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Biology subjects

Brown, R. M.

Publications and source records attributed to Brown, R. M..

14 recordsLinked to original sources

Multidimensional divergence supports parapatric speciation along an elevational gradient in ground-dwelling frogs on an oceanic island

Geographic isolation is a major driver of lineage divergence. However, strong ecological selection can promote reproductive isolation despite opportunities for gene flow in geographically continuous landscapes such as mountains. Here, we test whether ecological divergence across elevational gradients can promote speciation within a single mountain range. Integrating phylogenomic (ddRAD), morphological, and bioacoustic data, we test predictions of elevation-mediated parapatric speciation in Platymantis (Lahatnanguri) ground-dwelling frogs on Mindanao Island, Philippines. Phylogenomic analyses recovered an endemic radiation across neighboring mountain ranges and revealed a hierarchical pattern of diversification among three monophyletic lineages, with deeper divergence separating the mountain lineages Highland 1 and Highland 2 and more recent divergence occurring within a single mountain range. This topology identified a morphologically and acoustically distinct low-elevation lineage (<1,400 m a.s.l.) as closely related to the high-elevation Highland 1 lineage (>1,400 m a.s.l.), providing a natural test of divergence along an elevational gradient. The parapatric Lowland and Highland 1 lineages appear to have diverged relatively recently, as reflected in their shallow genome-wide differentiation, yet exhibit pronounced morphological and acoustic divergence. Population genomic analyses further recover discrete genomic clusters and no evidence of contemporary hybridization between the parapatric lineages, indicating independent evolutionary trajectories despite geographic continuity. Together, these findings are consistent with parapatric speciation along an elevational gradient and demonstrate how substantial phenotypic and reproductive-isolation divergence can accumulate despite limited genome-wide differentiation. More broadly, our results indicate that the exceptional biodiversity of oceanic archipelagos may arise not only from diversification among islands (and among mountains within islands) but also from lineage divergence along elevational gradients within mountains themselves. These empirical results support the biological plausibility of parapatric speciation within single mountain systems and highlight an underrecognized mechanism contributing to biodiversity in topographically complex oceanic archipelagos.

evolutionary biology↗

Vitamin D deficiency alters prostate epithelial differentiation and increases prostate cancer aggressiveness in ex vivo and in vivo models

Here, we examined the consequences of biologically relevant vitamin D deficiency, a known risk factor for aggressive prostate cancer, using ex vivo and in vivo models. Phenotypic and single-cell RNA sequencing of mouse prostate organoids showed that vitamin D deficiency stunted luminal cell differentiation more than androgen deficiency, which is a known driver of prostate development. Mice fed a vitamin D-deficient diet showed significantly altered expression of androgen-responsive genes in their prostate luminal cells, as determined by single-cell RNA sequencing. MDA-PCa-2b human prostate cancer cells, when maintained for 6 months in 1,25-dihydroxyvitamin D, lost the ability to form xenografts, despite normal proliferation in vitro. RNA sequencing showed that these cells also had disruptions in androgen signaling and multiple cancer-related pathways. This study offers new insights and validation of vitamin Ds role in both benign and malignant prostate biology, underscoring its essential hormonal functions and supporting strategies for vitamin D supplementation to reduce prostate cancer risk in vulnerable populations. STATEMENT OF SIGNIFICANCEVitamin D is an essential hormone, however, the non-calcemic consequences of vitamin D deficiency remain poorly defined, despite its high prevalence in the population. This study demonstrates significant biological consequences of vitamin D deficiency on prostate cells at biologically relevant levels in multiple systems.

cancer biology↗

Sampling bias obscures biodiversity patterns, reveals data gaps in priority conservation areas: a call for improved documentation

