Biology subjects

Duncan, K.

Publications and source records attributed to Duncan, K..

11 recordsLinked to original sources

bioRxiv2026

When clades collide: Genomic admixture in blacklegged ticks (Ixodes scapularis) from the Great Plains

Ixodes scapularis ticks transmit a number of pathogens important to human health, including Borrelia burgdorferi, the causative agent of Lyme disease. While I. scapularis is found across the Eastern United States, Lyme disease transmission is largely limited to the Northeast and Upper Midwest and is nearly absent in the South. This indicates that differences in northern versus southern clades of I. scapularis are associated with differences in Lyme disease transmission risk. I. scapularis is undergoing range expansion, including into the Great Plains region of the United States. Determining where I. scapularis populations in the Great Plains originated can inform future risk of Lyme disease transmission in this region. In this study, we use a population genomics framework to characterize diversity, structure, and B. burgdorferi infection rates of I. scapularis populations in the Great Plains region. We generated whole genome sequence data and single nucleotide polymorphism (SNP) datasets from I. scapularis ticks collected in Iowa, Kansas, Nebraska, and South Dakota to compare to publicly available data from across the species range. Our analysis of 200 I. scapularis SNP datasets indicated geographically well-defined populations that correspond to historical northern and southern ancestral clades of I. scapularis. Ticks from South Dakota, Iowa, and northeastern Nebraska are genetically similar populations from the Upper Midwest, while ticks from Kansas are more genetically similar to ticks from the Southeast. Ticks collected in the central eastern region of Nebraska, however, represent an evenly admixed population of both northern and southern genomic backgrounds. Analysis of B. burgdorferi reads from genomic datasets shows [~]50% infection rate in ticks from Iowa and northeastern Nebraska, whereas ticks from Kansas show no evidence of B. burgdorferi infection. Of note, evenly admixed ticks from the central eastern region of Nebraska also show no evidence of B. burgdorferi infection. These results provide further evidence that tick genomics may influence traits associated with B. burgdorferi infection status, and thus the potential for Lyme disease transmission. As the range of I. scapularis continues to expand, bringing historically isolated populations into contact, there is a clear need to understand the consequence of genomic admixture for B. burgdorferi transmission potential to inform future risk of Lyme disease in the United States.

genomics↗

bioRxiv2026

Zfp750 prevents oral adhesions and promotes temporary epithelial fusions

The differentiation cascade that converts basal keratinocytes into suprabasal layers, including periderm, depends on the activity of transcription factors. Mutations in the genes encoding many of these transcription factors, including TP63, IRF6 and GRHL3, disrupt periderm development. Such mutations can also interfere with embryonic fusion and septation events that depend on periderm development, including palatogenesis, digit separation and the formation of temporary epithelial fusions between digits, between eyelids, and between pinnae and the scalp. ZNF750 (Zfp750 in the mouse) is a transcription factor required for keratinocyte differentiation, but whether mutations in ZNF750 contribute risk for orofacial cleft, and the role of Zfp750 in periderm development, are unknown. To address these questions we sequenced ZNF750 in 5,659 individuals including 2,125 with nonsyndromic OFC. We identify 33 rare missense variants with frequencies less than 0.1% in gnomAD. Of these, about half are predicted to be damaging with in silico tools. Collectively, these missense variants are not overtransmitted from parents to children with OFCs. Two of the variants have lower activity than the reference variant in a zebrafish embryo-based assay but no phenotype in the corresponding murine model. However, in murine embryos homozygous for a frame-shift mutation in Zfp750 (Zfp750fs) that we generated, palatal shelves are fused but intra-oral adhesions are present, a phenotype seen in murine mutants of several bonafide OFC genes. In addition, temporary epithelial fusions are absent in Zfp750fs neonates. RNA sequencing of forelimbs from Zfp750fs embryos reveals decreased expression of epidermal terminal differentiation genes, and both increased and decreased expression of distinct periderm genes. Immunofluorescence shows the consistent presence of periderm proteins within the oral adhesions in Zfp750fs/fs embryos. Together these studies suggest that while mutations in ZNF750 are not a major contributor to OFC risk, Zfp750 does contribute to periderm-dependent morphogenic events.

