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Johnson, G.

Publications and source records attributed to Johnson, G..

At least 19 recordsLinked to original sources

Predicting taxon-specific benthic cyanobacterial mat cover and anatoxin concentrations in northern California rivers

Ecological forecasts often rely on established relationships between the ecological process of interest and predictor variables that are more easily measured. Proliferations of benthic (i.e., bottom-dwelling) cyanobacteria have been increasingly observed in rivers globally and are an emerging ecological forecasting issue as they pose a public health threat due to the production of potent neurotoxins known as anatoxins. Controls on these benthic cyanobacteria are poorly understood, thus predicting or forecasting their extent and anatoxin production is a significant challenge. Here, we measured benthic cyanobacterial cover and anatoxin concentrations for two common taxa associated with anatoxins (Microcoleus and Anabaena) at biweekly to weekly intervals during June to September in 2022 and 2023 in three northern Californian rivers. We then built predictive models to test how incorporation of a biotic predictor (river reach-scale gross primary productivity [GPP]) affected predictive accuracy in addition to widely measured abiotic predictors (i.e., nutrients, discharge, and temperature). Temporal patterns in taxon-specific benthic cyanobacterial cover and anatoxin concentrations were highly variable among rivers and between taxa. While Microcoleus cover peaked in rivers during periods of relatively low GPP, there were no clear relationships between GPP and Anabaena cover nor anatoxin concentrations of either taxon among rivers. Among multiple reaches sampled weekly in the South Fork Eel River, magnitudes of taxon-specific benthic cyanobacterial cover and anatoxin concentrations differed, but the timing of peak taxon-specific cover and anatoxin concentrations were generally consistent. Furthermore, Anabaena displayed a hysteresis relationship where increases in cover were followed by increases in anatoxin concentrations while Microcoleus lacked such relationship. While incorporating GPP as a covariate improved our predictions of Anabaena cover, we had more success predicting Microcoleus cover than Anabaena cover due to its strong negative relationship with discharge. In contrast, our models predicting Anabaena anatoxin concentrations outperformed those predicting Microcoleus anatoxin concentrations due to the hysteresis relationship between Anabaena cover and anatoxins. Overall, our predictive modeling results highlight the application of ecological forecasting for benthic cyanobacterial cover and anatoxin concentrations in rivers and demonstrate the importance of incorporating taxon-specific predictors into future forecasts of benthic cyanobacteria.

ecology↗

AGC kinase homology requires and enables co-targeting for CNS regeneration

Axon regrowth in the central nervous system (CNS) is constrained by robust regulatory networks. Here we show that optimal neurite outgrowth in rodent and human CNS neurons is achieved by co-inhibition of kinases across four closely related clades within the protein kinase A, G, and C (AGC) family. The kinases derive from ancestral regulators of cytoskeletal dynamics, resource allocation, and polarized cell growth. Their shared domain architecture makes polypharmacology (co-engagement by a single small molecule) feasible. Phenotype-guided optimization of a tool compound with established efficacy in mouse spinal cord injury models yielded TMP-316, a drug candidate engaging these AGC kinases with selectivity against the broader kinome. A single intrathecal dose of TMP-316 produced sustained motor recovery in a rat cervical hemicontusion model. These findings reveal conditions under which polypharmacology is simultaneously required and enabled by shared evolutionary origins, illuminating a therapeutic discovery principle for pathologies governed by functionally overlapping targets.

neuroscience↗

From TD50 to Benchmark Dose in Nitrosamine Risk Assessment: Evidence from N-Nitrosotrimetazidine Carcinogenicity and TGR Mutation Data.

