Island restoration to rebuild seabird populations and amplify coral reef functioning.

Mobile organisms like seabirds can provide important nutrient flows between ecosystems, but this connectivity has been interrupted by the degradation of island ecosystems. Island restoration (via invasive species eradications and the restoration of native vegetation) can reestablish seabird populations and their nutrient transfers between their foraging areas, breeding colonies, and adjacent nearshore habitats. Its diverse benefits are making island restoration increasingly common and scalable to larger islands and whole archipelagos. We identified the factors that influence breeding seabird abundances throughout the Chagos Archipelago in the Indian Ocean and conducted predictive modeling to estimate the abundances of seabirds that the archipelago could support under invasive predator eradication and native vegetation restoration scenarios. We explored whether the prey base exists to support restored seabird populations across the archipelago, calculated the nitrogen that restored populations of seabirds might produce via their guano, and modeled the cascading conservation gains that island restoration could provide. Restoration was predicted to increase breeding pairs of seabirds to over 280,000, and prey was predicted to be ample to support the revived seabird populations. Restored nutrient fluxes were predicted to result in increases in coral growth rates, reef fish biomasses, and parrotfish grazing and bioerosion rates. Given these potential cross-ecosystem benefits, our results support island restoration as a conservation priority that could enhance resilience to climatic change effects, such as sea-level rise and coral bleaching. We encourage the incorporation of our estimates of cross-ecosystem benefits in prioritization exercises for island restoration.

Restauración en islas para reconstruir las poblaciones de aves marinas y amplificar la funcionalidad de los arrecifes de coral Resumen Los organismos móviles como las aves marinas pueden proporcionar flujos importantes de nutrientes entre los ecosistemas, aunque esta conectividad ha sido interrumpida por la degradación de los ecosistemas isleñas. La restauración de islas (por medio de la erradicación de especies invasoras y la restauración de la vegetación nativa) puede reestablecer las poblaciones de aves marinas y su transferencia de nutrientes entre las áreas de forrajeo, las colonias reproductoras y los hábitats adyacentes a la costa. Los diferentes beneficios de la restauración de islas hacen que sea cada vez más común y escalable a islas más grandes y archipiélagos completos. Identificamos los factores que influyen sobre la abundancia de aves reproductoras en todo el archipiélago de Chagos en el Océano Índico y realizamos un modelo predictivo para estimar la abundancia de aves que podría soportar el archipiélago bajo escenarios de la erradicación de un depredador invasor y la restauración de la vegetación nativa. Exploramos si existe la base de presas para soportar las poblaciones restauradas de aves marinas en el archipiélago, calculamos el nitrógeno que las poblaciones restauradas podrían producir mediante el guano y modelamos la conservación en cascada que podría proporcionar la restauración de la isla. Se pronosticó que la restauración incrementaría las parejas reproductoras a más de 280,000 y que las presas serían las suficientes para soportar las poblaciones restauradas de aves marinas. También se pronosticó que los flujos restaurados de nutrientes resultarían en un incremento de la tasa de crecimiento de los corales, la biomasa de los peces del arrecife y las tasas de bio­erosión y de alimentación de los peces loro. Dados estos beneficios potenciales entre los ecosistemas, nuestros resultados respaldan a la restauración de islas como una prioridad de conservación que podría incrementar la resiliencia a los efectos del cambio climático, como el incremento en el nivel del mar y el blanqueamiento de los corales. Promovemos que se incorporen nuestras estimaciones de los beneficios transecosistémicos dentro de los ejercicios de priorización para la restauración de islas.

Merging Metabolic Modeling and Imaging for Screening Therapeutic Targets in Colorectal Cancer.

Cancer-associated fibroblasts (CAFs) play a key role in metabolic reprogramming and are well-established contributors to drug resistance in colorectal cancer (CRC). To exploit this metabolic crosstalk, we integrated a systems biology approach that identified key metabolic targets in a data-driven method and validated them experimentally. This process involved high-throughput computational screening to investigate the effects of enzyme perturbations predicted by a computational model of CRC metabolism to understand system-wide effects efficiently. Our results highlighted hexokinase (HK) as one of the crucial targets, which subsequently became our focus for experimental validation using patient-derived tumor organoids (PDTOs). Through metabolic imaging and viability assays, we found that PDTOs cultured in CAF conditioned media exhibited increased sensitivity to HK inhibition. Our approach emphasizes the critical role of integrating computational and experimental techniques in exploring and exploiting CRC-CAF crosstalk.