Where and how species are sampled can shape biodiversity knowledge, spatial patterns, and data-driven conservation. In megadiverse regions of the Global South, sampling remains uneven, and available data often lack synthesis needed to assess spatial heterogeneity in recorded biodiversity for conservation planning. This limitation is also evident in areas designated for biodiversity conservation. We examine this in the Philippines, where long-term research effort and policy development have supported expansion of conservation-relevant areas (hereafter "Philippine conservation-relevant areas" or PCAs). Using over a century of digitally accessible species occurrence records compiled and manually curated, we analyzed the country-wide spatial distribution of observed amphibian and squamate reptile species richness. We further tested whether observed richness across PCAs is associated with area, topographic relief, and sampling effort, and whether these relationships differ between protected and conserved areas (with management or governance schemes) and key biodiversity areas (unmanaged but priority areas for conservation). Results show strong spatial heterogeneity in occurrence records, with preserved specimens comprising 92% of all records and strongly influencing observed richness patterns. Citizen-science data tend to reinforce already well-sampled regions, whereas literature-derived records provide additional coverage in comparatively undersampled areas. PCAs show variable representation in the dataset, with observed richness and sampling effort generally increasing with area. However, this richness-area relationship weakens with increasing topographic relief. Differences in predictor-richness relationships between PCA types are also evident, with stronger area and sampling effects in protected and conserved areas and a relatively stronger elevational effect in key biodiversity areas. Notably, several high-richness areas occur outside formally designated protected areas. These results highlight uneven biodiversity data coverage and suggest that observed richness patterns may reflect both sampling structure and spatial variation. We emphasize integrating multiple biodiversity data sources and identifying undersampled regions to improve future biodiversity assessments.

ecology↗

SOX2 utilizes FOXA1 as a heteromeric transcriptional partner to drive proliferation in therapy-resistant prostate cancer

Treatment options and diagnostic outlook for men with advanced, therapy resistant prostate cancer (PCa) are extremely poor; this is primarily due to the common lack of durable response to androgen receptor (AR) targeted therapies and phenotypic transdifferentiation into a particularly lethal subtype known as neuroendocrine prostate cancer (NEPC). In this study, we mechanistically determine that SOX2 (a transcription factor originally repressed by AR) physically binds and acts in a concerted manner with FOXA1 (a key AR pioneering cofactor) to regulate a subset of genes which promote cell cycle progression, and lineage plasticity in AR-refractory prostate cancers. Our findings assert the SOX2/FOXA1 interaction as an important mediator of resistance to AR-targeted therapy and a driver of NEPC and lineage plasticity; their coordinated action and downstream signaling offers a potential novel therapeutic opportunity in late-stage PCa.

cancer biology↗

Hunger alters approach-avoidance behaviours differently in male and female mice

BackgroundThe decision about whether to approach or avoid a reward while under threat requires balancing competing demands. Sex-specific prioritisations (e.g. mating, maternal care), or generalised prioritisations (e.g. feeding, drinking, sleeping) may differently influence approach-avoidance behaviours based on the level of "risk" and homeostatic need state of the organism. However, given known sex differences in key aspects that may influence this behaviour, direct comparison of how male and female mice make decisions to approach or avoid a dangerous area while in a fasted state have yet to be conducted. MethodsWe conducted several approach-avoidance tasks with varied levels of risk and reward in male and female mice that were either fasted or sated (fed). Mice underwent a light-dark box, elevated plus maze, baited large open field and runway task to assess their approach and avoidance behaviour. ResultIn the light-dark box and elevated plus maze, when no reward was available, fasted female mice showed greater approach behaviours than male counterparts. In the baited large open field, when reward was available, both sexes showed increased approach behaviours when fasted. However, when sated, male mice conversely showed greater approach behaviours compared to sated female mice. In the runway task, while sated mice failed to learn, fasted male mice inhibited their reward consumption in response to increased shock intensity; however, fasted female mice were resistant to increased shock intensity. ConclusionsOur study identifies sex differences in decision making behaviour in mice based on satiety state across a number of approach-avoidance tasks. We highlight several nuances of these differences based on reward availability and punishment intensity. These results shine a lens on fundamental differences between the sexes in innate, survival driven behaviours that should be taken into account for future studies. Plain English summaryEveryday decision making is often accompanied by conflict - whether we make the most appropriate decision or not can be influenced by both internal and external factors. Environmental threats and physiological pressures, such as hunger, can influence decision-making processes skewing the risk/reward ratio, yet how this may differ between the sexes has not been explored in detail. Here we used several tasks that assess decision-making in mice while manipulating the levels of risk or reward. Our findings show fasted female mice are more willing to engage in "risky" behaviour compared to fed female mice when risk levels were low, and no food reward was available. However, when a food reward was available, but risk levels were low, both male and female fasted mice were more likely to engage in risky behaviour compared to fed mice. Finally, when risk levels were high and food reward was available, fasted female mice continued to engage in risky behaviour, while male fasted mice were not. Together our study identifies nuanced sex differences in how male and female mice make decisions influenced by both physiological (hunger) and environmental threats and highlight the importance of understanding fundamental differences between the sexes in behaviour. Highlights- Fasted female mice showed greater approach behaviours compared to fasted male counterparts in tasks without reward availability. - Fasted mice of both sexes displayed greater approach behaviours when a reward was available, compared to sated controls. - Fasted male mice inhibited reward consumption under increased shock intensity, whereas fasted female mice were resistant to mild foot shock.

