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1.
Nature ; 572(7770): 461-466, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31340216

RESUMO

Effective ocean management and the conservation of highly migratory species depend on resolving the overlap between animal movements and distributions, and fishing effort. However, this information is lacking at a global scale. Here we show, using a big-data approach that combines satellite-tracked movements of pelagic sharks and global fishing fleets, that 24% of the mean monthly space used by sharks falls under the footprint of pelagic longline fisheries. Space-use hotspots of commercially valuable sharks and of internationally protected species had the highest overlap with longlines (up to 76% and 64%, respectively), and were also associated with significant increases in fishing effort. We conclude that pelagic sharks have limited spatial refuge from current levels of fishing effort in marine areas beyond national jurisdictions (the high seas). Our results demonstrate an urgent need for conservation and management measures at high-seas hotspots of shark space use, and highlight the potential of simultaneous satellite surveillance of megafauna and fishers as a tool for near-real-time, dynamic management.


Assuntos
Migração Animal , Pesqueiros/estatística & dados numéricos , Mapeamento Geográfico , Oceanos e Mares , Tubarões/fisiologia , Análise Espaço-Temporal , Animais , Densidade Demográfica , Medição de Risco , Tubarões/classificação , Navios , Fatores de Tempo
2.
Proc Natl Acad Sci U S A ; 119(20): e2117440119, 2022 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-35533277

RESUMO

Marine traffic is increasing globally yet collisions with endangered megafauna such as whales, sea turtles, and planktivorous sharks go largely undetected or unreported. Collisions leading to mortality can have population-level consequences for endangered species. Hence, identifying simultaneous space use of megafauna and shipping throughout ranges may reveal as-yet-unknown spatial targets requiring conservation. However, global studies tracking megafauna and shipping occurrences are lacking. Here we combine satellite-tracked movements of the whale shark, Rhincodon typus, and vessel activity to show that 92% of sharks' horizontal space use and nearly 50% of vertical space use overlap with persistent large vessel (>300 gross tons) traffic. Collision-risk estimates correlated with reported whale shark mortality from ship strikes, indicating higher mortality in areas with greatest overlap. Hotspots of potential collision risk were evident in all major oceans, predominantly from overlap with cargo and tanker vessels, and were concentrated in gulf regions, where dense traffic co-occurred with seasonal shark movements. Nearly a third of whale shark hotspots overlapped with the highest collision-risk areas, with the last known locations of tracked sharks coinciding with busier shipping routes more often than expected. Depth-recording tags provided evidence for sinking, likely dead, whale sharks, suggesting substantial "cryptic" lethal ship strikes are possible, which could explain why whale shark population declines continue despite international protection and low fishing-induced mortality. Mitigation measures to reduce ship-strike risk should be considered to conserve this species and other ocean giants that are likely experiencing similar impacts from growing global vessel traffic.


Assuntos
Tubarões , Animais , Espécies em Perigo de Extinção , Plâncton , Navios
3.
Am Nat ; 201(4): 586-602, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36958006

RESUMO

AbstractUnifying models have shown that the amount of space used by animals (e.g., activity space, home range) scales allometrically with body mass for terrestrial taxa; however, such relationships are far less clear for marine species. We compiled movement data from 1,596 individuals across 79 taxa collected using a continental passive acoustic telemetry network of acoustic receivers to assess allometric scaling of activity space. We found that ectothermic marine taxa do exhibit allometric scaling for activity space, with an overall scaling exponent of 0.64. However, body mass alone explained only 35% of the variation, with the remaining variation best explained by trophic position for teleosts and latitude for sharks, rays, and marine reptiles. Taxon-specific allometric relationships highlighted weaker scaling exponents among teleost fish species (0.07) than sharks (0.96), rays (0.55), and marine reptiles (0.57). The allometric scaling relationship and scaling exponents for the marine taxonomic groups examined were lower than those reported from studies that had collated both marine and terrestrial species data derived using various tracking methods. We propose that these disparities arise because previous work integrated summarized data across many studies that used differing methods for collecting and quantifying activity space, introducing considerable uncertainty into slope estimates. Our findings highlight the benefit of using large-scale, coordinated animal biotelemetry networks to address cross-taxa evolutionary and ecological questions.


