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1.
BMC Plant Biol ; 24(1): 222, 2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-38539100

RESUMO

BACKGROUND: Genomic selection (GS) is an efficient breeding strategy to improve quantitative traits. It is necessary to calculate genomic estimated breeding values (GEBVs) for GS. This study investigated the prediction accuracy of GEBVs for five fruit traits including fruit weight, fruit width, fruit height, pericarp thickness, and Brix. Two tomato germplasm collections (TGC1 and TGC2) were used as training populations, consisting of 162 and 191 accessions, respectively. RESULTS: Large phenotypic variations for the fruit traits were found in these collections and the 51K Axiom™ SNP array generated confident 31,142 SNPs. Prediction accuracy was evaluated using different cross-validation methods, GS models, and marker sets in three training populations (TGC1, TGC2, and combined). For cross-validation, LOOCV was effective as k-fold across traits and training populations. The parametric (RR-BLUP, Bayes A, and Bayesian LASSO) and non-parametric (RKHS, SVM, and random forest) models showed different prediction accuracies (0.594-0.870) between traits and training populations. Of these, random forest was the best model for fruit weight (0.780-0.835), fruit width (0.791-0.865), and pericarp thickness (0.643-0.866). The effect of marker density was trait-dependent and reached a plateau for each trait with 768-12,288 SNPs. Two additional sets of 192 and 96 SNPs from GWAS revealed higher prediction accuracies for the fruit traits compared to the 31,142 SNPs and eight subsets. CONCLUSION: Our study explored several factors to increase the prediction accuracy of GEBVs for fruit traits in tomato. The results can facilitate development of advanced GS strategies with cost-effective marker sets for improving fruit traits as well as other traits. Consequently, GS will be successfully applied to accelerate the tomato breeding process for developing elite cultivars.


Assuntos
Solanum lycopersicum , Solanum lycopersicum/genética , Teorema de Bayes , Frutas/genética , Melhoramento Vegetal , Fenótipo , Genômica/métodos , Polimorfismo de Nucleotídeo Único/genética , Modelos Genéticos , Genótipo
2.
JAMA ; 331(13): 1109-1121, 2024 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-38497797

RESUMO

Importance: Since 2015, US government and related personnel have reported dizziness, pain, visual problems, and cognitive dysfunction after experiencing intrusive sounds and head pressure. The US government has labeled these anomalous health incidents (AHIs). Objective: To assess whether participants with AHIs differ significantly from US government control participants with respect to clinical, research, and biomarker assessments. Design, Setting, and Participants: Exploratory study conducted between June 2018 and July 2022 at the National Institutes of Health Clinical Center, involving 86 US government staff and family members with AHIs from Cuba, Austria, China, and other locations as well as 30 US government control participants. Exposures: AHIs. Main Outcomes and Measures: Participants were assessed with extensive clinical, auditory, vestibular, balance, visual, neuropsychological, and blood biomarkers (glial fibrillary acidic protein and neurofilament light) testing. The patients were analyzed based on the risk characteristics of the AHI identifying concerning cases as well as geographic location. Results: Eighty-six participants with AHIs (42 women and 44 men; mean [SD] age, 42.1 [9.1] years) and 30 vocationally matched government control participants (11 women and 19 men; mean [SD] age, 43.8 [10.1] years) were included in the analyses. Participants with AHIs were evaluated a median of 76 days (IQR, 30-537) from the most recent incident. In general, there were no significant differences between participants with AHIs and control participants in most tests of auditory, vestibular, cognitive, or visual function as well as levels of the blood biomarkers. Participants with AHIs had significantly increased fatigue, depression, posttraumatic stress, imbalance, and neurobehavioral symptoms compared with the control participants. There were no differences in these findings based on the risk characteristics of the incident or geographic location of the AHIs. Twenty-four patients (28%) with AHI presented with functional neurological disorders. Conclusions and Relevance: In this exploratory study, there were no significant differences between individuals reporting AHIs and matched control participants with respect to most clinical, research, and biomarker measures, except for objective and self-reported measures of imbalance and symptoms of fatigue, posttraumatic stress, and depression. This study did not replicate the findings of previous studies, although differences in the populations included and the timing of assessments limit direct comparisons.


