Biology subjects

Kimball, K.

Publications and source records attributed to Kimball, K..

5 recordsLinked to original sources

bioRxiv2025

Investigation of Powassan virus lineage II pathogenesis and neurotropism in mice

Powassan virus (POWV) is an emerging tick-borne flavivirus that causes disease in humans. POWV has considerable genetic and phenotypic diversity, including highly variable replication in vitro and pathogenesis in mice. This study sought to define the extent of variability in pathogenesis within POWV lineage II in mice and investigate possible viral determinants. Relative to other strains, two New York-derived isolates, NY.19.12 and NY.19.32, caused earlier clinical signs and earlier detection of viral RNA (vRNA) in the spleen and brain compared to mice infected with virus derived from a lineage II infectious clone (WI.97.ic). Sequencing revealed these strains share three amino acid substitutions in envelope, NS1, and NS5 compared to other lineage II strains, which were engineered into a mutant infectious clone. At early time points post-infection, clinical signs, vRNA detection in the cerebellum, and viral distribution in the brain were similar between NY.19.12 and the mutant clone, suggesting these mutations may play a role in disease progression and early neuroinvasion. However, NY.19.12 vRNA was detected in the spleen at significantly higher rates compared to both WI.97.ic and the mutant clone, indicating factors other than these mutations are responsible for increased spleen infection. Importantly, this study highlights the complexity of POWV pathogenesis and suggests that POWV lineage II strains have varying disease phenotypes likely driven by multiple genetic differences. ImportanceTick-borne flaviviruses exhibit considerable genetic and phenotypic diversity in nature, influencing their transmission and pathogenesis. Defining the mechanisms of pathogenesis requires understanding how inter-strain variation translates to phenotypic differences in viral dissemination and neuroinvasion. This study demonstrates that even closely related Powassan virus (POWV) lineage II strains display distinct disease phenotypes that are only partially attributable to nonsynonymous consensus mutations within the viral coding sequence. By highlighting the complexity of POWV infection dynamics in mice, these findings provide valuable insights into how POWV lineage II diversity may shape disease progression and severity in humans.

microbiology↗

bioRxiv2024

G protein Inactivation as a Mechanism for Addiction Treatment

The endogenous dynorphin/kappa opioid receptor (KOR) system in the brain mediates the dysphoric effects of stress, and KOR antagonists may have therapeutic potential for the treatment of drug addiction, depression, and psychosis. One class of KOR antagonists, the long-acting norBNI-like antagonists, have been suggested to act by causing KOR inactivation through a cJun-kinase mechanism rather than by competitive inhibition. In this study, we screened for other opioid ligands that might produce norBNI-like KOR inactivation and found that nalfurafine (a G-biased KOR agonist) and nalmefene (a KOR partial agonist) also produce long-lasting KOR inactivation. Neither nalfurafine nor nalmefene are completely selective KOR ligands, but KOR inactivation was observed at doses 10-100 fold lower than necessary for mu opioid receptor actions. Daily microdosing with nalfurafine or nalmefene blocked KORs responsible for antinociceptive effects, blocked KORs mediating stress-induced aversion, and mitigated the aversion during acute and protracted withdrawal in fentanyl-dependent mice. Both nalfurafine and nalmefene have long histories of safety and use in humans and could potentially be repurposed for the treatment of dynorphin-mediated stress disorders.

neuroscience↗

bioRxiv2024

Structure-guided engineering of a fast genetically encoded sensor for real-time H2O2 monitoring.

Hydrogen Peroxide (H2O2) is a central oxidant in redox biology due to its pleiotropic role in physiology and pathology. However, real-time monitoring of H2O2 in living cells and tissues remains a challenge. We address this gap with the development of an optogenetic hydRogen perOxide Sensor (oROS), leveraging the bacterial peroxide binding domain OxyR. Previously engineered OxyR-based fluorescent peroxide sensors lack the necessary sensitivity or response speed for effective real-time monitoring. By structurally redesigning the fusion of Escherichia coli (E. coli) ecOxyR with a circularly permutated green fluorescent protein (cpGFP), we created a novel, green-fluorescent peroxide sensor oROS-G. oROS-G exhibits high sensitivity and fast on-and-off kinetics, ideal for monitoring intracellular H2O2 dynamics. We successfully tracked real-time transient and steady-state H2O2 levels in diverse biological systems, including human stem cell-derived neurons and cardiomyocytes, primary neurons and astrocytes, and mouse neurons and astrocytes in ex vivo brain slices. These applications demonstrate oROSs capabilities to monitor H2O2 as a secondary response to pharmacologically induced oxidative stress, G-protein coupled receptor (GPCR)-induced cell signaling, and when adapting to varying metabolic stress. We showcased the increased oxidative stress in astrocytes via A{beta}-putriscine-MAOB axis, highlighting the sensors relevance in validating neurodegenerative disease models. oROS is a versatile tool, offering a window into the dynamic landscape of H2O2 signaling. This advancement paves the way for a deeper understanding of redox physiology, with significant implications for diseases associated with oxidative stress, such as cancer, neurodegenerative disorders, and cardiovascular diseases.

bioengineering↗

bioRxiv2021

Adaptive shifts underlie the divergence in wing morphology in bombycoid moths

The evolution of flapping flight is linked to the prolific success of insects. Across Insecta, wing morphology diversified, strongly impacting aerodynamic performance. In the presence of ecological opportunity, discrete adaptive shifts and early bursts are two processes hypothesized to give rise to exceptional morphological diversification. Here, we use the sister-families Sphingidae and Saturniidae to answer how the evolution of aerodynamically important traits is linked to clade divergence and through what process(es) these traits evolve. Many agile Sphingidae evolved hover-feeding behaviors, while adult Saturniidae lack functional mouth parts and rely on a fixed energy budget as adults. We find that Sphingidae underwent an adaptive shift in wing morphology coincident with life history and behavior divergence, evolving small high aspect-ratio wings advantageous for power reduction that can be moved at high frequencies, beneficial for flight control. In contrast, Saturniidae, which do not feed as adults, evolved large wings and morphology which surprisingly does not reduce aerodynamic power, but could contribute to their erratic flight behavior, aiding in predator avoidance. We suggest that after the evolution of flapping flight, diversification of wing morphology can be potentiated by adaptative shifts, shaping the diversity of wing morphology across insects.

evolutionary biology↗

bioRxiv2020

Wing shape evolution in bombycoid moths reveals two distinct strategies for maneuverable flight

Across insects, wing shape and size have undergone dramatic divergence even in closely related sister groups, but we do not yet know morphology changes in tandem with kinematics to support body weight within available aerodynamic power and how the specific force production patterns are linked to changes in behavior. Hawkmoths and wild silkmoths are two such diverse sister families with divergent wing morphology. Using 3d kinematics and quasi-steady aerodynamic modeling, we compare the aerodynamics and the contributions of wing shape, size, and kinematics in 10 moth species. We find that wing movement also diverges between the clades and underlies two distinct strategies for flight. Hawkmoths use wing kinematics, especially high frequencies, to enhance force, but wing morphologies that reduces power. Silkmoths use wing morphology to enhance force, and high amplitude wingstrokes to reduce power. Both strategies converge on similar aerodynamic power and can support similar body mass ranges, but their within-wingstroke force profiles are quite different and linked to the hovering flight of hawkmoths and the bobbing flight of silkmoths. These two groups of moths each fly more like other, distantly related insects than they do each other, demonstrating the convergence and diversity of flapping flight evolution.

physiology↗