Assuntos
Organismos Aquáticos , Peixes , Animais , Comportamento de Retorno ao Território Vital
4.
J Cardiovasc Electrophysiol ; 34(7): 1552-1560, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37293826

RESUMO

INTRODUCTION: Accurate localization of septal outflow tract premature ventricular contractions (PVCs) is often difficult due to frequent mid-myocardial or protected origin. Compared with traditional activation mapping, CARTO Ripple mapping provides visualization of all captured electrogram data without assignment of a specific local activation time and thus may enhance PVC localization. METHODS: Electroanatomic maps for consecutive catheter ablation procedures for septal outflow tract PVCs (July 2018-December 2020) were analyzed. For each PVC, we identified the earliest local activation point (EA), defined by the point of maximal -dV/dt in a simultaneously recorded unipolar electrogram, and the earliest Ripple signal (ERS), defined as the earliest point at which three grouped simultaneous Ripple bars appeared in late diastole. Immediate success was defined as full suppression of the clinical PVC. RESULTS: Fifty-seven unique PVCs in 55 procedures were included. When ERS and EA were in the same chamber (RV, LV, or CS), the odds ratio for the successful procedure was 13.1 (95% confidence interval [CI] 2.2-79.9, p = .005). Discordance between sites was associated with a higher likelihood of needing multi-site ablation (odds ratio [OR] 7.9 [1.4-4.6; p = .020]). Median EA-ERS distance in successful versus unsuccessful cases was 4.6 mm (interquartile range 2.9-8.5) versus 12.5 mm (7.8-18.5); (p = .020). CONCLUSION: Greater EA-ERS concordance was associated with higher odds of single-site PVC suppression and successful septal outflow tract PVC ablation. Visualization of complex signals via automated Ripple mapping may offer rapid localization information complementary to local activation mapping for PVCs of mid-myocardial origin.


Assuntos
Ablação por Cateter , Complexos Ventriculares Prematuros , Humanos , Complexos Ventriculares Prematuros/diagnóstico , Complexos Ventriculares Prematuros/cirurgia , Complexos Ventriculares Prematuros/complicações , Resultado do Tratamento , Ablação por Cateter/efeitos adversos , Ablação por Cateter/métodos , Catéteres
5.
Heredity (Edinb) ; 131(3): 189-200, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37400518

RESUMO

Oceanic islands play a central role in the study of evolution and island biogeography. The Galapagos Islands are one of the most studied oceanic archipelagos but research has almost exclusively focused on terrestrial organisms compared to marine species. Here we used the Galapagos bullhead shark (Heterodontus quoyi) and single nucleotide polymorphisms (SNPs) to examine evolutionary processes and their consequences for genetic divergence and island biogeography in a shallow-water marine species without larval dispersal. The sequential separation of individual islands from a central island cluster gradually established different ocean depths between islands that pose barriers to dispersal in H. quoyi. Isolation by resistance analysis suggested that ocean bathymetry and historical sea level fluctuations modified genetic connectivity. These processes resulted in at least three genetic clusters that exhibit low genetic diversity and effective population sizes that scale with island size and the level of geographic isolation. Our results exemplify that island formation and climatic cycles shape genetic divergence and biogeography of coastal marine organisms with limited dispersal comparable to terrestrial taxa. Because similar scenarios exist in oceanic islands around the globe our research provides a new perspective on marine evolution and biogeography with implications for the conservation of island biodiversity.


Assuntos
Biodiversidade , Deriva Genética , Ilhas , Oceanos e Mares , Organismos Aquáticos
6.
J Fish Biol ; 102(3): 718-720, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36601795

RESUMO

Here the authors report on a possible range extension in the rare and understudied winghead shark (Eusphyra blochii). A specimen was captured by recreational fishermen in Moreton Bay, Queensland, Australia, c. 800 km south of its current distribution. As winghead sharks show a clumped distribution in Australia associated with river outflow, Moreton Bay, with its large catchment area, may represent a suitable habitat for the species and previous occurrence may have gone undetected. Alternatively, climate change may have caused a recent southward shift in winghead sharks, as observed in other elasmobranch species along Australia's East Coast.


