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bioRxiv2021

Insight into Canary Island pine physiology provided by stable isotope patterns of water and plant tissues along an altitudinal gradient

The Canary Islands, an archipelago east of Moroccos Atlantic coast, present steep altitudinal gradients covering various climatic zones from hot deserts to subalpine Mediterranean, passing through fog-influenced cloud forests. Unlike the majority of the Canarian flora, Pinus canariensis grow along most of these gradients, allowing the study of plant functioning in contrasting ecosystems. Here we assess the water sources (precipitation, fog) of P. canariensis and its physiological behavior in its different natural environments. We analyzed carbon and oxygen isotope ratios of water and organics from atmosphere, soil and different plant organs and tissues (including 10-year annual time series of tree-ring cellulose) of six sites from 480 to 1990 m asl on the Canary island La Palma. We found a decreasing {delta}18O trend in source water that was overridden by an increasing {delta}18O trend in needle water, leaf assimilates and tree-ring cellulose with increasing altitude, suggesting site-specific tree physiological responses to relative humidity. Fog-influenced and fog-free sites showed similar {delta}13C values, suggesting photosynthetic activity to be limited by stomatal closure and irradiance at certain periods. Besides, we observed an 18O-depletion (fog-free and timberline sites) and 13C-depletion (fog-influenced and fog-free sites) in latewood compared to earlywood caused by seasonal differences in: (i) water uptake (i.e. deeper ground water during summer drought, fog water frequency and interception) and (ii) meteorological conditions (stem radial growth and latewood {delta}18O correlated with winter precipitation). In addition, we found evidence for foliar water uptake and strong isotopic gradients along the pine needle axis in water and assimilates. These gradients are likely the reason for an unexpected underestimation of pine needle water {delta}18O when applying standard leaf water {delta}18O models. Our results indicate that soil water availability and air humidity conditions are the main drivers of the physiological behavior of pine along the Canary Islands altitudinal gradients.

ecology↗

bioRxiv2021

Preparation of Asymmetric Vesicles with Trapped CsCl Avoids Osmotic Imbalance, Non-Physiological External Solutions, and Minimizes Leakage

The natural asymmetry of cellular membranes influences their properties. In recent years, methodologies for preparing asymmetric vesicles have been developed that rely on the methyl--cyclodextrin catalyzed exchange of lipids between donor lipid multilamellar vesicles and acceptor lipid unilamellar vesicles, and the subsequent separation of the, now asymmetric, acceptor vesicles from the donors. Isolation is accomplished by pre-loading acceptor vesicles with a high concentration of sucrose, typically 25% (w/w), and separating from donor and cyclodextrin by sucrose gradient centrifugation. We found that when the asymmetric vesicles were dispersed under hypotonic conditions using physiological salt solutions, there was enhanced leakage of an entrapped probe, 6-carboxyfluorescein. Studies with symmetric vesicles showed this was due to osmotic pressure and was specific to hypotonic solutions. Inclusion of cholesterol partly reduced leakage but did not completely eliminate it. To avoid having to use hypotonic conditions or to suspend vesicles at non-physiological solute concentrations to minimize leakage, a method for preparing asymmetric vesicles using acceptor vesicle-entrapped CsCl at a physiological salt concentration (100 mM) was developed. Asymmetric vesicles prepared with the entrapped CsCl protocol were highly resistant to 6-carboxyfluorescein.

biophysics↗

bioRxiv2021

Genome-wide association mapping and systems-level analysis reveal genetic architecture and physiological mechanisms linked with tolerance to flooding during germination in rice

