Biology subjects

Lynch, K.

Publications and source records attributed to Lynch, K..

7 recordsLinked to original sources

bioRxiv2025

Lifespan Trajectories of the Brains Functional Complexity Characterized by Multiscale Sample Entropy

Resting state functional magnetic resonance imaging (rs-fMRI) is a widely used imaging modality that can capture spontaneous neural activity of the brain. The human brain is a complex system, and emerging evidence suggests that the complexity of neural activity may serve as an index of the brains capacity of information processing. In this study we used multiscale sample entropy (MSE) to analyze the complexity of rs-fMRI timeseries of 504 healthy subjects between the age of 6 to 85 years. We constructed the global and regional trajectories of brains functional complexity over the lifespan and analyzed its correlation with executive function. We observed a nonlinear trajectory of fMRI-complexity over the lifespan with a peak age occurring at 23 (95% CI 21.27, 26.38 years) years of age. Males reach the peak age of complexity at 26 years (95% CI 19.95, 33.14 years) whereas females at 23 (95% CI 20.16, 29.18 years). We found significant correlations between complexity and Number-Letter Switching of Trail Making Test in parietal and medial temporal lobes while Inhibition and Inhibition/Switching of Color Word Interference Test also revealed a significant negative correlation with rs-fMRI complexity in lateral and medial frontal cortex. These results help to understand behavior of fMRI-complexity with aging and reveals association with executive function of the brain. As a non-invasive biomarker, fMRI-complexity could provide novel approach to understand information processing capacity in the brain and deficits thereof in illness.

neuroscience↗

bioRxiv2024

Histone variant H2BE enhances chromatin accessibility in neurons to promote synaptic gene expression and long-term memory

Regulation of histone proteins affects gene expression through multiple mechanisms including exchange with histone variants. However, widely expressed variants of H2B remain elusive. Recent findings link histone variants to neurological disorders, yet few are well studied in the brain. We applied new tools including novel antibodies, biochemical assays, and sequencing approaches to reveal broad expression of the H2B variant H2BE, and defined its role in regulating chromatin structure, neuronal transcription, and mouse behavior. We find that H2BE is enriched at promoters and a single unique amino acid allows it to dramatically enhance chromatin accessibility. Lastly, we show that H2BE is critical for synaptic gene expression and long-term memory. Together, these data reveal a novel mechanism linking histone variants to chromatin regulation, neuronal function, and memory. This work further identifies the first widely expressed H2B variant and uncovers a single histone amino acid with profound effects on genomic structure.

genetics↗

bioRxiv2022

Autoantibody discovery across monogenic, acquired, and COVID19-associated autoimmunity with scalable PhIP-Seq

Phage Immunoprecipitation-Sequencing (PhIP-Seq) allows for unbiased, proteome-wide autoantibody discovery across a variety of disease settings, with identification of disease-specific autoantigens providing new insight into previously poorly understood forms of immune dysregulation. Despite several successful implementations of PhIP-Seq for autoantigen discovery, including our previous work (Vazquez et al. 2020), current protocols are inherently difficult to scale to accommodate large cohorts of cases and importantly, healthy controls. Here, we develop and validate a high throughput extension of PhIP-seq in various etiologies of autoimmune and inflammatory diseases, including APS1, IPEX, RAG1/2 deficiency, Kawasaki Disease (KD), Multisystem Inflammatory Syndrome in Children (MIS-C), and finally, mild and severe forms of COVID19. We demonstrate that these scaled datasets enable machine-learning approaches that result in robust prediction of disease status, as well as the ability to detect both known and novel autoantigens, such as PDYN in APS1 patients, and intestinally expressed proteins BEST4 and BTNL8 in IPEX patients. Remarkably, BEST4 antibodies were also found in 2 patients with RAG1/2 deficiency, one of whom had very early onset IBD. Scaled PhIP-Seq examination of both MIS-C and KD demonstrated rare, overlapping antigens, including CGNL1, as well as several strongly enriched putative pneumonia-associated antigens in severe COVID19, including the endosomal protein EEA1. Together, scaled PhIP-Seq provides a valuable tool for broadly assessing both rare and common autoantigen overlap between autoimmune diseases of varying origins and etiologies.

immunology↗

bioRxiv2021

Stromal cell sialylation suppresses T cells in inflammatory tumour microenvironments: A new tumour stromal cell immune checkpoint?

Immunosuppressive tumour microenvironments (TME) reduce the effectiveness of immune responses in cancer. Non-haematopoietic mesenchymal stromal cells (MSC), the precursor to cancer associated fibroblasts (CAFs), dictate tumour progression by enhancing immune cell suppression. Hyper-sialylation of glycans promotes immune evasion in cancer, but the role of sialyation in stromal cell-mediated immunosuppression is unknown. Here we study changes in sialyltransferase (ST) enzymes and associated surface expressed sialic acid in stromal cells following inflammatory and tumour secretome conditioning. We show that tumour conditioned stromal cells have increased levels of sialyltransferases, 2,3/6 linked sialic acid and siglec ligands. In tumour models of solid (colorectal cancer) and haematological (multiple myeloma) stromal rich tumours, stromal cell sialylation is associated with enhanced immunosuppression. Using datasets and patient samples, we confirm that targeting sialylation in tumour stromal cells reverses immune cell exhaustion. Targeting stromal cell sialylation may represent a novel immune checkpoint to reactivate anti-tumour immunity.

