Biology subjects

Strickland, J.

Publications and source records attributed to Strickland, J..

7 recordsLinked to original sources

bioRxiv2026

Metrics matter: Modelling plant-frugivore networks in a tropical dry forest ecosystem

Arboreal camera trapping is an emerging remote sensing tool for building plant-frugivore interaction networks with enormous potential to provide new insights into seed dispersal as an eco-evolutionary process. Interaction data derived from camera trap videos broadly falls into two categories: visitation, indicating the presence of an animal in a tree, and intake, indicating true fruit consumption. These linked approximations of seed dispersal may or may not provide distinct sets of information, shaping our understanding of network dynamics, yet the extent to which emergent network structure depends on variable choice is unknown. To address this gap, we deployed camera traps in the canopy of 21 plant species in the Costa Rican tropical dry forest, an endangered biome with sparse community-wide plant-frugivore interaction data. Our objectives were: 1) Quantify plant-frugivore network structure in the tropical dry forest via network, group, and species-level metrics; and 2) Compare metrics between visitation and intake networks. We find strong structural patterns of low connectance, low nestedness, high modularity, and low niche overlap that differ significantly from null expectations in the same direction in both networks. The visitation network exhibited significantly greater modularity & species degree than the intake network, while the intake network exhibited significantly greater plant niche overlap than the visitation network. These findings suggest that the likelihood of consuming fruit on camera differs across species, which may have downstream consequences on other emerging metric estimations. Researchers seeking to build quantitative plant-frugivore networks should therefore consider visitation and intake variables in concert when relying on camera trap data. This work provides foundational plant-frugivore interaction data for a critically endangered biome and enhances our understanding of camera trapping as a remote sensing tool in frugivory and seed dispersal research.

ecology↗

bioRxiv2025

The small molecule ML233 is a direct inhibitor of tyrosinase function

Melanogenesis is the biological process regulating the synthesis of melanin pigments in melanocytes. Defective melanogenesis is associated with numerous human skin diseases, including, but not limited to, albinism, vitiligo, melasma, and hypo- and hyperpigmentation disorders. Tyrosinase is the rate-limiting enzyme controlling melanogenesis, and hence tremendous efforts have been made to identify potent and safe inhibitors of tyrosinase function. However, despite decades of research, currently there is no effective treatment that inhibits melanogenesis or tyrosinase activity with no adverse side effects. In this study, we report characterization of the ML233 chemical as a potent inhibitor of tyrosinase activity in vivo and in vitro. We demonstrate that ML233 reduces melanin production in the zebrafish model with no observable significant toxic side effects, and in murine melanoma cells. We also predict that these effects are mediated through direct tyrosinase-ML233 interaction, i.e., binding of the ML233 molecule to the active site of the protein to inhibit its function. Together, our results reveal that ML233 plays roles in both healthy and pathological skin cells via inhibition of melanin production. ML233-mediated tyrosinase inhibition is a potentially safe and effective approach to alleviate the symptoms of melanocyte-associated diseases and thereby substantially improve human health.

pharmacology and toxicology↗

bioRxiv2023

Self-extinguishing relay waves enable homeostaticcontrol of human neutrophil swarming

Neutrophils exhibit self-amplified swarming to sites of injury and infection. How swarming is controlled to ensure the proper level of neutrophil recruitment is unknown. Using an ex vivo model of infection, we find that human neutrophils use active relay to generate multiple pulsatile waves of swarming signals. Unlike classic active relay systems such as action potentials, neutrophil swarming relay waves are self-extinguishing, limiting the spatial range of cell recruitment. We identify an NADPH-oxidase-based negative feedback loop that is needed for this self-extinguishing behavior. Through this circuit, neutrophils adjust the number and size of swarming waves for homeostatic levels of cell recruitment over a wide range of initial cell densities. We link a broken homeostat to neutrophil over-recruitment in the context of human chronic granulomatous disease.

cell biology↗

bioRxiv2022

The ATLAS™ screening assay reveals distinct CD4+ and CD8+ SARS-CoV-2 antigen response profiles which have implications to Omicron cellular immunity

The emergence of SARS-CoV-2 variants are a persistent threat to the efficacy of currently developed prophylactic vaccines and therapeutic antibodies. These variants accumulate mutations in the spike protein which encodes the epitopes necessary for neutralizing antibody binding. Moreover, emerging evidence suggest that robust antibody responses are insufficient to prevent severe disease and long-lasting viral immunity requires T cells. Thus, understanding how the T cell antigen landscape evolves in the context of these emerging variants remains crucial. T cells responses are durable and recognize a wider breadth of epitopes reducing the possibility of immune escape through mutation. Here, we deploy the ATLAS assay which identifies CD4+ and CD8+ T cell antigens by utilizing the endogenous HLA class-I and class-II peptide processing pathways. Profiling of T cells from exposed and unexposed donors revealed rich and complex patterns which highlighted the breadth of antigenic potential encoded in SARS-CoV-2. ATLAS revealed several common or frequent antigenic regions as well as an abundance of responses in the unexposed cohort potentially the result of pre-exposure to related coronaviruses. ORF10 was a common CD4+ response in the unexposed cohort while spike was identified as a common and frequent target in both cohorts. Moreover, the spike response profiles allowed us to accurately predict the impact of Omicron spike mutations. This analysis could thus be applied to study the impact of future emerging VOCs.

immunology↗

bioRxiv2021

Constructing threat probability, fear behaviour, and aversive prediction error in the brainstem.