Rice is the staple food of more than half of the worlds population; yet, it faces numerous challenges to meet the rising food demands and worsening climates. An urgent global imperative is to address imminent food shortages through intensive and sustainable agri-food systems and steady genetic gains. Intensification of rice production through direct-seeded rice (DSR) has been progressively practiced but is hindered by poor germination of existing high-yielding varieties in flooded soils. Identifying donors of anaerobic germination (AG) tolerance in rice will expedite the development of varieties suitable for DSR and will lead to enhanced and sustained agricultural productivity. This study aims to dissect the genetic architecture and physiological mechanisms of AG tolerance using systems biology and omics approaches. A Rice Diversity Panel (343 accessions) consisting of 5 subpopulations was screened for AG tolerance under greenhouse conditions, mapped through genome-wide association study (GWAS), and profiled for metabolites. Analyses revealed that most of the AG-tolerant varieties are japonicas with few indicas) and aus. Tolerant japonicas employed better root growth or rapid shoot extension, while tolerant indicas exhibited only the latter. A total of 51 significant GWAS peaks were detected across the genome, some of which were co-localized with known quantitative trait loci while others were novel, more so tolerance was found to involve different genetic controls across subpopulations. AG stress causes distinct biochemical signatures for tolerant genotypes and the profiles contrast among subpopulations implicating divergent metabolic adjustments, including shifts in sugars, intermediates, amino acids, antioxidants, and hormones. This study provides a systems-level approach for underpinning physiological mechanisms of AG tolerance; elucidating phenotypic heterogeneity, genetic architecture, transcriptomic networks, and metabolic landscapes from a genome-wide perspective. ONE SENTENCE SUMMARYThe integration of GWA mapping, gene network analysis and, non-targeted metabolite profiling elucidates genetic architecture and physiological mechanisms of tolerance to germination and early seedling growth under anaerobic conditions in rice.

plant biology↗

bioRxiv2021

Cognitive functions and respective parameters of human brain physiology are chronotype-dependent

Circadian rhythms have natural relative variations among humans known as chronotype. Chronotype or being a morning or evening person, has a specific physiological, behavioural, and also genetic manifestation. Whether and how chronotype modulates human brain physiology and cognition is, however, not well understood. Here we examine how cortical excitability, neuroplasticity, and cognition are associated with chronotype in early and late chronotype individuals. We monitor motor cortical excitability, brain stimulation-induced neuroplasticity, and examine motor learning and cognitive functions at circadian-preferred and non-preferred times of day in 32 individuals. Motor learning and cognitive performance (working memory, and attention) along with their electrophysiological components are significantly enhanced at the circadian-preferred, compared to the non-preferred time. This outperformance is associated with enhanced cortical excitability (prominent cortical facilitation, diminished cortical inhibition), and long-term potentiation/depression-like plasticity. Our data show convergent findings of chronotype can modulate human brain functions from basic physiological mechanisms to behaviour and higher cognitive functions.

neuroscience↗

bioRxiv2021

Recurrent allopolyploidization events diversify eco-physiological traits in marsh orchids

Whole-genome duplication, in particular allopolyploidy, has shaped the evolution of angiosperms and other organisms. Structural reorganization of chromosomes and repatterning of gene expression is frequently observed in early generation allopolyploids, with potential ecological consequences. The relative contributions of environmental and intrinsic drivers to these changes are unknown. We show here that in marsh orchids (Dactylorhiza, Orchidaceae), recurrently-formed allopolyploids are characterized by distinct eco-physiologies matching their respective environments, providing us with an excellent study system to address this question. Here we integrate eco-physiological and transcriptomic comparative studies to reveal a complex suite of intertwined, pronounced differences between sibling allopolyploids. We show that Dactylorhiza majalis that is distributed in Central and Southern Europe favors meadows with mesic soils. Its sibling allopolyploid D. traunsteineri occurs in fens, characterized by soils depleted by macro- and micronutrients, mainly in previously glaciated European areas. We further uncover distinct features in their nutrient transport, leaf elemental chemistry, light-harvesting, photoprotection, and stomata activity, that appear all linked to their distinct ecologies, in particular soil chemistry differences at their native sites. Recurrent polyploidization hence enriches biodiversity through eco-physiological diversification, providing the opportunity for sibling allopolyploids to evolve as distinct evolutionary units, despite pervasive interspecific gene flow. Significance StatementWhole-genome duplication resulting in polyploidy has underpinned the evolution of flowering plants and other organisms, and is important for many crops. However, the ecological implications of polyploidy remain little understood. Here, we demonstrate that two sibling allopolyploid marsh orchid species prefer distinct habitats, and have evolved a suite of distinctive ecophysiological characters (e.g. nutrient transport, energy harvesting and photoprotection). We argue that the divergence of these characters in the nascent polyploids drove adaptation into distinct ecological niches (low nutrient fens versus meadows with mesic soils), generating ecological barriers that maintains distinct, independent lineages, even in the presence of interspecific gene flow.

