes. Rubisco, chloroplast fructose 1,6-biphosphatase (FBPase), and sucrose phosphate synthase (SPS) activities were measured spectrophotometrically. Rubisco activity did not decrease under HS in any of the genotypes. FBPase activity was reduced by HS indicating that triose phosphate flux to starch synthesis was reduced, while SPS was not affected, and thus, sucrose synthesis was maintained. HS reduced aerial biomass in the 10 chosen genotypes. Genotypes SOKWB.1, SOKWB.3, and BORLAUG100 maintained their yield under HS, pointing to a potential success in their introduction in this region for breeding heat-tolerant bread wheat.
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Ribulosa-Bifosfato Carboxilasa , Triticum , Triticum/genética , Temperatura , Fosfatos , TriosasRESUMEN
Wheat (Triticum aestivum L.) radiation use efficiency (RUE) must be raised through crop breeding to further increase the yield potential, as the harvest index is now close to its theoretical limit. Field experiments including 209 wheat cultivars which have been widely cultivated in China since the 1940s were conducted in two growing seasons (2018-2019 and 2019-2020) to evaluate the variations of phenological, physiological, plant architectural, and yield-related traits and their contributions to RUE and to identify limiting factors for wheat yield potential. The average annual genetic gain in grain yield was 0.60% (or 45.32 kg ha-1 year-1 ; R2 = 0.44, P < 0.01), mainly attributed to the gain in RUE (r = 0.85, P < 0.01). The net photosynthetic rates were positively and closely correlated with grain RUE and grain yield, suggesting source as a limiting factor to future yield gains. Thirty-four cultivars were identified, exhibiting not only high RUE, but also traits contributing to high RUE and 11 other critical traits - of known genetic basis - as potential parents for breeding to improve yield and RUE. Our findings reveal wheat traits and the associated loci conferring RUE, which are valuable for facilitating marker-assisted breeding to improve wheat RUE and yield potential.
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Fitomejoramiento , Triticum , Triticum/genética , Fenotipo , Grano Comestible/genética , Fotosíntesis/genéticaRESUMEN
BACKGROUND: Data examining associations among social support, survival, and healthcare utilization are lacking in patients with advanced cancer. METHODS: We conducted a cross-sectional secondary analysis using data from a prospective longitudinal cohort study of 966 hospitalized patients with advanced cancer at Massachusetts General Hospital from 2014 through 2017. We used NLP to identify extent of patients' social support (limited versus adequate as defined by NLP-aided review of the Electronic Health Record (EHR)). Two independent coders achieved a Kappa of 0.90 (95% CI: 0.84-1.00) using NLP. Using multivariable regression models, we examined associations of social support with: 1) OS; 2) death or readmission within 90 days of hospital discharge; 3) time to readmission within 90 days; and 4) hospital length of stay (LOS). RESULTS: Patients' median age was 65 (range: 21-92) years, and a plurality had gastrointestinal (GI) cancer (34.3%) followed by lung cancer (19.5%). 6.2% (60/966) of patients had limited social support. In multivariable analyses, limited social support was not significantly associated with OS (HR = 1.13, P = 0.390), death or readmission (OR = 1.18, P = 0.578), time to readmission (HR = 0.92, P = 0.698), or LOS (ß = -0.22, P = 0.726). We identified a potential interaction suggesting cancer type (GI cancer versus other) may be an effect modifier of the relationship between social support and OS (interaction term P = 0.053). In separate unadjusted analyses, limited social support was associated with lower OS (HR = 2.10, P = 0.008) in patients with GI cancer but not other cancer types (HR = 1.00, P = 0.991). CONCLUSION: We used NLP to assess the extent of social support in patients with advanced cancer. We did not identify significant associations of social support with OS or healthcare utilization but found cancer type may be an effect modifier of the relationship between social support and OS. These findings underscore the potential utility of NLP for evaluating social support in patients with advanced cancer.
