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Open Access Publications from the University of California

Scholarly Works (26 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2015)

Purpose: This study aims to investigate metabolic patterns in the brain during early

neurodevelopment.

Methods: Spectroscopic data from 35 high-quality single-voxel spectroscopy scans

performed on a total of 27 participants was processed and analyzed. These scans were

performed as part of a study to investigate eects of preterm birth on neurodevelopment

at UCSF.

Results: An increase in the N-Acetyl Aspartate/Creatine ratio and a decrease in

both Choline/Creatine and myo-Inositol/Creatine with increasing age were found to

be statistically signicant.

Conclusions: The decrease in myo-Inositol was consistent with previous ndings of a

decrease in myo-Inositol concentration from birth to 5 years of age. This decrease may

be due to myelin maturation and a reduction in cell turnover, but further investigation

is needed to evaluate this hypothesis.

    Cover page: Longitudinal Metabolic Changes in Premature Newborns
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2017)
    Both behavioral and neural responses to sounds are generally modified by the acoustic context in which they are encountered. As an example, in the auditory cortex, preceding sounds can powerfully suppress responses to later, spectrally similar sounds-a phenomenon called forward suppression (FWS). Whether cortical inhibitory networks shape such suppression or whether it is wholly regulated by common mechanisms such as synaptic depression or spike frequency adaptation is controversial. Here, we show that optogenetically suppressing somatostatin-positive (Sst+) interneurons weakens forward suppression, often revealing facilitation in neurons that are normally forward-suppressed. In contrast, inactivating parvalbumin-positive (Pvalb+) interneurons strengthens forward suppression and alters its frequency dependence. In a simple network model, we show that these effects can be accounted for by differences in short-term synaptic dynamics of inputs onto Pvalb+ and Sst+ interneurons. These results demonstrate separate roles for somatostatin and parvalbumin interneurons in regulating the context dependence of auditory processing.
      Cover page: Cortical Interneurons Differentially Regulate the Effects of Acoustic Context.
      • Thesis
      • Peer Reviewed
      UC San Francisco Electronic Theses and Dissertations (2017)

      The precise pattern of neural activity in the auditory cortex, which governs our perception of sound, is continuously shaped by synaptic inhibition. Cortical inhibition is generated by local GABAergic interneurons, which fall into several subtypes on the basis of their morphology, gene expression, biophysical properties, and innervation patterns. Each subtype is hypothesized to modulate auditory processing in intricate and distinctive ways, yet the links between each subtype and the computations they support have not been definitively made. Using a combination of in vivo extracellular recordings in the primary auditory cortex, optogenetic perturbations, and computational modeling, this thesis explores in what ways, and under what conditions, these inhibitory microcircuits might support different aspects of auditory processing. Firstly, we demonstrate that the two most common types of cortical interneuron – somatostatin-positive (Sst+) and parvalbumin-positive (Pvalb+) interneurons – can differentially alter the gain and tuning of spectral receptive fields, but that observing these differences critically depends on whether one increases or decreases their activity to read out their functions, as well as on the activity state of the network in which they are embedded. Secondly, we show that the ways in which cells process temporal aspects of sound (specifically, stimulus history) are quite diverse, and that this diversity can be explained, in part, by cell-to-cell variability in the overall strength of synaptic inhibition. Finally, we find that inhibition from Sst+ and Pvalb+ interneurons contributes to such temporal processing in distinct ways, potentially stemming from differences in how they are activated by their afferents over time. This thesis demonstrates that cortical circuits can recruit distinct inhibitory microcircuits to differentially fine-tune the spectro-temporal representations of sound, in ways that depend on sensory context and the state of the cortical network.

        Cover page: Inhibitory microcircuits differentially fine-tune the spectro-temporal representations of sound in auditory cortex
        • Article
        • Peer Reviewed
        UCSF Open Access Publishing Fund (2017)
          • Article
          • Peer Reviewed
          UC San Diego Previously Published Works (2023)
            Creative Commons 'BY' version 4.0 license
            • Article
            • Peer Reviewed
            UC San Diego Previously Published Works (2017)

            Background

            Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare, severe adverse event during treatment with raltegravir. The occurrence of DRESS syndrome during treatment with other drugs is strongly associated with particular HLA alleles.

            Methods

            We performed HLA testing in 3 of the 5 patients previously reported to have developed raltegravir-induced DRESS syndrome and in 1 previously unreported patient. We then used virtual modeling to visualize interactions between raltegravir and the imputed HLA molecule.

            Results

            Five of the 6 patients who developed raltegravir-induced DRESS syndrome were African, and 1 was Hispanic. HLA typing was performed in 4 patients, all of whom carried both the HLA-B*53 allele and the HLA-C*04 allele to which it is commonly haplotypic. No other HLA alleles were shared by all of the tested patients. Given the approximate prevalence of HLA-B*53 carriage in African (20%) and Hispanic (6%) populations, the probability of all 4 patients being HLA-B*53 carriers, and 2 of 3 African patients being homozygous for HLA-B*53:01, is approximately 0.00002.