Assuntos
Família , Governo , Masculino , Humanos , Feminino , Adulto , Biomarcadores , Fadiga , Medidas de Segurança
3.
JAMA ; 331(13): 1122-1134, 2024 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-38497822

RESUMO

Importance: US government personnel stationed internationally have reported anomalous health incidents (AHIs), with some individuals experiencing persistent debilitating symptoms. Objective: To assess the potential presence of magnetic resonance imaging (MRI)-detectable brain lesions in participants with AHIs, with respect to a well-matched control group. Design, Setting, and Participants: This exploratory study was conducted at the National Institutes of Health (NIH) Clinical Center and the NIH MRI Research Facility between June 2018 and November 2022. Eighty-one participants with AHIs and 48 age- and sex-matched control participants, 29 of whom had similar employment as the AHI group, were assessed with clinical, volumetric, and functional MRI. A high-quality diffusion MRI scan and a second volumetric scan were also acquired during a different session. The structural MRI acquisition protocol was optimized to achieve high reproducibility. Forty-nine participants with AHIs had at least 1 additional imaging session approximately 6 to 12 months from the first visit. Exposure: AHIs. Main Outcomes and Measures: Group-level quantitative metrics obtained from multiple modalities: (1) volumetric measurement, voxel-wise and region of interest (ROI)-wise; (2) diffusion MRI-derived metrics, voxel-wise and ROI-wise; and (3) ROI-wise within-network resting-state functional connectivity using functional MRI. Exploratory data analyses used both standard, nonparametric tests and bayesian multilevel modeling. Results: Among the 81 participants with AHIs, the mean (SD) age was 42 (9) years and 49% were female; among the 48 control participants, the mean (SD) age was 43 (11) years and 42% were female. Imaging scans were performed as early as 14 days after experiencing AHIs with a median delay period of 80 (IQR, 36-544) days. After adjustment for multiple comparisons, no significant differences between participants with AHIs and control participants were found for any MRI modality. At an unadjusted threshold (P < .05), compared with control participants, participants with AHIs had lower intranetwork connectivity in the salience networks, a larger corpus callosum, and diffusion MRI differences in the corpus callosum, superior longitudinal fasciculus, cingulum, inferior cerebellar peduncle, and amygdala. The structural MRI measurements were highly reproducible (median coefficient of variation <1% across all global volumetric ROIs and <1.5% for all white matter ROIs for diffusion metrics). Even individuals with large differences from control participants exhibited stable longitudinal results (typically, <±1% across visits), suggesting the absence of evolving lesions. The relationships between the imaging and clinical variables were weak (median Spearman ρ = 0.10). The study did not replicate the results of a previously published investigation of AHIs. Conclusions and Relevance: In this exploratory neuroimaging study, there were no significant differences in imaging measures of brain structure or function between individuals reporting AHIs and matched control participants after adjustment for multiple comparisons.


Assuntos
Imagem de Tensor de Difusão , Substância Branca , Humanos , Feminino , Adulto , Masculino , Imagem de Tensor de Difusão/métodos , Reprodutibilidade dos Testes , Teorema de Bayes , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Imageamento por Ressonância Magnética/métodos , Neuroimagem , Substância Branca/patologia , Família , Governo , Medidas de Segurança
4.
J Biol Chem ; 298(2): 101564, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34999118

RESUMO

The mitochondrial enzyme glutaminase C (GAC) is upregulated in many cancer cells to catalyze the first step in glutamine metabolism, the hydrolysis of glutamine to glutamate. The dependence of cancer cells on this transformed metabolic pathway highlights GAC as a potentially important therapeutic target. GAC acquires maximal catalytic activity upon binding to anionic activators such as inorganic phosphate. To delineate the mechanism of GAC activation, we used the tryptophan substitution of tyrosine 466 in the catalytic site of the enzyme as a fluorescent reporter for glutamine binding in the presence and absence of phosphate. We show that in the absence of phosphate, glutamine binding to the Y466W GAC tetramer exhibits positive cooperativity. A high-resolution X-ray structure of tetrameric Y466W GAC bound to glutamine suggests that cooperativity in substrate binding is coupled to tyrosine 249, located at the edge of the catalytic site (i.e., the "lid"), adopting two distinct conformations. In one dimer within the GAC tetramer, the lids are open and glutamine binds weakly, whereas, in the adjoining dimer, the lids are closed over the substrates, resulting in higher affinity interactions. When crystallized in the presence of glutamine and phosphate, all four subunits of the Y466W GAC tetramer exhibited bound glutamine with closed lids. Glutamine can bind with high affinity to each subunit, which subsequently undergo simultaneous catalysis. These findings explain how the regulated transitioning of GAC between different conformational states ensures that maximal catalytic activity is reached in cancer cells only when an allosteric activator is available.