Species eradication for ecosystem restoration.

Many of the world's ecosystems are under unprecedented stress as human pressures have escalated to be a dominant driver of ecosystem composition and condition. Direct impacts such as agriculture, extraction, and development are impacting vast swathes of land and ocean, while the effects of human-caused climate change are felt even in the most remote parts of marine and terrestrial wildernesses. These impacts are resulting in changes ranging from ecosystem collapse or replacement to novel mixes of species due to temperature-driven range shifts. While reducing human pressures is paramount for the future viability of vulnerable ecosystems, much attention is now also focused on whether degraded areas can be restored. Indeed, the UN has declared 2021-2030 the Decade on Ecosystem Restoration, which aims to "prevent, halt and reverse the degradation of ecosystems on every continent and in every ocean".

Mutations in the postsynaptic density signaling hub TNIK disrupt PSD signaling in human models of neurodevelopmental disorders.

A large number of synaptic proteins have been recurrently associated with complex brain disorders. One of these proteins, the Traf and Nck interacting kinase (TNIK), is a postsynaptic density (PSD) signaling hub, with many variants reported in neurodevelopmental disorder (NDD) and psychiatric disease. While rodent models of TNIK dysfunction have abnormal spontaneous synaptic activity and cognitive impairment, the role of mutations found in patients with TNIK protein deficiency and TNIK protein kinase activity during early stages of neuronal and synapse development has not been characterized. Here, using hiPSC-derived excitatory neurons, we show that TNIK mutations dysregulate neuronal activity in human immature synapses. Moreover, the lack of TNIK protein kinase activity impairs MAPK signaling and protein phosphorylation in structural components of the PSD. We show that the TNIK interactome is enriched in NDD risk factors and TNIK lack of function disrupts signaling networks and protein interactors associated with NDD that only partially overlap to mature mouse synapses, suggesting a differential role of TNIK in immature synapsis in NDD.

Testing for concordance between predicted species richness, past prioritization, and marine protected area designations in the western Indian Ocean.

Scientific advances in environmental data coverage and machine learning algorithms have improved the ability to make large-scale predictions where data are missing. These advances allowed us to develop a spatially resolved proxy for predicting numbers of tropical nearshore marine taxa. A diverse marine environmental spatial database was used to model numbers of taxa from ∼1000 field sites, and the predictions were applied to all 7039 6.25-km2 reef cells in 9 ecoregions and 11 nations of the western Indian Ocean. Our proxy for total numbers of taxa was based on the positive correlation (r2 = 0.24) of numbers of taxa of hard corals and 5 highly diverse reef fish families. Environmental relationships indicated that the number of fish species was largely influenced by biomass, nearness to people, governance, connectivity, and productivity and that coral taxa were influenced mostly by physicochemical environmental variability. At spatial delineations of province, ecoregion, nation, and strength of spatial clustering, we compared areas of conservation priority based on our total species proxy with those identified in 3 previous priority-setting reports and with the protected area database. Our method identified 119 locations that fit 3 numbers of taxa (hard coral, fish, and their combination) and 4 spatial delineations (nation, ecoregion, province, and reef clustering) criteria. Previous publications on priority setting identified 91 priority locations of which 6 were identified by all reports. We identified 12 locations that fit our 12 criteria and corresponded with 3 previously identified locations, 65 that aligned with at least 1 past report, and 28 that were new locations. Only 34% of the 208 marine protected areas in this province overlapped with identified locations with high numbers of predicted taxa. Differences occurred because past priorities were frequently based on unquantified perceptions of remoteness and preselected priority taxa. Our environment-species proxy and modeling approach can be considered among other important criteria for making conservation decisions.

