RESUMO
Homologous recombination (HR) deficiency is associated with DNA rearrangements and cytogenetic aberrations1. Paradoxically, the types of DNA rearrangements that are specifically associated with HR-deficient cancers only minimally affect chromosomal structure2. Here, to address this apparent contradiction, we combined genome-graph analysis of short-read whole-genome sequencing (WGS) profiles across thousands of tumours with deep linked-read WGS of 46 BRCA1- or BRCA2-mutant breast cancers. These data revealed a distinct class of HR-deficiency-enriched rearrangements called reciprocal pairs. Linked-read WGS showed that reciprocal pairs with identical rearrangement orientations gave rise to one of two distinct chromosomal outcomes, distinguishable only with long-molecule data. Whereas one (cis) outcome corresponded to the copying and pasting of a small segment to a distant site, a second (trans) outcome was a quasi-balanced translocation or multi-megabase inversion with substantial (10 kb) duplications at each junction. We propose an HR-independent replication-restart repair mechanism to explain the full spectrum of reciprocal pair outcomes. Linked-read WGS also identified single-strand annealing as a repair pathway that is specific to BRCA2 deficiency in human cancers. Integrating these features in a classifier improved discrimination between BRCA1- and BRCA2-deficient genomes. In conclusion, our data reveal classes of rearrangements that are specific to BRCA1 or BRCA2 deficiency as a source of cytogenetic aberrations in HR-deficient cells.
Assuntos
Proteína BRCA1 , Proteína BRCA2 , Aberrações Cromossômicas , Reparo do DNA , Neoplasias , Humanos , Proteína BRCA1/deficiência , Proteína BRCA1/genética , Proteína BRCA2/deficiência , Proteína BRCA2/genética , Inversão Cromossômica , Reparo do DNA/genética , Neoplasias/genética , Translocação Genética/genética , Recombinação Homóloga , Análise Citogenética , Aberrações Cromossômicas/classificaçãoRESUMO
Here, we describe the identification of an antibiotic class acting via LpxH, a clinically unexploited target in lipopolysaccharide synthesis. The lipopolysaccharide synthesis pathway is essential in most Gram-negative bacteria and there is no analogous pathway in humans. Based on a series of phenotypic screens, we identified a hit targeting this pathway that had activity on efflux-defective strains of Escherichia coli. We recognized common structural elements between this hit and a previously published inhibitor, also with activity against efflux-deficient bacteria. With the help of X-ray structures, this information was used to design inhibitors with activity on efflux-proficient, wild-type strains. Optimization of properties such as solubility, metabolic stability and serum protein binding resulted in compounds having potent in vivo efficacy against bloodstream infections caused by the critical Gram-negative pathogens E. coli and Klebsiella pneumoniae. Other favorable properties of the series include a lack of pre-existing resistance in clinical isolates, and no loss of activity against strains expressing extended-spectrum-ß-lactamase, metallo-ß-lactamase, or carbapenemase-resistance genes. Further development of this class of antibiotics could make an important contribution to the ongoing struggle against antibiotic resistance.
Assuntos
Antibacterianos , Lipopolissacarídeos , Humanos , Antibacterianos/química , Escherichia coli/metabolismo , Bactérias Gram-Negativas/metabolismo , beta-Lactamases/genética , Testes de Sensibilidade MicrobianaRESUMO
Prostate cancer is a heritable disease with ancestry-biased incidence and mortality. Polygenic risk scores (PRSs) offer promising advancements in predicting disease risk, including prostate cancer. While their accuracy continues to improve, research aimed at enhancing their effectiveness within African and Asian populations remains key for equitable use. Recent algorithmic developments for PRS derivation have resulted in improved pan-ancestral risk prediction for several diseases. In this study, we benchmark the predictive power of six widely used PRS derivation algorithms, including four of which adjust for ancestry, against prostate cancer cases and controls from the UK Biobank and All of Us cohorts. We find modest improvement in discriminatory ability when compared with a simple method that prioritizes variants, clumping, and published polygenic risk scores. Our findings underscore the importance of improving upon risk prediction algorithms and the sampling of diverse cohorts.
