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  1. Speed-dependent interlimb coordination allows animals to maintain stable locomotion under different circumstances. The V3 neurons are known to be involved in interlimb coordination. We previously modeled the locomotor spinal circuitry controlling interlimb coordination (Danner et al., 2017). This model included the local V3 neurons that mediate mutual excitation between left and right rhythm generators (RGs). Here, our focus was on V3 neurons involved in ascending long propriospinal interactions (aLPNs). Using retrograde tracing, we revealed a subpopulation of lumbar V3 aLPNs with contralateral cervical projections. V3 OFF mice, in which all V3 neurons were silenced, had a significantly reduced maximal locomotormore »speed, were unable to move using stable trot, gallop, or bound, and predominantly used a lateral-sequence walk. To reproduce this data and understand the functional roles of V3 aLPNs, we extended our previous model by incorporating diagonal V3 aLPNs mediating inputs from each lumbar RG to the contralateral cervical RG. The extended model reproduces our experimental results and suggests that locally projecting V3 neurons, mediating left–right interactions within lumbar and cervical cords, promote left–right synchronization necessary for gallop and bound, whereas the V3 aLPNs promote synchronization between diagonal fore and hind RGs necessary for trot. The model proposes the organization of spinal circuits available for future experimental testing.« less
    Free, publicly-accessible full text available April 27, 2023
  2. Mammalian locomotion is generated by central pattern generators (CPGs) in the spinal cord, which produce alternating flexor and extensor activities controlling the locomotor movements of each limb. Afferent feedback signals from the limbs are integrated by the CPGs to provide adaptive control of locomotion. Responses of CPG-generated neural activity to afferent feedback stimulation have been previously studied during fictive locomotion in immobilized cats. Yet, locomotion in awake, behaving animals involves dynamic interactions between central neuronal circuits, afferent feedback, musculoskeletal system, and environment. To study these complex interactions, we developed a model simulating interactions between a half-center CPG and the musculoskeletalmore »system of a cat hindlimb. Then, we analyzed the role of afferent feedback in the locomotor adaptation from a dynamic viewpoint using the methods of dynamical systems theory and nullcline analysis. Our model reproduced limb movements during regular cat walking as well as adaptive changes of these movements when the foot steps into a hole. The model generates important insights into the mechanism for adaptive locomotion resulting from dynamic interactions between the CPG-based neural circuits, the musculoskeletal system, and the environment.« less
    Free, publicly-accessible full text available April 8, 2023
  3. ABSTRACT The largest uncertainty on measurements of dark energy using type Ia supernovae (SNeIa) is presently due to systematics from photometry; specifically to the relative uncertainty on photometry as a function of wavelength in the optical spectrum. We show that a precise constraint on relative photometry between the visible and near-infrared can be achieved at upcoming survey telescopes, such as at the Vera C. Rubin Observatory, via a laser source tuned to the 342.78 nm vacuum excitation wavelength of neutral sodium atoms. Using a high-power laser, this excitation will produce an artificial star, which we term a ‘laser photometric ratio star’ (LPRS)more »of de-excitation light in the mesosphere at wavelengths in vacuum of 589.16, 589.76, 818.55, and 819.70 nm, with the sum of the numbers of 589.16 and 589.76 nm photons produced by this process equal to the sum of the numbers of 818.55 and 819.70 nm photons, establishing a precise calibration ratio between, for example, the r and $z$ filters of the LSST camera at the Rubin Observatory. This technique can thus provide a novel mechanism for establishing a spectrophotometric calibration ratio of unprecedented precision for upcoming telescopic observations across astronomy and atmospheric physics; thus greatly improving the performance of upcoming measurements of dark energy parameters using type SNeIa. The second paper of this pair describes an alternative technique to achieve a similar, but brighter, LPRS than the technique described in this paper, by using two lasers near resonances at 589.16 and 819.71 nm, rather than the single 342.78 nm on-resonance laser technique described in this paper.« less
    Free, publicly-accessible full text available October 22, 2022
  4. ABSTRACT This paper is the second in a pair of papers on the topic of the generation of a two-colour artificial star [which we term a laser photometric ratio star (LPRS)] of de-excitation light from neutral sodium atoms in the mesosphere, for use in precision telescopic measurements in astronomy and atmospheric physics, and more specifically for the calibration of measurements of dark energy using type Ia supernovae. The two techniques, respectively, described in both this and the previous paper would each generate an LPRS with a precisely 1:1 ratio of yellow (589/590 nm) photons to near-infrared (819/820 nm) photons produced in the mesosphere. Bothmore »techniques would provide novel mechanisms for establishing a spectrophotometric calibration ratio of unprecedented precision, from above most of Earth’s atmosphere, for upcoming telescopic