genetics↗

bioRxiv2024

Spatiotemporal dynamic models of Amblyomma americanum questing activity in the Central Great Plains

Ticks represent important vectors of a number of bacterial and viral disease agents, owing to their hematophagous nature and their questing behavior (the process in which they seek new hosts). Questing activity is notably seasonal with spatiotemporal dynamics that needs to be understood in detail as part of mediating and mitigating tick-borne disease risk. Models of the geography of tick questing activity developed to date, however, have ignored the temporal dimensions of that behavior; more fundamentally, they have often not considered the sampling underlying available occurrence data. Here, we have addressed these shortfalls for Amblyomma americanum, the most commonly encountered tick in the central Great Plains, via (1) detailed, longitudinal sampling to characterize the spatiotemporal dimensions of tick questing activity; (2) randomization tests to establish in which environmental dimensions a species is manifesting selective use; and (3) modeling methods that include both presence data and absence data, taking fullest advantage of the information available in the data resource. The outcome was a detailed picture of geographic and temporal variation in suitability for the species through the two-year course of this study. Such models that take full advantage of available information will be crucial in understanding the risk of tick-borne disease into the future.

ecology↗

bioRxiv2024

Precise Timing Matters: Modulating Human Memory by Synchronizing Hippocampal Stimulation to Saccadic Event Related Potentials

Episodic memory, the ability to record and relive experiences, is intricately connected to visual exploration in most humans. This study explores the possibility that eye movements create physiological states relevant for memory, analogous to those associated with hippocampal theta. Previous work has demonstrated that saccadic eye movements, which occur roughly at theta frequency, elicit hippocampal event-related potentials (ERPs). Building on the Separate Phases of Encoding and Retrieval (SPEAR) model, we asked if the peaks and troughs of this saccadic ERP are differentially important for memory formation. Specifically, we applied saccade-contingent hippocampal electrical stimulation at estimated ERP peaks and troughs while individuals with epilepsy visually explored natural scenes across 59 sessions. We subsequently assessed their recognition memory for scenes and their recall of associated targets. Results indicate that memory is robust when stimulation precisely targets the peak or trough, contrasting with impairments observed with random stimulation. Moreover, memory impairment is prominent when stimulation is applied within 100 ms of saccade initiation, a time that reflects high medial temporal lobe inhibition. Our findings suggest that the hippocampus rapidly evolves through memory-relevant states following each eye movement, while also challenging the assumption that human saccadic ERP peaks and troughs mirror the encoding and retrieval phases of theta rhythms studied in rodents. The study sheds light on the dynamic interplay between eye movements, hippocampal activity, and memory formation, offering theoretical insights with potential applications for memory modulation in neurological disorders. Significance StatementWhy do eye-movements enhance memory formation? Here, we causally tested if eye-movements initiate short-lived states critical for memory formation within the hippocampus, a brain region known to support memory. We built a system that could precisely apply hippocampal electrical stimulation at key moments after eye-movements to test how the timing of this stimulation influenced peoples ability to form memories. We found that stimulation was particularly disruptive to memory formation when applied within 100 ms of initiating an eye movement. By contrast, memory was robust to stimulation precisely timed to the peak and trough of hippocampal eye-movement responses. We interpret this temporal evolution of memory-relevant states within a prominent model of how theta phases relate to rodent memory.

neuroscience↗

bioRxiv2023

Interference with the HNF4-dependent gene regulatory network diminishes ER stress in hepatocytes

In all eukaryotic cell types, the unfolded protein response (UPR) upregulates factors that promote protein folding and misfolded protein clearance to help alleviate endoplasmic reticulum (ER) stress. Yet ER stress in the liver is uniquely accompanied by the suppression of metabolic genes, the coordination and purpose of which is largely unknown. Here, we used unsupervised machine learning to identify a cluster of correlated genes that were profoundly suppressed by persistent ER stress in the liver. These genes, which encode diverse functions including metabolism, coagulation, drug detoxification, and bile synthesis, are likely targets of the master regulator of hepatocyte differentiation HNF4. The response of these genes to ER stress was phenocopied by liver-specific deletion of HNF4. Strikingly, while deletion of HNF4 exacerbated liver injury in response to an ER stress challenge, it also diminished UPR activation and partially preserved ER ultrastructure, suggesting attenuated ER stress. Conversely, pharmacological maintenance of hepatocyte identity in vitro enhanced sensitivity to stress. Several pathways potentially link HNF4 to ER stress sensitivity, including control of expression of the tunicamycin transporter MFSD2A; modulation of IRE1/XBP1 signaling; and regulation of Pyruvate Dehydrogenase. Together, these findings suggest that HNF4 activity is linked to hepatic ER homeostasis through multiple mechanisms.

