Biology subjects

Mahmoudi, N.

Publications and source records attributed to Mahmoudi, N..

14 recordsLinked to original sources

bioRxiv2026

Deep nanoparticle protein corona plasma proteomics resolves a stage-specific peripheral signature of Alzheimer's disease

Structured AbstractO_ST_ABSINTRODUCTIONC_ST_ABSAlzheimers disease (AD) progresses over decades, yet plasma biomarkers that resolve disease stage rather than simply detect disease remain scarce. This distinction is clinically consequential because effective AD intervention depends on identifying patients before disease biology has progressed beyond a therapeutically responsive stage. METHODSWe used small-molecule-modulated protein corona proteomics to profile plasma from 90 individuals in the Australian Imaging, Biomarker and Lifestyle cohort, stratified by Centiloid (CL) A{beta}-amyloid burden (30 amyloid- negative, CL < 15; 30 moderate-to-high, CL 26 to 100; 30 very high, CL > 100). We quantified 3,176 proteins and applied differential abundance and actual causality analyses to identify stage-specific and candidate causal proteins. RESULTSDifferential protein abundance was exclusively captured during the moderate-to-high AD transition, revealing a discrete proteomic "switch." The switch was marked by accumulation of the autophagy receptor CALCOCO1, together with coordinated depletion of the S100A8/S100A9 calprotectin complex and core erythroid-cytoskeletal network structural markers (e.g., SPTA1, SPTB, ANK1). Adhesion G protein-coupled receptor G6 (ADGRG6) showed a significant moderate positive monotonic association with absolute CL burden, providing a proportional molecular anchor for cumulative disease burden. Actual causality analysis identified COL6A2, FOXRED2, P3H1, PRR4, and GOLGA5 as candidate upstream drivers linking matrix remodeling, Golgi trafficking, and collagen processing to AD progression. DISCUSSIONThese findings suggest a candidate blood-accessible framework for staging AD by active disease biology, which, if replicated in independent cohorts, may have implications for therapeutic selection and mechanism-guided clinical trials. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=92 SRC="FIGDIR/small/740710v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1ead718org.highwire.dtl.DTLVardef@cfa523org.highwire.dtl.DTLVardef@62a367org.highwire.dtl.DTLVardef@1d5c9a5_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

The effects of thermal alteration on organic matter bioavailability in deeply buried marine sediments

A substantial fraction of marine sediments experience elevated temperatures due to burial or hydrothermal activity. These conditions can fundamentally reshape both microbial activity and the chemical nature of sedimentary organic matter (OM). Laboratory incubations have demonstrated that moderate heating of marine sediments can lead to the production of labile organic compounds such as acetate, however, it remains unclear whether heating alters the bioavailability of the remaining OM pool. In this study, we experimentally tested the effect of temperature on the bioavailability of OM through a series of bioreactor experiments using deeply buried sediment collected from Guaymas Basin (Gulf of California). We measured acetate concentrations in sterilized Guaymas Basin sediments before and after artificial heating (70{degrees}C for 7 days) to quantify abiotic acetate generation. We then conducted incubations of a model marine bacterium with sterilized, artificially heated sediment and tracked respired CO2 production and its associated 13C and 14C signatures. Our study revealed that sediment depth and hydrothermal history strongly control abiotic acetate production, with higher acetate yields from shallower, cooler sediments. Respiration rates in control and heated sediment incubations were nearly identical, indicating that heating does not measurably alter the bioavailability of bulk sedimentary OM. Moreover, the {delta}13C values of respired CO2 were indistinguishable between control and heated sediment incubations while the {Delta}14C values were more depleted in the first 24 hours in incubations with heated sediment. This transient offset suggests that low-temperature heating mobilizes a small pool of older material due to desorption of mineral-bound OM without altering overall bioavailability. Our findings shed light on the role of thermal alteration in shaping carbon cycling in marine sediments by influencing how OM is made available to sedimentary microorganisms.

microbiology↗

bioRxiv2026

Tracing the evolution of microbial alkaline phosphatases and their role in phosphorus recycling through time

