Biology subjects

Kramer, N.

Publications and source records attributed to Kramer, N..

10 recordsLinked to original sources

bioRxiv2026

Coral Guard substrates accelerate growth and fragment fusion for coral restoration

Coral reefs are declining globally, creating an urgent need for scalable technologies that improve the efficiency and effectiveness of active reef restoration. Coral reef restoration is increasingly constrained by algal overgrowth, which suppresses coral growth, survival, and restoration efficiency. Building on the recently developed Coral Guard platform, we evaluate its restoration performance under long-term in situ coral nursery conditions and introduce Fusion Guard Tiles, a geometry-optimized Coral Guard design that accelerates microfragment fusion. We evaluated Coral Guard Plugs using the branching coral Stylophora pistillata under complementary ex situ conditions and Fusion Guard Tiles using the massive reef-building coral Porites evermanni in in situ coral nurseries. In P. evermanni, Fusion Guard Tiles increased lateral tissue growth 2.6-fold and three-dimensional tissue surface area growth by >2.7-fold after 6 months compared with conventional substrates. After 12 months, colony height and volume were approximately 4.0-fold and 2.2-fold greater, respectively, while complete fragment fusion occurred only on Fusion Guard Tiles. In S. pistillata, Coral Guard Plugs increased lateral tissue growth by [~]1.7-fold. Microcomputed tomography revealed 10-13% higher skeletal density in both species. In P. evermanni, Fusion Guard Tiles also increased symbiont density by 70% and tissue protein content by [~]2.5-fold relative to controls. Together, these findings demonstrate that Coral Guard substrates suppress algal competition while accelerating coral growth, skeletal development, and microfragment fusion, providing a scalable, low-maintenance technology to enhance coral nursery productivity and reef restoration.

bioengineering↗

bioRxiv2026

A Human Next Generation PBK Model for PFOA

The human toxicological risk assessment of per- and polyfluoroalkyl substances (PFAS) is challenging, due to their sheer number and structural diversity, but also the paucity of the toxicity data required to characterize them. The development of Next Generation Physiologically Based Kinetic (NG-PBK) models may assist in overcoming this challenge. The mechanistic nature of NG-PBK models allows for their extrapolation from data-rich PFAS, such as perfluorooctanoic acid (PFOA), to data-poor ones, facilitating their application in Next Generation Risk Assessment (NGRA). The present study proposes a NG-PBK model for PFOA in humans, parametrized exclusively using in vitro-, and in silico-derived data. The model describes the toxicokinetic processes of 1) partitioning to plasma and tissue proteins, 2) partitioning to cell membrane lipids, 3a) transporter-mediated entero-hepatic circulation and 3b) renal elimination and reabsorption, and 4) elimination via menstruation. Global sensitivity analysis indicated that the model was most sensitive to the fraction unbound in plasma, active-transport parameters, and tissue-plasma partition coefficients. The model was equivalent to already available validated human PFOA-PBK models, while compared to those, it is not calibrated to observed animal, nor human data, illustrating its strength in being mechanistic. The serum concentrations and half-lives predicted by the NG-PBK model were within the ranges of those reported in human volunteer and biomonitoring (HBM) studies, demonstrating the models capacity to accurately predict PFOA toxicokinetics on exposure estimates. Extrapolation of the NG-PBK model to other PFAS, in conjunction with its integration with HBM data, will facilitate the NGRA of PFAS. This is particularly relevant given the paucity of in vivo data for most PFAS, ensuring compliance with the 3R principles.

pharmacology and toxicology↗

bioRxiv2025

Subcellular assessment of algal carbon storage and chloroplasts across the microenvironmental landscape of a photosymbiotic coral