The presence of N-nitrosamine drug substance-related impurities (NDSRIs) in pharmaceuticals represents a significant regulatory and safety challenge due to their classification as "cohort of concern" compounds. This paper describes the toxicological evaluation of N-Nitrosotrimetazidine (NTMZ), performed to refine the initial default acceptable intake (AI) limits of 18 to 26.5 ng/day established by regulatory authorities. The evaluation followed a tiered approach: NTMZ was first confirmed as mutagenic in vitro via the standard Ames test. To further investigate its genotoxic potential, two in vivo studies were conducted in Wistar and transgenic rats. Detection of DNA strand breaks in the liver and duodenum (comet assay) together with positive results in the cII mutation assay confirmed an in vivo mutagenic mode of action. Benchmark Dose (BMD) analysis of the transgenic rat data yielded a BMDL50 of 7 mg/kg/day in the male liver. To characterize long-term carcinogenic risk, a GLP-compliant 2-year carcinogenicity study was conducted in Wistar rats. Chronic exposure induced dose-dependent increases in liver tumors (hemangiosarcomas, hepatocellular carcinomas and adenomas) and intestinal tumors (adenomas and adenocarcinomas), leading to a Tumor Dose 50 (TD50) of 23 mg/kg/day in male rats. Benchmark dose analysis of tumor incidence identified a lowest BMDL10 of 2.6 mg/kg/day in females, which served as the basis for deriving an AI of 13 microg/day. This assessment demonstrates a strong predictive correlation between the BMD derived from the in vivo transgenic model, the BMDL10 and the final TD50 values obtained in the 2-year carcinogenicity study. These findings provided the scientific basis for establishing a conservative AI of 13 microg/person/day based on the BMDL10 and further support the regulatory acceptance and use of BMD-derived approaches for the evaluation of nitrosamine impurities.

pharmacology and toxicology↗

Overcoming Daraxonrasib Resistance: Allele-Specific Mechanisms Guide Salvage Therapy in Pancreatic Cancer

Clinical-grade RAS inhibitors raise an unresolved question as to whether KRAS-alleles impose constraints on adaptive resistance that can be exploited therapeutically. Using daraxonrasib (RMC-6236), a multi-selective RAS(ON) inhibitor, we compared resistance mechanisms between KRASG12D and KRASG12R, alleles with fundamentally different RAS network dynamics. Daraxonrasib inhibited KRASMUT primarily through steric occlusion of effector binding, while engaging RASWT only modestly ([~]20%). KRASG12R is marked by its inability to transactivate RASWT, and it was observed that daraxonrasib resistant KRASG12R PDAC cells utilize EGFR/RASWT-GTP signaling as the dominant adaptive route. In contrast, KRASG12D resistance arose through retained KRASG12D-GTP signaling, with a decrease of cyclophilin A (CypA) protein, the binding partner required for daraxonrasib activity. The shift from KRASG12R dependence to the EGFR/RASWT conferred sensitivity to trametinib. We confirmed this clinically: a KRASG12R PDAC patient who progressed after 10 months on daraxonrasib showed intratumoral EGFR/RASWT activation, and rapid 3D-bioprinted patient-derived toroid modeling predicted sensitivity to trametinib-based combination therapy. Given the aggressive disease trajectory and lack of response to the two immediately preceding lines of therapy, sixth-line trametinib-based combination therapy achieved approximately 5 months of disease control. This patient ultimately achieved 40 months of overall survival, far exceeding the 8-12 month median for metastatic PDAC. Collectively, these data establish a framework in which allele-specific RAS network topology dictates the adaptive resistance landscape, enabling rational selection of targeted therapies with meaningful clinical benefit in metastatic PDAC. STATEMENT OF SIGNIFICANCEDaraxonrasib resistance mechanisms have allele-specific routes: CypA becomes downregulated in KRASG12D and reliance on EGFR/RASWT in KRASG12R. Rapid patient-derived toroids identified sixth-line targeted therapy strategies with an overall survival of 40 months.

cancer biology↗

Epigenetic Reactivation of Lineage Differentiation to Target Leukemia

Chromatin regulation critically influences gene expression and cancer progression, yet the functions of chromatin adaptors remain incompletely defined. Using focused CRISPR screening, we identified TRIM28, a multi-domain chromatin adaptor, as a dependency in acute leukemia, where its depletion impaired leukemia cell proliferation in vitro and in vivo, while activating neutrophil differentiation programs. Integrative transcriptomic and chromatin profiling revealed that TRIM28 acts as a co-repressor of neutrophil-associated loci independently of H3K9 methylation, and that TRIM28 loss drives terminal differentiation of leukemia cells into functionally mature neutrophil-like cells with reduced leukemic potential. We developed a selective small-molecule TRIM28 inhibitor that binds the TRIM28 PHD-bromodomain, phenocopies TRIM28 loss across biochemical and cellular assays, exhibits low micromolar anti-leukemia activity, induces neutrophil differentiation, and synergizes with Menin inhibition. Together, these findings, spanning target discovery, mechanism of action, and chemical probe development, establish TRIM28 as a regulator of myeloid cell fate and a promising pro-differentiation therapeutic target in acute leukemia.