Assuntos
Tubarões , Animais , Austrália , Queensland , Ecossistema
7.
Oecologia ; 198(1): 111-124, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34787703

RESUMO

Globally, marine animal distributions are shifting in response to a changing climate. These shifts are usually considered at the species level, but individuals are likely to differ in how they respond to the changing conditions. Here, we investigate how movement behaviour and, therefore, redistribution, would differ by sex and maturation class in a wide-ranging marine predator. We tracked 115 tiger sharks (Galeocerdo cuvier) from 2002 to 2020 and forecast class-specific distributions through to 2030, including environmental factors and predicted occurrence of potential prey. Generalised Linear and Additive Models revealed that water temperature change, particularly at higher latitudes, was the factor most associated with shark movements. Females dispersed southwards during periods of warming temperatures, and while juvenile females preferred a narrow thermal range between 22 and 23 °C, adult female and juvenile male presence was correlated with either lower (< 22 °C) or higher (> 23 °C) temperatures. During La Niña, sharks moved towards higher latitudes and used shallower isobaths. Inclusion of predicted distribution of their putative prey significantly improved projections of suitable habitats for all shark classes, compared to simpler models using temperature alone. Tiger shark range off the east coast of Australia is predicted to extend ~ 3.5° south towards the east coast of Tasmania, particularly for juvenile males. Our framework highlights the importance of combining long-term movement data with multi-factor habitat projections to identify heterogeneity within species when predicting consequences of climate change. Recognising intraspecific variability will improve conservation and management strategies and help anticipate broader ecosystem consequences of species redistribution due to ocean warming.


Assuntos
Mudança Climática , Tubarões , Distribuição Animal , Animais , Ecossistema , Feminino , Humanos , Masculino , Temperatura
10.
Biol Conserv ; 256: 108995, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34580542

RESUMO

COVID-19 restrictions have led to an unprecedented global hiatus in anthropogenic activities, providing a unique opportunity to assess human impact on biological systems. Here, we describe how a national network of acoustic tracking receivers can be leveraged to assess the effects of human activity on animal movement and space use during such global disruptions. We outline variation in restrictions on human activity across Australian states and describe four mechanisms affecting human interactions with the marine environment: 1) reduction in economy and trade changing shipping traffic; 2) changes in export markets affecting commercial fisheries; 3) alterations in recreational activities; and 4) decline in tourism. We develop a roadmap for the analysis of acoustic tracking data across various scales using Australia's national Integrated Marine Observing System (IMOS) Animal Tracking Facility as a case study. We illustrate the benefit of sustained observing systems and monitoring programs by assessing how a 51-day break in white shark (Carcharodon carcharias) cage-diving tourism due to COVID-19 restrictions affected the behaviour and space use of two resident species. This cessation of tourism activities represents the longest break since cage-diving vessels started day trips in this area in 2007. Long-term monitoring of the local environment reveals that the activity space of yellowtail kingfish (Seriola lalandi) was reduced when cage-diving boats were absent compared to periods following standard tourism operations. However, white shark residency and movements were not affected. Our roadmap is globally applicable and will assist researchers in designing studies to assess how anthropogenic activities can impact animal movement and distributions during regional, short-term through to major, unexpected disruptions like the COVID-19 pandemic.

11.
J Fish Biol ; 96(3): 835-840, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31925780

RESUMO

The known distribution of manta rays in Australian waters is patchy, with records primarily centred around tourism hotspots. We collated 11,614 records of Mobula alfredi from photo-ID databases (n = 10,715), aerial surveys (n = 378) and online reports (n = 521). The study confirms an uninterrupted coastal distribution from north of 26°S and 31°S on the west and east coasts, respectively. More southerly M. alfredi records relate to warm-water events with a southernmost extent at 34°S. Coastal sightings of Mobula birostris were rare (n = 32), likely reflecting a preference for offshore waters, but encompass a wider latitudinal extent than M. alfredi of 10-40°S.