Light availability plays a central role in shaping the photophysiology and energy metabolism of photosymbiotic organisms such as reef-building corals. Although light varies greatly within coral colonies, the effects of this spatial heterogeneity on the subcellular organization and energy storage of symbiotic algae (Symbiodiniaceae) remain poorly understood. Here, we combined microscale measurements of light and oxygen across both light-exposed upper regions and shaded basal regions of a Favites abdita colony with three-dimensional subcellular imaging using Focused Ion Beam Scanning Electron Microscopy (FIB-SEM). Our multi-scale approach revealed subcellular heterogeneity among symbiont populations, suggesting different cell cycle stages and physiological states across a spatial stratification in the coral. Subcellular morphometrics revealed that symbiont cells at the top of the colony were twice more voluminous than those at the shaded base with similar plastid volume occupancy. Compared to symbionts at the top of the colony, symbionts in the basal region accumulated nearly three times more starch relative to their cell volume. These findings show that light gradients within coral colonies shape symbiont morphology and energy storage patterns, with important implications for coral stress tolerance and resilience.

cell biology↗

bioRxiv2025

Cell-state specific drug-responses are associated with differences in signaling network wiring.

Intracellular signaling pathways form networks through which information is transmitted, often in the form of kinase-mediated phosphorylation events, to interpret extracellular signals and elicit appropriate cellular responses. Yet, even isogenic cells in a homogenous environment show heterogeneity in their intracellular "cell-state", as well as their response to extracellular signals. Here, we aimed to better understand this relation between these phenomena by investigating how information flows through the EGF-receptor centered network upon targeted drug treatment, and how this is affected by cell-to-cell-state differences. Using single-cell ID-seq, we profiled the cell-state and signaling activity of primary human epidermal stem cells by measuring 69 (phospho-)proteins upon inhibition of the Erk/MAPK (p90RSK) and Akt/mTOR (p70S6K) routes downstream of the EGF pathway. We found that the effects of drug treatment propagated from the EGF-signaling pathway to other connected parts of the cellular signaling network, indicating altered signaling flow. We identified nine distinct cell-states that show pervasive state-dependent drug-responses for many (phospho-)proteins. Computational modeling of the signaling network using single-cell Comparative Network Reconstruction showed that many interactions between phospho-proteins (i.e. network wiring) were quantitatively different between cell-states. Furthermore, (phospho-)proteins with a cell-state dependent drug response, were more likely to be involved in interactions that showed a cell-state dependent strength. Overall, our results indicate that drug treatment response and signaling interactions between proteins are closely related and modulated by cell-state.

systems biology↗

bioRxiv2024

Response splicing QTLs in primary human chondrocytes identifies putative osteoarthritis risk genes

Osteoarthritis affects millions worldwide, yet effective treatments remain elusive due to poorly understood molecular mechanisms. While genome-wide association studies (GWAS) have identified over 100 OA-associated loci, identifying the genes impacted at each locus remains challenging. Several studies have mapped expression quantitative trait loci (eQTL) in chondrocytes and colocalized them with OA GWAS variants to identify putative OA risk genes; however, the degree to which genetic variants influence OA risk via alternative splicing has not been explored. We investigated the role of alternative splicing in OA pathogenesis using RNA-seq data from 101 human chondrocyte samples treated with PBS (control) or fibronectin fragment (FN-f), an OA trigger. We identified 590 differentially spliced genes between conditions, with FN-f inducing splicing events similar to those in primary OA tissue. We used CRISPR/Cas9 to mimic an SNRNP70 splicing event observed in OA and FN-f-treated chondrocytes and found that it induced an OA-like expression pattern. Integration with genotyping data revealed 7,188 splicing quantitative trait loci (sQTL) affecting 3,056 genes. While many sQTLs were shared, we identified 738 and 343 condition-specific sQTLs for control and FN-f, respectively. We identified 15 RNA binding proteins whose binding sites were enriched at sQTL splice junctions and found that expression of those RNA binding proteins correlated with exon inclusion. Colocalization with OA GWAS identified 6 putative risk genes, including a novel candidate, PBRM1. Our study highlights the significant impact of alternative splicing in OA and provides potential therapeutic targets for future research.

genetics↗

bioRxiv2021

Characterization of morpho-functional traits in mesophotic corals reveals optimized light capture and photosynthesis