evolutionary biology↗

bioRxiv2021

History-Dependent Physiological Adaptation to Lethal Genetic Modification under Antibiotic Exposure

Genetic modifications, such as gene deletion and mutations, could lead to significant changes in physiological states or even cell death. Bacterial cells can adapt to diverse external stresses, such as antibiotic exposure, but can they also adapt to detrimental genetic modification? To address this issue, we visualized the response of individual Escherichia coli cells to deletion of the antibiotic resistance gene under chloramphenicol (Cp) exposure, combining the light-inducible genetic recombination and microfluidic long-term single-cell tracking. We found that a significant fraction ([~] 40%) of resistance-gene-deleted cells demonstrated a gradual restoration of growth and stably proliferated under continuous Cp exposure without additional mutations. Such physiological adaptation to genetic modification was not observed when the deletion was introduced in 10 h or more advance before Cp exposure. Resistance gene deletion under Cp exposure disrupted the stoichiometric balance of ribosomal large and small subunit proteins (RplS and RpsB). However, the balance was gradually recovered in the cell lineages with restored growth. These results demonstrate that bacterial cells can adapt even to lethal genetic modifications by plastically gaining physiological resistance. However, the access to the resistance states is limited by the environmental histories and the timings of genetic modification.

genetics↗

bioRxiv2021

Distinct and diverse chromatin-proteomes of ageing mouse organs reveal protein signatures that correlate with physiological functions

Temporal molecular changes in ageing mammalian organs are of relevance to disease etiology because many age-related diseases are linked to changes in the transcriptional and epigenetic machinery that regulate gene expression. We performed quantitative proteome analysis of chromatin-enriched protein extracts to investigate the dynamics of the chromatin-proteomes of the mouse brain, heart, lung, kidney, liver, and spleen at 3, 5, 10, and 15 months of age. Each organ exhibited a distinct chromatin-proteome and sets of unique proteins. The brain and spleen chromatin-proteomes were the most extensive, diverse, and heterogenous among the six organs. The spleen chromatin proteome appeared static during the lifespan, presenting a young phenotype that reflects the permanent alertness state and important role of this organ in physiological defense and immunity. We identified a total of 5928 proteins, including 2472 nuclear or chromatin associated proteins across the six mouse organs. Up to 3125 proteins were quantified in each organ demonstrating distinct and organ-specific temporal protein expression timelines and regulation at the post-translational level. Bioinformatics meta- analysis of these chromatin proteomes revealed distinct physiological and ageing- related features for each organ. Our results demonstrate the efficiency of organelle specific proteomics for in vivo studies of a model organism and consolidate the hypothesis that chromatin-associated proteins are involved in distinct and specific physiological functions in ageing organs. HIGHLIGHTSO_LIQuantitative chromatin-proteome analysis during mouse lifespan; C_LIO_LIChromatin analysis in vitro and in vivo mouse models; C_LIO_LIDistinct chromatin proteomes of six organs during mouse lifespan; C_LIO_LICorrelations between ageing and chromatin regulation in mammalian lifespan. C_LI

cell biology↗

bioRxiv2021

Physiological noise optimizes multiplexed coding of vibrotactile-like signals in somatosensory cortex

