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MacDonald, A. J.

Publications and source records attributed to MacDonald, A. J..

10 recordsLinked to original sources
bioRxiv2026

Water availability has stronger effects on West Nile virus dynamics in water-limited regions

West Nile virus dynamics are shaped by hydrological conditions that influence mosquito habitat and pathogen transmission, but identifying causal relationships is difficult in managed landscapes where irrigation decouples local water conditions from precipitation, complicating climate-disease inference. We address this challenge using a 21-year panel of more than 19 million Culex tarsalis mosquitoes from Californias Central Valley, applying fixed-effects panel models to estimate how surface water availability affects mosquito abundance and infection rates while accounting for spatial differences and shared temporal variation. We find that wetter conditions lead to higher mosquito abundance but slightly lower infection rates, suggesting divergent responses of vector population growth and pathogen amplification. These patterns are consistent across multiple hydrological measures, including drought indices, soil moisture, surface water, and evapotranspiration. Effects are strongest in water-limited regions, where hydrological variability is greatest and buffering by snowmelt-fed river systems is weakest. Overall, hydrological conditions exert contrasting effects on key components of West Nile virus dynamics, and these relationships are strongly conditioned by human water management. Our results highlight how irrigation decouples local hydrological conditions from broader climatic variability, underscoring the need for fine-scale hydrological data and panel-based approaches to identify drivers of disease dynamics in human managed landscapes.

ecology↗
bioRxiv2026

Acute Ethanol Exposure Induces Stage-Specific Bioenergetic, Mitochondrial and Neurodevelopmental Transcriptional Remodeling in Human Forebrain Progenitors

Prenatal alcohol exposure (PAE) is associated with long-term neurodevelopmental risk, yet how neuronal progenitor metabolism responds to alcohol across developmental stages remains unclear. Here, we integrated brain-isoform-focused analysis of public datasets with targeted transcriptional, translational, and functional mitochondrial assessments in human iPSC-derived cortical progenitor models representing distinct bioenergetic states. Re-analysis of prior PAE studies revealed broad metabolic gene downregulation in embryonic systems, whereas neurodevelopmental models showed limited and non-coherent transcriptional signatures. In vitro, acute ethanol exposure (AEE) induced stage-dependent transcriptional remodeling in iPSC-derived neuronal progenitor cells. Early progenitors exhibited selective upregulation of mitochondrial-associated transcripts alongside increased neuronal lineage markers. In contrast, late progenitors showed broader increases in glycolytic, lipid, and mitochondrial gene expression. Despite these transcriptional changes, mitochondrial ATP production and mitochondrial protein abundance remained unchanged in both models with altered dynamics being restricted to late progenitors. These findings indicate that ethanol exposure is associated with developmental stage-dependent neuronal remodeling of bioenergetic genes. Measurements of mitochondrial-neural frameworks after AEE showed no major alterations in either model. Overall, our results reveal a dissociation between transcriptional, translational, and functional bioenergetic outputs in models of early human neurodevelopment and highlight that transcriptional alterations of mitochondria and cellular bioenergetics under AEE should be interpreted in the context of developmental stage rather than in isolation as evidence of energetic dysfunction.

neuroscience↗
bioRxiv2025

Climate warming and urbanization may expand dengue transmission risk in California