Phosphorus (P) recycling in seawater is critical for maintaining nutrient availability and marine primary productivity. This process is catalyzed by alkaline phosphatases enzymes, which hydrolyze dissolved organic phosphorus (DOP) compounds, releasing inorganic P for cellular assimilation. Here, we reconstructed the evolutionary history of three major alkaline phosphatase families through deep time using phylogenetic reconciliation across the tree of life. We further quantified their distribution and cellular localization across major metabolic groups using extant genomes to assess how the oceans capacity for P regeneration has changed through time. Our results demonstrate that alkaline phosphatases emerged early in the Archaean, indicating that DOP has sustained marine ecosystems for most of Earths history. A pronounced expansion and diversification of alkaline phosphatases occurred during the Neoproterozoic, coinciding with the rise and ecological diversification of algae. Across metabolic groups, extracellular alkaline phosphatases are particularly concentrated in ferric iron reducers, fermenters, and aerobic heterotrophs, but are comparatively rare in other metabolisms. This distribution suggests that the efficiency of marine P recycling has been strongly influenced by prevailing metabolic strategies and environmental redox conditions. Overall, our results provide new insights into the enzymatic drivers of marine P cycling and the mechanisms that maintained marine productivity as Earths surface became progressively oxygenated and biologically complex.

microbiology↗

bioRxiv2026

Modulating Inflammation in Post-Traumatic Osteoarthritis using iPSC-derived Anti-inflammatory Macrophages

Post-traumatic osteoarthritis (PTOA) is a common long-term consequence of joint injury and a major cause of chronic pain and disability, yet no disease-modifying therapies are currently available. A central barrier to effective intervention is the persistence of maladaptive synovial inflammation, driven in part by macrophage-mediated signaling that sustains tissue degeneration and pain. Here, we developed a scalable, chemically defined platform to generate human induced pluripotent stem cell (iPSC)-derived anti-inflammatory macrophages (iMac-M2) as an off-the-shelf cell therapy designed to restore joint immune homeostasis after injury. These cells maintained a stable anti-inflammatory phenotype and function under osteoarthritis-relevant inflammatory conditions and suppressed inflammatory and catabolic responses in human joint cell co-culture systems. In a preclinical model of PTOA, intra-articular delivery of iMac-M2 after injury improved functional and structural outcomes while modulating synovial inflammatory and pain-associated transcriptional programs. Treatment was well tolerated, with no evidence of systemic immune activation or ectopic tissue formation. Together, these findings support iPSC-derived macrophage therapy as a clinically translatable immunomodulatory strategy to interrupt early inflammatory drivers of PTOA and preserve joint health following injury.

cell biology↗

bioRxiv2026

Glacier-induced upwelling shapes microbial communities in Arctic marine systems

The Canadian Arctic Archipelago (CAA) is warming at an unprecedented rate, leading to sea ice loss and glacial retreat. Marine-terminating (tidewater) glaciers can fuel summertime marine productivity by delivering nutrient-rich deep waters via upwelling to the surface ocean. While the impact of glacier-induced upwelling has been well-studied in the context of phytoplankton and primary productivity, its effects on broader marine microbial communities remain poorly understood. We investigated how glacier-driven upwelling shapes marine microbial (bacterial and archaeal) communities across a series of sites in the CAA. At upwelling sites, the upper 50 m of the water column exhibited elevated nutrient concentrations and physical characteristics that resembled deeper waters, which were associated with differences in microbial community composition relative to non-upwelling sites. Our results indicate that upwelling influences microbial communities in surface waters in two ways. It directly introduces typically deeper-water-associated taxa into surface waters and reshapes ecological niches by enhancing nutrient supply and stimulating primary production, indirectly driving changes in microbial communities. The enrichment of Candidatus Nitrosopumilus, a deep water nitrifier, likely affects nitrogen cycling and raises the possibility of active nitrification in surface waters. Likewise, the increased abundance of taxa known to be associated with phytoplankton-derived organic matter in upwelling regions suggests an enhanced capacity to process organic matter generated from elevated primary productivity. Ultimately, as tidewater glaciers continue to retreat, the resulting changes in the glacially-driven upwelling regime will likely shift marine microbial communities towards assemblages adapted to less productive ecosystems, with implications for nutrient cycling in these systems. ImportanceClimate change has a disproportionate impact on the Arctic, with rising temperatures causing increased marine-terminating glacier retreat and changes in the marine water column structure. The consequent loss of the ability of these glaciers to upwell deep water to the surface ocean results in a reduction of nutrient delivery and mixing in these ecosystems. Previous work has highlighted the importance of marine-terminating glaciers in sustaining phytoplankton productivity during the summer season through this delivery of deep-water nutrients to the surface ocean. The impact of glacially-induced upwelling on marine bacterial and archaeal communities, however, remains underexplored. We found that in regions with glacially-driven upwelling, the surface ocean showed enrichment of phytoplankton-associated taxa and nitrifiers commonly associated with deep waters. This work underscores the role of glacially-driven upwelling in structuring both microbial communities and nutrient cycling, suggesting that glacier loss could reshape community composition and biogeochemical processes in a rapidly changing Arctic.

