Biology subjects

Hines, J.

Publications and source records attributed to Hines, J..

13 recordsLinked to original sources

bioRxiv2026

Forest degradation reshapes trophic functioning in vertebrate food webs across Amazonian forests

The Amazon is a mosaic of ecosystems, accounting for 13% of all known species globally, and responsible for providing a variety of ecosystem services, including a key role in global climate regulation. However, 18% of the Amazon forest cover has been lost completely and a further 38% degraded, threatening biodiversity and millions of local livelihoods. Currently, little is known about how this impacts the functioning of ecological communities. Here, we combine an energetic approach with biodiversity metrics to quantify ecosystem functioning in mammal and bird food webs across Amazonia, along a gradient of forest degradation linked to road proximity. We show that even under relatively low disturbance, ecosystem functions shift: carnivory increases closer to roads, driven by generalist species that persist under these conditions, whereas herbivory declines mainly due to reduced herbivore biomass and species richness. This suggests that processes associated with forest degradation can alter energy flow even where biodiversity metrics remain relatively unchanged, highlighting energetic approaches as sensitive indicators of ecosystem disruption.

ecology↗

bioRxiv2025

Bidirectional Crosstalk Between Bladder Cancer Cells and Normal Fibroblasts Drives Phenotypic Reprogramming and Modulates Chemosensitivity

During early bladder cancer progression, invading tumour cells first encounter normal fibroblasts (NFs) residing in the lamina propria. Whether and how this interaction shapes tumour behaviour and treatment response, however, has not been systematically examined. While cancer-associated fibroblasts (CAFs) are established drivers of tumour progression and therapy resistance, the role of their precursor NFs in shaping bladder cancer behaviour has been largely overlooked. Here we dissect bidirectional interactions between bladder cancer cells and NFs using indirect (conditioned media) and direct co-culture systems. Fibroblast-conditioned media (FCM) significantly reduced proliferation while accelerating migration in both RT112 and T24 bladder cancer cells, consistent with a pro-migratory "go-or-grow" phenotypic shift. Immunofluorescence revealed FCM-induced cadherin switching reduced E-cadherin and elevated N-cadherin, indicative of an epithelial-to-mesenchymal transition (EMT)-like state. Reciprocally, NFs acquired CAF-like features within 48 hours of tumour cell exposure, with significant upregulation of SMA and FAP confirmed by both immunofluorescence and flow cytometry. Functionally, increasing fibroblast-to-cancer cell ratio progressively attenuated mitomycin C (MMC)-induced cytotoxicity, demonstrating a stromal-mediated, ratio-dependent protective effect against intravesical chemotherapy. Data from the Cancer Genome Atlas (TCGA) for Urothelial Bladder Carcinoma provided corroboratory evidence that fibroblast-enriched tumours exhibited a strong transcriptional correlation with EMT, elevated resistance-associated transcriptional signatures, and significantly poorer overall survival. Collectively, these findings establish tumour-NF crosstalk as a critical and bidirectional regulator of bladder cancer phenotypic plasticity and chemoresistance, and suggest that fibroblast-targeting strategies combined with intravesical chemotherapy may offer a rational approach to overcoming stromal-mediated treatment failure.

cancer biology↗

bioRxiv2023

Regulated Induced Proximity Targeting Chimeras (RIPTACs): a Novel Heterobifunctional Small Molecule Therapeutic Strategy for Killing Cancer Cells Selectively

While specific cell signaling pathway inhibitors have yielded great success in oncology, directly triggering cancer cell death is one of the great drug discovery challenges facing biomedical research in the era of precision oncology. Attempts to eradicate cancer cells expressing unique target proteins, such as antibody-drug conjugates (ADCs), T-cell engaging therapies, and radiopharmaceuticals have been successful in the clinic, but they are limited by the number of targets given the inability to target intracellular proteins. More recently, heterobifunctional small molecules such as Proteolysis Targeting Chimera (PROTACs) have paved the way for protein proximity inducing therapeutic modalities. Here, we describe a proof-of-concept study using novel heterobifunctional small molecules called Regulated Induced Proximity Targeting Chimeras or RIPTACs, which elicit a stable ternary complex between a target protein selectively expressed in cancer tissue and a pan-expressed protein essential for cell survival. The resulting cooperative protein:protein interaction (PPI) abrogates the function of the essential protein, thus leading to cell death selectively in cells expressing the target protein. This approach not only opens new target space by leveraging differentially expressed intracellular proteins but also has the advantage of not requiring the target to be a driver of disease. Thus, RIPTACs can address non-target mechanisms of resistance given that cell killing is driven by inactivation of the essential protein. Using the HaloTag7-FKBP model system as a target protein, we describe RIPTACs that incorporate a covalent or non-covalent target ligand connected via a linker to effector ligands such as JQ1 (BRD4), BI2536 (PLK1), or multi-CDK inhibitors such as TMX3013 or dinaciclib. We show that these RIPTACs exhibit positive co-operativity, accumulate selectively in cells expressing HaloTag7-FKBP, form stable target:RIPTAC:effector trimers in cells, and induce an anti-proliferative response in target-expressing cells. We propose that RIPTACs are a novel heterobifunctional therapeutic modality to treat cancers that are known to selectively express a specific intracellular protein.