Assuntos
Glutaminase , Glutamina , Mitocôndrias , Domínio Catalítico , Glutaminase/química , Glutaminase/metabolismo , Glutamina/química , Glutamina/metabolismo , Mitocôndrias/enzimologia , Mitocôndrias/metabolismo , Fosfatos/química , Fosfatos/metabolismo , Conformação Proteica , Tirosina/química , Tirosina/metabolismo
5.
J Biol Chem ; 298(2): 101535, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34954143

RESUMO

Cancer cells frequently exhibit uncoupling of the glycolytic pathway from the TCA cycle (i.e., the "Warburg effect") and as a result, often become dependent on their ability to increase glutamine catabolism. The mitochondrial enzyme Glutaminase C (GAC) helps to satisfy this 'glutamine addiction' of cancer cells by catalyzing the hydrolysis of glutamine to glutamate, which is then converted to the TCA-cycle intermediate α-ketoglutarate. This makes GAC an intriguing drug target and spurred the molecules derived from bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (the so-called BPTES class of allosteric GAC inhibitors), including CB-839, which is currently in clinical trials. However, none of the drugs targeting GAC are yet approved for cancer treatment and their mechanism of action is not well understood. Here, we shed new light on the underlying basis for the differential potencies exhibited by members of the BPTES/CB-839 family of compounds, which could not previously be explained with standard cryo-cooled X-ray crystal structures of GAC bound to CB-839 or its analogs. Using an emerging technique known as serial room temperature crystallography, we were able to observe clear differences between the binding conformations of inhibitors with significantly different potencies. We also developed a computational model to further elucidate the molecular basis of differential inhibitor potency. We then corroborated the results from our modeling efforts using recently established fluorescence assays that directly read out inhibitor binding to GAC. Together, these findings should aid in future design of more potent GAC inhibitors with better clinical outlook.


Assuntos
Inibidores Enzimáticos , Glutaminase , Neoplasias , Sulfetos , Tiadiazóis , Cristalografia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glutaminase/antagonistas & inibidores , Glutaminase/química , Glutaminase/metabolismo , Glutamina/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Sulfetos/química , Sulfetos/farmacologia , Temperatura , Tiadiazóis/química , Tiadiazóis/farmacologia
6.
J Biomech Eng ; 144(7)2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34897379

RESUMO

Energized fragments from explosive devices have been the most common mechanism of injury to both military personnel and civilians in recent conflicts and terrorist attacks. Fragments that penetrate into the thoracic cavity are strongly associated with death due to the inherent vulnerability of the underlying structures. The aim of this study was to investigate the impact of fragment-simulating projectiles (FSPs) to tissues of the thorax in order to identify the thresholds of impact velocity for perforation through these tissues and the resultant residual velocity of the FSPs. A gas-gun system was used to launch 0.78-g cylindrical and 1.13-g spherical FSPs at intact porcine thoracic tissues from different impact locations. The sternum and rib bones were the most resistant to perforation, followed by the scapula and intercostal muscle. For both FSPs, residual velocity following perforation was linearly proportional to impact velocity. These findings can be used in the development of numerical tools for predicting the medical outcome of explosive events, which in turn can inform the design of public infrastructure, of personal protection, and of medical emergency response.


Assuntos
Explosões , Animais , Metais , Suínos , Ferimentos e Lesões
7.
J Biol Chem ; 295(5): 1328-1337, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-31871054

