Biology subjects

Brown, S.

Publications and source records attributed to Brown, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Participatory science methods to monitor water quality and ground truth remote sensing of the Chesapeake Bay

Measurements by volunteer scientists using participatory science methods in combination with high resolution remote sensing can improve our ability to monitor water quality changes in highly vulnerable and economically valuable nearshore and estuarine habitats. In the Chesapeake Bay (USA), tidal tributaries are a focus of watershed and shoreline management efforts to improve water quality. The Chesapeake Water Watch program seeks to enhance the monitoring of tributaries by developing and testing methods for volunteer scientists to easily measure chlorophyll, turbidity, and colored dissolved organic matter (CDOM) to inform Bay stakeholders and improve algorithms for analogous remote sensing (RS) products. In the program, trained volunteers have measured surface turbidity using a smartphone app, HydroColor, calibrated with a photographers gray card. In vivo chlorophyll and CDOM fluorescence were assessed in surface samples with hand-held fluorometers (Aquafluor) located at sample processing "hubs" where volunteers drop-off samples for same day processing. In validation samples, HydroColor turbidity and Aquafluor in vivo chlorophyll and CDOM fluorescence were linearly related to standard analytical measures of turbidity, chlorophyll and CDOM, respectively, with R2 values ranging from 0.65 to 0.85. These methods are being used for both repeat sampling at fixed sites of interest and ad-hoc "blitzes" to synoptically sample tributaries all around the Bay in coordination with satellite overpasses. All data is accessible on a public database (serc.fieldscope.org) and can be a resource to monitor long-term trends in the tidal tributaries as well as detect and diagnose causes of events of concern such as algal blooms and storm-induced reductions in water clarity.

ecology↗

bioRxiv2024

CoralBleachRisk- Global projections of coral bleaching risk in the 21st century

Timing, duration, and severity of marine heatwaves are changing rapidly in response to anthropogenic climate change, thereby increasing the frequency of coral bleaching events. Mass coral bleaching events occur because of cumulative heat stress, which is commonly quantified through Degree Heating Weeks (DHW). Here we introduce CoralBleachRisk, a daily-resolution global dataset that characterises sea surface temperatures, heat stress anomalies, and the timing, duration, and magnitude of severe coral bleaching conditions from the recent past (1985) to the future (2100) under three contrasting Shared Socioeconomic Pathways. Our projections are downscaled to a 0.5{degrees} resolution (~50km), bias-corrected and validated using remotely sensed data of sea surface temperatures and a global dataset of historical coral bleaching events. An accompanying online software tool allows non-specialist users to access aggregated metrics of coral bleaching risk and generate time series projections of coral vulnerability for Earths coral reefs. More broadly, our dataset enables regional to global comparisons of future trends in severe coral bleaching risk and the identification of potential climate refugia for corals.

ecology↗

bioRxiv2024

Cancer-Associated Hypercalcemia Signals Through the Hindbrain to cause Anorexia

Hypercalcemia, caused by tumor secretion of parathyroid hormone-related protein (PTHrP), is associated with anorexia and weight loss. We demonstrate that overexpression of PTHrP by tumor cells in a transgenic model of breast cancer causes anorexia and rapid weight loss. These changes are accompanied by activation of neurons in the area postrema (AP), the nucleus tractus solitarius (NTS) and the parabrachial nucleus (PBN), a hindbrain circuit regulating food intake. Blocking hypercalcemia prevents anorexia and activation of these brain centers in tumor bearing mice, whereas injecting calcium activates the same circuit in wild-type mice. Neurons in the AP express the calcium-sensing receptor (CaSR) and the same AP/NTS/PBN circuit is stimulated by treating WT mice with cinacalcet, an allosteric activator of the CaSR. Finally, treating diet-induced obese mice with cinacalcet reduces food intake and causes weight loss. These results suggest that CaSR-expressing neurons in the AP might be a pharmacologic target for obesity.