BackgroundWhile primarily a disease of tropical and subtropical regions, dengue outbreaks are increasing in non-endemic regions due to environmental change and increasing travel and trade. For these non-endemic regions, estimating the risk of dengue is challenging as transmission is driven by both local environmental conditions and the introduction of viremic travelers. In this study, we aimed to estimate current and future dengue risk in California, USA--a region that has recently experienced its first cases of locally-acquired dengue. MethodsWe modeled dengue risk as the product of three key components needed for local transmission--vector presence, temperature-suitability for pathogen transmission, and viral introductions via travel-associated cases--estimated using vector and case surveillance, sociodemographic, and environmental data. We estimated risk for locations and months where local transmission was reported in 2023-2024 to define a threshold level of risk. We then projected monthly, census tract-level risk under both current conditions and future scenarios of climate warming and urban expansion. FindingsApproximately 18.2 million (95% CI: 17.9-18.3) California residents--primarily in the Central Valley and the Los Angeles and San Diego metropolitan areas--currently live in areas where peak monthly dengue risk exceeds levels estimated during observed local transmission. Under moderate scenarios of climate warming and urban expansion, an additional 4.1 million (95% CI: 3.7-4.6) California residents may be at risk by mid-century, with the largest increase in risk estimated for September and for the Sacramento Valley and coastal southern California regions. Outside the summer months and beyond the Central Valley and southern California, current and future risk remains low due to one or more major bottlenecks to transmission. InterpretationOur study identifies the specific regions and months conducive to dengue transmission in the non-endemic setting of California. At present, this covers a substantial portion of the state and is projected to expand under on-going climate warming and urbanization. Our results underscore the need for sustained vector control, and timely detection and management of travel-associated cases. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSDengue is considered endemic in over 125 countries and rapidly expanding its range, aided by climate warming, urbanization, and global travel and trade. Estimating transmission risk in newly emerging regions is critical for public health preparedness and depends on both local environmental conditions and the introduction of viremic travelers. We searched PubMed from database inception to May 8, 2025, for articles published in English using search terms "dengue", "model", "non-endemic", and their common textual variants. We identified 75 relevant studies modeling dengue transmission risk in non-endemic settings. However, nearly all were focused on one or two major determinants of transmission (eg, climate, vector population dynamics, or case importations) and/or did not include future projections. We found no studies that developed and validated a model of dengue transmission risk in non-endemic settings that incorporated vector, pathogen, and human suitability factors, and applied this model to project future risk. Added value of this studyThis study provides a novel approach to model dengue transmission risk in emerging regions that integrates the major factors driving transmission--vector presence, temperature suitability, and travel-associated cases. We apply this model to California--an emerging center of transmission risk in the continental USA--to identify the times and regions where risk exceeds levels observed during recent local transmission. We found that approximately 18.2 million California residents may be at risk based on this threshold, with an additional 4.1 million potentially at risk by mid-century under a moderate scenario of warming and urban expansion. Implications of all the available evidenceOur study identifies the hotspots of dengue transmission risk at a fine spatial and temporal resolution (census tract, month) in a highly populous and globally-connected region of emerging dengue risk. These risk estimates, and the regionally-specific bottlenecks to transmission that we identify can inform targeted disease surveillance and prevention strategies. Further, our findings have implications for other emerging regions including the southern USA and southern Europe, suggesting that the risk of local dengue transmission may increase under ongoing climate warming, urbanization, and global travel.

ecology↗
bioRxiv2025

The paradoxical impact of drought on West Nile virus risk: insights from long-term ecological data

Mosquito-borne diseases are deeply embedded within ecological communities, with environmental changes - particularly climate change - shaping their dynamics. Increasingly intesense droughts across the globe have profound implications for the transmission of these diseases, as drought conditions can alter mosquito breeding habitats, host-seeking behaviors, and mosquito-host contact rates. To quantify the effect of drought on disease transmission, we use West Nile virus (WNV) as a model system and leverage a robust mosquito and virus dataset consisting of over 500,000 trap nights collected from 2010-2023, spanning a historic drought period followed by atmospheric rivers. We pair this surveillance dataset with a novel modeling approach that incorporates monthly changes in bird host community competence, along with drought conditions, to estimate the effect of drought severity on WNV risk using panel regression models. Our results show that while drought decreases mosquito abundances, it paradoxically increases WNV infection rates. This counterintuitive pattern likely stems from reduced water availability, which concentrates mosquitos and pathogen-amplifying bird hosts around limited water sources, thereby increasing disease transmission risk. However, the magnitude of the effect depends critically on mosquito species, suggesting species-specific behavioral traits are key to understanding the effect of drought on mosquito-borne disease risk across real landscapes.

ecology↗
bioRxiv2023

Reference genome of the endangered eastern quoll (Dasyurus viverrinus)