RESUMO

The glutaminase C (GAC) isoform of mitochondrial glutaminase is overexpressed in many cancer cells and therefore represents a potential therapeutic target. Understanding the regulation of GAC activity has been guided by the development of spectroscopic approaches that measure glutaminase activity in real time. Previously, we engineered a GAC protein (GAC(F327W)) in which a tryptophan residue is substituted for phenylalanine in an activation loop to explore the role of this loop in enzyme activity. We showed that the fluorescence emission of Trp-327 is enhanced in response to activator binding, but quenched by inhibitors of the BPTES class that bind to the GAC tetramer and contact the activation loop, thereby constraining it in an inactive conformation. In the present work, we took advantage of a tryptophan substitution at position 471, proximal to the GAC catalytic site, to examine the conformational coupling between the activation loop and the substrate-binding cleft, separated by ∼16 Å. Comparison of glutamine binding in the presence or absence of the BPTES analog CB-839 revealed a reciprocal relationship between the constraints imposed on the activation loop position and the affinity of GAC for substrate. Binding of the inhibitor weakened the affinity of GAC for glutamine, whereas activating anions such as Pi increased this affinity. These results indicate that the conformations of the activation loop and the substrate-binding cleft in GAC are allosterically coupled and that this coupling determines substrate affinity and enzymatic activity and explains the activities of CB-839, which is currently in clinical trials.


Assuntos
Benzenoacetamidas/farmacologia , Glutaminase/química , Glutamina/metabolismo , Mitocôndrias/enzimologia , Tiadiazóis/farmacologia , Regulação Alostérica/genética , Sítio Alostérico/genética , Substituição de Aminoácidos/genética , Animais , Engenharia Biomédica , Domínio Catalítico/genética , Glutaminase/metabolismo , Cinética , Camundongos , Mitocôndrias/química , Modelos Moleculares , Mutação , Isoformas de Proteínas , Estrutura Terciária de Proteína/genética , Proteínas Recombinantes , Sulfetos/farmacologia
8.
Am J Med Genet A ; 185(5): 1399-1413, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33559393

RESUMO

In CLN3 disease, impairments in motor function are frequently reported to have later onset compared to visual and cognitive decline, but upper limb motor function has yet to be explored in this population. In a cohort of 22 individuals with CLN3, we used a novel application of multiple measures to (1) characterize motor function, particularly of the upper limbs, in activities of daily living (ADLs), and (2) explore associations between motor function and age as well as visual ability, disease severity, and cognitive function, as evaluated by the Unified Batten Disease Rating Scale (UBDRS), a validated CLN3 disease measure. ADLs that required coordination, speed, and fine motor control were particularly challenging for children with CLN3 based on item-level performance across direct assessments (Jebsen-Taylor Hand Function Test [JTHFT] and MyoSet Tools) and caregiver reports (Pediatric Evaluation of Disability Inventory-Computer Adaptive Testing [PEDI-CAT] and Patient-Reported Outcomes Measurement Information System [PROMIS] Pediatric Upper Extremity). Poorer visual ability, disease severity, and cognitive function were associated with worse performance on these measures, whereas age had limited impact. These findings support the need for children with CLN3 to receive skilled clinical evaluation and treatment tailored to their individual needs, particularly in the context of ADLs, as their symptom profile progresses.


Assuntos
Atividades Cotidianas , Glicoproteínas de Membrana/genética , Chaperonas Moleculares/genética , Transtornos Motores/terapia , Extremidade Superior/fisiopatologia , Adolescente , Criança , Pré-Escolar , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Humanos , Transtornos Motores/genética , Transtornos Motores/fisiopatologia , Acuidade Visual/genética , Acuidade Visual/fisiologia
9.
J Biomech Eng ; 143(2)2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32793978

RESUMO

Pelvic blast injury is one of the most severe patterns of injury to be sustained by casualties of explosions. We have previously identified the mechanism of injury in a shock tube-mediated murine model, linking outward flail of the lower limbs to unstable pelvic fractures and vascular injury. As current military pelvic protection does not protect against lower limb flail, in this study we have utilized the same murine model to investigate the potential of novel pelvic protection to reduce injury severity. Fifty cadaveric mice underwent shock-tube blast testing and subsequent injury analysis. Pelvic protection limiting lower limb flail resulted in a reduction of pelvic fracture incidence from both front-on (relative risk (RR) 0.5, 95% confidence intervals (CIs) 0.3-0.9, p < 0.01) and under-body (RR 0.3, 95% CI 0.1-0.8 p < 0.01) blast, with elimination of vascular injury in both groups (p < 0.001). In contrast, pelvic protection, which did not limit flail, had no effect on fracture incidence compared to the control group and was only associated with a minimal reduction in vascular injury (RR 0.6, 95% CI 0.4-1.0, p < 0.05). This study has utilized a novel strategy to provide proof of concept for the use of pelvic protection, which limits limb flail to mitigate the effects of pelvic blast injury.