cell biology↗

bioRxiv2022

A Versatile Enhanced Freeze-Substitution Protocol for Volume Electron Microscopy

Volume electron microscopy, a powerful approach to generate large three-dimensional cell and tissue volumes at electron microscopy resolutions, is rapidly becoming a routine tool for understanding fundamental and applied biological questions. One of the enabling factors for its adoption has been the development of conventional fixation protocols with improved heavy metal staining. However, freeze-substitution with organic solvent-based fixation and staining has not realized the same level of benefit. Here, we report a straightforward approach including 2% osmium tetroxide, acetone and up to 3% water substitution fluid (compatible with traditional or fast freeze-substitution protocols), warm-up and transition from organic solvent to aqueous 2% OsO4. Once fully hydrated, samples were processed in aqueous based potassium ferrocyanide, thiocarbohydrazide, osmium tetroxide, uranyl acetate and lead acetate before resin infiltration and polymerization. We observed a consistent and substantial increase in heavy metal staining across diverse and difficult-to-fix test organisms and tissue types, including plant tissues, nematodes, yeast, and bacteria. Our approach opens new possibilities to combine the benefits of cryo-preservation with enhanced contrast for volume electron microscopy in diverse organisms.

plant biology↗

bioRxiv2021

A corollary discharge mediates saccade related inhibition of single units in mnemonic structures of the human brain

Despite the critical link between visual exploration and memory, little is known about how single-unit activity (SUA) in the human mesial temporal lobe (MTL) is modulated by saccadic eye movements (SEMs). Here we characterize SEM associated SUA modulations, unit-by-unit, and contrast them to image onset, and to occipital lobe SUA. We reveal evidence for a corollary discharge (CD)-like modulatory signal that accompanies SEMs, inhibiting/exciting a unique population of broad/narrow spiking units, respectively, before and during SEMs, and with directional selectivity. These findings comport well with the timing, directional nature, and inhibitory circuit implementation of a CD. Additionally, by linking SUA to event-related potentials (ERPs), which are directionally modulated following SEMs, we recontextualize the ERP associated with SEM as a proxy for both the strength of inhibition and saccade direction, providing a mechanistic underpinning for the more commonly recorded SEM-related ERP in the human brain.

neuroscience↗

bioRxiv2020

Analysis of zebrafish periderm enhancers facilitates identification of a regulatory variant near human KRT8/18

Genome wide association studies for non-syndromic orofacial cleft (OFC) have identified single nucleotide polymorphisms (SNPs) at loci where the presumed risk-relevant gene is expressed in oral periderm. The functional subsets of such SNPs are difficult to predict because the sequence underpinnings of periderm enhancers are unknown. We applied ATAC-seq to models of human palate periderm, including zebrafish periderm, mouse embryonic palate epithelia, and a human oral epithelium cell line, and to complementary mesenchymal cell types. We identified sets of enhancers specific to the epithelial cells and trained gapped-kmer support-vector-machine classifiers on these sets. We used the classifiers to predict the effect of 14 OFC-associated SNPs at 12q13 near KRT18. All the classifiers picked the same SNP as having the strongest effect, but the significance was highest with the classifier trained on zebrafish periderm. Reporter and deletion analyses support this SNP as lying within a periderm enhancer regulating KRT18/KRT8 expression.