cancer biology↗

Spatiotemporal biogenesis of thylakoid membranes in the green alga Chlamydomonas reinhardtii

Thylakoid membranes are essential for oxygenic photosynthesis, yet the mechanisms underlying their spatial and temporal biogenesis remain poorly understood. Here, using a light-induced membrane regeneration system in Chlamydomonas reinhardtii, we generate a time-resolved map of thylakoid formation and photosynthetic complex assembly at unprecedented spatial and temporal resolution by integrating super-resolution fluorescence microscopy, cryo-electron tomography, proteomics, and spectroscopy. We show that thylakoid biogenesis is globally distributed and multipolar, with new membrane formation occurring at multiple sites across the chloroplast, including regions adjacent to the inner envelope membranes in both basal and lobe regions. We identify F-ATP synthase storage membranes and map the redistribution of translating ribosomes from T-zone enrichment to a chloroplast-wide distribution at early stages of thylakoid formation, consistent with decentralized synthesis of photosynthetic complexes. We further delineate the hierarchical assembly of photosystem supercomplexes, starting with formation of reaction centers. Together, these findings refine the spatial organization of photosynthetic membrane biogenesis and establish a unified spatiotemporal framework linking thylakoid formation, translational activation, and functional maturation, providing a mechanistic basis for plastid engineering to enhance photosynthetic efficiency.

Cell Biology↗

Discovery and Preclinical Validation of a Clinically Optimized Mitochondrial Complex I Modulator for Alzheimer's Disease

Alzheimers disease (AD) is characterized by diminished capacity to mount adaptive cellular stress responses required to maintain energy homeostasis and proteostasis. An emerging therapeutic strategy is to restore adaptive stress responses by inducing mild energetic stress through inhibition of mitochondrial complex I (mtCI). However, pharmacological inhibition of the respiratory chain has remained challenging, as it can induce bioenergetic failure rather than beneficial signaling. Here, we describe C273, a brain-penetrant small molecule that delivers controlled, weak attenuation of mtCI activity to therapeutically restore endogenous adaptive stress pathways. This work establishes a first-in-class mechanism in which calibrated activation of multifaceted adaptive mechanisms enhances cellular resilience, rather than impairing mitochondrial function. Structure-activity relationship optimization yielded a compound with high potency against A{beta}-induced cellular toxicity, strong selectivity for mtCI, and favorable drug-like properties. C273 demonstrated excellent oral bioavailability, metabolic stability in mouse, rat, and human microsomes, minimal CYP liabilities, and a clean ancillary pharmacology profile in the Eurofins CEREP44 panel. In vivo, C273 readily crosses the blood-brain barrier and activates AMP-activated protein kinase (AMPK), initiating a coordinated hormetic response characterized by enhanced antioxidant defenses, suppression of inflammatory signaling, induction of autophagy, and increased mitochondrial biogenesis and turnover. Genetic deletion of AMPK1/2 abolished these responses, establishing AMPK as a critical mediator of C273 activity. Pharmacological competition experiments further confirmed the target, as pretreatment with non-toxic concentrations of rotenone blocked C273 interaction with the quinone-binding site of mtCI and eliminated its neuroprotective effects. Repeated oral administration of C273 (20-80 mg/kg/day) to wild-type mice for one month produced no detectable cardiac or hepatic toxicity, indicating a favorable in vivo safety margin. Importantly, C273 activated these mechanisms and reduced A{beta} and p-Tau levels in induced pluripotent stem cell-derived cerebral organoids from patients with sporadic AD. Collectively, these results establish controlled mtCI modulation as a therapeutic strategy and position C273 as a promising disease-modifying candidate for AD.

neuroscience↗

Investigating the use of human COVID-19 rapid assays to detect antibody and antigen in domesticated dogs (Canis lupus familiaris) and cats (Felis catus)