The eastern quoll (Dasyurus viverrinus) is an endangered marsupial mesopredator native to Australia. Since the extirpation of the last mainland Australian populations in the late 20th century, wild populations of this species have been restricted to two islands at the far southern end of its historical range. Eastern quolls are the subject of captive breeding programs and attempts have recently been made to re-establish a population in mainland Australia through translocations. However, few resources currently exist to guide the genetic management of this species. Here, we generated a chromosome-scale reference genome for the eastern quoll, along with gene annotations supported by multi-tissue transcriptomes. Through comparisons with related species, we find that our reference genome is among the most complete marsupial assemblies currently available. Using this assembly, we infer the species demographic history and identify potential evidence of a long-term decline beginning in the late Pleistocene. Finally, we identify a deletion at the ASIP locus that likely drives differences in pelage color between the eastern quoll and the closely related Tasmanian devil (Sarcophilus harrisii). The genomic resources we present are valuable new tools for evolutionary and conservation genomic studies.

genomics↗
bioRxiv2021

Astrocytes in the dorsal vagal complex are not activated by systemic glucoprivation and their chemogenetic activation does not elicit homeostatic glucoregulatory responses in mice

The dorsal vagal complex (DVC) is a brainstem site regulating diverse aspects of physiology including food intake and blood glucose homeostasis. Astrocytes are purported to play an active role in regulating DVC function and, by extension, physiological parameters. Previous work has demonstrated that DVC astrocytes directly sense hormones that regulate food intake and blood glucose and are critical for their effect. In addition, DVC astrocytes in ex vivo slices respond to low tissue glucose. The response of neurons, including catecholaminergic neurons, to low glucose is conditional on intact astrocyte signalling in slice preparations suggesting astrocytes are possibly the primary sensors of glucose deprivation (glucoprivation). Based on these findings we hypothesised that if DVC astrocytes act as glucoprivation sensors in vivo they would both show a response to systemic glucoprivation and drive physiological responses to restore blood glucose. We found that 2 hours of systemic glucoprivation induced neither FOS nor glial fibrillary acidic protein (GFAP)-immunoreactivity in DVC astrocytes, specifically those in the nucleus of the solitary tract (NTS). Furthermore, we found that while chemogenetic activation of DVC astrocytes suppressed food intake by reducing both meal size and meal number, this manipulation also suppressed food intake under conditions of glucoprivation. Chemogenetic activation of DVC astrocytes did not increase basal blood glucose nor protect against insulin-induced hypoglycaemia. In male mice chemogenetic DVC astrocyte activation did not alter glucose tolerance, in female mice the initial glucose excursion was reduced, suggesting enhanced glucose absorption. Taken together this suggests that as a whole-population DVC astrocytes do not function as glucoprivation sensors in vivo in mice. Instead, we propose that DVC astrocytes play an indispensable, homeostatic role to maintain the function of glucoregulatory neuronal circuitry.

neuroscience↗
bioRxiv2021

Land-use planning for health: Tradeoffs and nonlinearities govern how land-use change impacts vector-borne disease risk

Patterns of land-use can affect the transmission of many infectious diseases with human health implications; yet, applied ecosystem service models have rarely accounted for disease transmission risk. A mechanistic understanding of how land-use changes alter infectious disease transmission would help to target public health interventions and to minimize human risk of disease with either ecosystem degradation or restoration. Here, we present a spatially explicit model of disease transmission on heterogeneous landscapes that is designed to serve as a road map for modeling the multifaceted impacts of land-use on disease transmission. We model the transmission of three vector-borne diseases with distinct transmission dynamics (parameterized using published literature to represent dengue, yellow fever, and malaria) on simulated landscapes of varying spatial heterogeneity in tree cover and urban area. Overall, we find that these three diseases depend on the biophysical landscape in different nonlinear ways, leading to tradeoffs in disease risk across the landscape; rarely do we predict disease risk to be high for all three diseases in a local setting. We predict that dengue risk peaks in areas of high urban intensity and human population density, yellow fever risk peaks in areas with low to moderate human population density and high tree cover, and malaria risk peaks where patchy tree cover abuts urban area. To examine how this approach can inform land use planning, we applied the model to a small landscape to the northwest of Bogota, Colombia under multiple restoration scenarios. We predict that in an area inhabited by both Aedes aegypti and Ae. albopictus, any increase in overall tree cover would increase dengue and yellow fever risk, but that risk can be minimized by pursuing a large contiguous reforestation project as opposed to many small, patchy projects. A large contiguous reforestation project is also able to both reduce overall malaria risk and the number of malaria hotspots. As sustainable development goals make ecosystem restoration and biodiversity conservation top priorities, it is imperative that land use planning account for potential impacts on both disease transmission and other ecosystem services. Open Research statementAll data and code used in this study are available in the online supplemental material. Code and data are also hosted at: https://github.com/morgankain/Land-Use_Disease_Model.