cancer biology↗

bioRxiv2024

Anti-Immune Complex Antibodies are Elicited During Repeated Immunization with HIV Env Immunogens

Vaccination strategies against HIV-1 aim to elicit broadly neutralizing antibodies (bnAbs) using prime-boost regimens with HIV envelope (Env) immunogens. Early antibody responses to easily accessible epitopes on these antigens are directed to non-neutralizing epitopes instead of bnAb epitopes. Autologous neutralizing antibody responses appear upon boosting once immunodominant epitopes are saturated. Here we report another type of antibody response that arises after repeated immunizations with HIV Env immunogens and present the structures of six anti-immune complexes discovered using polyclonal epitope mapping. The anti-immune complex antibodies target idiotopes composed of framework regions of antibodies bound to Env. This work sheds light on current vaccine development efforts for HIV, as well as for other pathogens, in which repeated exposure to antigen is required. One Sentence SummaryPolyclonal epitope mapping reveals anti-immune complex antibodies which target idiotopes on antibodies bound to HIV Env.

immunology↗

bioRxiv2024

Impact of genomic background and developmental state on signaling pathways and response to therapy in Glioblastoma patient-derived cells

Glioblastoma (GBM) tumors represents diverse genomic epigenomic, and transcriptional landscapes, with significant intratumoral heterogeneity that challenges standard of care treatments involving radiation (RT) and the DNA-alkylating agent temozolomide (TMZ). In this study, we employed targeted proteomics to assess the response of a genomically-diverse panel of GBM patient-derived cancer stem cells (CSCs) to astrocytic differentiation, growth factor withdrawal and traditional high fetal bovine serum culture. Our findings revealed a complex crosstalk and co-activation of key oncogenic signaling in CSCs and diverse patterns of response to these external stimuli. Using RNA sequencing and DNA methylation, we observed common adaptations in response to astrocytic differentiation of CSCs across genomically distinct models, including BMP-Smad pathway activation, reduced cholesterol biosynthesis, and upregulation of extracellular matrix components. Notably, we observed that these differentiated CSC progenies retained a subset of stemness genes and the activation of cell survival pathways. We also examined the impact of differentiation state and genomic background on GBM cell sensitivity and transcriptional response to TMZ and RT. Differentiation of CSCs increased resistance to TMZ but not to RT. While transcriptional responses to these treatments were predominantly regulated by p53 in wild-type p53 GBM cells, its transcriptional activity was modulated by the differentiation status and treatment modality. Both mutant and wild-type p53 models exhibited significant activation of a DNA-damage associated interferon response in CSCs and differentiated cells, suggesting this pathway may play a wider role in GBM response to TMZ and RT. Our integrative analysis of the impact of GBM cell developmental states, in the context of genomic and molecular diversity of patient-derived models, provides valuable insights for pre-clinical studies aimed at optimizing treatment strategies.

cancer biology↗

bioRxiv2024

The Topology of Representational Geometry

Representational similarity analysis (RSA) is a powerful tool for abstracting and then comparing neural representations across brains, regions, models and modalities. However, typical RSA analyses compares pairs of representational dissimilarities to judge similarity of two neural systems, and we argue that such methods can not capture the shape of representational spaces. By leveraging tools from computational topology, which can probe the shape of high-dimensional data, we augment RSA to be able to detect more subtle yet real differences and similarities of representational geometries. This new method could be used in conjunction with regular RSA in order to make new inferences about neural function. Significance StatementBig data in high-dimensional spaces, like neuroimaging datasets, contain important shape structures. These shape structures can be analyzed to identify the underlying features and dynamics which drive the system. We showed that such analyses, applied to neural activity patterns elicited by viewing various objects, can identify real but subtle and complex features of those objects which are encoded in the brain.

