Biology subjects

Miller, J. E.

Publications and source records attributed to Miller, J. E..

6 recordsLinked to original sources

bioRxiv2026

Vocal biomarkers of aging and Parkinson's disease in a songbird

PurposeSimilar vocal impairments occur in normative aging and Parkinsons disease (PD), making differential diagnosis challenging in early stages. The brains role in age and PD-related vocal dysfunction is unclear. This motivated our use of the zebra finch songbird model. We applied human acoustic analysis to evaluate aging and parkinsonian-like birdsong for shared and distinct features. MethodTwo open-access datasets of zebra finch song were analyzed using an expanded set of parameters that, in the case of humans, can detect subtle changes in voice. The aging dataset included younger, middle-aged, and older birds. The PD dataset included birds receiving viral injections into Area X to induce -synuclein overexpression or control treatment, recorded pre- and post-injection. Songs were automatically segmented into motifs using cross-correlation. Acoustic measures were extracted from harmonic, noisy, and mixed syllables. ResultsMiddle-aged birds differed from younger and older birds, showing non-linear trajectories in fundamental frequency measures and age-related increases in spectral slope, spectral emphasis, and intensity variability, whereas temporal parameters remained stable. In PD, pre-post changes occurred in both ASYN and controls, with ASYN birds exhibiting larger effects for fundamental frequency variability, decreasing frequency modulation, and vocal intensity measures. ConclusionsVocal aging in zebra finches was characterized by non-linear trajectories and prominent spectral and intensity-related changes. In a gene-driven PD state there were greater alterations in fundamental frequency variability and intensity regulation, features that may distinguish aging-from disease-related vocal variability. These findings further support the zebra finch as a translational model for vocal biomarker research.

animal behavior and cognition↗

bioRxiv2025

Voice Changes in Aging Birdsong: A Longitudinal Study in Adult Male Zebra Finches

By 2030, 1.4 billion people worldwide will be 60 years or older. A significant proportion will experience changes in voice, which can indicate early signs of neurodegenerative disease. Most research and treatment studies have focused on the larynx because of its accessibility and known role in moderating pitch, loudness, and voice quality. Pre-clinical animal models offer important insight into brain mechanisms involved in aging vocalizations. Previously, we conducted a cross-sectional analysis in adult male zebra finches, discovering that song changes occur at transitional timepoints, between young adult, middle age, and older ages. Song changes are accompanied by re-organization of gene networks in a song-dedicated basal ganglia brain nucleus at middle age that degrade in old age. To more precisely examine how aging alters songs during these transitional timepoints, we followed individual male zebra finches longitudinally over adulthood. Measurements of aging human voice, including duration, intensity, smoothed cepstral peak prominence, and fundamental frequency (fo mean, median, standard deviation, and coefficient of variation), were carried out on birdsong syllables. Our results show that changes in fo mean and intensity are the measurements most sensitive to aging and consistent across multiple mornings in the finches. Notably, acoustic changes were also more pronounced in the transition from young adult to middle age, a time at which changes in aging voice also emerge. Our findings strengthen the validity of the finch model for use in aging research and motivate future investigations exploring the relative contributions of laryngeal and brain mechanisms to aging vocalizations.

neuroscience↗

bioRxiv2025

Alpha-synuclein overexpression reduces neural activity within a basal ganglia vocal nucleus in a zebra finch model

Changes in vocal pitch, loudness, and timing are prevalent in Parkinsons Disease (PD) and a target for early intervention and treatment. The neural mechanisms underlying these impairments are not understood, motivating work in animal models. The adult male zebra finch songbird is uniquely poised for these studies given vocally-dedicated brain nuclei and a quantifiable output (birdsong). Our prior publication revealed that injection of an adeno-associated virus (AAV5) expressing the human (h) alpha-synuclein (hSNCA, a-syn) gene into basal ganglia vocal nucleus Area X results in elevated insoluble a-syn protein and parkinsonian-like changes including softer, shorter, and reduced vocalizations compared to controls. Here, we test the hypothesis that AAV-hSNCA overexpression reduces the firing rate of specific neuronal sub-types in Area X using in vivo recordings in anesthetized finches. Five classes of neurons were differentiated in AAV-treated finches based on waveform width (narrow vs. wide) and firing rates (low vs. fast). Wide-waveform/low-rate activity is a consistent feature of striatal medium spiny neurons (MSNs), a dominant cell type in Area X and in mammalian basal ganglia. Reduced firing rates and enhanced post-peak rebound were detected in the AAV-hSNCA group for putative MSN neurons compared to AAV controls. No differences in firing rate nor waveform shape were detected for the narrow waveform neurons. Our findings provide the first characterization of early a-syn-driven neural activity changes in vocal control neurocircuitry.