When faced with potential threat we must estimate its probability, respond advantageously, and leverage experience to update future estimates. Threat estimates are the proposed domain of the forebrain, while behaviour is elicited by the brainstem. Yet, the brainstem is also a source of prediction error, a learning signal to acquire and update threat estimates. Neuropixels probes allowed us to record single-unit activity across a 21-region brainstem axis during probabilistic fear discrimination with foot shock outcome. Against a backdrop of diffuse behaviour signaling, a brainstem network with a dorsal hub signaled threat probability. Neuronal function remapping during the outcome period gave rise to brainstem networks signaling prediction error and shock on multiple timescales. The results reveal construction of threat probability, behaviour, and prediction error along a single brainstem axis. One-Sentence SummaryThe brainstem constructs threat probability, behaviour, and prediction error from neuronal building blocks.

neuroscience↗

bioRxiv2021

Interleukin-6 Drives Key Pathologic Outcomes in Experimental Acetaminophen-induced Liver Failure

Background and AimsIn severe cases of acetaminophen (APAP) overdose, acute liver injury rapidly progresses to acute liver failure (ALF), producing life-threatening complications including, hepatic encephalopathy (HE) and multi-organ failure (MOF). Systemic levels of interleukin-6 (IL-6) and IL-10 are highest in ALF patients with the most severe complications and the poorest prognosis. The mechanistic basis for dysregulation of these cytokines, and their association with outcome in ALF, remain poorly defined. MethodsTo investigate the impact of IL-6 and IL-10 in ALF, we used an experimental setting of failed liver repair after APAP overdose in which a high dose of APAP is administered (i.e., 500-600 mg/kg). Mice were treated with neutralizing antibodies to block IL-6 and IL-10. ResultsIn mice with APAP-induced ALF, high levels of IL-10 reduced monocyte recruitment and trafficking in the liver resulting in impaired clearance of dead cell debris. Kupffer cells in these mice, displayed features of myeloid-derived suppressor cells, including high level expression of IL-10 and PD-L1, which were increased in an IL-6-dependent manner. Similar to ALF patients with HE, cerebral blood flow was reduced in mice with APAP-induced ALF. Remarkably, although IL-6 is hepatoprotective in mice treated with low doses of APAP (i.e., 300 mg/kg), IL-6 neutralization in mice with APAP-induced ALF fully restored cerebral blood flow and reduced mortality. ConclusionCollectively, these studies demonstrate that exaggerated production of IL-6 in APAP-induced ALF triggers immune suppression (i.e., high levels of IL-10 and PD-L1), reduces cerebral blood flow (a feature of hepatic encephalopathy), disrupts liver repair (i.e., failed clearance of dead cells), and increases mortality.

pathology↗

bioRxiv2020

Robust Sequence Determinants of α-Synuclein Toxicity in Yeast Implicate Membrane Binding

Protein conformations are shaped by cellular environments, but how environmental changes alter the conformational landscapes of specific proteins in vivo remains largely uncharacterized, in part due to the challenge of probing protein structures in living cells. Here, we use deep mutational scanning to investigate how a toxic conformation of -synuclein, a dynamic protein linked to Parkinsons disease, responds to perturbations of cellular proteostasis. In the context of a course for graduate students in the UCSF Integrative Program in Quantitative Biology, we screened a comprehensive library of -synuclein missense mutants in yeast cells treated with a variety of small molecules that perturb cellular processes linked to -synuclein biology and pathobiology. We found that the conformation of -synuclein previously shown to drive yeast toxicity--an extended, membrane-bound helix--is largely unaffected by these chemical perturbations, underscoring the importance of this conformational state as a driver of cellular toxicity. On the other hand, the chemical perturbations have a significant effect on the ability of mutations to suppress -synuclein toxicity. Moreover, we find that sequence determinants of -synuclein toxicity are well described by a simple structural model of the membrane-bound helix. This model predicts that -synuclein penetrates the membrane to constant depth across its length but that membrane affinity decreases toward the C terminus, which is consistent with orthogonal biophysical measurements. Finally, we discuss how parallelized chemical genetics experiments can provide a robust framework for inquiry-based graduate coursework.

biochemistry↗