neuroscience↗

bioRxiv2024

The collective application of shorebird tracking data to conservation

Addressing urgent conservation issues, like the drastic declines of North American migratory birds, requires creative, evidence-based, efficient, and collaborative approaches. Over 50% of monitored North American shorebird populations have lost over 50% of their abundance since 1980. To address these declines, we developed a partnership of scientists and practitioners called the Shorebird Science and Conservation Collective (hereinafter "the Collective"). Here, we present this successful case study as an example for others engaged in translational science. The Collective acts as an intermediary whereby dedicated staff collate and analyze data contributions from scientists to support knowledge requests from conservation practitioners. Data contributions from 74 organizations include over 6.7 million shorebird locations forming movement paths of 3,345 individuals representing 36 species tracked across the Americas. We describe the founding and structure of the Collective and conservation activities we supported in our first two years. As the volume of scientific data on animal movements continues to grow, groups like the Collective can be vital liaisons to rapidly integrate and interpret research to support conservation action.

ecology↗

bioRxiv2023

Spatiotemporal modeling reveals high-resolution invasion states in glioblastoma

Diffuse invasion of glioblastoma cells through normal brain tissue is a key contributor to tumor aggressiveness, resistance to conventional therapies, and dismal prognosis in patients. A deeper understanding of how components of the tumor microenvironment (TME) contribute to overall tumor organization and to programs of invasion may reveal opportunities for improved therapeutic strategies. Towards this goal, we applied a novel computational workflow to a spatiotemporally profiled GBM xenograft cohort, leveraging the ability to distinguish human tumor from mouse TME to overcome previous limitations in analysis of diffuse invasion. Our analytic approach, based on unsupervised deconvolution, performs reference-free discovery of cell types and cell activities within the complete GBM ecosystem. We present a comprehensive catalogue of 15 tumor cell programs set within the spatiotemporal context of 90 mouse brain and TME cell types, cell activities, and anatomic structures. Distinct tumor programs related to invasion were aligned with routes of perivascular, white matter, and parenchymal invasion. Furthermore, sub-modules of genes serving as program network hubs were highly prognostic in GBM patients. The compendium of programs presented here provides a basis for rational targeting of tumor and/or TME components. We anticipate that our approach will facilitate an ecosystem-level understanding of immediate and long-term consequences of such perturbations, including identification of compensatory programs that will inform improved combinatorial therapies.

cancer biology↗

bioRxiv2023

Fusion crystallization reveals the behavior of both the 1TEL crystallization chaperone and the TNK1 UBA domain

Human thirty-eight-negative kinase-1 (TNK1) is implicated in cancer progression. The TNK1-UBA domain binds polyubiquitin and plays a regulatory role in TNK1 activity and stability. Sequence analysis suggests an unusual architecture for the TNK1 UBA domain, but an experimentally-validated molecular structure is undetermined. To gain insight into TNK1 regulation, we fused the UBA domain to the 1TEL crystallization chaperone and obtained crystals diffracting as far as 1.53 [A]. A 1TEL search model enabled solution of the X-ray phases. GG and GSGG linkers allowed the UBA to reproducibly find a productive binding mode against its host 1TEL polymer and to crystallize at protein concentrations as low as 0.1 mg/mL. Our studies support a mechanism of TELSAM fusion crystallization and show that TELSAM fusion crystals require fewer crystal contacts than traditional protein crystals. Modeling and experimental validation suggest the UBA domain may be selective for both the length and linkages of polyubiquitin chains.