immunology↗

bioRxiv2019

Discrete Community Assemblages Within Hypersaline Paleolake Sediments of Pilot Valley, Utah

Hypersaline paleolake sediments are understudied ecosystems whose microbial ecology is largely unknown. Here we present mineralogical, geochemical, and small-subunit 16S rRNA gene sequence data on one such environment, the Pilot Valley Basin (PVB), a sub-basin of ancient Lake Bonneville located in northwest Utah. PVB exhibits a variety of aqueous minerals including phyllosilicates, carbonates, and sulfates, as well as microbially-induced sedimentary structures. As perchlorate occurs naturally (up to 6.5 ppb) in Pilot Valley sediments, and because recent evidence suggests that it is subject to biotic reduction, PVB has been proposed as a Mars analog site for astrobiological studies. 16S rRNA gene sequencing was used to investigate microbial diversity and community structure along horizontal and vertical transects within the upper basin sediments and beta diversity analyses indicate that the microbial communities in Pilot Valley are structured into three discrete groups. Operational taxonomic units (OTUs) belonging to the main archaeal phylum, Euryarchaeota, make up ~23% of the sequences, while OTUs belonging to three bacterial phyla, Proteobacteria, Bacteroides and Gemmatimonadetes, constitute ~60-70% of the sequences recovered at all sites. Diversity analyses indicate that the specific composition of each community correlates with sediment grain size, and with biogeochemical parameters such as nitrate and sulfate concentrations. Interestingly, OTUs belonging to the phylum Gemmatimonadetes are co-located with extreme halophilic archaeal and bacterial taxa, which suggests a potential new attribute, halophilicity, of this newly-recognized phylum. Altogether, results of this first comprehensive geomicrobial study of Pilot Valley reveal that basin sediments harbor a complex and diverse ecosystem.

microbiology↗

bioRxiv2018

Socially regulated estrogen in an eavesdropping brood parasite

Social regulation of reproductive hormones is a means by which conspecific males and females orchestrate successful reproductive efforts. There is variation, however, in the range of social cues that will initiate a hormone response in the receiver of social signals. We investigate whether social cues modify activity within the hypothalamic-pituitary-gonadal (HPG) axis and the specificity of this response in a social parasite that is known to eavesdrop on the communication signals of other species: the brown-headed cowbird (Molothrus ater). Brown-headed cowbirds are obligate brood parasites that do not build nests or care for their own young. Instead, obligate brood parasites always leave their eggs in the nest of a host species thereby receiving the benefits of parental care toward offspring without paying any of the costs. Thus, social parasites must coordinate their breeding attempts with conspecifics as well as potential heterospecific hosts and therefore, social parasites such as cowbirds rely on the communication signals of host species to help locate nests to parasitize during the breeding season. Here, we explore whether the vocal signals of potential host species can also be used as a social cue that modifies the HPG axis of female brown-headed cowbirds. Results reveal that both conspecific and heterospecific song-exposed females exhibit significantly greater circulating estradiol concentrations as compared to silence-exposed females. While conspecific song induces the greatest elevation in circulating estradiol, there is no significant difference in circulating estradiol levels in females exposed to either conspecific or heterospecific songs. This pattern suggests both song types are effective at evoking a reproductive physiological response. On the other hand, circulating progesterone concentrations did not differ among the song- and silence-exposed groups nor did the size of the females ovarian follicles. These results indicate that heterospecific vocal communication signals can effectively be used as a social cue that simultaneously provides necessary information regarding breeding status of hosts and modifies breeding condition of the eavesdropper.\n\nHighlights\n\nO_LIBrood parasites may coordinate reproductive attempts with potential hosts.\nC_LIO_LITherefore, parasites eavesdrop on other species, which helps them find nests.\nC_LIO_LIVocal signals from conspecific and heterospecifics elevate estrogen in parasites.\nC_LIO_LIHearing potential host songs may enhance reproductive hormones in brood parasites.\nC_LI

animal behavior and cognition↗

bioRxiv2018

Losing maternal care: Neotenic gene expression in the preoptic area of avian brood parasites

Parental care for is critical for offspring survival in many species. However, parental behaviors have been lost in roughly 1% of avian species known as the obligate brood parasites. To shed light on molecular and neurobiological mechanisms mediating brood parasitic behavior, brain gene expression patterns between two brood parasitic species and one closely related non-parasitic Icterid (blackbird) species were compared. Our analyses focused on gene expression changes specifically in the preoptic area (POA), a brain region known to play a critical role in maternal behavior across vertebrates. Using comparative transcriptomic approaches, we identified gene expression patterns associated with brood parasitism and evaluated two alternative explanations for the evolution of brood parasitism: reduced expression of parental-related genes in the POA versus retention of juvenile (neotenic) gene expression. While we did not find evidence for large scale gene downregulation, expression patterns did reflect substantial evidence for neotenic POA gene expression in parasitic birds. Differentially expressed genes with previously established roles in parental care were identified. Targeted examination of these selected candidate genes in additional hypothalamic regions revealed species differences in gene expression patterns is not POA-specific. Together, these results provide new insights into neurogenomics underlying maternal behavior loss in avian brood parasites.

animal behavior and cognition↗