microbiology↗

bioRxiv2026

Poly(acrylamido) PEG-alternatives Enhance mRNA-LNP Efficacy in Immune Cells and Evade anti-PEG Antibodies During Repeated Dosing

Following the successes of the messenger RNA (mRNA) lipid nanoparticle (LNP) vaccines during the COVID-19 pandemic, mRNA-LNPs are being explored for many critical disease indications including infectious disease vaccination, cancer immunotherapies, and protein replacement therapies. LNPs require a polymer coating to provide stability in storage, and to minimise clearance from the body by reducing protein adsorption after injection. Poly(ethylene glycol)-lipids (PEG-lipids) have fulfilled this role to date, however increasing prevalence of antibodies against PEG in the general population jeopardises the efficacy of future PEGylated LNP doses and increases the likelihood of adverse pseudo-allergic responses. There is, therefore, an urgent unmet need to develop LNPs with new surfaces of PEG-alternative polymers which can evade anti-PEG antibodies, particularly where repeat dosing is required. Here, we present a family of polymer lipids, poly(acrylamido) (PAM) lipids, which effectively replace conventional PEG-lipids in mRNA-LNP formulations. We identify key design parameters to show that PAM-lipid monomer chemistry, molar mass and end-group all have critical effects on LNP size, polydispersity and in vitro transfection efficiencies, while having little impact on LNP morphology or internal structure. We determine that side-group (monomer) chemistry is a key mediator in alleviating anti-polymer antibody cross-reactivity. Compared to clinical benchmark PEGylated LNPs, several PAM-LNPs displayed improved transfection efficacy across multiple mRNA cargos in diverse cell types, organs, and routes of administration, both in vitro and in vivo. In particular, mRNA transfection improved in immune cells both in vitro (up-to 120-fold), and in vivo (up-to 5-fold), including superior mRNA expression in lymph nodes (2.5-fold). In part, this is likely because PAMs increase LNP uptake/association with primary immune cells (BMDCs), and increase biodistribution to the lymphoid tissues (LNs, spleen). Crucially, PAM-LNPs avoid circulating anti-PEG antibodies to recover lost mRNA efficacy after repeated dosing in vivo, 300% higher than PEG-LNPs. Overall, our findings establish the PAM-lipid family as a versatile platform of chemically varied PEG-alternatives, towards the next generation of therapeutic mRNA-LNP technologies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/708093v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@107de1aorg.highwire.dtl.DTLVardef@186b6eforg.highwire.dtl.DTLVardef@1542371org.highwire.dtl.DTLVardef@e2d47f_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

Spatially precise neuron formation via hydrogel mediated modulation of the host astrocyte response