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus that causes coronavirus disease-2019 (COVID-19) in humans, is also known to infect animals including dogs (Canis lupus familiaris) and cats (Felis catus). This study evaluated the efficacy of human COVID-19 rapid antigen and antibody tests in dogs and cats. Nasal/oral swabs from 60 animals (32 dogs, 28 cats) and serum from 40 animals (20 dogs, 20 cats) were tested. Rapid antigen tests used on respiratory swabs showed low-to-moderate sensitivity (75% dogs, 57% cats) and moderate-to-high specificity (79% dogs, 95% cats) compared to RT-PCR. Rapid antibody tests used on serum samples demonstrated low-to-moderate sensitivity (70% dogs, 50% cats) and moderate-high specificity (60% dogs, 100% cats) compared to PRNT. While imperfect, these test kits may have some utility for field surveillance studies, particularly when species-specific rapid SARS-CoV-2 assays for dogs and cats are unavailable. These test characteristics in dogs and cats are similar to the findings from studies of the same types of tests in humans which have found an average sensitivity and specificity of common commercially available kits in the US range from 50.0-84.3% and 64.5-74.3%, respectively, when used with human samples (1,2).

zoology↗

Two axolotl-adapted cell-ablation platforms reveal macrophage-dependent processes essential for spinal-cord and skeletal regeneration

The axolotl (Ambystoma mexicanum) has emerged as the premier model organism for studying scarless repair and adult tissue regeneration, supported by an expanding collection of tissue-specific transgenic lines and translucent skin that enables high-quality live imaging and cell tracking. However, functional characterization of specific cell types during regeneration has been limited by the absence of validated cell-specific ablation systems. Here, we developed and rigorously compared two independent inducible genetic cell-ablation platforms -- bacterial nitroreductase (NTR 2.0) and mammalian inducible caspase-9 (iCasp9), across developmental stages, animal sizes, and administration routes using various transgenic lines and grafting approaches. The NTR 2.0 platform showed limited applicability due to drug toxicity and solubility constraints, restricting its use primarily to larval stages via immersion. In contrast, the iCasp9 system demonstrated superior efficacy across all life stages, including large adults, with multiple viable administration routes. We further validated these platforms by systematically ablating CD68+ macrophages and examined functional consequences during tail regeneration. Sustained depletion revealed essential macrophage-dependent processes despite continuous macrophage repopulation from hematopoietic reservoirs: skeletal-element regeneration was completely abolished, spinal-cord axons degenerated without recovery, and neural crest-derived cells exhibited severe disorganization. These findings establish macrophages as critical orchestrators of central and peripheral nervous-system regeneration and skeletogenesis in axolotls, while providing validated tools for cell-type-specific functional studies across the axolotl lifespan.

developmental biology↗

A Course-Undergraduate Research Experience (CURE) to explore the effect of structural variants on gene expression in C. elegans balancers

Bioinformatics, a discipline at the crossroads of Biology and Computational Sciences, also referred to as Computational Biology, is nowadays widely spread in research programs. However, implementing any Bioinformatics projects requires the ability to comprehend biological concepts and apply computational approaches, and rare are the undergraduate programs offering such multi-disciplinary training. In addition, understanding the dynamic between Biology research projects and Bioinformatics analyses is challenging with no real-life experience. Course-based undergraduate research experience (CURE) courses are innovative programs that allow more students to acquire research experience and provide the perfect setting to introduce students to applied bioinformatics. As a part of the Bachelor of Health Sciences of the Cumming School of Medicine at the University of Calgary (Canada), a CURE applied bioinformatics was implemented in the Winter of 2023 to 2025. Students investigated the effect of structural variants (SVs, genetic variants larger than 50 bp) on gene expression in the model organism Caenorhabditis elegans (a hermaphrodite 1-mm long roundworm). The students detected and characterized SVs by analyzing genome and transcriptome sequencing data of C. elegans strains called balancers, as they are known to carry large genomic variations balancing regions of the genome by limiting recombination and allowing maintenance of lethal mutations. They used Galaxy, a public web-based supercomputing resource, but also a local High-Performance computing system, and R, to report different effects of SVs on gene expression and splicing. Students research explained the molecular mechanism behind the uncoordinated phenotype caused by the reciprocal translocation eT1(III;V) and uncovered unexpected effects on gene expression on an understudied gene. We evaluated the courses impact on student learning journeys and showed that the CURE favored students understanding of the Bioinformatics field and fostered their research interest. We provide here guidelines to facilitate the CURE implementations to improve access for undergraduate students to bioinformatics research experiences.