biochemistry↗

bioRxiv2023

A structural competition involving WDR5 times circadian oscillations

In the mammalian circadian clock, the transcription factor BMAL1/CLOCK cycles between an active state recruiting co-activators like MLL1, and repressed states associated with the clock proteins Period1/2 (PER1/2) and Cryptochrome1/2 (CRY1/2). The MLL1 complex component WDR5 was also found in a repressive PER complex, but the roles of WDR5-PER interactions are unknown. Here we show that WDR5 directly binds to the C-terminal CRY binding domain (CBD) regions of PER1 and PER2. PER2 binds WDR5 via a WDR5 binding (WBM) motif within the PER2/CRY interface, imposing a molecular choice between PER2/WDR5- and PER2/CRY complexes. PER1 predominantly binds WDR5 via a WDR5 interacting (WIN) motif outside the CBD and exhibits a 15-fold higher WDR5 affinity than PER2. Thereby PER1 can form trimeric PER1WIN/WDR5/RbBP5WBM - and PER1/WDR5/CRY complexes as potential transition states between activating MLL1WIN/WDR5/RbBP5WBM - and repressive PER/CRY complexes. Overexpressing WDR5 in mammalian cells increases the circadian amplitude, whereas a compound targeting the WIN motif binding site of WDR5 weakens PER1-WDR5 interactions and shortens the circadian oscillation period by 2 to 3 hours. Together, our studies uncover WDR5 as direct PER interaction partner at the interface between active- and repressed states of BMAL1/CLOCK and suggest a functional role of WDR5 and its WIN site interactions in the mammalian clock by both enhancing circadian oscillations and creating a temporal delay.

biochemistry↗

bioRxiv2022

Rickettsia parkeri Hijacks Tick Hemocytes to Manipulate Cellular and Humoral Transcriptional Responses

Blood-feeding arthropods rely on robust cellular and humoral immunity to control pathogen invasion and replication. Tick hemocytes produce factors that can facilitate or suppress microbial infection and pathogenesis. Despite the importance of hemocytes in regulating microbial infection, understanding of their basic biology and molecular mechanisms remains limited. Here we combined histomorphology and functional analysis to identify five distinct phagocytic and non-phagocytic hemocyte populations circulating within the Gulf Coast tick Amblyomma maculatum. Depletion of phagocytic hemocytes using clodronate liposomes revealed their function in eliminating bacterial infection. We provide the first direct evidence that an intracellular tick-borne pathogen, Rickettsia parkeri, infects phagocytic hemocytes in Am. maculatum to modify tick cellular immune responses. A massive RNA-seq dataset generated from hemocytes isolated from uninfected and R. parkeri-infected partially blood-fed ticks generated [~]40,000 differentially regulated transcripts, >11,000 of which were immune genes. Silencing two differentially regulated phagocytic immune marker genes (nimrod B2 and eater) significantly reduced hemocyte phagocytosis. Together, these findings represent a significant step forward in understanding how hemocytes regulate microbial homeostasis and vector competence.

immunology↗

bioRxiv2022

GAME BIRD CARCASSES ARE LESS PERSISTENT THAN RAPTOR CARCASSES, BUT CAN PREDICT RAPTOR PERSISTENCE DYNAMICS

Researchers conduct post-construction fatality monitoring (PCFM) to determine a wind energy facilitys direct impacts on wildlife. Results of PCFM can be used to evaluate compliance with permitted take, potentially triggering adaptive management measures or offsetting mitigation; reducing uncertainty in fatality rates benefits wind companies, wildlife agencies, and other stakeholders. As part of PCFM, investigators conduct carcass persistence trials to account for imperfect detection during carcass surveys. In most PCFM studies, pen-raised game birds and other non-raptor surrogates have been used to estimate persistence of all large birds, including raptors. However, there is a growing body of evidence showing carcass persistence varies by bird type; raptor fatality estimates based on game bird carcass persistence may therefore be biased high. We conducted raptor and game bird carcass persistence field trials for 1 year at 6 wind energy facilities. Raptor carcass persistence varied by habitat and season, whereas the best-supported game bird model only included habitat. Raptor persistence probabilities were higher than corresponding game bird persistence probabilities for 13 of the 16 habitat and season combinations. Analysis of a meta-dataset showed that raptor carcass persistence varied by season, habitat, and region. The probability of persisting through a 30-day search interval ranged from 0.44 to 0.99 for raptors and from 0.16 to 0.79 for game birds. Raptor persistence was significantly higher than game bird persistence for 95% of the sampled strata. We used these carcass persistence estimates to develop linear mixed-effects models that predict raptor persistence probabilities based on estimated game bird persistence probabilities. Our scaling model provides an important statistical method to address gaps in raptor persistence data at sites in a broad range of landscape contexts in the continental United States and should be used to inform fatality estimation when site-specific raptor persistence data are limited or absent.