Neurons can use different aspects of their spiking to simultaneously represent (multiplex) different features of a stimulus. For example, some pyramidal neurons in primary somatosensory cortex (S1) use the rate and timing of their spikes to respectively encode the intensity and frequency of vibrotactile stimuli. Doing so has several requirements. Because they fire at low rates, pyramidal neurons cannot entrain 1:1 with high-frequency (100-600 Hz) inputs and instead must skip (i.e. not respond to) some stimulus cycles. The proportion of skipped cycles must vary inversely with stimulus intensity for firing rate to encode stimulus intensity. Spikes must phase lock to the stimulus for spike times (intervals) to encode stimulus frequency but, in addition, skipping must occur irregularly to avoid aliasing. Using simulations and in vitro experiments in which S1 pyramidal neurons were stimulated with inputs emulating those induced by vibrotactile stimuli, we show that fewer cycles are skipped as stimulus intensity increases, as required for rate coding, and that physiological noise induces irregular skipping without disrupting phase locking, as required for temporal coding. This occurs because the reliability and precision of spikes evoked by small- amplitude, fast-onset signals are differentially sensitive to noise. Simulations confirmed that differences in stimulus intensity and frequency can be well discriminated based on differences in spike rate or timing, respectively, but only in the presence of noise. Our results show that multiplexed coding by S1 pyramidal neurons is facilitated rather than degraded by physiological levels of noise. In fact, multiplexing is optimal under physiologically noisy conditions.

neuroscience↗

bioRxiv2021

Genomic and physiological characterization of Novosphingobium terrae sp. nov., an alphaproteobacterium isolated from Cerrado soil containing a megasized chromid

A novel bacterial strain, designated GeG2T, was isolated from soils of native Cerrado, a highly biodiverse savanna-like Brazilian biome. 16S rRNA gene sequence analysis of strain GeG2T revealed high sequence identity (100%) to the alphaproteobacterium Novosphingobium rosa, however, comparisons with N. rosa DSM7285T showed several distinctive features, prompting a full characterization of the new strain in terms of growth, morphology, biochemistry and, ultimately, its genome. GeG2T cells were Gram-stain negative bacilli, facultatively anaerobic, motile, positive for catalase and oxidase activities and for starch hydrolysis. Strain GeG2T presented planktonic-sessile dimorphism and cell aggregates surrounded by extracellular matrix and nanometric spherical structures were observed in liquid cultures, suggesting the production of exopolysaccharides (EPS) and outer membrane vesicles (OMVs). Whole genome assembly revealed four circular replicons: a 4.1 Mb chromosome, a 2.7 Mb extrachromosomal megareplicon and two plasmids (212.7 and 68.6 kb). The megareplicon contains few core genes and plasmid-type replication/maintenance systems, consistent with its classification as a chromid. Genome annotation shows a vast repertoire of carbohydrate active enzymes and genes involved in the degradation of aromatic compounds, highlighting the biotechnological potential of the new isolate obtained from Cerrado soils, especially regarding EPS production and biodegradation of recalcitrant compounds. Chemotaxonomic features, including polar lipid and fatty acid profiles, as well as physiological, molecular and whole genome comparisons showed significant differences between strain GeG2T and a N. rosa, clearly indicating that it represents a novel species, for which the name Novosphingobium terrae is proposed. The type strain is GeG2T (=CBMAI 2313T =CBAS 753T). IMPORTANCENovosphingobium is an alphaproteobacterial genus presenting diverse physiological profiles and broad biotechnological applications. However, many aspects regarding the biology of this important bacterial group remain elusive. A novel Novosphingobium strain was isolated from soils of Cerrado, an important Brazilian biome. Despite 100% 16S rRNA gene identity with Novosphingobium rosa, polyphasic characterizations, including physiological, chemotaxonomic, and whole genome- based analyses revealed significant differences between GeG2T and N. rosa DSM7285T, reinforcing resolution limitations in phylogenetic analysis based solely on 16S RNA and highlighting the importance of employing different approaches for the description of bacterial species. Using short and long read sequencing approaches, a high-quality fully resolved genome assembly was generated and one of the largest chromids reported to date was identified. A comprehensive characterization of environmental isolates allows us to better elucidate the diversity and biology of members of this bacterial group with potential biotechnological importance, guiding future bioprospecting efforts and genomic studies.