cancer biology↗

bioRxiv2022

Landscape heterogeneity and soil biota are central to multi-taxa diversity for landscape restoration

How to enhance biodiversity in monoculture-dominated landscapes is a key sustainability question that requires considering the spatial organization of ecological communities (beta diversity). Here, we experimentally tested if increasing landscape heterogeneity - through tree islands - is a suitable landscape restoration strategy when aiming to enhance multi-taxa diversity. We found that multi-taxa diversity resulted from islands fostering unique species (turnover: between 0.18 - 0.73) rather than species losses and gains (nestedness: between 0.03 - 0.34), suggesting that tree islands enhance diversity at the landscape scale. Through partial correlation networks, we revealed that landscape heterogeneity is associated with multi-taxa diversity (strength = 0.84). Soil biota were also central to the overall community by connecting beta diversity patterns across taxa. Our results show that increasing landscape heterogeneity enhances multi-taxa diversity in monoculture-dominant landscapes. Furthermore, we highlight that strategies aiming to enhance multi-taxa diversity should consider that spatial distributions of above- and below-ground communities are associated.

ecology↗

bioRxiv2022

Hijacking Methyl Reader proteins for Nuclear-Specific Protein Degradation

Targeted protein degradation (TPD) by PROTACs is a promising strategy to control disease-causing protein levels within the cell. While TPD is emerging as an innovative drug discovery paradigm, there are currently only a limited number of E3 ligase: ligand pairs that are employed to induce protein degradation. Herein, we report a novel approach to induce protein degradation by hijacking a methyl reader: E3 ligase complex. L3MBTL3 is a methyl lysine reader protein that binds to the Cul4DCAF5 E3 ligase complex and targets methylated proteins for proteasomal degradation. By co-opting this natural mechanism, we report the design and biological evaluation of L3MBTL3-recruiting PROTACs and demonstrate nuclear-specific degradation of FKBP12 and BRD2. We envision this as a generalizable approach to utilize other reader protein-associated E3 ligase complexes in PROTAC design to expand the E3 ligase toolbox and explore the full potential of TPD.

pharmacology and toxicology↗

bioRxiv2020

Identification of subfunctionalized aggregate-remodeling J-domain proteins in plants

Hsp70s and J-domain proteins (JDPs) are among the most critical components of the cellular protein quality control machinery, playing crucial roles in preventing and solubilizing cytotoxic protein aggregates. Bacteria, yeast and plants additionally have large, multimeric Hsp100-class disaggregases which, allow the resolubilization of otherwise "dead-end" aggregates, including amyloids. JDPs interact with aggregated proteins and specify the aggregate remodeling activities of Hsp70s and Hsp100s. Plants have a complex network of cytosolic Hsp70s and JDPs, however the aggregate remodeling properties of plant JDPs are not well understood. Here we identify evolutionary-conserved Class II JDPs in the model plant Arabidopsis thaliana with distinct aggregate remodeling functionalities. We identify eight plant orthologs of the yeast protein, Sis1, the principal JDP responsible for directing the yeast chaperone machinery for remodeling protein aggregates. Expression patterns vary dramatically among the eight paralogous proteins under a variety of stress conditions, indicating their subfunctionalization to address distinct stressors. Consistent with a role in solubilizing cytotoxic protein aggregates, six of these plant JDPs associate with heat-induced protein aggregates in vivo as well as colocalize with plant Hsp101 to distinct heat-induced protein aggregate centers. Finally, we show that these six JDPs can differentially remodel multiple model protein aggregates in yeast confirming their involvement in aggregate resolubilization. These results demonstrate that compared to complex metazoans, plants have a robust network of JDPs involved in aggregate remodeling activities with the capacity to process a variety of protein aggregate conformers.