The regenerative capacity of the central nervous system after injury or disease is limited. Advancements in genetic and epigenetic reprogramming of non-neuronal cells into induced neurons presents a promising strategy for neuronal replacement and circuit reconstruction yet is hindered by suboptimal reprogramming efficacy. Here, we have achieved high astrocyte-to-neuron reprogramming efficacy through the ectopic expression of a SOX2 transcription factor using adeno-associated viral vectors. We subsequently designed a hybrid composite biomaterial to act as an implantable reprogramming workshop that perform sequential operations. Once injected, this bespoke system forms a tissue mimetic hydrogel encouraging the ingress of astrocytes to act as our raw material. We demonstrate that the system localized and enhanced the spatially confined delivery of reprogramming factors, entrapping astrocytes to then pass through an intermediate neuroblast state to robustly yield mature neurons. Sustained delivery of valproic acid within the system further promoted neuronal maturation. Overall, using design rules informed by requirements of the reprogramming strategy, we have designed a smart delivery system optimized for both the target tissue and reprogramming factors in a minimally invasive manner to enhance neural repair. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=163 HEIGHT=200 SRC="FIGDIR/small/695501v1_ufig1.gif" ALT="Figure 1"> View larger version (65K): org.highwire.dtl.DTLVardef@397e41org.highwire.dtl.DTLVardef@90047forg.highwire.dtl.DTLVardef@1175831org.highwire.dtl.DTLVardef@19f30eb_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

Microbial exoenzymes catalyzed the transition to an oxygenated Earth

Microbial exoenzymes--extracellular enzymes secreted to degrade complex organic polymers-- are essential for recycling carbon and nutrients, thus sustaining primary productivity in todays oceans1. Yet, their evolutionary history and role in shaping Earths early biosphere remain entirely unexplored. Here, we trace the origins of microbial exoenzymes and reveal their previously unrecognized role in driving planetary oxygenation. Our results show that exoenzymes are more common in microorganisms utilizing high-energy metabolisms, likely reflecting the energetic costs of enzyme biosynthesis and secretion. They are especially advantageous in environments rich in particulate organic matter (POM). A refined carbon cycle model indicates that early Archean oceans offered few such habitats, as low productivity and intense UV radiation rapidly photodegraded POM. However, with a Paleoproterozoic rise of atmospheric oxygen2, increased oxidative weathering boosted marine primary productivity and POM accumulation3, creating conditions favoring exoenzyme evolution. Molecular clock analyses further indicate that alkaline phosphatase, a key phosphorus-releasing exoenzyme, had likely emerged with the permanent rise of oxygen, enabling more efficient phosphorus recycling. We propose that exoenzymes initiated a positive feedback loop: by accelerating nutrient regeneration, they fueled cyanobacterial productivity and oxygen release, which in turn favored greater exoenzyme capacity, reinforcing long-term oxygenation of the planet.

microbiology↗

bioRxiv2025

Testing the priming effect in the deep ocean: are microbes too starved to consume recalcitrant organic carbon?

Deep ocean dissolved organic carbon (DOC) is one of the largest pools of reduced carbon on Earth. Many DOC compounds escape microbial degradation and persist for thousands of years in the ocean. Although many hypotheses have been proposed, the mechanisms responsible for this long-term stability remain unresolved. Heterotrophic microorganisms in the deep ocean are energetically starved and exhibit low metabolic activity. Here, we investigated whether the severe energy limitation in deep sea environments acts as a barrier to microbial degradation of DOC. We hypothesized that alleviating this energetic barrier through the addition of labile compounds (i.e., the priming effect) could stimulate microbial consumption of DOC. We conducted 62-day bottle incubations with deep seawater from the Southern Ocean that were amended with simple organic carbon, nitrogen- and/or phosphorus-containing compounds. We tracked DOC concentration, cell abundance and microbial community structure over the course of the experiment. Our results show no evidence of a priming effect regardless of the priming compound. However, priming compounds selected for distinct microbial populations with little overlap among amended bottles even when compounds were chemically similar. Pseudoalteromonas and Pseudomonas were enriched across all amended bottles, and their competition for labile substrates likely contributed to observed variations in DOC consumption. Our results reveal that the persistence of DOC is not driven by the energetic state of deep-sea microbes. In contrast, our results suggest that inputs of fresh carbon to the deep ocean are more likely to increase DOC sequestration, via the microbial carbon pump, rather than stimulate DOC consumption. IMPORTANCEThe oceans store vast amounts dissolved organic carbon (DOC) that can resist microbial degradation for thousands of years. The mechanisms that underlie the long-term stability of DOC in the ocean are still debated. Microorganisms in this environment exhibit low metabolic activity and are energetically starved. We tested whether the microbial degradation of DOC could be stimulated through the addition of labile compounds. Surprisingly, alleviating energetic constraints did not stimulate the consumption of deep ocean DOC. Additionally, our results suggest that competition among taxa is an important constraint on dissolved organic carbon consumption, with implications for ecosystem processing. Our study indicates that an increase in fresh organic carbon to the deep ocean may enhance carbon sequestration since marine microbes are known to produce recalcitrant compounds. Among other applications, this finding is of consequence for ongoing geoengineering efforts that aim to remove atmospheric carbon by increasing carbon export to the deep sea.