observations across astronomy and atmospheric physics; thus greatly improving the performance of upcoming measurements of dark energy parameters using type Ia supernovae. The technique described in this paper has the advantage of producing a much brighter (specifically, brighter by approximately a factor of 103) LPRS, using lower power (≤30 W average power) lasers, than the technique using a single 500 W average power laser described in the first paper of this pair. However, the technique described here would require polarization filters to be installed into the telescope camera in order to sufficiently remove laser atmospheric Rayleigh backscatter from telescope images, whereas the technique described in the first paper would only require more typical wavelength filters in order to sufficiently remove laser Rayleigh backscatter.« less
    Free, publicly-accessible full text available October 22, 2022
  5. Neuronal circuits in the spinal cord are essential for the control of locomotion. They integrate supraspinal commands and afferent feedback signals to produce coordinated rhythmic muscle activations necessary for stable locomotion. For several decades, computational modeling has complemented experimental studies by providing a mechanistic rationale for experimental observations and by deriving experimentally testable predictions. This symbiotic relationship between experimental and computational approaches has resulted in numerous fundamental insights. With recent advances in molecular and genetic methods, it has become possible to manipulate specific constituent elements of the spinal circuitry and relate them to locomotor behavior. This has led to computationalmore »modeling studies investigating mechanisms at the level of genetically defined neuronal populations and their interactions. We review literature on the spinal locomotor circuitry from a computational perspective. By reviewing examples leading up to and in the age of molecular genetics, we demonstrate the importance of computational modeling and its interactions with experiments. Moving forward, neuromechanical models with neuronal circuitry modeled at the level of genetically defined neuronal populations will be required to further unravel the mechanisms by which neuronal interactions lead to locomotor behavior.« less
  6. Free, publicly-accessible full text available September 1, 2022
  7. Abstract High-risk neuroblastoma remains therapeutically challenging to treat, and the mechanisms promoting disease aggression are poorly understood. Here, we show that elevated expression of dihydrolipoamide S-succinyltransferase (DLST) predicts poor treatment outcome and aggressive disease in patients with neuroblastoma. DLST is an E2 component of the α-ketoglutarate (αKG) dehydrogenase complex, which governs the entry of glutamine into the tricarboxylic acid cycle (TCA) for oxidative decarboxylation. During this irreversible step, αKG is converted into succinyl-CoA, producing NADH for oxidative phosphorylation (OXPHOS). Utilizing a zebrafish model of MYCN-driven neuroblastoma, we demonstrate that even modest increases in DLST expression promote tumor aggression, while monoallelicmore »dlst loss impedes disease initiation and progression. DLST depletion in human MYCN-amplified neuroblastoma cells minimally affected glutamine anaplerosis and did not alter TCA cycle metabolites other than αKG. However, DLST loss significantly suppressed NADH production and impaired OXPHOS, leading to growth arrest and apoptosis of neuroblastoma cells. In addition, multiple inhibitors targeting the electron transport chain, including the potent IACS-010759 that is currently in clinical testing for other cancers, efficiently reduced neuroblastoma proliferation in vitro. IACS-010759 also suppressed tumor growth in zebrafish and mouse xenograft models of high-risk neuroblastoma. Together, these results demonstrate that DLST promotes neuroblastoma aggression and unveils OXPHOS as an essential contributor to high-risk neuroblastoma. Significance: These findings demonstrate a novel role for DLST in neuroblastoma aggression and identify the OXPHOS inhibitor IACS-010759 as a potential therapeutic strategy for this deadly disease.« less
  8. Over the past five decades, many studies have examined the Janzen-Connell hypothesis, which posits that host-specific natural enemies, such as insect herbivores and fungal pathogens, promote plant species coexistence by providing a recruitment advantage to rare plant species. Recently, researchers have been exploring new and exciting angles on plant-enemy interactions that have yielded novel insights into this long-standing hypothesis. Here, we highlight some empirical advances in our understanding of plant-enemy interactions in tropical forests, including improved understanding of variation in plant species’ susceptibility to enemy effects, as well as insect and pathogen host ranges. We then review recent advances inmore »related ecological theory. These theoretical studies have confirmed that specialist natural enemies can promote tree diversity. However, they have also shown that the impact of natural enemies may be weakened, or that natural enemies could even cause species exclusion, depending on enemy host range, the spatial extent of enemy effects, and variation among plant species in seed dispersal or enemy susceptibility. Finally, we end by discussing how human impacts on tropical forests, such as fragmentation, hunting, and climate change, may alter the plant-enemy interactions that contribute to tropical forest diversity.« less