molecular biology↗

bioRxiv2020

Mutant-selective Degradation by BRAF-targeting PROTACs

Over 300 BRAF missense mutations have been identified in patients, yet currently approved drugs target V600 mutants alone. Moreover, acquired resistance inevitably emerges, primarily due to RAF lesions that prevent inhibition of BRAF V600 with current treatments. Therefore, there is a need for new therapies that target other mechanisms of activated BRAF. In this study, we use the Proteolysis Targeting Chimera (PROTAC) technology, which promotes ubiquitination and degradation of neo-substrates, to address the limitations of BRAF inhibitor-based therapies. Using vemurafenib-based PROTACs, we successfully achieve sub-nanomolar degradation of all classes of BRAF mutants, but spare degradation of WT RAF family members. Our lead PROTAC outperforms vemurafenib in inhibiting cancer cell growth and shows in vivo efficacy in a Class 2 BRAF xenograft model. Mechanistic studies reveal that BRAFWT is spared due to weak ternary complex formation in cells owing to its quiescent inactivated conformation, and activation of BRAFWT sensitizes it to degradation. This study highlights the degree of selectivity achievable using degradation-based therapies by targeting mutant BRAF-driven cancers while sparing BRAFWT and thus expanding the therapeutic window using a new anti-tumor drug modality.

cancer biology↗

bioRxiv2019

A cross-scale assessment of productivity-diversity relationships

AimBiodiversity and ecosystem productivity vary across the globe and considerable effort has been made to describe their relationships. Biodiversity-ecosystem functioning research has traditionally focused on how experimentally controlled species richness affects net primary productivity (S[->]NPP) at small spatial grains. In contrast, the influence of productivity on richness (NPP[->]S) has been explored at many grains in naturally assembled communities. Mismatches in spatial scale between approaches have fostered debate about the strength and direction of biodiversity-productivity relationships. Here we examine the direction and strength of productivitys influence on diversity (NPP[->]S) and of diversitys influence on productivity (S[->]NPP), and how this varies across spatial grains. Locationcontiguous USA Time period1999 - 2015 Major taxa studiedwoody species (angiosperms and gymnosperms) MethodsUsing data from North American forests at grains from local (672 m2) to coarse spatial units (median area = 35,677 km2), we assess relationships between diversity and productivity using structural equation and random forest models, while accounting for variation in climate, environmental heterogeneity, management, and forest age. ResultsWe show that relationships between S and NPP strengthen with spatial grain. Within each grain, S[->]NPP and NPP[->]S have similar magnitudes, meaning that processes underlying S[->]NPP and NPP[->]S either operate simultaneously, or that one of them is real and the other is an artifact. At all spatial grains, S was one of the weakest predictors of forest productivity, which was largely driven by biomass, temperature, and forest management and age. Main conclusionsWe conclude that spatial grain mediates relationships between biodiversity and productivity in real-world ecosystems and that results supporting predictions from each approach (NPP[->]S and S[->]NPP) serve as an impetus for future studies testing underlying mechanisms. Productivity-diversity relationships emerge at multiple spatial grains, which should widen the focus of national and global policy and research to larger spatial grains.

ecology↗

bioRxiv2019

Neuronal Activity Enhances mRNA Localization to Myelin Sheaths During Development

Myelin is a specialized membrane produced by oligodendrocytes that insulates and supports axons. Oligodendrocytes extend numerous cellular processes, as projections of the plasma membrane, and simultaneously wrap multiple layers of myelin membrane around target axons. Notably, myelin sheaths originating from the same oligodendrocyte are variable in size, suggesting local mechanisms regulate myelin sheath growth. Purified myelin contains ribosomes and hundreds of mRNAs, supporting a model that mRNA localization and local protein synthesis regulate sheath growth and maturation. However, the mechanisms by which mRNAs are selectively enriched in myelin sheaths are unclear. To investigate how mRNAs are targeted to myelin sheaths, we tested the hypothesis that transcripts are selected for myelin enrichment through consensus sequences in the 3 untranslated region (3 UTR). Using methods to visualize mRNA in living zebrafish larvae, we identified candidate 3 UTRs that were sufficient to localize mRNA to sheaths and enriched near growth zones of nascent membrane. We bioinformatically identified motifs common in 3 UTRs from three myelin-enriched transcripts and determined that these motifs are required for mRNA transport to myelin sheaths. Finally, we show that one motif is highly enriched in the myelin transcriptome, suggesting that this sequence is a global regulator of mRNA localization during developmental myelination.

neuroscience↗

bioRxiv2018

Biodiversity trends are stronger in marine than terrestrial assemblages

Human activities have fundamentally altered biodiversity. Extinction rates are elevated and model projections suggest drastic biodiversity declines. Yet, observed temporal trends in recent decades are highly variable, despite consistent change in species composition. Here, we uncover clear spatial patterns within this variation. We estimated trends in the richness and composition of assemblages in over 50,000 time-series, to provide the most comprehensive assessment of temporal change in biodiversity across the planet to date. The strongest, most consistent pattern shows compositional change dominated by species turnover, with marine taxa experiencing up to fourfold the variation in rates of change of terrestrial taxa. Richness change ranged from no change to richness gains or losses of ~10% per year, with tropical marine biomes experiencing the most extreme changes. Earth is undergoing a process of spatial reorganisation of species and, while few areas are unaffected, biodiversity change is consistently strongest in the oceans.