Evaluación de la concordancia entre la riqueza de especies pronosticada, priorizaciones pasadas y la designación de áreas marinas protegidas en el oeste del Océano Índico Resumen Los avances científicos en la cobertura de datos ambientales y los algoritmos de aprendizaje automatizado han mejorado la capacidad de predecir a gran escala cuando hacen falta datos. Estos avances nos permiten desarrollar un representante con resolución espacial para predecir la cantidad de taxones marinos en las costas tropicales. Usamos una base de datos espaciales de diversos ambientes marinos para modelar la cantidad de taxones a partir de ∼1000 sitios de campo y aplicamos las predicciones a las 7039 celdas arrecifales de 6.25­km2 en nueve ecorregiones y once países del oeste del Océano Índico. Nuestro representante para la cantidad total de taxones se basó en la correlación positiva (r2=0.24) de la cantidad de taxones de corales duros y cinco familias de peces arrecifales con diversidad alta. Las relaciones ambientales indicaron que el número de especies de peces estuvo influenciado principalmente por la biomasa, la cercanía a las personas, la gestión, la conectividad y la productividad y que los taxones de coral estuvieron influenciados principalmente por la variabilidad ambiental fisicoquímica. Comparamos la prioridad de las áreas de conservación a nivel de las delimitaciones espaciales de provincia, ecorregión, nación y fuerza del agrupamiento espacial basado en nuestro total de especies representantes con aquellas especies identificadas en tres reportes previos de establecimiento de prioridades y con la base de datos de áreas protegidas. Con nuestro método identificamos 119 localidades aptas para tres cantidades de taxones (corales duros, peces y su combinación) y cuatro criterios de delimitación espacial (nación, ecorregión, provincia y grupo de arrecifes). Las publicaciones previas sobre el establecimiento de prioridades identificaron 91 localidades prioritarias de las cuales seis fueron identificadas por todos los reportes. Identificamos doce localidades que se ajustan a nuestros doce criterios y se correspondieron con tres localidades identificadas previamente, 65 que se alinearon con al menos un reporte anterior y 28 que eran nuevas localidades. Sólo 34% de las 208 áreas marinas protegidas en esta provincia se traslaparon con localidades identificadas con un gran número de taxones pronosticados. Hubo diferencias porque en el pasado se priorizaba frecuentemente con base en las percepciones no cuantificadas de lo remoto y prioritario de los taxones preseleccionados. Nuestra especie representante del ambiente y nuestra estrategia de modelo pueden considerarse entre otros criterios importantes para tomar decisiones de conservación.

Seabird nutrient subsidies enrich mangrove ecosystems and are exported to nearby coastal habitats.

Eutrophication by human-derived nutrient enrichment is a major threat to mangroves, impacting productivity, ecological functions, resilience, and ecosystem services. Natural mangrove nutrient enrichment processes, however, remain largely uninvestigated. Mobile consumers such as seabirds are important vectors of cross-ecosystem nutrient subsidies to islands but how they influence mangrove ecosystems is poorly known. We assessed the contribution, uptake, cycling, and transfer of nutrients from seabird colonies in remote mangrove systems free of human stressors. We found that nutrients from seabird guano enrich mangrove plants, reduce nutrient limitations, enhance mangrove invertebrate food webs, and are exported to nearby coastal habitats through tidal flow. We show that seabird nutrient subsidies in mangroves can be substantial, improving the nutrient status and health of mangroves and adjacent coastal habitats. Conserving mobile consumers, such as seabirds, is therefore vital to preserve and enhance their role in mangrove productivity, resilience, and provision of diverse functions and services.

A naturally occurring variant of SHLP2 is a protective factor in Parkinson's disease.

Mitochondrial DNA single nucleotide polymorphisms (mtSNPs) have been associated with a reduced risk of developing Parkinson's disease (PD), yet the underlying mechanisms remain elusive. In this study, we investigate the functional role of a PD-associated mtSNP that impacts the mitochondrial-derived peptide (MDP) Small Humanin-like Peptide 2 (SHLP2). We identify m.2158 T > C, a mtSNP associated with reduced PD risk, within the small open reading frame encoding SHLP2. This mtSNP results in an alternative form of SHLP2 (lysine 4 replaced with arginine; K4R). Using targeted mass spectrometry, we detect specific tryptic fragments of SHLP2 in neuronal cells and demonstrate its binding to mitochondrial complex 1. Notably, we observe that the K4R variant, associated with reduced PD risk, exhibits increased stability compared to WT SHLP2. Additionally, both WT and K4R SHLP2 show enhanced protection against mitochondrial dysfunction in in vitro experiments and confer protection against a PD-inducing toxin, a mitochondrial complex 1 inhibitor, in a mouse model. This study sheds light on the functional consequences of the m.2158 T > C mtSNP on SHLP2 and provides insights into the potential mechanisms by which this mtSNP may reduce the risk of PD.

Seabirds boost coral reef resilience.