bioinformatics↗

Traumatic Brain Injury Exacerbates Alcohol Consumption and Neuroinflammation with Decline in Cognition and Cholinergic Activity

Traumatic brain injury (TBI) is a global health challenge, responsible for 30% of injury-related deaths and significantly contributing to disability. Annually, over 50 million TBIs occur worldwide, with most adult patients at emergency departments showing alcohol in their system. TBI is also a known risk factor for alcohol abuse, yet its interaction with alcohol consumption remains poorly understood. In this study, we demonstrate that the fluid percussion injury (FPI) model of TBI in mice significantly increases alcohol consumption and impairs cognitive function. At cellular levels, FPI markedly reduced the number and activity of striatal cholinergic interneurons (CINs) while increasing microglial cells. Notably, depleting microglial cells provided neuroprotection, mitigating cholinergic loss and enhancing cholinergic activity. These findings suggest that TBI may promote alcohol consumption and impair cognitive abilities through microglia activation and consequently reduced cholinergic function. Our research provides critical insights into the mechanisms linking TBI with increased alcohol use and cognitive deficits, potentially guiding future therapeutic strategies.

neuroscience↗

4D hybrid model interrogates agent-level rules and parameters driving hiPS cell colony dynamics

Iterating between data-driven research and generative computational models is a powerful approach for emulating biological systems, testing hypotheses, and gaining a deeper understanding of these systems. We developed a hybrid agent-based model (ABM) that integrates a Cellular Potts Model (CPM) designed to investigate cell shape and colony dynamics in human induced pluripotent stem cell (hiPS cell) colonies. This model aimed to first mimic and then explore the dynamics observed in real-world hiPS cell cultures. Initial outputs showed great potential, seeming to mimic small colony behaviors relatively well. However, longer simulations and quantitative comparisons revealed limitations, particularly with the CPM component, which lacked long-range interactions that might be necessary for accurate simulations. This challenge led us to thoroughly examine the hybrid models potential and limitations, providing insights and recommendations for systems where cell-wide mechanics play significant roles. The CPM supports 2D and 3D cell shapes using a Monte Carlo algorithm to prevent cell fragmentation. Basic "out of the box" CPM Hamiltonian terms of volume and adhesion were insufficient to match live cell imaging of hiPS cell cultures. Adding substrate adhesion resulted in flatter colonies, highlighting the need to consider environmental context in modeling. High-throughput parameter sweeps identified regimes that produced consistent simulated shapes and demonstrated the impact of specific model decisions on emergent dynamics. Full-scale simulations showed that while certain agent rules could form a hiPS cell monolayer in 3D, they could not maintain it over time. Our study underscores that "out of the box" 3D CPMs, which do not natively incorporate long-range cell mechanics like elasticity, may be insufficient for accurately simulating hiPS cell and colony dynamics. To address this limitation, future work could add mechanical constraints to the CPM Hamiltonian or integrate global agent rules. Alternatively, replacing the CPM with a methodology that directly represents cell mechanics might be necessary. Documenting and sharing our model development process fosters open team science and supports the broader research community in developing computational models of complex biological systems.

systems biology↗

Misspellings or miscellings- non-verifiable cell lines in cancer research publications

Reproducible laboratory research relies on correctly identified reagents. We have previously described human gene research papers with wrongly identified nucleotide sequence reagent(s), including papers studying miR-145. Manually verifying reagent identities in more recent miR-145 papers found 20/36 (56%) and 6/36 (17%) miR-145 papers with misidentified nucleotide sequence reagent(s) and human cell line(s), respectively. We also found 5 cell line identifiers in two miR-145 papers with wrongly identified nucleotide sequences and cell lines, and 18 identifiers published elsewhere that did not correspond to indexed cell lines. These cell line identifiers were described as non-verifiable, as their identities appeared uncertain. Studying 420 papers that mentioned 8 different non-verifiable cell line identifier(s) found 235 papers (56%) that appeared to refer to BGC-803, BSG-803, BSG-823, GSE-1, HGC-7901, HGC-803 and/or MGC-823 as independent cell lines. We could not find publications describing how these cell lines were established, and they were not indexed in claimed externally accessible cell line repositories. While some papers stated that STR profiles had been generated for BGC-803, GSE-1 and/or MGC-823 cells, no STR profiles were identified. In summary, non-verifiable human cell lines represent new challenges to research reproducibility and require further investigation to clarify their identities. Novelty and Impact StatementThrough verifying reagent identities in research publications, our team found 23 non-verifiable human cell line identifiers, most of which could represent misspellings of contaminated cancer cell lines. Of 8 identifiers studied in detail, 7 non-verifiable identifiers were unexpectedly referred to as independent cell lines across 235 publications. We therefore describe a process "miscelling", where published cell lines lack descriptions of how they were established, cannot be found in claimed external repositories and lack STR profiles.

