Biology subjects

Grant, A. D.

Publications and source records attributed to Grant, A. D..

4 recordsLinked to original sources

bioRxiv2021

Adolescent Development of Biological Rhythms: Estradiol Dependence and Effects of Combined Contraceptives

PurposeAdolescence is a period of continuous development, including the maturation of endogenous rhythms across systems and timescales. Although these dynamic changes are well recognized, their continuous structure and hormonal dependence have not been systematically characterized. Given the well-established link between core body temperature (CBT) and reproductive hormones in adults, we hypothesized that high-resolution CBT can be applied to passively monitor pubertal development and disruption with high fidelity. MethodsTo examine this possibility, we used signal processing to investigate the trajectory of CBT rhythms at the within-day (ultradian), daily (circadian), and ovulatory timescales, their dependence on estradiol, and the effects of hormonal contraceptives. ResultsPuberty onset was marked by a rise in fecal estradiol (fE2), followed by an elevation in CBT and circadian power. This time period marked the commencement of 4-day rhythmicity in fE2, CBT, and ultradian power marking the onset of the estrous cycle. The rise in circadian amplitude was accelerated by E2 treatment, indicating a role for this hormone in rhythmic development. Contraceptive administration in later adolescence reduced CBT and circadian power and resulted in disruption to 4-day cycles that persisted after discontinuation. ConclusionsOur data reveal with precise temporal resolution how biological rhythms change across adolescence and demonstrate a role for E2 in the emergence and preservation of multiscale rhythmicity. These findings also demonstrate how hormones delivered exogenously in a non-rhythmic pattern can disrupt rhythmic development. These data lay the groundwork for a future in which temperature metrics provide an inexpensive, convenient method for monitoring pubertal maturation and support the development of hormone therapies that better mimic and support human chronobiology.

physiology↗

bioRxiv2021

EVL and MIM/MTSS1 regulate actin cytoskeletal remodeling to promote dendritic filopodia in developing neurons

Dendritic spines are the postsynaptic compartment of a functional neuronal synapse, and are critical for synaptic connectivity and plasticity. The developmental precursor to dendritic spines, dendritic filopodia, are highly motile protrusions that facilitate synapse formation by sampling the environment for suitable axon partners during development and learning. Despite the significance of the actin cytoskeleton in driving these protrusions, the actin remodeling factors involved in this process are not fully characterized. In this work, we identify a critical function for the Ena/VASP protein EVL in the regulation of dendritic filopodia. Amongst the Ena/VASP proteins, EVL is uniquely required for the characteristic morphology and dynamics of dendritic filopodia. Using a combination of genetic and optogenetic manipulations, we demonstrate that EVL promotes protrusive motility through membrane-direct actin polymerization at dendritic filopodia tips. EVL forms a complex at nascent protrusions and dendritic filopodia tips with MIM/MTSS1, an I-BAR protein recently discovered to be important for initiation of dendritic filopodia. We propose a model in which EVL cooperates with MIM to elongate and coalesce branched actin filaments, establishing the dynamic lamellipodia-like architecture of dendritic filopodia in developing neurons.

cell biology↗

bioRxiv2020

Cell intrinsic signaling in MEN1 mutant pancreatic neuroendocrine tumors unveils novel signaling pathways associated with de-differentiation

ObjectivesPreliminary genomic analysis of primary pancreatic neuroendocrine tumors revealed a complex mutational landscape with four common oncogenic events; however, critical activation pathways responsible for pancreatic neuroendocrine tumor progression and metastasis have yet to be elucidated. Here, we analyzed six primary pancreatic neuroendocrine tumors to determine which pathways are deregulated and responsible for progression. MethodsSelected genomic profiling of six primary pancreatic neuroendocrine tumors was performed using the Ion Torrent Comprehensive Cancer Panel with matched transcriptomes analyzed by Affymetrix Clariom D arrays. Validation of gene expression changes were measured by quantitative PCR using TaqMan assays and immunohistochemistry on tumor specimens. ResultsMEN1 was mutated in half (50%) of our sequenced tumors while FGFR3 was mutated in 2/6 (33%). Transcriptome analysis revealed that ITGA2 and EZH2 were overexpressed in MEN1 mutant tumors whereas ALK and VEGFA were overexpressed in FGFR3 mutant tumors. Immunohistochemistry revealed increased nuclear ITGA2 and EZH2 staining along with increased VE-Cadherin staining and loss of membranous E-cadherin localization in MEN1 and FGFR3 mutant tumors. ConclusionsOur results suggest that pancreatic neuroendocrine tumors containing MEN1 and FGFR3 mutations are more aggressive and de-differentiated than their wild-type counterparts. Additionally, we provide novel chemotherapeutic target FGFR3 for patients with this disease.

cancer biology↗

bioRxiv2020

Ultradian Rhythms in Heart Rate Variability and Distal Body TemperatureAnticipate the Luteinizing Hormone Surge Onset

The human menstrual cycle is characterized by predictable patterns of physiological change across timescales, yet non-invasive anticipation of key events is not yet possible at individual resolution. Although patterns of reproductive hormones across the menstrual cycle have been well characterized, monitoring these measures repeatedly to anticipate the preovulatory luteinizing hormone (LH) surge is not practical for fertility awareness. In the present study, we explored whether non-invasive and high frequency measures of distal body temperature (DBT), sleeping heart rate (HR), sleeping heart rate variability (HRV), and sleep timing could be used to anticipate the preovulatory LH surge in women. To test this possibility, we used signal processing to examine these measures across the menstrual cycle. Cycles were examined from both pre- (n=45 cycles) and perimenopausal (n=10 cycles) women using days of supra-surge threshold LH and dates of menstruation for all cycles. For a subset of cycles, urinary estradiol and progesterone metabolites were measured daily around the time of the LH surge. Wavelet analysis revealed a consistent inflection point of ultradian rhythm (2-5 h) power of DBT and HRV that enabled anticipation of the LH surge at least 2 days prior to its onset in 100% of individuals. In contrast, the power of ultradian rhythms in heart rate, circadian rhythms in body temperature, and metrics of sleep duration and sleep timing were not predictive of the LH surge. Together, the present findings reveal fluctuations in distal body temperature and heart rate variability that consistently anticipate the LH surge and may aid in fertility awareness. Key PointsO_LIUltradian (2-5 h) rhythm power of distal body temperature and heart rate variability (RMSSD) exhibits a stereotyped inflection point and peak in the days leading up to the LH surge in premenopausal women. C_LIO_LICircadian rhythms of distal body temperature and single time-point/day metrics do not permit anticipation of the LH surge. C_LIO_LIMeasurement of continuous metabolic and autonomic outputs, enabling assessment of ultradian rhythms, may be of value to the fertility awareness method. C_LI

physiology↗