neuroscience↗

A shift in the host web occupancy of dew-drop spiders associated with genetic divergence in the Southwest Pacific

AimWe assessed the population genetic structure of the kleptoparasitic spider Argyrodes bonadea across the Southwestern Pacific islands. Our focus is on assessing the impact of overseas distances and, in particular, the Kerama gap, as potential drivers of genetic differentiation. We found that the spider kleptoparasites switch to a specific host species is associated with significant genetic variation at fine scales, whereas the same species adoption of a generalist host strategy has likely facilitated its broad dispersal, colonization, and recent range expansion across the southwestern Pacific, and is associated with a lack of geographically- structured genetic variation in these latter, subsequently-colonized landmasses. LocationSouthwestern Pacific Islands TaxonArgyrodes bonadea MethodsWe used mitochondrial Cytochrome Oxidase 1 (CO1) gene sequences, and Restriction Site-associated DNA Sequencing (RAD-seq) for our analyses. ResultsTwo strongly supported lineages, an Amami-Okinawa Lineage (AOL) and an Austral-Asia Lineage (AAL) correspond to two separate clades, roughly divided by the Kerama Gap, in phylogenetic trees estimated here. However, species delimitation led to the interpretation of only a single species present. The AOL exhibits complex, geographically-structured host web spider species specificity, wherein the Amami population utilizes Cyrtophora, but AOL samples in Okinawa associates exclusively with Nephila--and yet all broadly distributed AAL populations show no evidence of host web spider species specificity. Main conclusionThe population boundary between AOL and AAL likely results from local adaptation to novel hosts--instead of isolation by the Kerama Gap--following long-distance dispersal and range expansion. Our results suggest kleptoparasitic spiders have the capacity to overcome permanent deep-sea barriers and colonize distant landmasses. Whereas peripheral populations (AOL) demonstrate the capacity for specialization to a single host, which may have contributed to genetic differentiation and isolation, the broadly-distributed AAL persists and has successfully expanded its geographical range as a host generalist, which may contribute to ongoing gene flow inferred in this study.

evolutionary biology↗

Lactobacillus maintains IFNγ homeostasis to promote behavioral stress resilience.

The gut microbiome consists of the trillions of bacteria, fungi, and viruses that inhabit the digestive tract. These communities are sensitive to disruption from environmental exposures ranging from diet changes to illness. Disruption of the community of lactic acid producing bacteria, Lactobaccillacea, has been well documented in mood disorders and stress exposure. In fact, oral supplement with many Lactobacillus species can ameliorate these effects, preventing depression- and anxiety-like behavior. Here, for the first time, we utilize a gnotobiotic mouse colonized with the Altered Schaedler Flora to remove the two native species of Lactobaccillacea. Using this novel microbial community, we found that the Lactobacillus species themselves, and not the disrupted microbial communities are protective from environmental stressors. Further, we determine that Lactobaccillacea are maintaining homeostatic IFN{gamma} levels which are mediating these behavioral and circuit level responses. By utilizing the Altered Schaedler Flora, we have gained new insight into how probiotics influence behavior and give novel methods to study potential therapies developed to treat mood disorders.