neuroscience↗

bioRxiv2023

The dysregulated IL-23/TH17 axis in endometriosis pathophysiology

Endometriosis is a chronic inflammatory disease where endometrial-like tissue grows ectopically, resulting in pelvic pain and infertility. Interleukin (IL)-23 is established as a key contributor in the development and differentiation of a subset of T cells known as T-helper 17 (TH17) cells, driving TH17 cells towards a pathogenic profile. In a variety of inflammatory and autoimmune disorders, such as psoriasis and rheumatoid arthritis, TH17 cells secrete proinflammatory cytokines including IL-17, contributing to the disease pathophysiology. Our studies and others have implicated IL-17 and TH17 cell dysregulation in endometriosis, which is associated with disease severity. Here we address whether IL-23 driven TH17 cells contribute to the cardinal features of lesion proliferation, vascularization, and inflammation in endometriosis using patient samples, representative cell lines, and our established mouse model of endometriosis. Our results indicate significantly dysregulated expression of key genes in the IL-23/TH17 axis in patient ectopic and eutopic endometrial samples and increased IL-23 protein in patient plasma compared to healthy controls. In-vitro studies using primary human TH cells determined that IL-23 cocktail treatment significantly increased the frequency of pathogenic TH17 cells. Similarly, treatment with recombinant human (rh)IL-23 on cell lines (12Z, EECC, HUVEC, and hESC) representative of the endometriotic lesion microenvironment led to a significant increase in cytokines and growth factors known to play a role in lesion establishment and maintenance. In a syngeneic mouse model of endometriosis, treatment with recombinant mouse (rm)IL-23 led to significant alterations in numbers of myeloid and T cell subsets in peritoneal fluid and significantly increased numbers of giant cells within the lesion. Endometriotic lesions from rmIL-23 mice did not reveal significant alterations in proliferation and vascularization, although trends of increased proliferation and vascularization were observed. Collectively, these findings provide insights into the impact of the IL-23/TH17 axis on local immune dysfunction and broadly on the pathophysiology of endometriosis.

immunology↗

bioRxiv2020

CommDivMap: Modelling and mapping species richness at different spatial scales

1. Modern ecosystem models have the potential to greatly enhance our capacity to predict community responses to change, but they demand comprehensive spatial distribution information, creating the need for new approaches to gather and synthesize biodiversity data. 2. Metabarcoding or metagenomics can generate comprehensive biodiversity data sets at species-level resolution but they are limited to point samples. 3. CommDivMap contains a number of functions that can be used to turn OTU tables resulting from metabarcoding runs of bulk samples into species richness maps. We tested the method on a series of arthropod bulk samples obtained from various experimental agricultural plots. 4. The script runs smoothly and is reasonably fast. We hope that our assemble first, predict later approach to statistical modelling of species richness will set the stage for the transition from data-rich but finite sets of point samples to spatially continuous biodiversity maps.

bioinformatics↗

bioRxiv2018

Postmarketing commitments for novel drugs and biologics approved by the US Food and Drug Administration: a cross-sectional analysis

BackgroundPostmarketing commitments are clinical studies that drug sponsors agree to conduct at the time of FDA approval, but which are not required by statute or regulation. The objective of this study was to determine the characteristics, completion, and dissemination of postmarketing commitments agreed upon by sponsors at first FDA approval.\n\nMethodsWe performed a cross-sectional analysis of postmarketing commitments for new drugs and biologics approved 2009-2012. Using public FDA documents, ClinicalTrials.gov, and Scopus, we determined postmarketing commitments and their characteristics known at the time of FDA approval; number of postmarketing commitments subject to reporting requirements, for which FDA is required to make study status information available to the public (\"506B studies\"), and their statuses; and rates of registration and results reporting on ClinicalTrials.gov and publication in peer-reviewed journals for all clinical trials, with follow-up through July 2018.\n\nResultsAmong 110 novel drugs and biologics approved by the FDA between 2009-2012, 61 (55.5%) had at least one postmarketing commitment at the time of first approval. Of 331 total postmarketing commitments, 271 (81.9%) were non-human subjects research, predominantly chemistry, manufacturing, and controls studies; 49 (14.8%) were clinical trials (33 new and 16 ongoing trials for which follow-up results would be reported). Study descriptions for the new clinical trials often lacked information to establish study design features. Of the 89 (26.9%) 506B studies subject to public reporting requirements, of which 42 were clinical trials, 59 (66.3%) did not have an up-to-date status provided by FDA. Nearly all new clinical trials (28 of 31, 90.3%) were registered on ClinicalTrials.gov; of the 23 registered trials that were completed or terminated, 22 (95.7%) had reported results. Only half (14 of 29, 48.3%) of completed or terminated clinical trials, registered or unregistered, were published in peer-reviewed journals. Conclusions: The majority of postmarketing commitments agreed to by sponsors at the time of FDA approval for novel drugs and biologics approved between 2009-2012 were chemistry, manufacturing, and controls studies. While only 15% were clinical trials, these trials were nearly always registered with reported results on ClinicalTrials.gov. However, despite FDA public reporting requirements, up-to-date study status information was often unavailable for 506B studies.

epidemiology↗