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Procesamiento de Lenguaje Natural , Neoplasias , Humanos , Anciano , Estudios Longitudinales , Estudios Prospectivos , Estudios Transversales , Neoplasias/terapiaRESUMEN
Vaccine strategies aimed at eliciting human immunodeficiency virus (HIV)-specific CD8+ T cells are one major target of interest in HIV functional cure strategies. We hypothesized that CD8+ T cells elicited by therapeutic vaccination during antiretroviral therapy (ART) would be recalled and boosted by treatment with the interleukin 15 (IL-15) superagonist N-803 after ART discontinuation. We intravenously immunized four simian immunodeficiency virus-positive (SIV+) Mauritian cynomolgus macaques receiving ART with vesicular stomatitis virus (VSV), modified vaccinia virus Ankara strain (MVA), and recombinant adenovirus serotype 5 (rAd-5) vectors all expressing SIVmac239 Gag. Immediately after ART cessation, these animals received three doses of N-803. Four control animals received no vaccines or N-803. The vaccine regimen generated a high-magnitude response involving Gag-specific CD8+ T cells that were proliferative and biased toward an effector memory phenotype. We then compared cells elicited by vaccination (Gag specific) to cells elicited by SIV infection and unaffected by vaccination (Nef specific). We found that N-803 treatment enhanced the frequencies of both bulk and proliferating antigen-specific CD8+ T cells elicited by vaccination and the antigen-specific CD8+ T cells elicited by SIV infection. In sum, we demonstrate that a therapeutic heterologous prime-boost-boost (HPBB) vaccine can elicit antigen-specific effector memory CD8+ T cells that are boosted by N-803. IMPORTANCE While antiretroviral therapy (ART) can suppress HIV replication, it is not a cure. It is therefore essential to develop therapeutic strategies to enhance the immune system to better become activated and recognize virus-infected cells. Here, we evaluated a novel therapeutic vaccination strategy delivered to SIV+ Mauritian cynomolgus macaques receiving ART. ART was then discontinued and we delivered an immunotherapeutic agent (N-803) after ART withdrawal with the goal of eliciting and boosting anti-SIV cellular immunity. Immunologic and virologic analysis of peripheral blood and lymph nodes collected from these animals revealed transient boosts in the frequency, activation, proliferation, and memory phenotype of CD4+ and CD8+ T cells following each intervention. Overall, these results are important in educating the field of the transient nature of the immunological responses to this particular therapeutic regimen and the similar effects of N-803 on boosting T cells elicited by vaccination or elicited naturally by infection.
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Linfocitos T CD8-positivos , Vacunas contra el SIDAS , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Animales , Proliferación Celular , Macaca mulatta/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Vacunación , Virus VacciniaRESUMEN
Global nocturnal temperatures are rising more rapidly than daytime temperatures and have a large effect on crop productivity. In particular, stomatal conductance at night (gsn ) is surprisingly poorly understood and has not been investigated despite constituting a significant proportion of overall canopy water loss. Here, we present the results of 3 yr of field data using 12 spring Triticum aestivum genotypes which were grown in NW Mexico and subjected to an artificial increase in night-time temperatures of 2°C. Under nocturnal heating, grain yields decreased (1.9% per 1°C) without significant changes in daytime leaf-level physiological responses. Under warmer nights, there were significant differences in the magnitude and decrease in gsn , values of which were between 9 and 33% of daytime rates while respiration appeared to acclimate to higher temperatures. Decreases in grain yield were genotype-specific; genotypes categorised as heat tolerant demonstrated some of the greatest declines in yield in response to warmer nights. We conclude the essential components of nocturnal heat tolerance in wheat are uncoupled from resilience to daytime temperatures, raising fundamental questions for physiological breeding. Furthermore, this study discusses key physiological traits such as pollen viability, root depth and irrigation type may also play a role in genotype-specific nocturnal heat tolerance.
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Grano Comestible , Fitomejoramiento , Grano Comestible/genética , Hojas de la Planta/fisiología , Temperatura , CalorRESUMEN
The rate with which crop yields per hectare increase each year is plateauing at the same time that human population growth and other factors increase food demand. Increasing yield potential ( Y p ) of crops is vital to address these challenges. In this review, we explore a component of Y p that has yet to be optimised - that being improvements in the efficiency with which light energy is converted into biomass ( ε c ) via modifications to CO2 fixed per unit quantum of light (α), efficiency of respiratory ATP production ( ε prod ) and efficiency of ATP use ( ε use ). For α, targets include changes in photoprotective machinery, ribulose bisphosphate carboxylase/oxygenase kinetics and photorespiratory pathways. There is also potential for ε prod to be increased via targeted changes to the expression of the alternative oxidase and mitochondrial uncoupling pathways. Similarly, there are possibilities to improve ε use via changes to the ATP costs of phloem loading, nutrient uptake, futile cycles and/or protein/membrane turnover. Recently developed high-throughput measurements of respiration can serve as a proxy for the cumulative energy cost of these processes. There are thus exciting opportunities to use our growing knowledge of factors influencing the efficiency of photosynthesis and respiration to create a step-change in yield potential of globally important crops.