cancer biology↗

A phylogenomic approach, combined with morphological characters gleaned via machine learning, uncovers the hybrid origin and biogeographic diversification of the plum genus

The evolutionary histories of species have been shaped by genomic, environmental, and morphological variation. Understanding the interactions among these sources of variation is critical to infer accurately the biogeographic history of lineages. Here, using the geographically widely distributed plum genus (Prunus, Rosaceae) as a model, we investigate how changes in genomic and environmental variation drove the diversification of this group, and we quantify the morphological features that facilitated or resulted from diversification. We sequenced 587 nuclear loci and complete chloroplast genomes from 99 species representing all major lineages in Prunus, with a special focus on the understudied tropical racemose group. The environmental variation in extant species was quantified by synthesizing bioclimatic variables into principal components of environmental variation using thousands of georeferenced herbarium specimens. We used machine learning algorithms to classify and measure morphological variation present in thousands of digitized herbarium sheet images. Our phylogenomic and biogeographic analyses revealed that ancient hybridization and/or allopolyploidy spurred the initial rapid diversification of the genus in the early Eocene, with subsequent diversification in the north temperate zone, neotropics, and paleotropics. This diversification involved successful transitions between tropical and temperate biomes, an exceedingly rare event in woody plant lineages, accompanied by morphological changes in leaf and reproductive morphology. The machine learning approach detected morphological variation associated with ancient hybridization and quantified the breadth of morphospace occupied by major lineages within the genus. The paleotropical lineages of Prunus have diversified steadily since the late Eocene/early Oligocene, while the neotropical lineages diversified much later. Critically, both the tropical and temperate lineages have continued to diversify. We conclude that the genomic rearrangements created by reticulation deep in the phylogeny of Prunus may explain why this group has been more successful than other groups with tropical origins that currently persist only in either tropical or temperate regions, but not both.

evolutionary biology↗

Model-based deconvolution for DSC-MRI: A comparison of accuracy, precision, and computational complexity of parametric transit time distributions

ObjectDynamic susceptibility contrast MRI (DSC-MRI) is the current standard for cerebral perfusion estimation. Model-dependent approaches for DSC-MRI analysis involve assuming a parametric transit time distribution (TTD) to characterize the passage of contrast agent through tissue microvasculature. Here we compare the utility of four TTD models: namely, skewed-Gaussian, gamma, gamma-variate, and Weibull, to identify the optimal TTD for quantifying brain perfusion. Materials and MethodsDSC-MRI data were acquired in nine subjects at 1.5T, and normal-appearing white- and gray-matter signals were assessed. TTDs were compared in terms of: goodness-of-fit, evaluated using RMSE; noise sensitivity, assessed via Monte-Carlo-simulated noisy conditions; and fit stability, quantified as the proportion of total fits converging to the global minimum. Computation times for model-fitting were also calculated. ResultsThe gamma TTD showed higher fit stability, shorter computation times (p<0.008), and higher robustness against experimental noise as compared to other models. All functions showed similar RMSEs and the parameter estimates (p>0.008) were congruent with literature values. DiscussionThe gamma distribution represents the most suitable TTD for perfusion analysis. Moreover, due to its robustness against noise, the gamma TTD is expected to yield more reproducible estimates than the other models for establishing a standard, multi-center analysis pipeline.

neuroscience↗

Extremely low sample size allows age and growth estimation in a rare and threatened shark