            Conclusions

            These data implicate the prevalent African allele HLA-B*53:01 in the immunopathogenesis of raltegravir-induced DRESS syndrome. Although the immunopathogenic mechanisms are currently unknown, virtual modeling suggests that raltegravir may bind within the antigen binding cleft of the HLA-B*53:01 molecule, but not within the closely related HLA-B*35:01 molecule. Further studies are necessary to confirm the strength of the association between carriage of the HLA-B*53:01 allele and raltegravir-induced DRESS syndrome, and the potential utility of HLA screening before raltegravir treatment.
              Cover page: Association of the HLA-B*53:01 Allele With Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS) Syndrome During Treatment of HIV Infection With Raltegravir.Creative Commons 'BY' version 4.0 license
              • Article
              • Peer Reviewed
              UC San Francisco Previously Published Works (2015)
              Cortical function is regulated by a strikingly diverse array of local-circuit inhibitory neurons. We evaluated how optogenetically activating somatostatin- and parvalbumin-positive interneurons subtractively or divisively suppressed auditory cortical cells' responses to tones. In both awake and anesthetized animals, we found that activating either family of interneurons produced mixtures of divisive and subtractive effects and that simultaneously recorded neurons were often suppressed in qualitatively different ways. A simple network model shows that threshold nonlinearities can interact with network activity to transform subtractive inhibition of neurons into divisive inhibition of networks, or vice versa. Varying threshold and the strength of suppression of a model neuron could determine whether the effect of inhibition appeared divisive, subtractive, or both. We conclude that the characteristics of response inhibition specific to a single interneuron type can be "masked" by the network configuration and cellular properties of the network in which they are embedded.
                Cover page: Inhibitory Actions Unified by Network Integration
                • Article
                • Peer Reviewed
                UC San Diego Previously Published Works (2017)
                BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare, severe adverse event during treatment with raltegravir. The occurrence of DRESS syndrome during treatment with other drugs is strongly associated with particular HLA alleles. METHODS: We performed HLA testing in 3 of the 5 patients previously reported to have developed raltegravir-induced DRESS syndrome and in 1 previously unreported patient. We then used virtual modeling to visualize interactions between raltegravir and the imputed HLA molecule. RESULTS: Five of the 6 patients who developed raltegravir-induced DRESS syndrome were African, and 1 was Hispanic. HLA typing was performed in 4 patients, all of whom carried both the HLA-B*53 allele and the HLA-C*04 allele to which it is commonly haplotypic. No other HLA alleles were shared by all of the tested patients. Given the approximate prevalence of HLA-B*53 carriage in African (20%) and Hispanic (6%) populations, the probability of all 4 patients being HLA-B*53 carriers, and 2 of 3 African patients being homozygous for HLA-B*53:01, is approximately 0.00002. CONCLUSIONS: These data implicate the prevalent African allele HLA-B*53:01 in the immunopathogenesis of raltegravir-induced DRESS syndrome. Although the immunopathogenic mechanisms are currently unknown, virtual modeling suggests that raltegravir may bind within the antigen binding cleft of the HLA-B*53:01 molecule, but not within the closely related HLA-B*35:01 molecule. Further studies are necessary to confirm the strength of the association between carriage of the HLA-B*53:01 allele and raltegravir-induced DRESS syndrome, and the potential utility of HLA screening before raltegravir treatment.
                  Cover page: Association of the HLA-B*53:01 Allele With Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS) Syndrome During Treatment of HIV Infection With Raltegravir.
                  • Article
                  • Peer Reviewed
                  UC San Francisco Previously Published Works (2020)
                  Immune checkpoint inhibitors have emerged as a revolutionary treatment option for patients with various types of malignancy. Although these agents afford a significant improvement in outcomes for melanoma and other previously untreatable malignancies, their novel mechanism of action may predispose patients to immune-related adverse effects (irAEs). In the tumour neoantigen environment, these irAEs are due to the activation of the immune system by the blockade of suppressive checkpoints, leading to increases in T-cell activation and proliferation. IrAEs have been reported in almost any organ and at any point in time, even months to years after discontinuation of therapy. Certain populations with distinct physiological changes, genetic risk factors, and specific antigen exposures may be more highly predisposed to develop irAEs. This review discusses the incidence and mechanisms of irAEs and the relationship between host factors and irAE occurrence.
                    Cover page: Evolving insights into the mechanisms of toxicity associated with immune checkpoint inhibitor therapy.
                    • Article
                    • Peer Reviewed
                    UC Santa Cruz Previously Published Works (2024)
                    The Northern California Current is a highly productive marine upwelling ecosystem that is economically and ecologically important. It is home to both commercially harvested species and those that are federally listed under the U.S. Endangered Species Act. Recently, there has been a global shift from single-species fisheries management to ecosystem-based fisheries management, which acknowledges that more complex dynamics can reverberate through a food web. Here, we have integrated new research into an end-to-end ecosystem model (i.e., physics to fisheries) using data from long-term ocean surveys, phytoplankton satellite imagery paired with a vertically generalized production model, a recently assembled diet database, fishery catch information, species distribution models, and existing literature. This spatially-explicit model includes 90 living and detrital functional groups ranging from phytoplankton, krill, and forage fish to salmon, seabirds, and marine mammals, and nine fisheries that occur off the coast of Washington, Oregon, and Northern California. This model was updated from previous regional models to account for more recent changes in the Northern California Current (e.g., increases in market squid and some gelatinous zooplankton such as pyrosomes and salps), to expand the previous domain to increase the spatial resolution, to include data from previously unincorporated surveys, and to add improved characterization of endangered species, such as Chinook salmon (Oncorhynchus tshawytscha) and southern resident killer whales (Orcinus orca). Our model is mass-balanced, ecologically plausible, without extinctions, and stable over 150-year simulations. Ammonium and nitrate availability, total primary production rates, and model-derived phytoplankton time series are within realistic ranges. As we move towards holistic ecosystem-based fisheries management, we must continue to openly and collaboratively integrate our disparate datasets and collective knowledge to solve the intricate problems we face. As a tool for future research, we provide the data and code to use our ecosystem model.
                      Cover page: An updated end-to-end ecosystem model of the Northern California Current reflecting ecosystem changes due to recent marine heatwaves.
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