ecology↗

bioRxiv2018

The geography of the Anthropocene differs between the land and the sea

O_LIClimate change and other anthropogenic drivers of biodiversity change are unequally distributed across the world. The geographic patterns of different drivers, and the spatial overlap among these drivers, have important implications for the direction and pace of biodiversity change, yet are not well documented. Moreover, it is unknown if the geographic patterns of drivers differ between the terrestrial and marine realm, as expected due to marked differences in how humans interact with the land and ocean. C_LIO_LIWe compiled global gridded datasets on climate change, land-use, resource exploitation, pollution, species invasions, and human population density. We used multivariate statistics to examine the spatial relationships among the datasets and to characterize the typical combinations of drivers experienced by different parts of the world. C_LIO_LIWe found stronger positive correlations among drivers in the terrestrial than in the marine realm, leading to areas of high intensities of multiple drivers on land. Climate change tended to be negatively correlated with other drivers in the terrestrial realm (e.g., in the tundra and boreal forest with high climate change but low human use and pollution) whereas the opposite was true in the marine realm (e.g., in the Indo-Pacific with high climate change and high fishing). C_LIO_LIWe show that different regions of the world can be defined by anthropogenic threat complexes (ATCs), distinguished by different sets of drivers with varying intensities. The ATCs can be used to test hypothesis about the pattern of biodiversity change, especially the joint effects of multiple drivers. More generally, our global analysis highlights the broad conservation priorities needed to mitigate the effects of anthropogenic change on biodiversity responses, with different priorities emerging on land and in the ocean, and in different parts of the world. C_LI

ecology↗

bioRxiv2018

Sequential Specification of Oligodendrocyte and NG2 Cell Fates by Distinct Levels of Hedgehog Signaling

During development of the central nervous system oligodendrocyte precursor cells (OPCs) give rise to both myelinating oligodendrocytes and NG2 glia, which are the most proliferative cells in the adult mammalian brain. NG2 glia retain characteristics of OPCs, and some NG2 glia produce oligodendrocytes, but many others persist throughout adulthood. Why some OPCs differentiate as oligodendrocytes during development whereas others persist as OPCs and acquire characteristics of NG2 glia is not known. Using zebrafish spinal cord as a model, we found that OPCs that differentiate rapidly as oligodendrocytes and others that remain as OPCs arise in sequential waves from distinct neural progenitors. Additionally, oligodendrocyte and persistent OPC fates are specified during a defined critical period by small differences in Shh signaling and Notch activity, which modulates Shh signaling response. Thus, our data indicate that OPCs fated to produce oligodendrocytes or remain as OPCs during development are specified as distinct cell types, raising the possibility that the myelinating potential of OPCs is set by graded Shh signaling activity.

developmental biology↗

bioRxiv2017

fluxweb: a package to easily estimate energy fluxes in food webs

O_LIUnderstanding how changes in biodiversity will impact the stability and functioning of ecosystems is a central challenge in ecology. Food-web approaches have been advocated to link community composition with ecosystem functioning by describing the fluxes of energy among species or trophic groups. However, estimating such fluxes remains problematic because current methods become unmanageable as network complexity increases.\nC_LIO_LIWe developed a generalisation of previous indirect estimation methods assuming a steady state system [1, 2, 3]: the model estimates energy fluxes in a top-down manner assuming system equilibrium; each nodes losses (consumption and physiological) balances its consumptive gains. Jointly, we provide theoretical and practical guidelines to use the fluxweb R package (available on CRAN at https://bit.ly/2OC0uKF).\nWe also present how the framework can merge with the allometric theory of ecology [4] to calculate fluxes based on easily obtainable organism-level data (i.e. body masses and species groups -eg, plants animals), opening its use to food webs of all complexities. Physiological losses (metabolic losses or losses due to death other than from predation within the food web) may be directly measured or estimated using allometric relationships based on the metabolic theory of ecology, and losses and gains due to predation are a function of ecological efficiencies that describe the proportion of energy that is used for biomass production.\nC_LIO_LIThe primary output is a matrix of fluxes among the nodes of the food web. These fluxes can be used to describe the role of a species, a function of interest (e.g. predation; total fluxes to predators), multiple functions, or total energy flux (system throughflow or multitrophic functioning). Additionally, the package includes functions to calculate network stability based on the Jacobian matrix, providing insight into how resilient the network is to small perturbations at steady state.\nC_LIO_LIOverall, fluxweb provides a flexible set of functions that greatly increase the feasibility of implementing food-web energetic approaches to more complex systems. As such, the package facilitates novel opportunities for mechanistically linking quantitative food webs and ecosystem functioning in real and dynamic natural landscapes.\nC_LI

ecology↗