neuroscience↗

Spatial determination and prognostic impact of the fibroblast transcriptome in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma has a poor clinical outcome and responses to immunotherapy are suboptimal. Stromal fibroblasts are a dominant but heterogenous population within the tumor microenvironment and therapeutic targeting of stromal subsets may have therapeutic utility. Here we combined spatial transcriptomics and scRNA-Seq to define the transcriptome of tumor-proximal and tumor-distal cancer-associated fibroblasts (CAFs) and linked this to clinical outcome. Tumor-proximal fibroblasts comprised large populations of myofibroblasts, strongly expressed podoplanin, and were enriched for Wnt ligand signaling. In contrast, inflammatory CAFs were dominant within tumor-distal subsets and expressed complement components and the Wnt-inhibitor SFRP2. Poor clinical outcome was correlated with elevated HIF-1 and podoplanin whilst high level expression of inflammatory and complement genes was predictive of extended survival. These findings demonstrate the extreme transcriptional heterogeneity of CAFs and its determination by apposition to tumor. Selective targeting of tumor-proximal subsets, potentially combined with HIF-1 inhibition and immune stimulation, may offer a multimodal therapeutic approach for this disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=170 SRC="FIGDIR/small/524883v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@b34606org.highwire.dtl.DTLVardef@1ba47c3org.highwire.dtl.DTLVardef@bd75f1org.highwire.dtl.DTLVardef@8a602b_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

T cell Aryl Hydrocarbon Receptor Activity Tunes the Gut Microenvironment to Sustain Autoimmunity.

Multiple sclerosis (MS) is a T cell driven autoimmune disease that attacks the myelin of the central nervous system and currently has no cure. MS etiology is linked to both the gut flora and external environmental factors but this connection is not well understood. One immune system regulator responsive to non-pathogenic external stimuli is the aryl hydrocarbon receptor (AHR). The AHR, which binds diverse molecules present in the environment in barrier tissues, is a therapeutic target for MS. However, AHRs precise function in T lymphocytes, the orchestrators of MS, has not been described. Here we show that in a mouse model of MS, T cell specific Ahr knockout leads to recovery driven by a decrease in T cell fitness. At the mechanistic level, we demonstrate that the absence of AHR changes the gut microenvironment composition to generate metabolites that impact T cell viability, such as bile salts and short chain fatty acids. Our study demonstrates a newly emerging role for AHR in mediating the interdependence between T lymphocytes and the microbiota, while simultaneously identifying new potential molecular targets for the treatment of MS and other autoimmune diseases.

immunology↗

Irx3 Promotes Gap Junction Communication Between Uterine Stromal Cells to Regulate Vascularization during Embryo Implantation

Spontaneous abortions have been reported to affect up to 43% of parous women, with over 20% occurring before pregnancy is clinically diagnosed. Establishment of pregnancy is critically dependent on proper embryo-uterine interactions at the time of implantation. Besides oocyte abnormalities, implantation failure is a major contributor to early pregnancy loss. Previously, we demonstrated that two members of the Iroquois homeobox transcription factor family, IRX3 and IRX5, exhibited distinct and dynamic expression profiles in the developing ovary to promote oocyte and follicle survival. Elimination of each gene independently caused subfertility, but with different breeding pattern outcomes. Irx3 KO (Irx3LacZ/LacZ) females produced fewer pups throughout their reproductive lifespan which could only be partially explained by poor oocyte quality. Thus, we hypothesized that IRX3 is also expressed in the uterus where it acts to establish functional embryo-uterine interactions to support pregnancy. To test this hypothesis, we harvested pregnant uteri from control and Irx3 KO females to evaluate IRX3 expression profiles and the integrity of embryo implantation sites. Our results indicate that IRX3 is expressed in the endometrial stromal cells of the pregnant uterus. Notably, of the days evaluated, IRX3 expression expanded into the endometrial stroma starting at day 4 of pregnancy (D4) with peak expression at D5-6, and then greatly diminished by D7. This pattern corresponds to the critical window for implantation and remodeling of the vasculature network in mice. Further, histology and immunohistochemistry at D7 showed that while embryos were able to attach to the uterus, implantation sites in Irx3 KO pregnant mice exhibited impaired vascularization. In addition, our results showed significantly diminished expression of decidualization markers and disruptions in GJA1 organization in the decidual bed. These data, taken together with previous reports focused on the ovary, suggest that IRX3 promotes fertility via at least two different mechanisms: 1) promoting competent oocytes and 2) facilitating functional embryo-uterine interactions during implantation. Future research aims to tease apart the roles for IRX3 in the oocyte versus the uterus and the mechanisms by which it promotes early embryo survival and a successful pregnancy outcome.

