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Open Access Publications from the University of California

Scholarly Works (50 results)

  • Article
  • Peer Reviewed
UC San Diego Previously Published Works (2020)
Clonal hematopoiesis is a common premalignant condition defined by the abnormal expansion of clonally derived hematopoietic stem cells carrying somatic mutations in leukemia-associated genes. Apart from increasing age, this phenomenon occurs with higher frequency in individuals with lymphoid or solid tumors and is associated with exposures to genotoxic stress. Clonal hematopoiesis in this context confers a greater risk for developing therapy-related myeloid neoplasms and appears to contribute to adverse cancer-related survival through a variety of potential mechanisms. These include alterations of the bone marrow microenvironment, inflammatory changes in clonal effector cells and modulation of immune responses. Understanding how clonal hematopoiesis drives therapy-related myeloid neoplasm initiation and interactions with non-myeloid malignancies will inform screening and surveillance approaches and suggest targeted therapies in this vulnerable population. Here, we examine the clinical implications of clonal hematopoiesis in the cancer setting and discuss potential strategies to mitigate the adverse consequences of clonal expansion.
    Cover page: Clonal hematopoiesis in cancer.
    • Article
    • Peer Reviewed
    UC Irvine Previously Published Works (2024)
    Chronic stress is well known to erode cognitive functions. Yet, our understanding of how repeated stress exposure impacts one of the fundamental bases of cognition: sensory processing, remains limited. The posterior parietal cortex (PPC) is a high order visual region, known for its role in visually guided decision making, multimodal integration, attention, and working memory. Here, we used functional measures to determine how repeated exposure to multiple concurrent stressors (RMS) affects sensory processing in the PPC in adult male mice. A longitudinal experimental design, repeatedly surveying the same population of neurons using in vivo two-photon imaging, revealed that RMS disrupts the balanced turnover of visually responsive cells in layer 2/3 of the PPC. Across the population, RMS-induced changes in visual responsiveness followed a bimodal distribution suggesting idiosyncratic stress effects. In cells that maintained their responsiveness across recording sessions, we found that stress reduced visual response magnitudes and feature selectivity. While we did not observe stress-induced elimination of excitatory synapses, noise correlation statistics indicated that RMS altered visual input to the neuronal population. The impact of RMS was restricted to visually evoked responses and was not evident in neuronal activity associated with locomotion onset. Together, our results indicate that despite no apparent synaptic reorganization, stress exposure in adulthood can disrupt sensory processing in the PPC, with the effects showing remarkable individual variation.
      Cover page: Repeated exposure to multiple concurrent stressors alters visual processing in the adult posterior parietal cortex
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2023)
      Circulating tumor DNA (ctDNA) is a subset of circulating cell-free DNA released by lysed tumor cells that can be characterized by its shorter strand length and tumor genome-specific information. The relatively short half-life of ctDNA allows it to provide a real-time measure of tumor burden which has potential prognostic and surveillance value as a tumor biomarker. Merkel cell carcinoma (MCC) is a rare neuroendocrine skin cancer that requires close monitoring due to the high risk of relapse. There are currently no good tumor biomarkers for MCC patients, especially those who are negative for Merkel cell polyomavirus. ctDNA shows promise for improving the prognoses of MCC patients by monitoring tumor burden, identifying minimal residual disease (MRD), and stratifying patients by their likelihood of response to immune checkpoint inhibition or risk of relapse. In particular, bespoke ultra-sequencing platforms allow for the creation of patient-specific mutation panels that improve ctDNA detection, especially for patients with rare or uncharacteristic mutations. Leveraging bespoke ctDNA assays may improve physicians' ability to alter treatment plans for non-responsive or high-risk patients. In addition, ctDNA MRD monitoring may allow physicians to treat relapses early before clinically evident disease is present.
        Cover page: Evolving Applications of Circulating Tumor DNA in Merkel Cell Carcinoma
        • Thesis
        • Peer Reviewed
        UCLA Electronic Theses and Dissertations (2019)

        An individual's voice can vary dramatically depending on word choice, affect, and other factors. Such intrinsic within-talker variability causes considerable difficulties when distinguishing talkers by their voices, both for humans and machines. For machines, phonetic content variability substantially degrades performance when utterances are short (e.g., < 10 sec). Humans, on the contrary, are less influenced by content variability, and they perform better than machines in such conditions. Hence, understanding which and how acoustic features are related to human responses might provide insights to improve machine performance. Yet, little is known about human and machine voice discrimination ability under various kinds of intrinsic within-talker variabilities.