ecology↗

bioRxiv2022

Incidental Eagle Carcass Detection Can Contribute to Fatality Estimation at Operating Wind Facilities

Risk of birds colliding with wind turbines, especially protected species like bald eagle and golden eagle, is a fundamental wildlife challenge the wind industry faces when developing and operating projects. The U.S. Fish and Wildlife Service requires wind facilities that obtain eagle take permits to document permit compliance through eagle fatality monitoring. If trained Operations and Maintenance (O&M) staff can reliably detect and report carcasses during their normal routines, then their incidental detections could contribute substantially to meeting monitoring requirements required by eagle take permits. The primary objective of this study was to quantify incidental detection of eagle carcasses by O&M staff under a variety of landscape contexts and environmental conditions throughout 1 year. We used the incidental detection probabilities (proportion of decoys detected by O&M staff), along with raptor carcass persistence data and area adjustments, to calculate overall probability of incidental detection (i.e., incidental g). We used feathered turkey decoys as eagle-carcass surrogates for monthly detection trials at 6 study sites throughout the U.S. We evaluated the primary drivers of incidental detection using logit regression models including season, viewshed complexity, and a derived variable called the "density quartile" as covariates. We used an Evidence of Absence-based approach to estimate the overall probability of incidental detection. Detection probabilities decreased as viewshed complexity increased and as distance from the turbine increased. The resulting overall probability of incidental detection for the 12-month period ranged from 0.07 to 0.47 (mean = 0.31). The primary drivers of variability in incidental g were detection probability and the area adjustment. Results of our research show that O&M staff were capable of incidentally detecting trial carcasses while performing their typical duties. Incorporating incidental detection by O&M staff in eagle fatality monitoring efforts is a reliable means of improving estimates of a facilitys direct impacts on eagles.

ecology↗

bioRxiv2022

Precision Discovery of Novel Inhibitors of Human Cancer Target HsMetAP1 from Vast Unexplored Metagenomic Diversity

Microbial natural products have long been a rich source of human therapeutics. While the chemical diversity encoded in the genomes of microbes is large, this modality has waned as fermentation-based discovery methods have suffered from rediscovery, inefficient scaling, and incompatibility with target-based discovery paradigms. Here, we leverage a metagenomic partitioning strategy to sequence soil microbiomes at unprecedented depth and quality. We then couple these data with target-focused, in silico search strategies and synthetic biology to discover multiple novel natural product inhibitors of human methionine aminopeptidase-1 (HsMetAP1), a validated oncology target. For one of these, metapeptin B, we demonstrate sub-micromolar potency, strong selectivity for HsMetAP1 over HsMetAP2 and elucidate structure-activity relationships. Our approach overcomes challenges of traditional natural product methods, accesses vast, untapped chemical diversity in uncultured microbes, and demonstrates computationally-enabled precision mining of modulators of human proteins.

microbiology↗

bioRxiv2022

Eudicot primary cell wall glucomannan is related in synthesis, structure and function to xyloglucan

The functional differences between plant cell wall hemicelluloses such as glucomannan, xylan and xyloglucan (XyG) remain unclear. These polysaccharides influence assembly and properties of the wall, perhaps by interacting with cellulose to affect the deposition and bundling of the fibrils. As the most abundant hemicellulose, XyG is considered important in eudicot primary cell walls (PCWs), but plants devoid of XyG show relatively mild phenotypes. We report here that a patterned {beta}-galactoglucomannan ({beta}-GGM) is widespread in PCW of eudicots and shows remarkable similarities to XyG. The sugar linkages forming the backbone and side chains of {beta}-GGM are analogous to those that make up XyG, and moreover, these linkages are formed by glycosyltransferases from the same CAZy families. Solid-state NMR indicated that {beta}-GGM shows low mobility in the cell wall, consistent with interaction with cellulose. Although Arabidopsis {beta}-GGM synthesis mutants show no obvious growth defects, genetic crosses between {beta}-GGM and XyG mutants produce exacerbated phenotypes compared to XyG mutants. These findings demonstrate a related role of these two similar but distinct classes of hemicelluloses in PCWs. This work will provide new avenues to study the roles of both {beta}-GGM and XyG in PCWs. One sentence summaryPatterned {beta}-GGM resembles xyloglucan in structure, biosynthesis and function.

