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Open Access Publications from the University of California

Scholarly Works (47 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2001)

    Cover page: Nucleus accumbens circuitry mediating analgesia in the normal and tolerant rat
    • Thesis
    • Peer Reviewed
    UC San Francisco Electronic Theses and Dissertations (2010)

    Rodent pain models play an important role in understanding the mechanisms of nociception and have accelerated the search for new treatment approaches for pain. Creating an objective metric for orofacial nociception in these models presents significant technical obstacles. No animal assay accurately measures pain-induced orofacial dysfunction that is directly comparable to human orofacial dysfunction. We developed and validated a high throughput, objective, operant, nociceptive animal assay, and an instrument to perform the assay termed the dolognawmeter, for evaluation of conditions known to elicit orofacial pain in humans. Using the device our assay quantifies gnawing function in the mouse. We quantified a behavioral index of nociception and demonstrated blockade of nociception in three models of orofacial pain: (1) TMJ inflammation, (2) masticatory myositis, and (3) head and neck cancer. This assay will be useful in the study of nociceptive mediators involved in the development and progression of orofacial pain conditions and it will also provide a unique tool for development and assessment of new therapeutic approaches.

      Cover page: The dolognawmeter: A novel instrument and assay to quantify nociception in rodent models of orofacial pain
      • Thesis
      • Peer Reviewed
      UC San Francisco Electronic Theses and Dissertations (2011)

      Cancer pain creates a poor quality of life for cancer patients. Chronic

      cancer pain is a major public health problem in which little progress has been made in treatment. In this dissertation we propose that pain is the result of imbalance between algesic and analgesic mediators within the cancer microenvironment. Furthermore, this imbalance arises from downregulation by hypermethylation of genes coding for analgesic mediators, and re-expression of these mediators by demethylating drugs produces analgesia. We determine whether EDNRB and OPRM1, genes of receptors mediating analgesia, are hypermethylated in the tumors of oral cancer patients, compared to normal and oral dysplasia controls. To determine whether the expression of these genes mediates analgesia, we create an orthotopic oral cancer mouse model, where we re-express the EDNRB or OPRM1 gene using adenoviruses. Re-expression of EDNRB results in mechanical analgesia, and re-expression of OPRM1 results in mechanical and thermal analgesia in the mouse cancer pain model. Finally, we determine the analgesic potential of demethylating drugs decitabine and zebularine in the mouse cancer model. We show that combination therapy with these two drugs results in an antiproliferative and analgesic effect in the mouse model.

        Cover page: Epigenetic Silencing is a Novel Mechanism Controlling Cancer-Induced Pain
        • Article
        • Peer Reviewed
        UC Berkeley Previously Published Works (2016)
        The retina is the most accessible element of the central nervous system for linking behavior to the activity of isolated neurons. We unraveled behavior at the elementary level of single input units-the visual sensation generated by stimulating individual long (L), middle (M), and short (S) wavelength-sensitive cones with light. Spectrally identified cones near the fovea of human observers were targeted with small spots of light, and the type, proportion, and repeatability of the elicited sensations were recorded. Two distinct populations of cones were observed: a smaller group predominantly associated with signaling chromatic sensations and a second, more numerous population linked to achromatic percepts. Red and green sensations were mainly driven by L- and M-cones, respectively, although both cone types elicited achromatic percepts. Sensations generated by cones were rarely stochastic; rather, they were consistent over many months and were dominated by one specific perceptual category. Cones lying in the midst of a pure spectrally opponent neighborhood, an arrangement purported to be most efficient in producing chromatic signals in downstream neurons, were no more likely to signal chromatic percepts. Overall, the results are consistent with the idea that the nervous system encodes high-resolution achromatic information and lower-resolution color signals in separate pathways that emerge as early as the first synapse. The lower proportion of cones eliciting color sensations may reflect a lack of evolutionary pressure for the chromatic system to be as fine-grained as the high-acuity achromatic system.
          Cover page: The elementary representation of spatial and color vision in the human retina
          • Article
          • Peer Reviewed
          Lawrence Berkeley National Laboratory (2005)