        This dissertation presents studies of voice discrimination abilities of humans and machines under text, affect, and speaking-style variabilities. The main focus is in developing a feature set, based on a psychoacoustic model of voice quality, that can be used to improve machine performance and to find acoustic correlates with human responses. In order to systematically investigate the effects of within- and between-talker variability, a database was developed at UCLA. More than a hundred females and a hundred males were recorded with various speech styles, including sustained vowels, read sentences, affective speech, and pet-directed speech.

        Preliminary experiments indicated that the voice quality feature set (VQual1) was promising for predicting human responses, and for improving automatic speaker verification (ASV) performance which degraded significantly under text, affect and/or speaking-style variabilities. VQual1 was modified to another set (VQual2) to better differentiate talkers, leading to further improvements in short-utterance text-independent ASV tasks.

        Voice discrimination abilities of humans and machines for very short utterances (~ 2 sec) under high text and style variability were analyzed using read sentences and pet-directed speech. Humans were more accurate than machines for read sentence pairs, but the performance difference became small for style-mismatched pairs and for perceptually marked talkers. Humans' and machines' decision spaces were weakly correlated, indicating a weak or non-linear relationship between talker representations by humans and machines. However, for different-talker pairs, the VQual2-based system responses were highly correlated with human responses. Results also suggested that machines could supplement human decisions for perceptually marked talkers. Additionally, VQual2 was effective in perceived affect recognition, suggesting another application where voice quality features can contribute to predict human decisions.

          Cover page: Towards Understanding Voice Discrimination Abilities of Humans and Machines
          • Article
          • Peer Reviewed
          UCLA Previously Published Works (2016)

          Objectives/hypothesis

          Fundamental frequency (F0) and intensity sound pressure level (SPL) of voice are controlled by intrinsic laryngeal muscle (ILM) activation and subglottal pressure (Psub). Their interactions were investigated.

          Methods

          In an in vivo canine model, the thyroarytenoid (TA), lateral cricoarytenoid/interarytenoid (LCA/IA), and cricothyroid (CT) muscles were independently activated from threshold to maximal contraction by neuromuscular stimulation in various combinations, whereas airflow was increased to phonation onset pressure and beyond. The resultant acoustic output was analyzed for effects of Psub on vibratory stability, F0, and SPL. Muscle activation plots and vocal range profiles by individual ILM activation states were analyzed.

          Results

          Cricothyroid activation increased phonation onset F0, but vibration was less stable in high CT conditions and displayed vibratory mode change. In addition, a decrease in F0 with increased Psub was observed in high CT conditions. Intensity increased with Psub in all conditions, but the slope was greater at high CT, low TA/LCA/IA activations. Lateral cricoarytenoid/interarytenoid activation improved vocal efficiency. To maintain same F0 with increasing SPL (messa di voce), TA activation was decreased and LCA/IA activation was increased. The same F0 and SPL could be achieved with a variety of ILM activation combinations.

          Conclusion

          Cricothyroid is primarily required for increasing F0, whereas TA can increase or decrease F0 and SPL. Lateral cricoarytenoid/interarytenoid activation likely maintains vocal fold adduction during increased Psub and improves vocal efficiency. This study also demonstrates laryngeal motor equivalence, the ability of the larynx to achieve the same target F0 and SPL with multiple combinations of ILM activation.

          Level of evidence

          N/A. Laryngoscope, 126:1123-1130, 2016.
            Cover page: Interactions of subglottal pressure and neuromuscular activation on fundamental frequency and intensity
            • Article
            • Peer Reviewed
            UC San Diego Previously Published Works (2024)
            Cutaneous squamous cell carcinoma (cSCC) manifests through the complex interactions of UV-induced DNA damage, genetic mutations, and alterations in the tumor microenvironment. A high mutational burden is present in cSCC, as well as both cSCC precursors and normal skin, making driver genes difficult to differentiate. Despite this, several key driver genes have been identified, including TP53, the NOTCH family, CDKN2A, PIK3CA, and EGFR. In addition to mutations, the tumor microenvironment and the manipulation and evasion of the immune system play a critical role in cSCC progression. Novel therapeutic approaches, such as immunotherapy and EGFR inhibitors, have been used to target these dysregulations, and have shown promise in treating advanced cSCC cases, emphasizing the need for targeted interventions considering both genetic and microenvironmental factors for improved patient outcomes.
              Cover page: The Mutational and Microenvironmental Landscape of Cutaneous Squamous Cell Carcinoma: A Review.
              • Article
              • Peer Reviewed
              UC Irvine Previously Published Works (2021)
              Adolescence is a time of intense cortical development and a period of heightened sensitivity to insult. To determine how sex affects the short- and long-term outcomes of early-adolescent stress exposure, we subjected prepubescent (postnatal day 30) male and female mice to repeated multiple concurrent stressors (RMS). In the posterior parietal cortex (PPC), RMS caused the elimination of excitatory synapses in deeper layers while inhibitory synapse density was predominantly diminished in superficial layers. These short-term effects coincided with reduced visuo-spatial working memory and were similar in both sexes. The loss of excitatory synapses and impaired working memory persisted in males past a 30-day recovery period. In contrast, we observed a remarkable recovery of excitatory transmission and behavioral performance in females. Inhibitory synapse density recovered in both sexes. We have also observed a late onset anxiety phenotype in RMS exposed females that was absent in males. Overall, our results indicate that there are marked sex differences in the long-term effects of prepubescent stress on cortical synapses and behavior.
                Cover page: Sex-dependent long-term effects of prepubescent stress on the posterior parietal cortex
                • Article
                • Peer Reviewed
                UC San Diego Previously Published Works (2023)