Global climate change threatens tropical coral reefs, yet local management can influence resilience. While increasing anthropogenic nutrients reduce coral resistance and recovery, it is unknown how the loss, or restoration, of natural nutrient flows affects reef recovery. Here, we test how natural seabird-derived nutrient subsidies, which are threatened by invasive rats, influence the mechanisms and patterns of reef recovery following an extreme marine heatwave using multiyear field experiments, repeated surveys, and Bayesian modeling. Corals transplanted from rat to seabird islands quickly assimilated seabird-derived nutrients, fully acclimating to new nutrient conditions within 3 years. Increased seabird-derived nutrients, in turn, caused a doubling of coral growth rates both within individuals and across entire reefs. Seabirds were also associated with faster recovery time of Acropora coral cover (<4 years) and more dynamic recovery trajectories of entire benthic communities. We conclude that restoring seabird populations and associated nutrient pathways may foster greater coral reef resilience through enhanced growth and recovery rates of corals.

Climate change exacerbates nutrient disparities from seafood.

Seafood is an important source of bioavailable micronutrients supporting human health, yet it is unclear how micronutrient production has changed in the past or how climate change will influence its availability. Here combining reconstructed fisheries databases and predictive models, we assess nutrient availability from fisheries and mariculture in the past and project their futures under climate change. Since the 1990s, availabilities of iron, calcium and omega-3 from seafood for direct human consumption have increased but stagnated for protein. Under climate change, nutrient availability is projected to decrease disproportionately in tropical low-income countries that are already highly dependent on seafood-derived nutrients. At 4 oC of warming, nutrient availability is projected to decline by ~30% by 2100 in low income countries, while at 1.5-2.0 oC warming, decreases are projected to be ~10%. We demonstrate the importance of effective mitigation to support nutritional security of vulnerable nations and global health equity.

Trophic distribution of nutrient production in coral reef fisheries.

Coral reef fisheries supply nutritious catch to tropical coastal communities, where the quality of reef seafood is determined by both the rate of biomass production and nutritional value of reef fishes. Yet our understanding of reef fisheries typically uses targets of total reef fish biomass rather than individual growth (i.e. biomass production) and nutrient content (i.e. nutritional value of reef fish), limiting the ability of management to sustain the productivity of nutritious catches. Here, we use modelled growth coefficients and nutrient concentrations to develop a new metric of nutrient productivity of coral reef fishes. We then evaluate this metric with underwater visual surveys of reef fish assemblages from four tropical countries to examine nutrient productivity of reef fish food webs. Species' growth coefficients were associated with nutrients that vary with body size (calcium, iron, selenium and zinc), but not total nutrient density. When integrated with fish abundance data, we find that herbivorous species typically dominate standing biomass, biomass turnover and nutrient production on coral reefs. Such bottom-heavy trophic distributions of nutrients were consistent across gradients of fishing pressure and benthic composition. We conclude that management restrictions that promote sustainability of herbivores and other low trophic-level species can sustain biomass and nutrient production from reef fisheries that is critical to the food security of over 500 million people in the tropics.

Sustainable reference points for multispecies coral reef fisheries.

Sustainably managing fisheries requires regular and reliable evaluation of stock status. However, most multispecies reef fisheries around the globe tend to lack research and monitoring capacity, preventing the estimation of sustainable reference points against which stocks can be assessed. Here, combining fish biomass data for >2000 coral reefs, we estimate site-specific sustainable reference points for coral reef fisheries and use these and available catch estimates to assess the status of global coral reef fish stocks. We reveal that >50% of sites and jurisdictions with available information have stocks of conservation concern, having failed at least one fisheries sustainability benchmark. We quantify the trade-offs between biodiversity, fish length, and ecosystem functions relative to key benchmarks and highlight the ecological benefits of increasing sustainability. Our approach yields multispecies sustainable reference points for coral reef fisheries using environmental conditions, a promising means for enhancing the sustainability of the world's coral reef fisheries.

Hold big business to task on ecosystem restoration.

Corporate reporting must embrace holistic, scientific principles.

Reef-building corals farm and feed on their photosynthetic symbionts.