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Dióxido de Carbono , Productos Agrícolas , Citocromo P-450 CYP2B1 , Adenosina Trifosfato/metabolismo , Dióxido de Carbono/metabolismo , Productos Agrícolas/fisiología , Citocromo P-450 CYP2B1/metabolismo , Fotosíntesis , Ribulosa-Bifosfato Carboxilasa/metabolismoRESUMEN
Genetic markers can be linked with eco-physiological crop models to accurately predict genotype performance and individual markers' contributions in target environments, exploring interactions between genotype and environment. Here, wheat (Triticum aestivum L.) yield was dissected into seven traits corresponding to cultivar genetic coefficients in an eco-physiological model. Loci for these traits were discovered through the genome-wide association studies (GWAS). The cultivar genetic coefficients were derived from the loci using multiple linear regression or random forest, building a marker-based eco-physiological model. It is then applied to simulate wheat yields and design virtual ideotypes. The results indicated that the loci identified through GWAS explained 46%-75% variations in cultivar genetic coefficients. Using the marker-based model, the normalized root mean square error (nRMSE) between the simulated yield and observed yield was 13.95% by multiple linear regression and 13.62% by random forest. The nRMSE between the simulated and observed maturity dates was 1.24% by multiple linear regression and 1.11% by random forest, respectively. Structural equation modelling indicated that variations in grain yield could be well explained by cultivar genetic coefficients and phenological data. In addition, 24 pleiotropic loci in this study were detected on 15 chromosomes. More significant loci were detected by the model-based dissection method than considering yield per se. Ideotypes were identified by higher yield and more favourable alleles of cultivar genetic traits. This study proposes a genotype-to-phenotype approach and demonstrates novel ideas and tools to support the effective breeding of new cultivars with high yield through pyramiding favourable alleles and designing crop ideotypes.
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Estudio de Asociación del Genoma Completo , Triticum , Marcadores Genéticos , Triticum/genética , Estudio de Asociación del Genoma Completo/métodos , Desequilibrio de Ligamiento , Alelos , Sitios de Carácter Cuantitativo/genética , Fenotipo , Genotipo , Polimorfismo de Nucleótido SimpleRESUMEN
INTRODUCTION: Understanding symptom patterns in atrial fibrillation (AF) can help in disease management. We report on the application of natural language processing (NLP) to electronic medical records (EMRs) to capture symptom reports in patients with newly diagnosed (incident) AF. METHODS AND RESULTS: This observational retrospective study included adult patients with an index diagnosis of incident AF during January 1, 2016 through June 30, 2018, in the Optum datasets. The baseline and follow-up periods were 1 year before/after the index date, respectively. The primary objective was identification of the following predefined symptom reports: dyspnea or shortness of breath; syncope, presyncope, lightheadedness, or dizziness; chest pain; fatigue; and palpitations. In an exploratory analysis, the incidence rates of symptom reports and cardiovascular hospitalization were assessed in propensity-matched patient cohorts with incident AF receiving first-line dronedarone or sotalol. Among 30 447 patients with an index AF diagnosis, the NLP algorithm identified at least 1 predefined symptom in 9734 (31.9%) patients. The incidence rate of symptom reports was highest at 0-3 months post-diagnosis and lower at >3-6 and >6-12 months (pre-defined timepoints). Across all time periods, the most common symptoms were dyspnea or shortness of breath, followed by syncope, presyncope, lightheadedness, or dizziness. Similar temporal patterns of symptom reports were observed among patients with prescriptions for dronedarone or sotalol as first-line treatment. CONCLUSION: This study illustrates that NLP can be applied to EMR data to characterize symptom reports in patients with incident AF, and the potential for these methods to inform comparative effectiveness.