ecology↗

bioRxiv2023

Microbial Gladiators: Unraveling the dynamics of carbon substrate competition among heterotrophic microbes

Growing evidence suggests that interactions among heterotrophic microbes influence the efficiency and rate of organic matter turnover. These interactions are dynamic and shaped by the composition and availability of resources in their surrounding environment. Heterotrophic microbes inhabiting marine environments often encounter fluctuations in the quality and quantity of carbon inputs, ranging from simple sugars to large, complex compounds. Here, we experimentally tested how the chemical complexity of carbon substrates affects competition and growth dynamics between two heterotrophic marine isolates. We tracked cell density using species-specific PCR assays and measured rates of microbial CO2 production along with associated isotopic signatures (13C and 14C) to quantify the impact of these interactions on organic matter remineralization. The observed cell densities revealed substrate-driven interactions: one species exhibited a competitive advantage and quickly outgrew the other when incubated with a labile compound while both species seemed to coexist harmoniously in the presence of more complex organic matter. Rates of CO2 respiration revealed that co-incubation of these isolates enhanced organic matter turnover, sometimes by nearly twofold, compared to their incubation as mono-cultures. Isotopic signatures of respired CO2 indicated that co-incubation resulted in a greater remineralization of macromolecular organic matter. These results demonstrate that simple substrates promote competition while high substrate complexity reduces competitiveness and promotes the partitioning of degradative activities into distinct niches, facilitating coordinated utilization of the carbon pool. Taken together, this study yields new insight into how the quality of organic matter plays a pivotal role in determining microbial interactions within marine environments.

microbiology↗

bioRxiv2022

Resolving the fate of trace metals during microbial remineralization of phytoplankton biomass in precursor banded iron formation sediments

Banded Iron Formations (BIFs) have long been considered a sedimentary record of seawater trace metal composition during the Precambrian. However, recent work has suggested that the trace metal composition of BIFs was derived from phytoplankton biomass, not seawater. In this model, phytoplankton biomass settles from the photic zone to the seafloor sediments, where it is then oxidized by heterotrophic microbes, such as dissimilatory Fe(III) reducing (DIR) bacteria, for energy generation. Remineralization of this biomass released the trace metals associated with organic molecules from phytoplankton (i.e., in metalloproteins), allowing these metals to be captured by Fe (oxyhydr)oxides and preserved in BIFs. While there is compelling evidence that the phytoplankton biomass served as a trace metal shuttle to precursor BIF sediments, it is unclear whether the degradation of biomass by DIR bacteria would liberate the biogenic trace metals as the model proposes. This work tests this hypothesis by using anoxic incubations of a model DIR bacterium (Shewanella oneidensis MR-1) with phytoplankton biomass as energy and carbon sources and ferrihydrite, a poorly crystalline Fe(III) oxyhydroxide (Fe(OH)3), as electron acceptor. Our results show that while S. oneidensis MR-1 can consume some of the carbon substrates found in phytoplankton biomass, there is no evidence that S. oneidensis MR-1 degraded metalloproteins which would have liberated trace metals. In the context of the Precambrian, these data imply that other heterotrophic bacteria, such as fermenters, may have had a larger role in the liberation of trace metals from dead biomass during early BIF development. HighlightsO_LIPhytoplankton are the proposed source of trace metals to banded iron formations C_LIO_LIIron reducers are hypothesized to release metals from phytoplankton biomass C_LIO_LIExperiments show that iron reducers do not liberate metals when degrading biomass C_LIO_LIOther microbial heterotrophs must have liberated the biogenic trace metals C_LI