ecology↗
bioRxiv2020

Impact of prior and projected climate change on US Lyme disease incidence

Lyme disease is the most common vector-borne disease in temperate zones and a growing public health threat in the United States (US). The life cycles of the tick vectors and spirochete pathogen are highly sensitive to climate, but determining the impact of climate change on Lyme disease burden has been challenging due to the complex ecology of the disease and the presence of multiple, interacting drivers of transmission. Here we incorporated 18 years of annual, county-level Lyme disease case data in a panel data statistical model to investigate prior effects of climate variation on disease incidence while controlling for other putative drivers. We then used these climate-disease relationships to project Lyme disease cases using CMIP5 global climate models and two potential climate scenarios (RCP4.5 and RCP8.5). We find that interannual variation in Lyme disease incidence is associated with climate variation in all US regions encompassing the range of the primary vector species. In all regions, the climate predictors explained less of the variation in Lyme disease incidence than unobserved county-level heterogeneity, but the strongest climate-disease association detected was between warming annual temperatures and increasing incidence in the Northeast. Lyme disease projections indicate that cases in the Northeast will increase significantly by 2050 (23,619 {+/-} 21,607 additional cases), but only under RCP8.5, and with large uncertainty around this projected increase. Significant case changes are not projected for any other region under either climate scenario. The results demonstrate a regionally variable and nuanced relationship between climate change and Lyme disease, indicating possible nonlinear responses of vector ticks and transmission dynamics to projected climate change. Moreover, our results highlight the need for improved preparedness and public health interventions in endemic regions to minimize the impact of further climate change-induced increases in Lyme disease burden.

ecology↗
bioRxiv2019

Empirical dynamic modeling reveals ecological drivers of dengue dynamics

Experiments and models suggest that climate affects mosquito-borne disease transmission. However, disease transmission involves complex nonlinear interactions between climate and population dynamics, which makes detecting climate drivers at the population level challenging. By analyzing incidence data, estimated susceptible population size, and climate data with methods based on nonlinear time series analysis (collectively referred to as empirical dynamic modeling), we identified drivers and their interactive effects on dengue dynamics in San Juan, Puerto Rico. Climatic forcing arose only when susceptible availability was high: temperature and rainfall had net positive and negative effects, respectively. By capturing mechanistic, nonlinear, and context-dependent effects of population susceptibility, temperature, and rainfall on dengue transmission empirically, our model improves forecast skill over recent, state-of-the-art models for dengue incidence. Together, these results provide empirical evidence that the interdependence of host population susceptibility and climate drive dengue dynamics in a nonlinear and complex, yet predictable way.

ecology↗
bioRxiv2019

Regulation of food intake by astrocytes in the brainstem dorsal vagal complex

Food intake is controlled by the coordinated action of numerous brain regions but a complete understanding remains elusive. Of these brain regions the brainstem dorsal vagal complex (DVC) is the first site for integration of visceral synaptic and hormonal cues that act to inhibit food intake. The DVC consists of three nuclei: the nucleus of the solitary tract (NTS), area postrema (AP) and dorsal motor nucleus of the vagus (DMX). Targeted chemogenetic activation of appetite-responsive NTS neuronal populations causes short term decreases in food intake. Astrocytes are a class of glial cell which provide metabolic and structural support to neurons and play an active role in modulating neurotransmission. Within the hypothalamic arcuate nucleus (ARC) astrocytes are regulated by both positive and negative energy balance and express receptors for hormones that influence satiety and hunger. Chemogenetic activation of these ARC astrocytes alters food intake. Since NTS astrocytes respond to vagal stimulation, we hypothesised that they may be involved in mediating satiety. Here we show that NTS astrocytes show plastic alterations in morphology following excess food consumption and that chemogenetic activation of DVC astrocytes causes a decrease in food intake, by recruiting an appetite-inhibiting circuit, without producing aversion. These findings are the first using genetically-targeted manipulation of DVC astrocytes to demonstrate their role in the brains regulation of food intake.

neuroscience↗