plant biology↗

bioRxiv2022

Single-cell atlas of human liver development reveals pathways directing hepatic cell fates

The liver has been studied extensively due to the broad number of diseases affecting its vital functions. However, therapeutic advances, especially in regenerative medicine, are currently hampered by the lack of knowledge concerning human hepatic cell development. Here, we addressed this limitation by describing the developmental trajectories of different cell types comprising the human fetal liver at single-cell resolution. These transcriptomic analyses revealed that sequential cell-to-cell interactions direct functional maturation of hepatocytes, with non-parenchymal cells playing critical, supportive roles during organogenesis. We utilised this information to derive bipotential hepatoblast organoids and then exploited this novel model system to validate the importance of key signalling pathways and developmental cues. Furthermore, these insights into hepatic maturation enabled the identification of stage-specific transcription factors to improve the functionality of hepatocyte-like cells generated from human pluripotent stem cells. Thus, our study establishes a new platform to investigate the basic mechanisms of human liver development and to produce cell types for clinical applications.

developmental biology↗

bioRxiv2022

Chemically modified dsRNA induces RNAi effects in insects in vitro and in vivo: A potential new tool for improving RNA-based plant protection

Global agriculture loses over $100 billion of produce annually to crop pests such as insects. Many of these crop pests either have no current means of control or have developed resistance against chemical pesticides. Long dsRNAs are capable of inducing RNA interference (RNAi) in insects and are emerging as novel highly selective alternatives for sustainable insect management strategies. However, there are significant challenges associated with RNAi efficacy in insects. In this study, we synthesised a range of chemically modified long dsRNA in an approach to improve nuclease resistance and RNAi efficacy in insects. The results showed that dsRNA containing phosphorothioate modifications demonstrated increased resistance to southern green stink bug saliva nucleases. Phosphorothioate and 2-fluoro modified dsRNA also demonstrated increased resistance to degradation by soil nucleases and increased RNAi efficacy in Drosophila melanogaster cell cultures. In live insects, chemically modified long dsRNA successfully resulted in mortality in both stink bug and corn rootworm. The results provide further mechanistic insight of RNAi efficacy dependence on modifications in the sense or antisense strand of the dsRNA in insects and demonstrate for the first time that RNAi can successfully be triggered by chemically modified long dsRNA in insect cells or live insects.

bioengineering↗

bioRxiv2021

The neural cell adhesion molecule NrCAM regulates development of hypothalamic tanycytes

Hypothalamic tanycytes are neural stem and progenitor cells, but little is known of how they are regulated. Here we provide evidence that the cell adhesion molecule, NrCAM, regulates tanycytes in the adult niche. NrCAM is strongly expressed in adult mouse tanycytes. Immunohistochemical and in situ hybridization analysis revealed that NrCAM loss of function leads to both a reduced number of tanycytes and reduced expression of tanycyte-specific cell markers, along with a small reduction in tyrosine hydroxylase-positive arcuate neurons. Similar analyses of NrCAM mutants at E16 identify few changes in gene expression or cell composition, indicating that NrCAM regulates tanycytes, rather than early embryonic hypothalamic development. Neurosphere and organotypic assays support the idea that NrCAM governs cellular homeostasis. Single-cell RNA sequencing (scRNA-Seq) shows that tanycyte-specific genes, including a number that are implicated in thyroid hormone metabolism, show reduced expression in the mutant mouse. However, the mild tanycyte depletion and loss of markers observed in NrCAM-deficient mice were associated with only a subtle metabolic phenotype.

neuroscience↗