Assuntos
Distribuição Animal , Elasmobrânquios/fisiologia , Animais , Austrália , Oceanos e Mares
12.
Pacing Clin Electrophysiol ; 42(11): 1440-1447, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31544956

RESUMO

BACKGROUND: Compared with medical therapy, catheter ablation of atrial fibrillation (AF) in patients with heart failure (HF) improves cardiovascular outcomes. Risk scores (CAAP-AF and APPLE) have been developed to predict the likelihood of AF recurrence after ablation, have not been validated specifically in patients with AF and HF. METHODS: We analyzed baseline characteristics, risk scores, and rates of AF recurrence 12 months postablation in a cohort of 230 consecutive patients with AF and HF undergoing PVI in the Duke Center for Atrial Fibrillation registry from 2009-2013. RESULTS: During a follow-up period of 12 months, 76 of 230 (33%) patients with HF experienced recurrent AF after ablation. The median APPLE and CAAP-AF scores were 1.5 ([Q1, Q3]: [1.0, 2.0]) and 4.0 ([Q1, Q3]: [3.0, 5.0]), respectively and were not different from those patients with and without recurrent AF. Freedom from AF was not different according to APPLE and CAAP-AF scores. Discrimination for recurrent AF with the CAAP-AF score was modest with a C-statistic of 0.60 (95% CI 0.52-0.67). Discrimination with the APPLE score was similarly modest, with a C-statistic of 0.54 (95% CI: 0.47-0.62). CONCLUSIONS: Validated predictive risk scores for recurrent AF after catheter ablation exhibit limited predictive ability in cohorts of AF and HF. Additional tools are needed to facilitate risk stratification and patient selection for AF ablation in patients with concomitant HF.


Assuntos
Fibrilação Atrial/etiologia , Fibrilação Atrial/cirurgia , Ablação por Cateter , Insuficiência Cardíaca/complicações , Medição de Risco/métodos , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Recidiva , Estudos Retrospectivos
14.
Glob Chang Biol ; 24(5): 1884-1893, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29516588

RESUMO

The redistribution of species has emerged as one of the most pervasive impacts of anthropogenic climate warming, and presents many societal challenges. Understanding how temperature regulates species distributions is particularly important for mobile marine fauna such as sharks given their seemingly rapid responses to warming, and the socio-political implications of human encounters with some dangerous species. The predictability of species distributions can potentially be improved by accounting for temperature's influence on performance, an elusive relationship for most large animals. We combined multi-decadal catch data and bio-logging to show that coastal abundance and swimming performance of tiger sharks Galeocerdo cuvier are both highest at ~22°C, suggesting thermal constraints on performance may regulate this species' distribution. Tiger sharks are responsible for a large proportion of shark bites on humans, and a focus of controversial control measures in several countries. The combination of distribution and performance data moves towards a mechanistic understanding of tiger shark's thermal niche, and delivers a simple yet powerful indicator for predicting the location and timing of their occurrences throughout coastlines. For example, tiger sharks are mostly caught at Australia's popular New South Wales beaches (i.e. near Sydney) in the warmest months, but our data suggest similar abundances will occur in winter and summer if annual sea surface temperatures increase by a further 1-2°C.


Assuntos
Distribuição Animal/fisiologia , Tubarões/fisiologia , Temperatura , Animais , Ecossistema , New South Wales , Oceanos e Mares , Estações do Ano
15.
Europace ; 20(FI_3): f337-f342, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29016785

RESUMO

Aims: To assess whether obstructive sleep apnea (OSA) was associated with increased rotor burden among atrial fibrillation (AF) patients. Methods and results: We studied 33 consecutive patients who were scheduled for focal impulse and rotor modulation (FIRM) ablation at our institution to describe the mapping, ablation, and outcomes, among patients with and without OSA. Patients underwent biatrial FIRM mapping in AF with ablation of stable rotors in addition to conventional ablation lesion sets. Differences between groups were tested with student's t-tests and Fisher's exact tests, as appropriate. Survival analyses were performed using the Kaplan-Meier method. Twelve of the 33 (36%) patients had OSA and 8 (66%) used continuous positive airway pressure ventilation (CPAP). Obstructive sleep apnea patients had a higher body mass index (BMI) (33.6 vs. 28.8 kg/m2, P = 0.01) and were more commonly on beta blockers (67% vs. 29%, P = 0.03) but were otherwise similar regarding baseline characteristics, medication use, and prior AF treatments, including antiarrhythmic drugs and prior ablation. Focal impulse and rotor modulation mapping demonstrated increased rotor burden in the OSA patients (2.6 ± 0.9 vs. 2.0 ± 1.0, P =0.03). The increased rotor burden was more evident in the right atrium (RA) (1.0 ± 0.7 vs. 0.5 ± 0.7, P =0.04 compared with left atrium (1.7 ± 0.8 vs. 1.4 ± 0.7, P = 0.15). There was no correlation between BMI and total number of rotors (r = 0.0961, P = 0.59). Among the population of patients with OSA, CPAP therapy was associated with a lower number of RA rotors (0.8 ± 0.7 vs. 1.5 ± 0.6, P = 0.05) but no significant difference in overall rotors (P = 0.33). Conclusion: Obstructive sleep apnea patients demonstrate increased rotor prevalence, driven predominantly by an increase in RA rotors. CPAP therapy was associated with fewer RA rotors.