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Fibrilación Atrial , Adulto , Humanos , Fibrilación Atrial/tratamiento farmacológico , Dronedarona , Antiarrítmicos/uso terapéutico , Sotalol , Mareo/tratamiento farmacológico , Estudios Retrospectivos , Registros Electrónicos de Salud , Procesamiento de Lenguaje Natural , Disnea , SíncopeRESUMEN
Identifying traits for improving sink strength is a bottleneck to increasing wheat yield. The interacting processes determining sink strength and yield potential are reviewed and visualized in a set of 'wiring diagrams', covering critical phases of development (and summarizing known underlying genetics). Using this framework, we reviewed and assembled the main traits determining sink strength and identified research gaps and potential hypotheses to be tested for achieving gains in sink strength. In pre-anthesis, grain number could be increased through: (i) enhanced spike growth associated with optimized floret development and/or a reduction in specific stem-internode lengths and (ii) improved fruiting efficiency through an accelerated rate of floret development, improved partitioning between spikes, or optimized spike cytokinin levels. In post-anthesis, grain, sink strength could be augmented through manipulation of grain size potential via ovary size and/or endosperm cell division and expansion. Prospects for improving spike vascular architecture to support all rapidly growing florets, enabling the improved flow of assimilate, are also discussed. Finally, we considered the prospects for enhancing grain weight realization in relation to genetic variation in stay-green traits as well as stem carbohydrate remobilization. The wiring diagrams provide a potential workspace for breeders and crop scientists to achieve yield gains in wheat and other field crops.
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Grano Comestible , Triticum , Triticum/genética , Fenotipo , EndospermoRESUMEN
Source traits are currently of great interest for the enhancement of yield potential; for example, much effort is being expended to find ways of modifying photosynthesis. However, photosynthesis is but one component of crop regulation, so sink activities and the coordination of diverse processes throughout the crop must be considered in an integrated, systems approach. A set of 'wiring diagrams' has been devised as a visual tool to integrate the interactions of component processes at different stages of wheat development. They enable the roles of chloroplast, leaf, and whole-canopy processes to be seen in the context of sink development and crop growth as a whole. In this review, we dissect source traits both anatomically (foliar and non-foliar) and temporally (pre- and post-anthesis), and consider the evidence for their regulation at local and whole-plant/crop levels. We consider how the formation of a canopy creates challenges (self-occlusion) and opportunities (dynamic photosynthesis) for components of photosynthesis. Lastly, we discuss the regulation of source activity by feedback regulation. The review is written in the framework of the wiring diagrams which, as integrated descriptors of traits underpinning grain yield, are designed to provide a potential workspace for breeders and other crop scientists that, along with high-throughput and precision phenotyping data, genetics, and bioinformatics, will help build future dynamic models of trait and gene interactions to achieve yield gains in wheat and other field crops.
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Grano Comestible , Triticum , Triticum/fisiología , Fenotipo , Grano Comestible/fisiología , Fotosíntesis/fisiología , Hojas de la PlantaRESUMEN
BACKGROUND AND AIMS: Physiological and morphological traits play essential roles in wheat (Triticum aestivum) growth and development. In particular, photosynthesis is a limitation to yield. Increasing photosynthesis in wheat has been identified as an important strategy to increase yield. However, the genotypic variations and the genomic regions governing morphological, architectural and photosynthesis traits remain unexplored. METHODS: Here, we conducted a large-scale investigation of the phenological, physiological, plant architectural and yield-related traits, involving 32 traits for 166 wheat lines during 2018-2020 in four environments, and performed a genome-wide association study with wheat 90K and 660K single nucleotide polymorphism (SNP) arrays. KEY RESULTS: These traits exhibited considerable genotypic variations in the wheat diversity panel. Higher yield was associated with higher net photosynthetic rate (r = 0.41, P < 0.01), thousand-grain weight (r = 0.36, P < 0.01) and truncated and lanceolate shape, but shorter plant height (r = -0.63, P < 0.01), flag leaf angle (r = -0.49, P < 0.01) and spike number per square metre (r = -0.22, P < 0.01). Genome-wide association mapping discovered 1236 significant stable loci detected in the four environments among the 32 traits using SNP markers. Trait values have a cumulative effect as the number of the favourable alleles increases, and significant progress has been made in determining phenotypic values and favourable alleles over the years. Eleven elite cultivars and 14 traits associated with grain yield per plot (GY) were identified as potential parental lines and as target traits to develop high-yielding cultivars. CONCLUSIONS: This study provides new insights into the phenotypic and genetic elucidation of physiological and morphological traits in wheat and their associations with GY, paving the way for discovering their underlying gene control and for developing enhanced ideotypes in wheat breeding.