physiology↗

FrogCap: A modular sequence capture probe set for phylogenomics and population genetics for all frogs, assessed across multiple phylogenetic scales

Despite the increasing use of high-throughput sequencing in phylogenetics, many phylogenetic relationships remain difficult to resolve because of conflict between gene trees and species trees. Selection of different types of markers (i.e. protein-coding exons, non-coding introns, ultra-conserved elements) is becoming important to alleviate these phylogenomic challenges. For evolutionary studies in frogs, we introduce the new publicly available FrogCap suite of genomic resources, which is a large and flexible collection of probes corresponding to [~]15,000 markers that unifies previous frog sequencing work. FrogCap is designed to be modular, such that subsets of markers can be selected based on the phylogenetic scale of the intended study. FrogCap uses a variety of molecular marker types that include newly obtained exons and introns, previously sequenced UCEs, and Sanger-sequencing markers, which span a range of alignment lengths (100-12,000 base pairs). We tested three probe sets from FrogCap using 105 samples across five phylogenetic scales, comparing probes designed using a consensus- or genome-based approach. We also tested the effects of using different bait kit sizes on depth of coverage and missing data. We found that larger bait kits did not result in lowered depth of coverage or increased missing data. We also found that sensitivity, specificity, and missing data are not related to genetic distance in the consensus-based probe design, suggesting that this approach has greater success and overcomes a major hurdle in probe design. We observed sequence capture success (in terms of missing data, quantity of sequence data, recovered marker length, and number of informative sites) and compared them at all phylogenetic scales. The incorporation of different molecular marker types allowed recovery of the variation required for resolving difficult phylogenetic relationships and for performing population genetic studies. Altogether, FrogCap is a valuable and adaptable resource for performing high-throughput sequencing projects across variable timescales.

genomics↗

Parachute geckos free fall into synonymy: Gekko phylogeny, and a new subgeneric classification, inferred from thousands of ultraconserved elements

Recent phylogenetic studies of gekkonid lizards have revealed unexpected, widespread paraphyly and polyphyly among genera, unclear generic boundaries, and a tendency towards the nesting of taxa exhibiting specialized, apomorphic morphologies within geographically widespread \"generalist\" clades. This is especially true in the Australasia, where the monophyly of Gekko proper has been questioned with respect to phenotypically ornate flap-legged geckos of the genus Luperosaurus, the Philippine false geckos of the genus Pseudogekko, and even the elaborately \"derived\" parachute geckos of the genus Ptychozoon. Here we employ sequence capture targeting 5060 ultraconserved elements to infer phylogenomic relationships among 42 representative ingroup gekkonine lizard taxa. We analyzed multiple datasets of varying degrees of completeness (10, 50, 75, 95, and 100 percent complete with 4715, 4051, 3376, 2366, and 772 UCEs, respectively) using concatenated maximum likelihood and multispecies coalescent methods. Our sampling scheme was designed to address four persistent systematic questions in this group: (1) Are Luperosaurus and Ptychozoon monophyletic and are any of these named species truly nested within Gekko? (2) Are prior phylogenetic estimates of Sulawesis L. iskandari as sister to Melanesian G. vittatus supported by our genome-scale dataset? (3) Is the high elevation L. gulat of Palawan Island correctly placed within Gekko? (4) And, finally, where do the enigmatic taxa P. rhacophorus and L. browni fall in a higher-level gekkonid phylogeny? We resolve these issues; confirm with strong support some previously inferred findings (placement of Ptychozoon taxa within Gekko; the sister relationship between L. iskandari and G. vittatus); resolve the systematic position of unplaced taxa (L. gulat, and L. browni); and transfer L. iskandari, L. gulat, L. browni, and all members of the genus Ptychozoon to the genus Gekko. Our unexpected and novel systematic inference of the placement of Ptychozoon rhacophorus suggests that this species is not related to Ptychozoon or even Luperosaurus (as previously expected) but may, in fact, be most closely related to several Indochinese species of Gekko. With our final, well-supported topologies, we recognize seven newly defined subgenera to accommodate [~]60 species within the more broadly defined and maximally-inclusive Australasian genus Gekko. The newly defined subgenera will aide taxonomists and systematists in species descriptions by allowing them to only diagnose putatively new species from the most relevant members of the same subgenus, not necessarily the phenotypically variable genus Gekko as a whole, and we argue that it appropriately recognizes geographically circumscribed units (e.g., a new subgenus for a novel clade, entirely endemic to the Philippines) while simultaneously recognizing several of the most systematically controversial, phenotypically distinct, and phylogenetically unique lineages. An added benefit of recognizing the most inclusive definition of Gekko, containing multiple phylogenetically-defined subgenera, is that this practice has the potential to alleviate taxonomic vandalism, if widely adopted, by creating formally available, supraspecific taxa, accompanied by character-based diagnoses and properly assigned type species, such that future, more atomized classifications would necessarily be required to adopt todays subgenera as tomorrows genera under the guidelines of The Code of Zoological Nomenclature. Not only does this simple practice effectively eliminate the nefarious motivation behind taxonomic vandalism, but it also ensures that supraspecific names are created only when accompanied by data, that they are coined with reference to a phylogenetic estimate, and that they explicitly involve appropriate specifiers in the form of type species and, ultimately, type specimens.