                Purpose

                To describe a case of bilateral retinal pigmentary changes in the setting of immune checkpoint inhibitor therapy (ICIT).

                Observations

                A 69-year-old man with a history of advanced cutaneous melanoma was started on combination ICIT with nivolumab and ipilimumab and stereotactic body radiation therapy. Soon after, he developed photopsias and nyctalopia with findings of discrete retinal pigmentary changes bilaterally. Initial visual acuities were 20/20 and 20/30 in the right and left eye, respectively. Multi-modal imaging revealed sub-retinal deposits with progressive changes in pigmentation and autofluorescence, associated with decreased peripheral fields on formal perimetry. A full-field electroretinogram revealed attenuated and delayed a- and b-waves. Positive serum retinal autoantibodies were identified. The patient developed left-sided optic nerve edema and center-involving cystoid macular edema which improved after treatment with sub-tenon's triamcinolone.

                Conclusions

                The use of ICIT has greatly expanded in oncologic practice with subsequent increases in immune related adverse events that pose significant systemic and ophthalmologic morbidities. We propose that the new retinal pigmentary changes seen in this case are the sequelae of an autoimmune inflammatory response against pigmented cells. This adds to the rare side effects that may occur after ICIT.
                  Cover page: Pigmentary retinopathy associated with immune therapy for advanced cutaneous melanoma
                  • Article
                  • Peer Reviewed
                  UCLA Previously Published Works (2018)
                  Little is known about human and machine speaker discrimination ability when utterances are very short and the speaking style is variable. This study compares text-independent speaker discrimination ability of humans and machines based on utterances shorter than 2 s in two different speaking styles (read sentences and speech directed towards pets, characterized by exaggerated prosody). Recordings of 50 female speakers drawn from the UCLA Speaker Variability Database were used as stimuli. Performance of 65 human listeners was compared to i-vector-based automatic speaker verification systems using mel-frequency cepstral coefficients, voice quality features, which were inspired by a psychoacoustic model of voice perception, or their combination by score-level fusion. Humans always outperformed machines, except in the case of style-mismatched pairs from perceptually-marked speakers. Speaker representations by humans and machines were compared using multi-dimensional scaling (MDS). Canonical correlation analysis showed a weak correlation between machine and human MDS spaces. Multiple regression showed that means of voice quality features could represent the most important human MDS dimension well, but not the dimensions from machines. These results suggest that speaker representations by humans and machines are different, and machine performance might be improved by better understanding how different acoustic features relate to perceived speaker identity.
                    Cover page: Towards understanding speaker discrimination abilities in humans and machines for text-independent short utterances of different speech styles.
                    • Article
                    • Peer Reviewed
                    UC Irvine Previously Published Works (2023)
                    Experiments that take advantage of head-fixed behavioral tasks have been a staple of systems neuroscience research for half a century. More recently, rodents came to the forefront of these efforts, primarily because of the rich experimental possibilities afforded by modern genetic tools. There is, however, a considerable barrier to entering this field, requiring expertise in engineering, hardware and software development, and significant time and financial commitment. Here, we present a comprehensive, open-source hardware and software solution to implement a head-fixed environment for rodent behaviors (HERBs). Our solution provides access to three frequently used experimental frameworks (two-alternative forced choice, Go-NoGo, or passive sensory stimulus presentation) in a single package. The required hardware can be built at a relatively low cost compared with commercially available solutions, from off-the-shelf components. Our graphical user interface-based software provides great experimental flexibility and requires no programming experience for either installation or use. Furthermore, an HERBs takes advantage of motorized components that allow the precise, temporal separation of behavioral phases (stimulus presentation, delays, response window and reward). Overall, we present a solution that will allow laboratories to join the growing community of systems neuroscience research at a substantially lower cost of entry.
                      Cover page: A Comprehensive, Affordable, Open-Source Hardware-Software Solution for Flexible Implementation of Complex Behaviors in Head-Fixed Mice.
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