Assuntos
Algoritmos , Benchmarking , Predisposição Genética para Doença , Herança Multifatorial , Neoplasias da Próstata , Humanos , Neoplasias da Próstata/genética , Masculino , Benchmarking/métodos , Predisposição Genética para Doença/genética , Herança Multifatorial/genética , Estudos de Coortes , Fatores de Risco , Polimorfismo de Nucleotídeo Único/genética , Estudo de Associação Genômica Ampla/métodos , Biologia Computacional/métodos , Medição de Risco/métodos , Estudos de Casos e Controles , Estratificação de Risco GenéticoRESUMO
The hydrogen 21-cm signal is predicted to be the richest probe of the young Universe, including those eras known as the cosmic Dark Ages, the Cosmic Dawn (when the first star and black hole formed) and the Epoch of Reionization. This signal holds the key to deciphering processes that take place at the early stages of cosmic history. In this opinion piece, we discuss the potential scientific merit of lunar observations of the 21-cm signal and their advantages over more affordable terrestrial efforts. The Moon is a prime location for radio cosmology which will enable precision observations of the low-frequency radio sky. The uniqueness of such observations is that they will provide an unparalleled opportunity to test cosmology and the nature of dark matter using the Dark Ages 21-cm signal. No less enticing is the opportunity to obtain a much clearer picture of the Cosmic Dawn than that currently achievable from the ground, which will allow us to determine the properties of the first stars and black holes. This article is part of a discussion meeting issue 'Astronomy from the Moon: the next decades (part 2)'.
RESUMO
The presence of large Northern Hemisphere ice sheets and reduced greenhouse gas concentrations during the Last Glacial Maximum fundamentally altered global ocean-atmosphere climate dynamics. Model simulations and palaeoclimate records suggest that glacial boundary conditions affected the El Niño-Southern Oscillation, a dominant source of short-term global climate variability. Yet little is known about changes in short-term climate variability at mid- to high latitudes. Here we use a high-resolution water isotope record from West Antarctica to demonstrate that interannual to decadal climate variability at high southern latitudes was almost twice as large at the Last Glacial Maximum as during the ensuing Holocene epoch (the past 11,700 years). Climate model simulations indicate that this increased variability reflects an increase in the teleconnection strength between the tropical Pacific and West Antarctica, owing to a shift in the mean location of tropical convection. This shift, in turn, can be attributed to the influence of topography and albedo of the North American ice sheets on atmospheric circulation. As the planet deglaciated, the largest and most abrupt decline in teleconnection strength occurred between approximately 16,000 years and 15,000 years ago, followed by a slower decline into the early Holocene.
RESUMO
BACKGROUND: Widespread transmission of COVID-19 continues to threaten public health, particularly of rural, American Indian communities. Although COVID-19 risk factors for severe disease and clinical characteristics are well described in the general population, there has been little shared on hospitalized American Indian populations. METHODS: In this observational study, we performed chart extractions on all persons hospitalized with COVID-19 from April 1 through July 31, 2020 among an exclusively American Indian population living on or near Tribal lands in eastern Arizona. We provide descriptive statistics for the cohort stratified by presentation, comparing those who self-presented or were referred by an outreach program. Exploratory analyses were performed to identify risk factors for morbidity and mortality. RESULTS: During the observation period, 2262 persons were diagnosed with COVID-19 and 490 (22%) were hospitalized. Hospitalized persons had a median age of 54 years; 92% had at least one comorbidity, 72% had greater than one comorbidity, and 60% had a BMI of > 30. Most persons required supplemental oxygen (83%), but the majority (62%) only required nasal cannula and only 11% were intubated. The case fatality rates were 1.7% for the population, 7.1% among hospitalizations, and 9.3% among hospitalized patients 50 years and older. All rates that are significantly lower than those reported nationally during the same period. CONCLUSIONS: We observed a cohort of American Indian patients hospitalized secondary to COVID-19 with greater number of comorbidities compared to the general population but with lower mortality rates. We posit that the primary driver of mortality reduction for this population and the hospitalized cohort was a community-based referral program that led to disproportionately lower fatality rates among the oldest persons.
Assuntos
COVID-19 , Hospitalização , Humanos , Pessoa de Meia-Idade , Indígena Americano ou Nativo do Alasca , Arizona/epidemiologia , Comorbidade , COVID-19/epidemiologia , COVID-19/mortalidade , Fatores de RiscoRESUMO
Animals play a central role in human livelihoods and welfare. Animal diseases have a great impact on the benefits humans derive from animals and can also pose a risk to human health. Better control of animal diseases generates wider societal benefits, including reducing the climate and ecological impacts of livestock and improving animal welfare. To better understand the scale of investment justified for the control and prevention of animal disease, the wide-ranging impacts of disease on animal production and health must be measured. The Global Burden of Animal Diseases (GBADs) programme is quantifying animal disease burden from the local to global levels. The GBADs programme includes country case studies for national- and local-level analysis. Ethiopia is the first case study country in which GBADs methods have been applied. GBADs'Ethiopia case study consists of three activity areas: i) stakeholder engagement; ii) livestock disease burden estimation, including data collection, analytics, evidence generation and communication; and iii) capacity building in animal health economics. At the start of the case study, various stakeholder communication platforms were used to familiarise stakeholders with GBADs and engage their support in various ways, including data access, and, through this engagement, to ensure the programme tools and outputs were relevant and useful to their needs. Existing data were retrieved from multiple sources and used to estimate disease burden. This process involved multiple steps, including estimation of biomass and economic value, the Animal Health Loss Envelope (farm-level disease burden), wider economic impacts and attribution of the disease burden to different levels of causes. This was carried out for major livestock species (cattle, sheep, goats and poultry) in Ethiopia. Capacity building on animal health economics was carried out for GBADs end users to increase competence in utilising animal health economic evidence, including GBADs outputs. This article documents experiences of the implementation of these activities in the GBADs Ethiopia case study.