Understanding life history parameters is key to assessing biological productivity, extinction risk, and informing the management of exploited fish populations. Age-and-growth analyses in chondrichthyan fishes (sharks, rays, and ghost sharks) is primarily undertaken through counting band pairs laid down in vertebrae. For rare, threatened, and protected species such as river sharks (family Carcharhinidae; genus Glyphis) of northern Australia, obtaining sufficient samples of vertebrae may not be possible. Here we use a very sample size, selective size-class sampling, and back-calculation techniques to provide age and growth data on the Speartooth Shark Glyphis glyphis from which comprehensive sampling is not possible. Ten individuals were sampled from the Adelaide River, Northern Territory, Australia. Length-at-age models were applied to the observed and back-calculated data with the sexes combined due to the small sample size and growth estimated using a multi-model framework. Band pair counts produced age estimates of 0-11 years. Most model parameter estimates for length-at-birth (L0) and asymptotic length (L{infty}) were biologically plausible. The model averaged parameters for the observed data were [Formula] total length (TL) and [Formula] TL, and for back-calculated data were [Formula] TL and [Formula] TL. Overall, the parameter standard errors and model residual standard errors were lower for the back-calculated data due to the addition of interpolated data. Analysed samples were restricted to juveniles and sub-adults as adult G. glyphis have not been encountered in the Northern Territory. The ageing results suggest an age-at-maturity of >12 years for this species. The lack of mature individuals in the sample means that this analysis should be considered as a partial growth curve with length-at-age estimates that are valid over the available age range. The results presented here provide the first age and growth estimation for river sharks.

zoology↗

M-Risk: A framework for assessing global fisheries management efficacy of sharks, rays, and chimaeras

Fisheries management is essential to guarantee sustainable capture of target species and avoid undesirable declines of incidentally captured species. A key challenge is halting and reversing declines of shark and ray species, and specifically assessing the degree to which management is sufficient to avoid declines in relatively data-poor fisheries. While ecological risk analyses focus on intrinsic productivity and extrinsic susceptibility, one would ideally consider the influence of fisheries management. Currently, there is no single management evaluation that can be applied to a combination of fishery types at the scale of individual country or Regional Fisheries Management Organisations (RFMOs). Here, we outline a management risk (M-Risk) framework for sharks, rays, and chimaeras used to evaluate species risk to overfishing resulting from ineffective management. We illustrate our approach with application to one country (Ecuador) and RFMO (Inter-American Tropical Tuna Commission) and illustrate the variation in scores among species. We found that while both management units assessed had similar overall scores, the scores for individual attributes varied. Ecuador scored higher in reporting-related attributes, while the IATTC scored higher in attributes related to data collection and use. We evaluated whether management of individual species was sufficient for their relative sensitivity by combining the management risk score for each species with their intrinsic sensitivity to determine a final M-Risk score. This framework can be applied to determine which species face the greatest risk of overfishing and be used by fisheries managers to identify effective management policies by replicating regulations from countries with lower risk scores.

ecology↗

Preventing ovariectomy-induced weight gain decreases tumor burden in rodent models of obesity and postmenopausal breast cancer.

Obesity and adult weight gain are linked to increased breast cancer risk and poorer clinical outcomes in postmenopausal women, particularly for hormone-dependent tumors. Menopause is a time when significant weight gain occurs in many women, and clinical and preclinical studies have identified menopause (or ovariectomy) as a period of vulnerability for breast cancer development and promotion. We hypothesized that preventing weight gain after ovariectomy (OVX) may be sufficient to prevent the formation of new tumors and decrease growth of existing mammary tumors. Here, we tested this hypothesis in a rat model of obesity and carcinogen-induced postmenopausal mammary cancer and validated our findings in a murine xenograft model with implanted human tumors. In both models, preventing weight gain after OVX significantly decreased obesity-associated tumor development and growth. Importantly, we did not induce weight loss in these animals, but simply prevented weight gain. In both lean and obese rats, preventing weight gain reduced visceral fat accumulation and associated insulin resistance. Similarly, the intervention decreased circulating tumor-promoting growth factors and inflammatory cytokines (ie, BNDF, TNF, FGF2), with greater effects in obese compared to lean rats. In obese rats, preventing weight gain decreased adipocyte size, adipose tissue macrophage infiltration, reduced expression of the tumor-promoting growth factor FGF-1, and reduced phosphorylated FGFR in tumors. Together, these findings suggest that the underlying mechanisms associated with the anti-tumor effects of weight maintenance are multifactorial, and that weight maintenance during the peri-/post-menopausal period may be a viable strategy for reducing obesity-associated breast cancer risk and progression in women.

cancer biology↗