Assuntos
Fibrilação Atrial/cirurgia , Ablação por Cateter , Pressão Positiva Contínua nas Vias Aéreas , Sistema de Condução Cardíaco/cirurgia , Frequência Cardíaca , Apneia Obstrutiva do Sono/terapia , Potenciais de Ação , Idoso , Antiarrítmicos/uso terapêutico , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/fisiopatologia , Técnicas Eletrofisiológicas Cardíacas , Feminino , Sistema de Condução Cardíaco/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , North Carolina/epidemiologia , Polissonografia , Prevalência , Recidiva , Estudos Retrospectivos , Fatores de Risco , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/epidemiologia , Apneia Obstrutiva do Sono/fisiopatologia , Resultado do Tratamento
16.
Europace ; 19(7): 1096-1100, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-27756767

RESUMO

AIMS: Antiarrhythmic medications for the treatment of atrial fibrillation (AF) have limited efficacy and rare but potentially life-threatening side effects. Ranolazine is an antianginal agent that may have antiarrhythmic activity in AF. METHODS AND RESULTS: Using the Duke Enterprise Data Unified Content Explorer database, we analysed a cohort of AF patients on ranolazine. Patients served as their own historic control. Electrocardiograms (ECGs) were analysed before and after ranolazine initiation to determine the effect of ranolazine on dominant frequency (DF), f-wave amplitude, and organizational index (OI). We identified 15 patients with ECGs in AF before and after ranolazine. Ranolazine was associated with lower DF by an average of 10% (5.10 ± 0.74 vs. 5.79 ± 0.96 Hz, P = 0.04) but not with changes in OI (0.47 ± 0.11 vs. 0.50 ± 0.12, P = 0.71) or amplitude (0.47 ± 0.43 vs. 0.41 ± 0.40 mV, P = 0.82). Ranolazine was also associated with lower DF in patients (n = 10) not on concomitant antiarrhythmic therapy (5.25 ± 0.78 vs. 6.03 ± 0.79 Hz, P = 0.04). CONCLUSION: Ranolazine is associated with lower AF DF but no change in OI or fibrillatory wave amplitude. Prospective trials are needed to evaluate ranolazine's potential as a novel antiarrhythmic drug for AF.


Assuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Ranolazina/uso terapêutico , Bloqueadores dos Canais de Sódio/uso terapêutico , Potenciais de Ação , Idoso , Idoso de 80 Anos ou mais , Antiarrítmicos/efeitos adversos , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/fisiopatologia , Bases de Dados Factuais , Eletrocardiografia , Feminino , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , North Carolina , Ranolazina/efeitos adversos , Estudos Retrospectivos , Bloqueadores dos Canais de Sódio/efeitos adversos , Resultado do Tratamento
18.
Oecologia ; 178(3): 761-72, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25740335

RESUMO

Capture-mark-recapture models are useful tools for estimating demographic parameters but often result in low precision when recapture rates are low. Low recapture rates are typical in many study systems including fishing-based studies. Incorporating auxiliary data into the models can improve precision and in some cases enable parameter estimation. Here, we present a novel application of acoustic telemetry for the estimation of apparent survival and abundance within capture-mark-recapture analysis using open population models. Our case study is based on simultaneously collecting longline fishing and acoustic telemetry data for a large mobile apex predator, the broadnose sevengill shark (Notorhynchus cepedianus), at a coastal site in Tasmania, Australia. Cormack-Jolly-Seber models showed that longline data alone had very low recapture rates while acoustic telemetry data for the same time period resulted in at least tenfold higher recapture rates. The apparent survival estimates were similar for the two datasets but the acoustic telemetry data showed much greater precision and enabled apparent survival parameter estimation for one dataset, which was inestimable using fishing data alone. Combined acoustic telemetry and longline data were incorporated into Jolly-Seber models using a Monte Carlo simulation approach. Abundance estimates were comparable to those with longline data only; however, the inclusion of acoustic telemetry data increased precision in the estimates. We conclude that acoustic telemetry is a useful tool for incorporating in capture-mark-recapture studies in the marine environment. Future studies should consider the application of acoustic telemetry within this framework when setting up the study design and sampling program.