Les animaux représentent une part substantielle des moyens de subsistance et contribuent de manière essentielle au bien-être humain. Les bénéfices que l'humanité peut retirer des animaux sont toutefois compromis par les maladies animales, qui font aussi peser un risque sur la santé publique. Les avantages sociétaux d'un meilleur contrôle des maladies animales dépassent la portée strictement sanitaire et recouvrent notamment l'atténuation de l'impact climatique et environnemental des animaux d'élevage et l'amélioration du bien-être animal. Pour mieux appréhender l'échelle des investissements requis pour contrôler et prévenir les maladies animales, il convient de mesurer les impacts très divers de ces maladies sur la production et la santé animales. Le programme " Impact mondial des maladies animales " (GBADs) procède actuellement à la quantification de la charge des maladies animales, du niveau local au niveau mondial. Il comprend aussi des études de cas conduites dans des pays choisis pour une analyse à l'échelle nationale, voire locale. L'Ethiopie est le premier pays à avoir fait l'objet d'une étude de cas nationale reprenant les méthodes du GBADs. L'étude comportait trois volets d'activités : i) la mobilisation des parties prenantes ; ii) l'estimation de la charge des maladies chez les animaux d'élevage, notamment la collecte de données, leur analyse, l'apport d'éléments probants et la communication ; et iii) le renforcement des capacités en économie de la santé animale. Au lancement de l'étude, plusieurs plateformes de communication professionnelles ont été utilisées pour mieux faire connaître le GBADs aux différents acteurs et solliciter leur soutien de diverses manières, en particulier en termes d'accès aux données, et pour s'assurer, grâce à cette mobilisation, que les outils et les résultats du programme étaient pertinents pour eux et répondaient à leurs besoins. Les données existantes ont été recueillies auprès de multiples sources et ont permis d'estimer la charge sanitaire. Ce processus comportait plusieurs étapes, dont l'estimation de la biomasse et de la valeur économique, la définition de l'enveloppe des pertes sanitaires animales (charge sanitaire à l'échelle des exploitations), l'appréciation des effets économiques au sens large et la répartition de la charge sanitaire en fonction des niveaux des causes attribuées. Les analyses portaient sur les principales espèces d'animaux d'élevage (bovins, ovins, caprins et volailles) en Ethiopie. Des activités de renforcement des capacités en économie de la santé animale ont été proposées aux utilisateurs finaux du GBADs afin de les former à l'utilisation des preuves économiques en santé animale. Les auteurs expliquent comment s'est déroulée la mise en oeuvre de ces activités lors de l'étude du GBADs conduite en Ethiopie.
Los animales desempeñan un papel fundamental en los medios de subsistencia y el bienestar humanos. En este sentido, las enfermedades animales tienen un gran impacto en los beneficios que los humanos obtienen de los animales y también pueden suponer un riesgo para la salud humana. Un mejor control de las enfermedades animales genera beneficios sociales más amplios, como la reducción del impacto climático y ecológico de la ganadería y la mejora del bienestar animal. Para comprender mejor la magnitud de la inversión justificada para el control y la prevención de las enfermedades animales, es preciso medir las amplias repercusiones de las enfermedades en la producción y la sanidad animal. El programa sobre el impacto global de las enfermedades animales (GBADs) cuantifica el impacto de las enfermedades animales desde el nivel local hasta el mundial. El programa GBADs incluye estudios de casos por países a fin de realizar un análisis a escala nacional y local. Etiopía es el primer país en el que se han aplicado los métodos del GBADs. El estudio de caso del GBADs en dicho país se divide en tres áreas de actividad: i) la participación de las partes interesadas; ii) la estimación del impacto de las enfermedades del ganado, incluida la recopilación de datos, el análisis, la generación de pruebas y la comunicación; y iii) el desarrollo de capacidades en el ámbito de la economía de la sanidad animal. Al inicio del estudio de caso, se utilizaron diversas plataformas de comunicación con las partes interesadas para familiarizarlas con el GBADs y recabar su apoyo a través de diversas vías, entre las que se incluía el acceso a los datos, y, mediante esta colaboración, garantizar que las herramientas y los resultados del programa fueran pertinentes y útiles para sus necesidades. Se obtuvieron datos de diversas fuentes que se utilizaron para estimar el impacto de las enfermedades. Este proceso implicó múltiples pasos, incluida la estimación de la biomasa y el valor económico, la cartera de pérdidas en sanidad animal (impacto de las enfermedades a nivel de explotación), los impactos económicos más amplios y la atribución del impacto de las enfermedades a diferentes categorías de causas. Esto se llevó a cabo para las principales especies ganaderas (bovinos, ovinos, caprinos y aves de corral) en Etiopía. Se realizaron actividades de capacitación en economía de la sanidad animal para los usuarios finales con el fin de aumentar su competencia en la utilización de los datos económicos sobre sanidad animal, incluidos los resultados del GBADs. Este artículo documenta las experiencias de la puesta en práctica de estas actividades en el estudio de caso del GBADs en Etiopía.