          To use type Ia supernovae as standard candles for cosmology we need accurate broadband magnitudes. In practice the observed magnitude may differ from the ideal magnitude-redshift relationship either through intrinsic inhomogeneities in the type Ia supernova population or through observational error. Here we investigate how we can choose filter bandpasses to reduce the error caused by both these effects. We find that bandpasses with large integral fluxes and sloping wings are best able to minimise several sources of observational error, and are also least sensitive to intrinsic differences in type Ia supernovae. The most important feature of a complete filter set for type Ia supernova cosmology is that each bandpass be a redshifted copy of the first. We design practical sets of redshifted bandpasses that are matched to typical high resistivity CCD and HgCdTe infra-red detector sensitivities. These are designed to minimise systematic error in well observed supernovae, final designs for specific missions should also consider signal-to-noise requirements and observing strategy. In addition we calculate how accurately filters need to be calibrated in order to achieve the required photometric accuracy of future supernova cosmology experiments such as the SuperNova-Acceleration-Probe (SNAP), which is one possible realisation of the Joint Dark-Energy mission (JDEM). We consider the effect of possible periodic miscalibrations that may arise from the construction of an interference filter.

            Cover page: Ideal bandpasses for type Ia supernova cosmology
            • Thesis
            • Peer Reviewed
            UC San Francisco Electronic Theses and Dissertations (2010)

            Cancer pain is a frequent and disabling consequence for many patients yet the mechanism of cancer pain remains unknown largely due to its complex etiology. The objective of this thesis work was to investigate the potential of a peptide produced by carcinoma cells, endothelin, as a novel target for cancer pain management. This study provided evidence in support of Hypothesis 1: Oral squamous carcinoma cells produce endogenous opioids in response to changes in endothelin-1 signaling. Effects of endothelin-1 (ET-1) signaling on secretion of opioids by oral squamous cell carcinoma (SCC) were studied in vitro. Oral SCC cell line HSC-3 produces abundant ET-1 that can act in both an autocrine or paracrine manner. In the untreated oral SCC cells, endogenous opioids were detected in both cultured media and cell lysates. When treated with Endothelin-A receptor antagonist, secreted levels of &beta-endorphin and leu-enkephalin were increased; whereas treatment with Endothelin-B receptor agonist increased production of only &beta-endorphin. This apparent regulation of endogenous opioid levels by endothelin receptor drugs in vitro procured evidence suggesting that Hypothesis 2: Endothelin-A receptor antagonist and Endothelin-B receptor agonist attenuate carcinoma-induced nociception in cancer animals through regulation of endogenous opioids. Endothelin-A (ET-AR) antagonism has been demonstrated previously to attenuate carcinoma-mediated hyperalgesia in an orthotopic cancer pain mouse model. In this study, effects of ET-BR agonist in vivo were evaluated and determined to also result in significant increase in paw withdrawal thresholds, indicating attenuation of cancer-induced nociception. When peripheral &mu- or &delta-opioid receptor antagonists were administered following ET-AR antagonism, nociceptive attenuation was completely reversed. Attenuation from ET-BR agonism was likewise reversed upon administration of &mu-opioid receptor antagonist. Combined results demonstrate that endogenous opioids are the likely mediators responsible for attenuation of carcinoma-induced nociception with either ET-AR antagonist or ET-BR agonist.

            These novel findings suggest that there exist innate modulation of pain by SCCs involving endogenous opioids that can be exploited through manipulation of endothelin activity in the cancer micro-environment. Regulation of ET-AR or ET-BR signaling may be targets for future innovations for cancer pain management.

