Biology subjects

Boyd, L.

Publications and source records attributed to Boyd, L..

4 recordsLinked to original sources

bioRxiv2024

A brain-body feedback loop driving HPA-axis dysfunction in breast cancer

Breast cancer patients often exhibit disrupted circadian rhythms in circulating glucocorticoids (GCs), such as cortisol. This disruption correlates with reduced quality of life and higher cancer mortality1-3. The exact cause of this phenomenon -- whether due to treatments, stress, age, co-morbidities, lifestyle factors, or the cancer itself remains unclear. Here, we demonstrate that primary breast cancer alone blunts host GC rhythms by disinhibiting neurons in the hypothalamus, and that circadian phase-specific neuromodulation of these neurons can attenuate tumor growth by enhancing anti-tumor immunity. We find that mice with mammary tumors exhibit blunted GC rhythms before tumors are palpable, alongside increased activity in paraventricular hypothalamic neurons expressing corticotropin-releasing hormone (i.e., PVNCRH neurons). Tumor-bearing mice have fewer inhibitory synapses contacting PVNCRH neurons and reduced miniature inhibitory post-synaptic current (mIPSC) frequency, leading to net excitation. Tumor-bearing mice experience impaired negative feedback on GC production, but adrenal and pituitary gland functions are largely unaffected, indicating that alterations in PVNCRH neuronal activity are likely a primary cause of hypothalamic-pituitary-adrenal (HPA) axis dysfunction in breast cancer. Using chemogenetics (hM3Dq) to stimulate PVNCRH neurons at different circadian phases, we show that stimulation just before the light-to-dark transition restores normal GC rhythms and reduces tumor progression. These mice have significantly more effector T cells (CD8+) within the tumor than non-stimulated controls, and the anti-tumor effect of PVNCRH neuronal stimulation is absent in mice lacking CD8+ T cells. Our findings demonstrate that breast cancer distally regulates neurons in the hypothalamus that control output of the HPA axis and provide evidence that therapeutic targeting of these neurons could mitigate tumor progression.

neuroscience↗

bioRxiv2024

The cytokine receptor Fn14 is a molecular brake on neuronal activity that mediates circadian function in vivo

To survive, organisms must adapt to a staggering diversity of environmental signals, ranging from sensory information to pathogenic infection, across the lifespan. At the same time, organisms intrinsically generate biological oscillations, such as circadian rhythms, without input from the environment. While the nervous system is well-suited to integrate extrinsic and intrinsic cues, how the brain balances these influences to shape biological function system-wide is not well understood at the molecular level. Here, we demonstrate that the cytokine receptor Fn14, previously identified as a mediator of sensory experience-dependent synaptic refinement during brain development, regulates neuronal activity and function in adult mice in a time-of-day-dependent manner. We show that a subset of excitatory pyramidal (PYR) neurons in the CA1 subregion of the hippocampus increase Fn14 expression when neuronal activity is heightened. Once expressed, Fn14 constrains the activity of these same PYR neurons, suggesting that Fn14 operates as a molecular brake on neuronal activity. Strikingly, differences in PYR neuron activity between mice lacking or expressing Fn14 were most robust at daily transitions between light and dark, and genetic ablation of Fn14 caused aberrations in circadian rhythms, sleep-wake states, and sensory-cued and spatial memory. At the cellular level, microglia contacted fewer, but larger, excitatory synapses in CA1 in the absence of Fn14, suggesting that these brain-resident immune cells may dampen neuronal activity by modifying synaptic inputs onto PYR neurons. Finally, mice lacking Fn14 exhibited heightened susceptibility to chemically induced seizures, implicating Fn14 in disorders characterized by hyperexcitation, such as epilepsy. Altogether, these findings reveal that cytokine receptors that mediates inflammation in the periphery, such as Fn14, can also play major roles in healthy neurological function in the adult brain downstream of both extrinsic and intrinsic cues. HighlightsO_LINeuronal activity induces Fn14 expression in pyramidal neurons of the hippocampus C_LIO_LIFn14 constrains neuronal activity near daily transitions between light and dark C_LIO_LILoss of Fn14 lengthens the endogenous circadian period and disrupts sleep-wake states and memory C_LIO_LIMicroglia contact excitatory synapses in an Fn14-dependent manner C_LI

neuroscience↗

bioRxiv2023

Nutritional and genetic variations within foxtail millet (Setaria italica) landraces collected from indigenous communities across the Philippines

Unknown to many, the Philippines is host to a few remaining accessions of the underutilized and understudied cereal foxtail millet (Setaria italica (L.) P. Beauv.). We collected together accessions from different eco-geographical locations within the Philippines, along with a few accessions from Lanyu, Taiwan, to undertake a study of the nutritional value and genetic diversity within accessions of foxtail millet grown in the Philippines. All accessions were field grown in 2022, dry season (DS) at the Institute of Plant Breeding (IPB) Experiment Station, Los Banos, Laguna, Philippines. The accessions were tested for micronutrients, including Zn and Fe, nitrogen as a proxy for protein, {beta}-carotene and a number of phenolic compounds with known nutritional potential. Of the 20 accessions tested, the accessions Bayaras and GB61438 had the highest level of Zn (107.1 mg/kg) and Fe (70.52 mg/kg), respectively, higher than levels found in traditional rice varieties. For {beta}-carotene the highest concentration was found in the accession Balles ([~]10{micro}g/g). Twelve phenolic compounds were detected, with catechin, syringic acid, ferulic acid and kaempferol having the highest concentrations and greatest variation between accessions. To assess the genetic diversity of these local foxtail millet accessions, we sequenced a core set of eight accessions to a depth of at least 25-fold. Analysis of the population structure, using genome-wide, high-quality SNPs, showed modest diversity among the accession, with two unadmixed groups. The accessions are monophyletic relative to their earliest common ancestor, with the very light brown accessions emerging earlier than the light brown and reddish-brown varieties. Analysis of Zinc/Iron permease (ZIP) transporters within the foxtail millet reference sequence, var. Yugu1 identified 17 putative ZIP transporters. Variant calling identified SNPs primarily within 3 and 5 regions, and introns, indicating variation between foxtail millet accessions within regulatory gene regions rather than in structural proteins. The local foxtail millet accessions found across the Philippines, therefore, represent a potential alternative source of nutrition that would help to address the problems of the double-burden of malnutrition found in the Philippines.

plant biology↗

bioRxiv2018

BED-domain containing immune receptors confer diverse resistance spectra to yellow rust

Introductory paragraph Introductory paragraph Main Methods Author contributions Data availability Competing interests References Crop diseases reduce wheat yields by ~25% globally and thus pose a major threat to global food security1. Genetic resistance can reduce crop losses in the field and can be selected for through the use of molecular markers. However, genetic resistance often breaks down following changes in pathogen virulence, as experienced with the wheat yellow (stripe) rust fungus Puccinia striiformis f. sp. tritici (Pst)2. This highlights the need to (i) identify genes that alone or in combination provide broad-spectrum resistance and (ii) increase our understanding of the underlying molecular mod ...

plant biology↗