Assuntos
Doenças dos Animais , Gado , Etiópia/epidemiologia , Animais , Doenças dos Animais/epidemiologia , Doenças dos Animais/prevenção & controle , Doenças dos Animais/economia , Humanos , Carga Global da Doença , Criação de Animais Domésticos/métodos , Criação de Animais Domésticos/economiaRESUMO
A major data gap in tropical river ecology is the limited documentation of natural water purification of upstream rivers. This study documented the improvement of water quality of downstream Balili River as affected by environmental factors and macrophyte diversity using a mixed-method approach (water quality assessment, plant inventory, field observation, canonical correspondence analysis, community interview). Results showed that the distance from pollution plays a significant role in the self-purification of the river while the floral diversity maintains the riparian from further contaminating the water and at the same time absorbing air pollutants. Generally, the pollution reduction and %change is exponential at 2 and 3 km from point source then taper at 4 and 5 km. At 3 km from the point source, 30% improvement in TDS, BOD and salinity, 25% for EC, 20% in TSS, 35% in WQI, 36% in CPI, and 50% for DO were noted. Key factors that influence the self-purification process in the river were distance from pollution source, elevation, human disturbance (as indicated by %tree canopy) and temperature. These findings highlight the importance of distance from pollution sources and floral diversity in driving water quality improvements, with implications for sustainable water resource management in tropical regions.
This study documented the improvement of water quality of downstream Balili River as affected by environmental factors and macrophyte diversity as contribution to the major data gap in tropical river ecology which currently has limited documentation on natural water purification of upstream rivers. The study also shows the mosaic interplay of water quality, plant diversity, distance from pollution, human disturbance, and air quality in understudied tropical river. Further, this study is unique in documenting the downstream of Balili River since majority of the previous studies were concentrated in the upstream portion of the river.
RESUMO
BACKGROUND: Neutrophil count:lymphocyte count ratio (NLR) may be a prognostic factor for men with advanced prostate cancer. We hypothesized that it is associated with prostate-specific antigen (PSA) response and survival in men treated with prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT). METHODS: Data of 180 men with metastatic castration-resistant prostate cancer (mCRPC) who were treated in sequential prospective radionuclide clinical trials from 2002 to 2021 (utilizing 177Lu-J591, 90Y-J591, 177Lu-PSMA-617, or 225Ac-J591) were retrospectively analyzed. We used a logistic regression to determine the association between NLR and ≥50% PSA decline (PSA50) and a Cox proportional hazards model to investigate the association between NLR and overall survival (OS). RESULTS: A total of 94 subjects (52.2%) received 177Lu-J591, 51 (28.3%) 177Lu-PSMA-617, 28 (15.6%) 225Ac-J591, and 7 (3.9%) 90Y-J591. The median NLR of 3.75 was used as cut-off (low vs. high NLR; n = 90, respectively). On univariate analysis, NLR was not associated with PSA50 (HR 1.08; 95% confidence interval [CI] 0.99-1.17, p = 0.067). However, it was associated with worse OS (hazard ratio [HR] 1.06, 95% CI 1.02-1.09, p = 0.002), also after controlling for circulating tumor cell count and cancer and leukemia group B risk group (HR 1.05; 95% CI 1.003-1.11, p = 0.036). Men with high NLR were at a higher hazard of death from all causes (HR 1.43, 95% CI 1.05-1.94, p = 0.024). CONCLUSIONS: NLR provides prognostic information in the setting of patients with mCRPC receiving treatment with PSMA-TRT.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Prognóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Actínio , Radioisótopos de Ítrio/uso terapêutico , Antígeno Prostático Específico/uso terapêutico , Neutrófilos/patologia , Estudos Retrospectivos , Estudos Prospectivos , Próstata/patologia , Linfócitos/patologia , Resultado do TratamentoRESUMO
BACKGROUND: Ultra-hypofractionated image-guided stereotactic body radiotherapy (SBRT) is increasingly used for definitive treatment of localized prostate cancer. Magnetic resonance imaging-guided radiotherapy (MRgRT) facilitates improved visualization, real-time tracking of targets and/or organs-at-risk (OAR), and capacity for adaptive planning which may translate to improved targeting and reduced toxicity to surrounding tissues. Given promising results from NRG-GU003 comparing conventional and moderate hypofractionation in the post-operative setting, there is growing interest in exploring ultra-hypofractionated post-operative regimens. It remains unclear whether this can be done safely and whether MRgRT may help mitigate potential toxicity. SHORTER (NCT04422132) is a phase II randomized trial prospectively evaluating whether salvage MRgRT delivered in 5 fractions versus 20 fractions is non-inferior with respect