zoology↗

Analysis of the gut and gill microbiome of resistant and susceptible lines of rainbow trout (Oncorhynchus mykiss)

Commensal microorganisms present at mucosal surfaces play a vital role in protecting the host organism from bacterial infection. There are multiple factors that contribute to selecting for the microbiome, key of which are host genetics. Flavobacterium psychrophillum, the causative agent of Bacterial Cold Water Disease in salmonids, accounts for acute losses in wild and farmed Rainbow Trout (Oncorhynchus mykiss). The U.S. National Center for Cool and Cold Water Aquaculture has used family-based selective breeding to generate a line of rainbow trout with enhanced resistance to F. psychrophilum. The goal of this study is to determine whether selective breeding impacts the gut and gill microbiome of the F. psychrophilum-resistant as compared to a background matched susceptible trout line. Mid-gut and gill samples were collected from juvenile fish (mean bwt 118g) and microbial diversity assessed by 16S rDNA amplicon sequencing. Results indicate that alpha diversity was significantly higher in the mid-gut of the susceptible line compared to the resistant line, while no significant differences in alpha diversity were observed in the gills. Mycoplasma sp. was the dominant taxon in the mid-gut of both groups, although it was present at a decreased abundance in the susceptible line. We also observed an increased abundance of taxa that could potentially be pathogenic in the susceptible line, including Brevinema sp. and Enterobacteriaceae members. Within the gills, both lines exhibited similar microbial profiles, with Candidatus Branchiomonas being the dominant taxon. Together, these results suggest that selectively bred Flavobacterium psychrophillum-resistant trout may harness a more resilient gut microbiome, attributing to the disease resistant phenotype, providing a framework for future experiments.

microbiology↗

The comparative biogeography of geckos challenges predictions from a paradigm of climate-driven vicariant diversification across an island archipelago

A primary goal of biogeography is to understand how large-scale environmental processes, like climate change, affect diversification One often-invoked but seldom tested process is the \"species-pump\" model, in which repeated bouts of co-speciation are driven by oscillating climate-induced habitat connectivity cycles. For example, over the past three million years, the landscape of the Philippine Islands has repeatedly coalesced and fragmented due to sea-level changes associated with glacial cycles. This repeated climate-driven vicariance has been proposed as a model of speciation across evolutionary lineages codistributed throughout the islands. This model predicts speciation times that are temporally clustered around the times when interglacial rises in sea level fragmented the islands. To test this prediction, we collected comparative genomic data from 16 pairs of insular gecko populations. We analyze these data in a full-likelihood, Bayesian model-choice framework to test for shared divergence times among the pairs. Our results provide support against the species-pump model prediction in favor of an alternative interpretation, namely that each pair of gecko populations diverged independently. These results suggest the repeated bouts of climate-driven landscape fragmentation has not been an important mechanism of speciation for gekkonid lizards on the Philippine Islands.

evolutionary biology↗