Assuntos
Traumatismos por Explosões , Adulto , Animais , Humanos , Camundongos , Pelve
10.
Biosci Biotechnol Biochem ; 83(11): 2144-2152, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31327302

RESUMO

Studies of Alzheimer's disease are based on model mice that have been altered by transgenesis and other techniques to elicit pathogenesis. However, changes in the gut microbiota were recently suggested to diminish cognitive function in patients, as well as in model mice. Accordingly, we have created model mice of the human gut microbiota by transplanting germ-free C57BL/6N mice with fecal samples from a healthy volunteer and from an affected patient. These humanized mice were stably colonized and reproduced the bacterial diversity in donors. Remarkably, performance on Object Location Test and Object Recognition Test was significantly reduced in the latter than in the former at 55 weeks of age, suggesting that gut microbiota transplanted from an affected patient affects mouse behavior. In addition, metabolites related to the nervous system, including γ-aminobutyrate, taurine, and valine, were significantly less abundant in the feces of mice transplanted with microbiota from the affected patient.


Assuntos
Doença de Alzheimer/microbiologia , Fezes/química , Microbioma Gastrointestinal , Vida Livre de Germes , Metabolômica , Animais , Comportamento Animal , Modelos Animais de Doenças , Fezes/microbiologia , Humanos , Masculino , Camundongos , Fatores de Tempo
11.
J R Army Med Corps ; 165(1): 33-37, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29794172

RESUMO

Injuries sustained due to attacks from explosive weapons are multiple in number, complex in nature, and not well characterised. Blast may cause damage to the human body by the direct effect of overpressure, penetration by highly energised fragments, and blunt trauma by violent displacements of the body. The ability to reproduce the injuries of such insults in a well-controlled fashion is essential in order to understand fully the unique mechanism by which they occur, and design better treatment and protection strategies to alleviate the resulting poor long-term outcomes. This paper reports a range of experimental platforms that have been developed for different blast injury models, their working mechanism, and main applications. These platforms include the shock tube, split-Hopkinson bars, the gas gun, drop towers and bespoke underbody blast simulators.


Assuntos
Pesquisa Biomédica , Traumatismos por Explosões , Explosões , Animais , Pesquisa Biomédica/instrumentação , Pesquisa Biomédica/métodos , Simulação por Computador , Humanos , Medicina Militar , Pressão , Ratos
12.
Chemistry ; 23(32): 7785-7790, 2017 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-28332756

RESUMO

A new 1,8-naphthalimide-based fluorescent probe for the detection of diethyl cyanophosphonate, a very common nerve agent simulant, is designed, synthesized, and characterized fully. The probe shows around 50-fold enhancement of fluorescence intensity over other nerve agent simulants. Importantly, the probe is able to work under aqueous conditions in a wide pH range. Two reactive groups, the oxime and the phenol, allow a dual emission with different kinetic reactions. The reaction of diethyl cyanophosphonate with the oxime group occurs in advance; the resulting time response of the fluorescence enhancement is observed within approximately 30 s. After the oxime reaction, then phenol also undergoes a substitution reaction with diethyl cyanophosphonate, resulting in a blue emission. The real application of this new probe is demonstrated through the use of silica plate assays for the detection of diethyl cyanophosphonate in both gas and liquid phases through dual emission channels.


Assuntos
Corantes Fluorescentes/química , Agentes Neurotóxicos/química , Água/química , Corantes Fluorescentes/síntese química , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética , Naftalimidas/síntese química , Naftalimidas/química , Organofosfonatos/química , Dióxido de Silício/química , Espectrometria de Fluorescência
13.
Nat Commun ; 15(1): 1971, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38438397

RESUMO

The glutaminase enzymes GAC and GLS2 catalyze the hydrolysis of glutamine to glutamate, satisfying the 'glutamine addiction' of cancer cells. They are the targets of anti-cancer drugs; however, their mechanisms of activation and catalytic activity have been unclear. Here we demonstrate that the ability of GAC and GLS2 to form filaments is directly coupled to their catalytic activity and present their cryo-EM structures which provide a view of the conformational states essential for catalysis. Filament formation guides an 'activation loop' to assume a specific conformation that works together with a 'lid' to close over the active site and position glutamine for nucleophilic attack by an essential serine. Our findings highlight how ankyrin repeats on GLS2 regulate enzymatic activity, while allosteric activators stabilize, and clinically relevant inhibitors block, filament formation that enables glutaminases to catalyze glutaminolysis and support cancer progression.