to gastrointestinal (GI) and genitourinary (GU) toxicities at 2-years post-treatment. METHODS: A total of 136 patients will be randomized in a 1:1 ratio to salvage MRgRT in 5 fractions or 20 fractions using permuted block randomization. Patients will be stratified according to baseline Expanded Prostate Cancer Index Composite (EPIC) bowel and urinary domain scores as well as nodal treatment and androgen deprivation therapy (ADT). Patients undergoing 5 fractions will receive a total of 32.5 Gy over 2 weeks and patients undergoing 20 fractions will receive a total of 55 Gy over 4 weeks, with or without nodal coverage (25.5 Gy over 2 weeks and 42 Gy over 4 weeks) and ADT as per the investigator's discretion. The co-primary endpoints are change scores in the bowel and the urinary domains of the EPIC. The change scores will reflect the 2-year score minus the pre-treatment (baseline) score. The secondary endpoints include safety endpoints, including change in GI and GU symptoms at 3, 6, 12 and 60 months from completion of treatment, and efficacy endpoints, including time to progression, prostate cancer specific survival and overall survival. DISCUSSION: The SHORTER trial is the first randomized phase II trial comparing toxicity of ultra-hypofractionated and hypofractionated MRgRT in the salvage setting. The primary hypothesis is that salvage MRgRT delivered in 5 fractions will not significantly increase GI and GU toxicities when compared to salvage MRgRT delivered in 20 fractions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04422132. Date of registration: June 9, 2020.
Assuntos
Neoplasias da Próstata , Radioterapia Guiada por Imagem , Masculino , Humanos , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/radioterapia , Antagonistas de Androgênios , Imageamento por Ressonância Magnética , Radioterapia Guiada por Imagem/efeitos adversos , PróstataRESUMO
Mantle plumes are buoyant upwellings of hot rock that transport heat from Earth's core to its surface, generating anomalous regions of volcanism that are not directly associated with plate tectonic processes. The best-studied example is the Hawaiian-Emperor chain, but the emergence of two sub-parallel volcanic tracks along this chain, Loa and Kea, and the systematic geochemical differences between them have remained unexplained. Here we argue that the emergence of these tracks coincides with the appearance of other double volcanic tracks on the Pacific plate and a recent azimuthal change in the motion of the plate. We propose a three-part model that explains the evolution of Hawaiian double-track volcanism: first, mantle flow beneath the rapidly moving Pacific plate strongly tilts the Hawaiian plume and leads to lateral separation between high- and low-pressure melt source regions; second, the recent azimuthal change in Pacific plate motion exposes high- and low-pressure melt products as geographically distinct volcanoes, explaining the simultaneous emergence of double-track volcanism across the Pacific; and finally, secondary pyroxenite, which is formed as eclogite melt reacts with peridotite, dominates the low-pressure melt region beneath Loa-track volcanism, yielding the systematic geochemical differences observed between Loa- and Kea-type lavas. Our results imply that the formation of double-track volcanism is transitory and can be used to identify and place temporal bounds on plate-motion changes.
RESUMO
INTRODUCTION: Real-time continuous glucose monitoring (rt-CGM) allows patients with diabetes to adjust insulin dosing, potentially improving glucose control. This study aimed to compare the long-term cost-effectiveness of the Dexcom G6 rt-CGM device versus self-monitoring of blood glucose (SMBG) and flash glucose monitoring (FGM) in Australia in people with type 1 diabetes (T1D). METHODS: Long-term costs and clinical outcomes were estimated using the CORE Diabetes Model. Clinical input data for the analysis of rt-CGM versus SMBG and FGM were sourced from the DIAMOND study and a network meta-analysis, respectively. Rt-CGM and FGM were associated with quality of life (QoL) benefits due to reduced fear of hypoglycaemia (FoH) and fingerstick testing. Analyses were performed over a lifetime time horizon from an Australian healthcare payer perspective, including direct costs from published data. Future costs and clinical outcomes were discounted at 5% per annum. RESULTS: Rt-CGM was associated with an increased quality-adjusted life expectancy of 1.199 quality-adjusted life years (QALYs), increased mean total lifetime costs of AUD 21,596 and an incremental cost-effectiveness ratio (ICER) of AUD 18,020 per QALY gained compared with SMBG. Compared with FGM, rt-CGM was associated with an increased quality-adjusted life expectancy of 0.569 QALYs, increased mean total lifetime costs of AUD 11,064 and an ICER of AUD 19,455 per QALY gained. Key drivers of outcomes included HbA1c benefits and QoL benefits associated with reduced FoH and fingerstick testing. CONCLUSIONS: Due to improved clinical outcomes and QoL gains rt-CGM is highly cost-effective compared with SMBG and FGM in people with T1D in Australia.