Assuntos
Ecologia/métodos , Modelos Biológicos , Tubarões , Telemetria/métodos , Acústica , Animais , Demografia/métodos , Modelos Estatísticos , Método de Monte Carlo , Densidade Demográfica , Tasmânia
19.
Sci Rep ; 14(1): 16307, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39009626

RESUMO

The frequency of unprovoked shark bites is increasing worldwide, leading to a growing pressure for mitigation measures to reduce shark-bite risk while maintaining conservation objectives. Personal shark deterrents are a promising and non-lethal strategy that can protect ocean users, but few have been independently and scientifically tested. In Australia, bull (Carcharhinus leucas), tiger (Galeocerdo cuvier), and white sharks (Carcharodon carcharias) are responsible for the highest number of bites and fatalities. We tested the effects of two electric deterrents (Ocean Guardian's Freedom+ Surf and Freedom7) on the behaviour of these three species. The surf product reduced the probability of bites by 54% across all three species. The diving product had a similar effect on tiger shark bites (69% reduction) but did not reduce the frequency of bites from white sharks (1% increase), likely because the electrodes were placed further away from the bait. Electric deterrents also increased the time for bites to occur, and frequency of reactions and passes for all species tested. Our findings reveal that both Freedom+ Surf and Freedom7 electric deterrents affect shark behaviour and can reduce shark-bite risk for water users, but neither product eliminated the risk of shark bites entirely. The increasing number of studies showing the ability of personal electric deterrents to reduce shark-bite risk highlights personal protection as an effective and important part of the toolbox of shark-bite mitigation measures.


Assuntos
Mordeduras e Picadas , Tubarões , Animais , Tubarões/fisiologia , Mordeduras e Picadas/prevenção & controle , Austrália , Conservação dos Recursos Naturais/métodos , Humanos , Eletricidade
20.
Pain ; 165(4): 922-940, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-37963235

RESUMO

ABSTRACT: Chronic pain associated with osteoarthritis (OA) remains an intractable problem with few effective treatment options. New approaches are needed to model the disease biology and to drive discovery of therapeutics. We present an in vitro model of OA pain, where dorsal root ganglion (DRG) sensory neurons were sensitized by a defined mixture of disease-relevant inflammatory mediators, here called Sensitizing PAin Reagent Composition or SPARC. Osteoarthritis-SPARC components showed synergistic or additive effects when applied in combination and induced pain phenotypes in vivo. To measure the effect of OA-SPARC on neural firing in a scalable format, we used a custom system for high throughput all-optical electrophysiology. This system enabled light-based membrane voltage recordings from hundreds of neurons in parallel with single cell and single action potential resolution and a throughput of up to 500,000 neurons per day. A computational framework was developed to construct a multiparameter OA-SPARC neuronal phenotype and to quantitatively assess phenotype reversal by candidate pharmacology. We screened ∼3000 approved drugs and mechanistically focused compounds, yielding data from over 1.2 million individual neurons with detailed assessment of functional OA-SPARC phenotype rescue and orthogonal "off-target" effects. Analysis of confirmed hits revealed diverse potential analgesic mechanisms including ion channel modulators and other mechanisms including MEK inhibitors and tyrosine kinase modulators. Our results suggest that the Raf-MEK-ERK axis in DRG neurons may integrate the inputs from multiple upstream inflammatory mediators found in osteoarthritis patient joints, and MAPK pathway activation in DRG neurons may contribute to chronic pain in patients with osteoarthritis.


Assuntos
Dor Crônica , Osteoartrite , Humanos , Dor Crônica/complicações , Osteoartrite/complicações , Células Receptoras Sensoriais/fisiologia , Eletrofisiologia , Mediadores da Inflamação/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Gânglios Espinais/metabolismo
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