Assuntos
Glutaminase , Neoplasias , Glutamina , Citoesqueleto , Catálise , Ácido Glutâmico
14.
Int J Biol Macromol ; 263(Pt 1): 130227, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38378121

RESUMO

A specific rheumatoid arthritis (RA)-microenvironment-triggered nanocarrier for RA treatment of a first-line antirheumatic drug (Methotrexate, MTX) has been proposed. Reduced glutathione (GSH) responsivity, cystamine, was first introduced on the alginate backbone, which was then used as the bridge to connect pluronic F127 (temperature-responsive factor) and folic acid (targeting factor for active immune cells), resulting in dual-responsive triggered targeting carrier, PCAC-FA. In vitro study demonstrated that PCAC-FA was preferentially taken up by activated macrophage cells rather than normal ones, suggesting the targeting of PCAC-FA to inflamed tissue. The loading capacity of the designed carrier was 21.23 ± 0.91 %. MTX from the PCAC-FA carrier was significantly accelerated release in the presentation of glutathione or in cold shock condition, proposing the efficacy-controlled release. MTX@PCAC-FA showed excellent hemocompatibility, confirming a suitable application with parenteral administration. Notably, the acute and subacute toxicity in the mice model showed that the toxicity of MTX had significantly reduced after encapsulating in the PCAC-FA carrier. These nanoplatforms not only provide an alternative safe strategy for the clinical treatment of rheumatoid arthritis with MTX but also deliver MTX selectively and provide on-demand drug release via external and internal signals, thus emerging as a promising therapeutic option for precise RA therapy.


Assuntos
Antirreumáticos , Artrite Reumatoide , Camundongos , Animais , Metotrexato , Ácido Fólico , Poloxâmero/uso terapêutico , Artrite Reumatoide/tratamento farmacológico
15.
J Mech Behav Biomed Mater ; 141: 105776, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36989869

RESUMO

Injury due to the penetration of fragments into parts of the body has been the major cause of morbidity and mortality after an explosion. Penetrating injuries into the heart present very high mortality, yet the risk associated with such injuries has not been quantified. Quantifying this risk is key in the design of personal protection and the design of infrastructure. This study is the first quantitative assessment of cardiac penetrating injuries from energised fragments. Typical fragments (5-mm sphere, 0.78-g right-circular cylinder and 1.1-g chisel-nosed cylinder) were accelerated to a range of target striking velocities using a bespoke gas-gun system and impacted ventricular and atrial walls of lamb hearts. The severity of injury was shown to not depend on location (ventricular or atrial wall). The striking velocity with 50% probability of critical injury (Abbreviated Injury Scale (AIS) 5 score) ranged between 31 and 36 m/s across all 3 fragments used. These findings can help directly in reducing morbidity and mortality from explosive events as they can be implemented readily into models that aim to predict casualties in an explosive event, inform protocols for first responders, and improve design of infrastructure and personal protective equipment.


Assuntos
Fibrilação Atrial , Traumatismos por Explosões , Ferimentos Penetrantes , Animais , Ovinos
16.
Future Drug Discov ; 4(4): FDD79, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37009252

RESUMO

Metabolic reprogramming is a major hallmark of malignant transformation in cancer, and part of the so-called Warburg effect, in which the upregulation of glutamine catabolism plays a major role. The glutaminase enzymes convert glutamine to glutamate, which initiates this pathway. Inhibition of different forms of glutaminase (KGA, GAC, or LGA) demonstrated potential as an emerging anti-cancer therapeutic strategy. The regulation of these enzymes, and the molecular basis for their inhibition, have been the focus of much recent research. This review will explore the recent progress in understanding the molecular basis for activation and inhibition of different forms of glutaminase, as well as the recent focus on combination therapies of glutaminase inhibitors with other anti-cancer drugs.


Many strategies exist to inhibit cancer progression, from chemotherapy to more targeted therapies that exploit differences between tumors and healthy tissue. One such targeted strategy involves inhibition of the enzyme glutaminase, which converts glutamine obtained from the bloodstream into nutrients that fuel tumor growth. Research into glutaminase is ongoing, with regulation of the enzyme, and novel molecular approaches to inhibit its activity, being key focus areas. Here, we review recent progress on targeting glutaminase enzymes for anti-cancer therapy, including several approaches in which glutaminase inhibitors are combined with inhibitors of other cancer-relevant targets, to increase the overall effectiveness of the treatment.