Assuntos
Diabetes Mellitus Tipo 1 , Hipoglicemia , Austrália/epidemiologia , Glicemia , Automonitorização da Glicemia , Análise Custo-Benefício , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/epidemiologia , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Hipoglicemia/prevenção & controle , Hipoglicemiantes , Qualidade de VidaRESUMO
BACKGROUND: Sea turtle hatchlings must avoid numerous predators during dispersal from their nesting beaches to foraging grounds. Hatchlings minimise time spent in predator-dense neritic waters by swimming almost continuously for approximately the first 24 h post-emergence, termed the 'frenzy'. Post-frenzy, hatchling activity gradually declines as they swim in less predator-dense pelagic waters. It is well documented that hatchlings exhibit elevated metabolic rates during the frenzy to power their almost continuous swimming, but studies on post-frenzy MRs are sparse. RESULTS: We measured the frenzy and post-frenzy oxygen consumption of hatchlings of five species of sea turtle at different activity levels and ages to compare the ontogeny of mass-specific hatchling metabolic rates. Maximal metabolic rates were always higher than resting metabolic rates, but metabolic rates during routine swimming resembled resting metabolic rates in leatherback turtle hatchlings during the frenzy and post-frenzy, and in loggerhead hatchlings during the post-frenzy. Crawling metabolic rates did not differ among species, but green turtles had the highest metabolic rates during frenzy and post-frenzy swimming. CONCLUSIONS: Differences in metabolic rate reflect the varying dispersal stratagems of each species and have important implications for dispersal ability, yolk consumption and survival. Our results provide the foundations for links between the physiology and ecology of dispersal of sea turtles.
RESUMO
INTRODUCTION: Exomphalos is an anterior abdominal wall defect resulting in herniation of contents into the umbilical cord. Severe associated chromosomal anomalies and congenital heart disease (CHD) are known to influence mortality, but it is not clear which cardiac anomalies have the greatest impact on survival. METHODS: We performed a retrospective review of the treatment and outcome of patients with exomphalos over a 30-year period (1990-2020), with a focus on those with the combination of exomphalos major and major CHD (EMCHD). RESULTS: There were 123 patients with exomphalos identified, 59 (48%) had exomphalos major (ExoMaj) (defect > 5 cm or containing liver), and 64 (52%) exomphalos minor (ExoMin). In the ExoMaj group; 17% had major CHD (10/59), M:F 28:31, 29% premature (< 37 weeks, 17/59) and 14% had low birth-weight (< 2.5 kg, 8/59). In the ExoMin group; 9% had major CHD (6/64), M:F 42:22, 18% premature and 10% had low birth-weight. The 5-year survival was 20% in the EMCHD group versus 90% in the ExoMaj with minor or no CHD [p < 0.0001]. Deaths in the EMCHD had mainly right heart anomalies and all of them required mechanical ventilation (MV) for pulmonary hypoplasia prior to cardiac intervention. In contrast, survivors did not require mechanical ventilation prior to cardiac intervention. CONCLUSION: EMCHD is associated with high mortality. The most significant finding was high mortality in those with right heart anomalies in combination with pulmonary hypoplasia, especially if pre-intervention mechanical ventilation is required.