Coral reefs are highly diverse ecosystems that thrive in nutrient-poor waters, a phenomenon frequently referred to as the Darwin paradox1. The energy demand of coral animal hosts can often be fully met by the excess production of carbon-rich photosynthates by their algal symbionts2,3. However, the understanding of mechanisms that enable corals to acquire the vital nutrients nitrogen and phosphorus from their symbionts is incomplete4-9. Here we show, through a series of long-term experiments, that the uptake of dissolved inorganic nitrogen and phosphorus by the symbionts alone is sufficient to sustain rapid coral growth. Next, considering the nitrogen and phosphorus budgets of host and symbionts, we identify that these nutrients are gathered through symbiont 'farming' and are translocated to the host by digestion of excess symbiont cells. Finally, we use a large-scale natural experiment in which seabirds fertilize some reefs but not others, to show that the efficient utilization of dissolved inorganic nutrients by symbiotic corals established in our laboratory experiments has the potential to enhance coral growth in the wild at the ecosystem level. Feeding on symbionts enables coral animals to tap into an important nutrient pool and helps to explain the evolutionary and ecological success of symbiotic corals in nutrient-limited waters.

Drug mechanism enrichment analysis improves prioritization of therapeutics for repurposing.

BACKGROUND: There is a pressing need for improved methods to identify effective therapeutics for diseases. Many computational approaches have been developed to repurpose existing drugs to meet this need. However, these tools often output long lists of candidate drugs that are difficult to interpret, and individual drug candidates may suffer from unknown off-target effects. We reasoned that an approach which aggregates information from multiple drugs that share a common mechanism of action (MOA) would increase on-target signal compared to evaluating drugs on an individual basis. In this study, we present drug mechanism enrichment analysis (DMEA), an adaptation of gene set enrichment analysis (GSEA), which groups drugs with shared MOAs to improve the prioritization of drug repurposing candidates. RESULTS: First, we tested DMEA on simulated data and showed that it can sensitively and robustly identify an enriched drug MOA. Next, we used DMEA on three types of rank-ordered drug lists: (1) perturbagen signatures based on gene expression data, (2) drug sensitivity scores based on high-throughput cancer cell line screening, and (3) molecular classification scores of intrinsic and acquired drug resistance. In each case, DMEA detected the expected MOA as well as other relevant MOAs. Furthermore, the rankings of MOAs generated by DMEA were better than the original single-drug rankings in all tested data sets. Finally, in a drug discovery experiment, we identified potential senescence-inducing and senolytic drug MOAs for primary human mammary epithelial cells and then experimentally validated the senolytic effects of EGFR inhibitors. CONCLUSIONS: DMEA is a versatile bioinformatic tool that can improve the prioritization of candidates for drug repurposing. By grouping drugs with a shared MOA, DMEA increases on-target signal and reduces off-target effects compared to analysis of individual drugs. DMEA is publicly available as both a web application and an R package at https://belindabgarana.github.io/DMEA .

Functional and phosphoproteomic analysis of ß-adrenergic receptor signaling at excitatory synapses in the CA1 region of the ventral hippocampus.

Activation of ß-adrenergic receptors (ß-ARs) not only enhances learning and memory but also facilitates the induction of long-term potentiation (LTP), a form of synaptic plasticity involved in memory formation. To identify the mechanisms underlying ß-AR-dependent forms of LTP we examined the effects of the ß-AR agonist isoproterenol on LTP induction at excitatory synapses onto CA1 pyramidal cells in the ventral hippocampus. LTP induction at these synapses is inhibited by activation of SK-type K+ channels, suggesting that ß-AR activation might facilitate LTP induction by inhibiting SK channels. However, although the SK channel blocker apamin enhanced LTP induction, it did not fully mimic the effects of isoproterenol. We therefore searched for potential alternative mechanisms using liquid chromatography-tandem mass spectrometry to determine how ß-AR activation regulates phosphorylation of postsynaptic density (PSD) proteins. Strikingly, ß-AR activation regulated hundreds of phosphorylation sites in PSD proteins that have diverse roles in dendritic spine structure and function. Moreover, within the core scaffold machinery of the PSD, ß-AR activation increased phosphorylation at several sites previously shown to be phosphorylated after LTP induction. Together, our results suggest that ß-AR activation recruits a diverse set of signaling pathways that likely act in a concerted fashion to regulate LTP induction.

Macroalgae exhibit diverse responses to human disturbances on coral reefs.

Scientists and managers rely on indicator taxa such as coral and macroalgal cover to evaluate the effects of human disturbance on coral reefs, often assuming a universally positive relationship between local human disturbance and macroalgae. Despite evidence that macroalgae respond to local stressors in diverse ways, there have been few efforts to evaluate relationships between specific macroalgae taxa and local human-driven disturbance. Using genus-level monitoring data from 1205 sites in the Indian and Pacific Oceans, we assess whether macroalgae percent cover correlates with local human disturbance while accounting for factors that could obscure or confound relationships. Assessing macroalgae at genus level revealed that no genera were positively correlated with all human disturbance metrics. Instead, we found relationships between the division or genera of algae and specific human disturbances that were not detectable when pooling taxa into a single functional category, which is common to many analyses. The convention to use percent cover of macroalgae as an indication of local human disturbance therefore likely obscures signatures of local anthropogenic threats to reefs. Our limited understanding of relationships between human disturbance, macroalgae taxa, and their responses to human disturbances impedes the ability to diagnose and respond appropriately to these threats.