17.
bioRxiv ; 2023 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-36824706

RESUMO

The glutaminase enzymes GAC and GLS2 catalyze the hydrolysis of glutamine to glutamate, satisfying the 'glutamine addiction' of cancer cells. They are the targets of anti-cancer drugs; however, their mechanisms of activation and catalytic activity have been unclear. Here we demonstrate that the ability of GAC and GLS2 to form filaments is directly coupled to their catalytic activity and present their cryo-EM structures which provide an unprecedented view of the conformational states essential for catalysis. Filament formation guides an 'activation loop' to assume a specific conformation that works together with a 'lid' to close over the active site and position glutamine for nucleophilic attack by an essential serine. Our findings highlight how ankyrin repeats on GLS2 regulate enzymatic activity, while allosteric activators stabilize, and clinically relevant inhibitors block, filament formation that enables glutaminases to catalyze glutaminolysis and support cancer progression.

18.
Front Bioeng Biotechnol ; 10: 808113, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35875481

RESUMO

Cerebrospinal fluid (CSF) cavitation is a likely physical mechanism for producing traumatic brain injury (TBI) under mechanical loading. In this study, we investigated CSF cavitation under blasts and helmeted impacts which represented loadings in battlefield and road traffic/sports collisions. We first predicted the human head response under the blasts and impacts using computational modelling and found that the blasts can produce much lower negative pressure at the contrecoup CSF region than the impacts. Further analysis showed that the pressure waves transmitting through the skull and soft tissue are responsible for producing the negative pressure at the contrecoup region. Based on this mechanism, we hypothesised that blast, and not impact, can produce CSF cavitation. To test this hypothesis, we developed a one-dimensional simplified surrogate model of the head and exposed it to both blasts and impacts. The test results confirmed the hypothesis and computational modelling of the tests validated the proposed mechanism. These findings have important implications for prevention and diagnosis of blast TBI.

19.
Psychol Res Behav Manag ; 15: 3513-3530, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36505671

RESUMO

Purpose: The purpose of this study was to investigate the direct and indirect effects of expectations for marital relationships and premarital sexual permissiveness on intent to marry of Vietnamese emerging adults. Patients and Methods: Our cross-sectional study was focused on emerging adults including 344 participants, undergraduate students from universities in Viet Nam. This study was assessed by using the PLS-SEM approach. Results: The main findings demonstrated that (i) sexual orientation have a significant effect on marital intention; (ii) individuals' expectations for marital relationship have a direct effect on marital intention; and (iii) premarital sexuality permissiveness mediates the relationship between expectations for marital relationship and marital intention. Conclusion: Our results contribute important documents and clearer understanding of emerging adults' expectations and requirements in a relationship for the marriage decision-making process.

20.
Hortic Res ; 8(1): 203, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34465758

RESUMO

Genome-wide association study (GWAS) is effective in identifying favorable alleles for traits of interest with high mapping resolution in crop species. In this study, we conducted GWAS to explore quantitative trait loci (QTL) for eight fruit traits using 162 tomato accessions with diverse genetic backgrounds. The eight traits included fruit weight, fruit width, fruit height, fruit shape index, pericarp thickness, locule number, fruit firmness, and brix. Phenotypic variations of these traits in the tomato collection were evaluated with three replicates in field trials over three years. We filtered 34,550 confident SNPs from the 51 K Axiom® tomato array based on < 10% of missing data and > 5% of minor allele frequency for association analysis. The 162 tomato accessions were divided into seven clusters and their membership coefficients were used to account for population structure along with a kinship matrix. To identify marker-trait associations (MTAs), four phenotypic data sets representing each of three years and combined were independently analyzed in the multilocus mixed model (MLMM). A total of 30 significant MTAs was detected over data sets for eight fruit traits at P < 0.0005. The number of MTA per trait ranged from one (brix) to seven (fruit weight and fruit width). Two SNP markers on chromosomes 1 and 2 were significantly associated with multiple traits, suggesting pleiotropic effects of QTL. Furthermore, 16 of 30 MTAs suggest potential novel QTL for eight fruit traits. These results facilitate genetic dissection of tomato fruit traits and provide a useful resource to develop molecular tools for improving fruit traits via marker-assisted selection and genomic selection in tomato breeding programs.

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