The morphology and skeleton architecture of photosynthetic corals modulates the light capture and functioning of the coral-algal symbiosis on shallow-water corals. Since corals can thrive on mesophotic reefs under extreme light-limited conditions, we hypothesized that microskeletal coral features optimize light capture under low-light environments. Using micro-computed tomography scanning, we conducted a comprehensive three-dimensional (3D) assessment of small-scale skeleton morphology of the depth-generalist coral Stylophora pistillata collected from shallow (5 m) and mesophotic (45 m) depths. We detected a high phenotypic diversity between depths, resulting in two distinct morphotypes, with calyx diameter, theca height, and corallite marginal spacing contributing to most of the variation between depths. To determine whether such depth-specific morphotypes affect coral light capture and photosynthesis on the corallite-scale, we developed 3D simulations of light propagation based on photosynthesis-irradiance parameters. We found that corals associated with shallow morphotypes dissipated excess light through self-shading microskeletal features; while mesophotic morphotypes facilitated enhanced light absorption and photosynthesis under low-light conditions. We conclude that the mesophotic coral architecture provides a greater ability to trap solar energy and efficiently exploit the limited light conditions, and suggest that morphological modifications play a key role in the photoadaptation response to low-light.

ecology↗

bioRxiv2020

Light-harvesting in mesophotic corals is powered by a spatially efficient photosymbiotic system between coral host and microalgae

The coral-algal photosymbiosis fuels global coral-reef primary productivity, extending from sea level to as deep as 150 m (i.e., mesophotic). Currently, it is largely unknown how such mesophotic reefs thrive despite extremely limited light conditions. Here, we show that corals exhibit a plastic response to mesophotic conditions that involves a spatially optimized regulation of the bio-optical properties by coral host and symbiont. In contrast to shallow corals, mesophotic corals absorbed up to three-fold more light, resulting in excellent photosynthetic response under light conditions of only ~3% of the incident surface irradiance. The enhanced light harvesting capacity of mesophotic corals is regulated by average refractive index fluctuations in the coral skeleton that give rise to optical scattering and facilitate light transport and absorption by densely pigmented host tissue. The results of this study provide fundamental insight into the energy efficiency and light-harvesting mechanisms underlying the productivity of mesophotic coral reef ecosystems, yet also raise concerns regarding their ability to withstand prolonged environmental disturbances.

biophysics↗

bioRxiv2019

Light environment drives the shallow to mesophotic coral community transition

AbstractLight quality is a crucial physical factor driving coral distribution along depth gradients. Currently, a 30 m depth limit, based on SCUBA regulations, separates shallow and deep mesophotic coral ecosystems (MCEs). This definition, however, fails to explicitly accommodate environmental variation. Here, we posit a novel definition for a regional or reef-to-reef outlook of MCEs based on the light vs. coral community-structure relationship. A combination of physical and ecological methods enabled us to clarify the ambiguity in relation to that issue. To characterize coral community structure with respect to the light environment, we conducted wide-scale spatial studies at five sites along shallow and MCEs of the Gulf of Eilat/Aqaba (0-100 m depth). Surveys were conducted by Tech-diving and drop-cameras, in addition to one year of light spectral measurements. We quantify two distinct coral assemblages: shallow (<40 m), and MCEs (40-100 m), exhibiting markedly different relationships with light. The depth ranges and morphology of 47 coral genera, was better explained by light than depth, mainly, due to the Photosynthetically Active Radiation (PAR) and Ultra Violet Radiation (1% at 76 m and 36 m, respectively). Branching coral species were found mainly at shallower depths i.e., down to 36 m. Among the abundant upper mesophotic specialist-corals, Leptoseris glabra, Euphyllia paradivisa and Alveopora spp., were found strictly between 36-76 m depth. The only lower mesophotic-specialist, Leptoseris fragilis, was found deeper than 80 m. We suggest that shallow coral genera are light-limited below a level of 1.25% surface PAR and that the optimal PAR for mesophotic communities is at 7.5%. This study contributes to moving MCEs ecology from a descriptive-phase into identifying key ecological and physiological processes structuring MCE coral communities. Moreover, it may serve as a model enabling the description of a coral zonation world-wide on the basis of light quality data.