              Cover page: Endothelin Receptor-mediated Attenuation of Carcinoma-induced Nociception is Opioid-dependent in Mice
              • Article
              • Peer Reviewed
              UC Berkeley Previously Published Works (2019)
              The human retina contains three classes of cone photoreceptors each sensitive to different portions of the visual spectrum: long (L), medium (M) and short (S) wavelengths. Color information is computed by downstream neurons that compare relative activity across the three cone types. How cone signals are combined at a cellular scale has been more difficult to resolve. This is especially true near the fovea, where spectrally-opponent neurons in the parvocellular pathway draw excitatory input from a single cone and thus even the smallest stimulus projected through natural optics will engage multiple color-signaling neurons. We used an adaptive optics microstimulator to target individual and pairs of cones with light. Consistent with prior work, we found that color percepts elicited from individual cones were predicted by their spectral sensitivity, although there was considerable variability even between cones within the same spectral class. The appearance of spots targeted at two cones were predicted by an average of their individual activations. However, two cones of the same subclass elicited percepts that were systematically more saturated than predicted by an average. Together, these observations suggest both spectral opponency and prior experience influence the appearance of small spots.
                Cover page: Spatial summation of individual cones in human color vision
                • Article
                • Peer Reviewed
                UC Berkeley Previously Published Works (2018)
                Color vision requires the activity of cone photoreceptors to be compared in post-receptoral circuitry. Decades of psychophysical measurements have quantified the nature of these comparative interactions on a coarse scale. How such findings generalize to a cellular scale remains unclear. To answer that question, we quantified the influence of surrounding light on the appearance of spots targeted to individual cones. The eye's aberrations were corrected with adaptive optics and retinal position was precisely tracked in real-time to compensate for natural movement. Subjects reported the color appearance of each spot. A majority of L-and M-cones consistently gave rise to the sensation of white, while a smaller group repeatedly elicited hue sensations. When blue sensations were reported they were more likely mediated by M- than L-cones. Blue sensations were elicited from M-cones against a short-wavelength light that preferentially elevated the quantal catch in surrounding S-cones, while stimulation of the same cones against a white background elicited green sensations. In one of two subjects, proximity to S-cones increased the probability of blue reports when M-cones were probed. We propose that M-cone increments excited both green and blue opponent pathways, but the relative activity of neighboring cones favored one pathway over the other.
                  Cover page: Sensations from a single M-cone depend on the activity of surrounding S-cones
                  • Article
                  • Peer Reviewed
                  Abstract Background Mechanistic biosimulation can be used in drug development to form testable hypotheses, develop predictions of efficacy before clinical trial results are available, and elucidate clinical response to therapy. However, there is a lack of tools to simultaneously (1) calibrate the prevalence of mechanistically distinct, large sets of virtual patients so their simulated responses statistically match phenotypic variability reported in published clinical trial outcomes, and (2) explore alternate hypotheses of those prevalence weightings to reflect underlying uncertainty in population biology. Here, we report the development of an algorithm, MAPEL (Mechanistic Axes Population Ensemble Linkage), which utilizes a mechanistically-based weighting method to match clinical trial statistics. MAPEL is the first algorithm for developing weighted virtual populations based on biosimulation results that enables the rapid development of an ensemble of alternate virtual population hypotheses, each validated by a composite goodness-of-fit criterion. Results Virtual patient cohort mechanistic biosimulation results were successfully calibrated with an acceptable composite goodness-of-fit to clinical populations across multiple therapeutic interventions. The resulting virtual populations were employed to investigate the mechanistic underpinnings of variations in the response to rituximab. A comparison between virtual populations with a strong or weak American College of Rheumatology (ACR) score in response to rituximab suggested that interferon β (IFNβ) was an important mechanistic contributor to the disease state, a signature that has previously been identified though the underlying mechanisms remain unclear. Sensitivity analysis elucidated key anti-inflammatory properties of IFNβ that modulated the pathophysiologic state, consistent with the observed prognostic correlation of baseline type I interferon measurements with clinical response. Specifically, the effects of IFNβ on proliferation of fibroblast-like synoviocytes and interleukin-10 synthesis in macrophages each partially counteract reductions in synovial inflammation imparted by rituximab. A multianalyte biomarker panel predictive for virtual population therapeutic responses suggested population dependencies on B cell-dependent mediators as well as additional markers implicating fibroblast-like synoviocytes. Conclusions The results illustrate how the MAPEL algorithm can leverage knowledge of cellular and molecular function through biosimulation to propose clear mechanistic hypotheses for differences in clinical populations. Furthermore, MAPEL facilitates the development of multianalyte biomarkers prognostic of patient responses in silico.
                    Cover page: Alternate virtual populations elucidate the type I interferon signature predictive of the response to rituximab in rheumatoid arthritis
                    • Article
                    • Peer Reviewed
                    UC Davis Previously Published Works (2019)
                    Cervicovaginal bacteria cause inflammation which in turn increases HIV risk. Profiling the cervicovaginal microbiome, therefore, is instrumental for vaccine development. We show that the microbiome profile captured by cervicovaginal lavage is comparable to samples obtained by vaginal swabs. Thus, lavage may serve as a sampling strategy in NHP vaccine studies.
                      Cover page: Comparison of sampling methods for profiling cervicovaginal microbiome in rhesus macaques
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