Terrestrial invasive species alter marine vertebrate behaviour.

Human-induced environmental changes, such as the introduction of invasive species, are driving declines in the movement of nutrients across ecosystems with negative consequences for ecosystem function. Declines in nutrient inputs could thus have knock-on effects at higher trophic levels and broader ecological scales, yet these interconnections remain relatively unknown. Here we show that a terrestrial invasive species (black rats, Rattus rattus) disrupts a nutrient pathway provided by seabirds, ultimately altering the territorial behaviour of coral reef fish. In a replicated ecosystem-scale natural experiment, we found that reef fish territories were larger and the time invested in aggression lower on reefs adjacent to rat-infested islands compared with rat-free islands. This response reflected changes in the economic defendability of lower-quality resources, with reef fish obtaining less nutritional gain per unit foraging effort adjacent to rat-infested islands with low seabird populations. These results provide a novel insight into how the disruption of nutrient flows by invasive species can affect variation in territorial behaviour. Rat eradication as a conservation strategy therefore has the potential to restore species interactions via territoriality, which can scale up to influence populations and communities at higher ecological levels.

Harnessing island-ocean connections to maximize marine benefits of island conservation.

Islands support unique plants, animals, and human societies found nowhere else on the Earth. Local and global stressors threaten the persistence of island ecosystems, with invasive species being among the most damaging, yet solvable, stressors. While the threat of invasive terrestrial mammals on island flora and fauna is well recognized, recent studies have begun to illustrate their extended and destructive impacts on adjacent marine environments. Eradication of invasive mammals and restoration of native biota are promising tools to address both island and ocean management goals. The magnitude of the marine benefits of island restoration, however, is unlikely to be consistent across the globe. We propose a list of six environmental characteristics most likely to affect the strength of land-sea linkages: precipitation, elevation, vegetation cover, soil hydrology, oceanographic productivity, and wave energy. Global databases allow for the calculation of comparable metrics describing each environmental character across islands. Such metrics can be used today to evaluate relative potential for coupled land-sea conservation efforts and, with sustained investment in monitoring on land and sea, can be used in the future to refine science-based planning tools for integrated land-sea management. As conservation practitioners work to address the effects of climate change, ocean stressors, and biodiversity crises, it is essential that we maximize returns from our management investments. Linking efforts on land, including eradication of island invasive mammals, with marine restoration and protection should offer multiplied benefits to achieve concurrent global conservation goals.

Kinetic and data-driven modeling of pancreatic ß-cell central carbon metabolism and insulin secretion.

Pancreatic ß-cells respond to increased extracellular glucose levels by initiating a metabolic shift. That change in metabolism is part of the process of glucose-stimulated insulin secretion and is of particular interest in the context of diabetes. However, we do not fully understand how the coordinated changes in metabolic pathways and metabolite products influence insulin secretion. In this work, we apply systems biology approaches to develop a detailed kinetic model of the intracellular central carbon metabolic pathways in pancreatic ß-cells upon stimulation with high levels of glucose. The model is calibrated to published metabolomics datasets for the INS1 823/13 cell line, accurately capturing the measured metabolite fold-changes. We first employed the calibrated mechanistic model to estimate the stimulated cell's fluxome. We then used the predicted network fluxes in a data-driven approach to build a partial least squares regression model. By developing the combined kinetic and data-driven modeling framework, we gain insights into the link between ß-cell metabolism and glucose-stimulated insulin secretion. The combined modeling framework was used to predict the effects of common anti-diabetic pharmacological interventions on metabolite levels, flux through the metabolic network, and insulin secretion. Our simulations reveal targets that can be modulated to enhance insulin secretion. The model is a promising tool to contextualize and extend the usefulness of metabolomics data and to predict dynamics and metabolite levels that are difficult to measure in vitro. In addition, the modeling framework can be applied to identify, explain, and assess novel and clinically-relevant interventions that may be particularly valuable in diabetes treatment.