Assuntos
Cardiopatias Congênitas , Hérnia Umbilical , Nascimento Prematuro , Humanos , Feminino , Hérnia Umbilical/terapia , Aberrações Cromossômicas , Respiração ArtificialRESUMO
Four-dimensional data sets are increasingly common in MRI and CT. While clinical visualization often focuses on individual temporal phases capturing the tissue(s) of interest, it may be possible to gain additional insight through exploring animated 3D reconstructions of physiological motion made possible by augmented or virtual reality representations of 4D patient imaging. Cardiac CT acquisitions can provide sufficient spatial resolution and temporal data to support advanced visualization, however, there are no open-source tools readily available to facilitate the transformation from raw medical images to dynamic and interactive augmented or virtual reality representations. To address this gap, we developed a workflow using free and open-source tools to process 4D cardiac CT imaging starting from raw DICOM data and ending with dynamic AR representations viewable on a phone, tablet, or computer. In addition to assembling the workflow using existing platforms (3D Slicer and Unity), we also contribute two new features: 1. custom software which can propagate a segmentation created for one cardiac phase to all others and export to surface files in a fully automated fashion, and 2. a user interface and linked code for the animation and interactive review of the surfaces in augmented reality. Validation of the surface-based areas demonstrated excellent correlation with radiologists' image-based areas (R > 0.99). While our tools were developed specifically for 4D cardiac CT, the open framework will allow it to serve as a blueprint for similar applications applied to 4D imaging of other tissues and using other modalities. We anticipate this and related workflows will be useful both clinically and for educational purposes.
Assuntos
Realidade Aumentada , Realidade Virtual , Humanos , Imageamento Tridimensional/métodos , Tomografia Computadorizada Quadridimensional , Imageamento por Ressonância Magnética/métodos , SoftwareRESUMO
BACKGROUND: Transcriptomic data has demonstrated utility to advance the study of physiological diversity and organisms' responses to environmental stressors. However, a lack of genomic resources and challenges associated with collecting high-quality RNA can limit its application for many wild populations. Minimally invasive blood sampling combined with de novo transcriptomic approaches has great potential to alleviate these barriers. Here, we advance these goals for marine turtles by generating high quality de novo blood transcriptome assemblies to characterize functional diversity and compare global transcriptional profiles between tissues, species, and foraging aggregations. RESULTS: We generated high quality blood transcriptome assemblies for hawksbill (Eretmochelys imbricata), loggerhead (Caretta caretta), green (Chelonia mydas), and leatherback (Dermochelys coriacea) turtles. The functional diversity in assembled blood transcriptomes was comparable to those from more traditionally sampled tissues. A total of 31.3% of orthogroups identified were present in all four species, representing a core set of conserved genes expressed in blood and shared across marine turtle species. We observed strong species-specific expression of these genes, as well as distinct transcriptomic profiles between green turtle foraging aggregations that inhabit areas of greater or lesser anthropogenic disturbance. CONCLUSIONS: Obtaining global gene expression data through non-lethal, minimally invasive sampling can greatly expand the applications of RNA-sequencing in protected long-lived species such as marine turtles. The distinct differences in gene expression signatures between species and foraging aggregations provide insight into the functional genomics underlying the diversity in this ancient vertebrate lineage. The transcriptomic resources generated here can be used in further studies examining the evolutionary ecology and anthropogenic impacts on marine turtles.
Assuntos
Tartarugas , Animais , Sequência de Bases , Especificidade da Espécie , Transcriptoma , Tartarugas/genéticaRESUMO
Microglia in human post-mortem tissue in schizophrenia patients' brains engulf synaptic material, but not differently to age-matched non-neurological control brains. Also, schizophrenia brains display similar levels of microgliosis to control brains.
Assuntos
Microglia/patologia , Córtex Pré-Frontal/patologia , Esquizofrenia/patologia , Sinapses/patologia , HumanosRESUMO
The biological fingerprint of environmental adversity may be key to understanding health and disease, as it encompasses the damage induced as well as the compensatory reactions of the organism. Metabolic and hormonal changes may be an informative but incomplete window into the underlying biology. We endeavored to identify objective blood gene expression biomarkers for psychological stress, a subjective sensation with biological roots. To quantify the stress perception at a particular moment in time, we used a simple visual analog scale for life stress in psychiatric patients, a high-risk group. Then, using a stepwise discovery, prioritization, validation, and testing in independent cohort design, we were successful in identifying gene expression biomarkers that were predictive of high-stress states and of future psychiatric hospitalizations related to stress, more so when personalized by gender and diagnosis. One of the top biomarkers that survived discovery, prioritization, validation, and testing was FKBP5, a well-known gene involved in stress response, which serves as a de facto reassuring positive control. We also compared our biomarker findings with telomere length (TL), another well-established biological marker of psychological stress and show that newly identified predictive biomarkers such as NUB1, APOL3, MAD1L1, or NKTR are comparable or better state or trait predictors of stress than TL or FKBP5. Over half of the top