microbiology↗

bioRxiv2021

The role of water mobility in protein misfolding

The propensity for intrinsically disordered proteins to aggregate is heavily influenced by their surrounding environment. Here, we show that the mobility of the surrounding water molecules directly influences the aggregation rate of -synuclein (aSyn), a protein associated with Parkinsons disease. We observe that the addition of NaCl reduces the mobility of water, while addition of CsI increases the mobility of water. In turn, this reduces and increases the mobility of aSyn, respectively, given the change in strength and lifetime of the intermolecular forces. The reduction of aSyn mobility in the presence of NaCl ions leads to increased aggregation rates, which may be due to aggregation-competent conformations being stable for longer, thereby increasing the likelihood of establishing interactions between two adjacent monomers. In contrast, aSyn is more mobile when CsI is dissolved in the aqueous phase which leads to a reduction of successful monomeric interactions. We thus highlight the importance of the surrounding environment and describe how ion content can influence water mobility and the misfolding rate of amyloidogenic proteins, such as aSyn. By modulating the cellular environment to increase water mobility or finding small molecules to increase protein dynamics, new therapeutic targets may be found.

biophysics↗

bioRxiv2019

Illuminating microbial species-specific effects on organic matter remineralization in marine sediments

Marine microorganisms play a fundamental role in the global carbon cycle by mediating the sequestration of organic matter in ocean waters and sediments. A better understanding of how biological factors, such as microbial community composition, influence the lability and fate of organic matter is needed. Here, we explored the extent to which organic matter remineralization is influenced by species-specific metabolic capabilities. We carried out aerobic time-series incubations of Guaymas basin sediments to quantify the dynamics of carbon utilization by two different heterotrophic marine isolates. Continuous measurement of respiratory CO2 production and its carbon isotopic compositions (13C and 14C) shows species-specific differences in the rate, quantity, and type of organic matter remineralized. Each species was incubated with hydrothermally-influenced vs. unimpacted sediments, resulting in a ~3-fold difference in respiratory CO2 yield across the experiments. Genomic analysis indicated that the observed carbon utilization patterns may be attributed in part to the number of gene copies encoding for extracellular hydrolytic enzymes. Our results demonstrate that the lability and remineralization of organic matter in marine environments is not only a function of chemical composition and/or environmental conditions, but also a function of the microorganisms that are present and active.

microbiology↗

bioRxiv2018

Impacts of Deep-Sea Mining on Microbial Ecosystem Services

Interest in extracting mineral resources from the seafloor through deep-sea mining has accelerated substantially in the past decade, driven by increasing consumer demand for various metals like copper, zinc, manganese, cobalt and rare earth elements. While there are many on-going discussions and studies evaluating potential environmental impacts of deep-sea mining activities, these focus primarily on impacts to animal biodiversity. The microscopic spectrum of life on the seafloor and the services that this microbial realm provides in the deep sea are rarely considered explicitly. In April 2018, a community of scientists met to define the microbial ecosystem services that should be considered when assessing potential impacts of deep-sea mining, and to provide recommendations for how to evaluate these services. Here we show that the potential impacts of mining on microbial ecosystem services in the deep sea vary substantially, from minimal expected impact to complete loss of services that cannot be remedied by protected area offsets. We conclude by recommending that certain types of ecosystems should be \"off limits\" until initial characterizations can be performed, and that baseline assessments of microbial diversity, biomass, and biogeochemical function need to be considered in environmental impact assessments of all potential instances of deep-sea mining.

microbiology↗