ecology↗

bioRxiv2019

LRRK2 modifies α-syn pathology and spread in mouse models and human neurons

Progressive aggregation of the protein alpha-synuclein (-syn) and loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) are key histopathological hallmarks of Parkinsons disease (PD). Accruing evidence suggests that -syn pathology can propagate through neuronal circuits in the brain, contributing to the progressive nature of the disease. Thus, it is therapeutically pertinent to identify modifiers of -syn transmission and aggregation as potential targets to slow down disease progression. A growing number of genetic mutations and risk factors have been identified in studies of both familial and sporadic forms of PD. However, how these genes affect -syn aggregation and pathological spread, and whether they can be targeted for therapeutic interventions, remains unclear. We performed a targeted genetic screen of risk genes associated with PD and parkinsonism for modifiers of -syn aggregation, using an -syn preformed-fibril (PFF) induction assay. We found that decreased expression of Lrrk2 and Gba modulated -syn aggregation in mouse primary neurons. Conversely, -syn aggregation increased in primary neurons from transgenic mice expressing the PD-linked LRRK2 G2019S mutation. In vivo, we investigated -syn spreading in a LRRK2 G2019S transgenic mouse model and observed acceleration of -syn aggregation and degeneration of dopaminergic neurons in the SNpc. Furthermore, LRRK2 G2019S transgenic mice displayed more pronounced degeneration-associated neuroinflammation and exacerbated behavioral deficits. To validate our findings in a human context, we established a human -syn transmission model using induced pluripotent stem cell (iPS)-derived neurons (iNs). Recombinant human -syn PFFs triggered aggregation of endogenous -syn in a time-dependent manner in human iNs. In isogenic lines of human iNs, the G2019S mutation enhanced -syn aggregation, whereas loss of LRRK2 decreased aggregation. Collectively, these findings establish a strong interaction between the PD risk gene LRRK2 and -syn transmission across mouse and human models. Since clinical trials of LRRK2 inhibitors in PD are currently underway, our findings raise the possibility that these may be effective in PD broadly, not just in the cases caused by LRRK2 mutations.

neuroscience↗

bioRxiv2017

Recurrent loss of heterozygosity correlates with clinical outcome in pancreatic neuroendocrine cancer

Pancreatic neuroendocrine tumors (pNETs) are uncommon cancers arising from pancreatic islet cells. Analysis of gene mutation, copy number and RNA expression of 57 sporadic pNETs showed that pNET genomes are dominated by aneuploidy. Remarkably, ~25% of pNETs had genomes characterized by recurrent loss of heterozygosity (LoH) of the same 10 chromosomes, accompanied by bi-allelic MEN1 inactivation, and these cases had generally poor clinical outcome. Another ~25% of all pNETs had chromosome 11 LoH and bi-allelic MEN1 inactivation, lacking the recurrent LoH pattern - these had universally good clinical outcome. Some level of aneuploidy was common, and overall ~80% of pNETs had LoH of [≥]1 chromosome. This aneuploidy led to changes in RNA expression at the level of whole chromosomes and allowed pathogenic germline variants (e.g. ATM) to be expressed unopposed, inactivating downstream tumor suppressor pathways. Some pNETs appear to utilize VHL gene methylation or mutation to activate pseudo-hypoxia. Contrary to expectation neither tumor morphology within well-differentiated pNETs nor single gene mutation had significant associations with clinical outcome, nor did expression of RNAs reflecting the activity of immune, differentiation, proliferative or tumor suppressor pathways. MEN1 was the only statistically significant recurrently mutated driver gene in pNETs. Only one pNET had clearly oncogenic and actionable SNVs (in PTEN and FLCN) confirmed by corroborating RNA expression changes. The two distinct patterns of aneuploidy described here, associated with markedly poor and good clinical outcome respectively, define a novel oncogenic mechanism and the first route to genomic precision oncology for this tumor type.

cancer biology↗