developmental biology↗

bioRxiv2019

Mnemonic prediction errors bias hippocampal states

In situations when our experience violates our predictions, it is adaptive to upregulate encoding of novel information, while down-weighting retrieval of erroneous memory predictions to promote an updated representation of the world. We asked whether mnemonic prediction errors promote distinct hippocampal processing states by leveraging recent results showing that encoding and retrieval processes are supported by distinct patterns of connectivity, or states, across hippocampal subfields. During fMRI scanning, participants were cued to retrieve well-learned room-images and were then presented with either an image identical to the learned room or a modified version (1-4 changes). We found that CA1-entorhinal connectivity increased, and CA1-CA3 connectivity decreased, with the number of changes to the learned rooms. Further, stronger memory predictions measured in CA1 during the cue correlated with the CA1-entorhinal connectivity increase in response to violations. Our findings provide a mechanism by which mnemonic prediction errors may drive memory updating - by biasing hippocampal states.

neuroscience↗

bioRxiv2019

In situ analysis of mucus residing bacterial community reveals an ecological niche key for gut microbiome stability

Mucus associated bacterial communities are critical for determining disease pathology and promoting colonization resistance. Yet the key ecological properties of mucus resident communities remain poorly defined. Using an approach that combines in situ hybridization, laser microdissection and 16s rRNA sequencing of spatially distinct regions of the mouse gut lumen, we discovered that a dense microbial community resembling a biofilm is embedded in the mucus layer. The mucus associated biofilm-like community excluded bacteria belonging to phylum Proteobacteria. Additionally, it was significantly more diverse and consisted of bacterial species that were unique to it. By employing germ-free mice deficient in T and B lymphocytes we found that formation of biofilm-like structure was independent of adaptive immunity. Instead the integrity of biofilm-like community depended on Gram-positive commensals such as Clostridia. Additionally, biofilm-like community in the mucus lost fewer Clostridia and showed smaller bloom of Proteobacteria compared to the lumen upon antibiotic treatment. When subjected to time restricted feeding biofilm like structure significantly enhanced in size and showed enrichment of Clostridia. Taken together our work discloses that mucus associated biofilm-like community represent a specialized community that is structurally and compositionally distinct that excludes aerobic bacteria while enriching for anaerobic bacteria such as Clostridia, exhibits enhanced stability to antibiotic treatment and that can be modulated by dietary changes.

ecology↗

bioRxiv2017

Time-resolved neural reinstatement and separation during memory decisions in human hippocampus

Mnemonic decision-making has long been hypothesized to rely on hippocampal dynamics that bias memory processing toward the formation of new memories or the retrieval of old ones. Successful memory encoding would be best optimized by pattern separation, whereby two highly similar experiences can be represented by underlying neural populations in an orthogonal manner. By contrast, successful memory retrieval is thought to be supported by a recovery of the same neural pattern laid down during encoding. Here we examined how hippocampal pattern completion and separation emerge over time during memory decisions. We measured electrocorticography activity in the human hippocampus and posterior occipitotemporal cortex (OTC) while participants performed continuous recognition of items that were new, repeated (old), or highly similar to a prior item (similar).During retrieval decisions of old items, both regions exhibited significant reinstatement of multivariate high frequency activity (HFA) associated with encoding. Further, the extent of reinstatement of encoding patterns during retrieval was correlated both with the strength (HFA power) of hippocampal encoding and with the strength of hippocampal retrieval. Evidence for encoding pattern reinstatement was also seen in OTC on trials requiring fine-grained discrimination of similar items. By contrast, hippocampal activity showed evidence for pattern separation during these trials. Together, these results underscore the critical role of the hippocampus in supporting both reinstatement of overlapping information and separation of similar events.\n\nSignificance StatementOne of the biggest computational challenges the memory systems faces is to disambiguate highly similar experiences while at the same time preserving and reinstating prior memories. Remarkably, hippocampal processes have been implicated in both of these functions. However, how this is accomplished is unknown. Leveraging the spatiotemporal resolution of electrocorticography, we found evidence for memory reinstatement in both the hippocampus and occipitotemporal cortex. Reinstatement was differentiated in time across these two regions with earlier reinstatement evident in occipitotemporal cortex. Interestingly, when a current experience was very similar, but not identical to a prior one, occipitotemporal cortical activity still showed reinstatement of the prior memory but hippocampal activity differentiated or disambiguated these two similar experiences.

neuroscience↗