predictive biomarkers for stress also had prior evidence of involvement in suicide, and the majority of them had evidence in other psychiatric disorders, providing a molecular underpinning for the effects of stress in those disorders. Some of the biomarkers are targets of existing drugs, of potential utility in patient stratification, and pharmacogenomics approaches. Based on our studies and analyses, the biomarkers with the best overall convergent functional evidence (CFE) for involvement in stress were FKBP5, DDX6, B2M, LAIR1, RTN4, and NUB1. Moreover, the biomarker gene expression signatures yielded leads for possible new drug candidates and natural compounds upon bioinformatics drug repurposing analyses, such as calcium folinate and betulin. Our work may lead to improved diagnosis and treatment for stress disorders such as PTSD, that result in decreased quality of life and adverse outcomes, including addictions, violence, and suicide.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/sangue , RNA Helicases DEAD-box/sangue , Proteínas Nogo/sangue , Proteínas Proto-Oncogênicas/sangue , Receptores Imunológicos/sangue , Estresse Psicológico/sangue , Proteínas de Ligação a Tacrolimo/sangue , Microglobulina beta-2/sangue , Adulto , Biomarcadores/sangue , Feminino , Expressão Gênica , Humanos , Masculino , Transtornos Mentais/sangue , Transtornos Mentais/genética , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Medicina de Precisão , Valor Preditivo dos Testes , Homeostase do TelômeroRESUMO
Short-term memory dysfunction is a key early feature of Alzheimer's disease (AD). Psychiatric patients may be at higher risk for memory dysfunction and subsequent AD due to the negative effects of stress and depression on the brain. We carried out longitudinal within-subject studies in male and female psychiatric patients to discover blood gene expression biomarkers that track short term memory as measured by the retention measure in the Hopkins Verbal Learning Test. These biomarkers were subsequently prioritized with a convergent functional genomics approach using previous evidence in the field implicating them in AD. The top candidate biomarkers were then tested in an independent cohort for ability to predict state short-term memory, and trait future positive neuropsychological testing for cognitive impairment. The best overall evidence was for a series of new, as well as some previously known genes, which are now newly shown to have functional evidence in humans as blood biomarkers: RAB7A, NPC2, TGFB1, GAP43, ARSB, PER1, GUSB, and MAPT. Additional top blood biomarkers include GSK3B, PTGS2, APOE, BACE1, PSEN1, and TREM2, well known genes implicated in AD by previous brain and genetic studies, in humans and animal models, which serve as reassuring de facto positive controls for our whole-genome gene expression discovery approach. Biological pathway analyses implicate LXR/RXR activation, neuroinflammation, atherosclerosis signaling, and amyloid processing. Co-directionality of expression data provide new mechanistic insights that are consistent with a compensatory/scarring scenario for brain pathological changes. A majority of top biomarkers also have evidence for involvement in other psychiatric disorders, particularly stress, providing a molecular basis for clinical co-morbidity and for stress as an early precipitant/risk factor. Some of them are modulated by existing drugs, such as antidepressants, lithium and omega-3 fatty acids. Other drug and nutraceutical leads were identified through bioinformatic drug repurposing analyses (such as pioglitazone, levonorgestrel, salsolidine, ginkgolide A, and icariin). Our work contributes to the overall pathophysiological understanding of memory disorders and AD. It also opens new avenues for precision medicine- diagnostics (assement of risk) as well as early treatment (pharmacogenomically informed, personalized, and preventive).
Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico , Biomarcadores/sangue , Reposicionamento de Medicamentos , Diagnóstico Precoce , Transtornos da Memória/sangue , Memória de Curto Prazo , Farmacocinética , Adulto , Idoso , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Feminino , Humanos , Masculino , Transtornos da Memória/diagnóstico , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Pessoa de Meia-Idade , Adulto JovemRESUMO
Although hydrogen isotopes (δ2H) are commonly used as tracers of animal movement, minimal research has investigated the use of δ2H as a proxy to quantify resource and habitat use. While carbon and nitrogen are ultimately derived from a single source (food), the proportion of hydrogen in consumer tissues originates from two distinct sources: body water and food. Before hydrogen isotopes can be effectively used as a resource and habitat tracer, we need estimates of (net) discrimination factors (Δ2HNet) that account for the physiologically mediated differences in the δ2H values of animal tissues relative to that of the food and water sources they use to synthesize tissues. Here, we estimated Δ2HNet in captive green turtles (Chelonia mydas) by measuring the δ2H values of tissues (epidermis and blood components) and dietary macromolecules collected in two controlled feeding experiments. Tissue δ2H and Δ2HNet values varied systematically among tissues, with epidermis having higher δ2H and Δ2HNet values than blood components, which mirrors patterns between keratinaceous tissues (feathers, hair) and blood in birds and mammals. Serum/plasma of adult female green turtles had significantly lower δ2H values compared with juveniles, likely due to increased lipid mobilization associated with reproduction. This is the first study to quantify Δ2HNet values in a marine ectotherm, and we anticipate that our results will further refine the use of δ2H analysis to better understand animal resource and habitat use in marine ecosystems, especially coastal areas fueled by a combination of marine (e.g. micro/macroalgae and seagrass) and terrestrial (e.g. mangroves) primary production.