microbiology↗

bioRxiv2021

The Physiological Landscape and Specificity of Antibody Repertoires

Diverse antibody repertoires spanning multiple lymphoid organs (e.g., bone marrow, spleen, lymph nodes) form the foundation of protective humoral immunity. Changes in their composition across lymphoid organs are a consequence of B-cell selection and migration events leading to a highly dynamic and unique physiological landscape of antibody repertoires upon antigenic challenge (e.g., vaccination). However, to what extent B cells encoding identical or similar antibody sequences (clones) are distributed across multiple lymphoid organs and how this is shaped by the strength of a humoral response, remains largely unexplored. Here, we performed an in-depth systems analysis of antibody repertoires across multiple distinct lymphoid organs of immunized mice, and discovered that organ-specific antibody repertoire features (e.g., germline V-gene usage and clonal expansion profiles) equilibrated upon a strong humoral response (multiple immunizations and high serum titers). This resulted in a surprisingly high degree of repertoire consolidation, characterized by highly connected and overlapping B-cell clones across multiple lymphoid organs. Finally, we revealed distinct physiological axes indicating clonal migrations and showed that antibody repertoire consolidation directly correlated with antigen-specificity. Our study uncovered how a strong humoral response resulted in a more uniform but redundant physiological landscape of antibody repertoires, indicating that increases in antibody serum titers were a result of synergistic contributions from antigen-specific B-cell clones distributed across multiple lymphoid organs. Our findings provide valuable insights for the assessment and design of vaccine strategies.

immunology↗

bioRxiv2021

Revisiting tolerance to ocean acidification: insights from a new framework combining physiological and molecular tipping points of Pacific oyster

Studies on the impact of ocean acidification on marine organisms involve exposing organisms to future acidification scenarios as projected for open ocean, which has limited relevance for coastal calcifiers. Characterization of reaction norms across a range of pH and identification of tipping points beyond which detrimental effects are observed has been limited and focus on only a few macro-physiological traits. Here we filled this knowledge gap by developing a framework to analyze the broad macro-physiological and molecular responses over a wide pH range of juvenile Pacific oyster, a model species for which the tolerance threshold to acidification remains unknown. We identify low tipping points for physiological traits at pH 7.3-6.9 that coincide with a major reshuffling in membrane lipids and transcriptome. In contrast, shell parameters exhibit effects with pH drop well before tipping points, likely impacting animal fitness. These findings were made possible by the development of an innovative methodology to synthesize and identify the main patterns of variations in large -omic datasets, fit them to pH and identify molecular tipping-points. We propose the application of our framework broadly to the assessment of effects of global change on other organisms.

zoology↗

bioRxiv2021

Recording of cellular physiological histories along optically readable self-assembling protein chains

Observing cellular physiological histories is key to understanding normal and disease-related processes, but longitudinal imaging is laborious and equipment-intensive. A tantalizing possibility is that cells could record such histories in the form of digital biological information within themselves, for later high-throughput readout. Here we show that this concept can be realized through information storage in the form of growing protein chains made out of multiple self-assembling subunits bearing different labels, each corresponding to a different cellular state or function, so that the physiological history of the cell can be visually read out along the chain of proteins. Conveniently, such protein chains are fully genetically encoded, and easily readable with simple, conventional optical microscopy techniques, compatible with visualization of cellular shape and molecular content. We use such expression recording islands (XRIs) to record gene expression timecourse downstream of pharmacological and physiological stimuli, in cultured neurons and in living mouse brain.

synthetic biology↗

bioRxiv2021

STAT3 and HIF1α cooperatively mediate the transcriptional and physiological responses to hypoxia

STAT3 and HIF1 are two fundamental transcription factors involved in many merging processes, like angiogenesis, metabolism, and cell differentiation. Notably, under pathological conditions, the two factors have been shown to interact genetically, but both the molecular mechanisms underlying such interactions and their relevance under physiological conditions remain unclear. Here we report that STAT3 is required for the HIF1-dependent response to hypoxia. In Stat3 knock-out pluripotent embryonic stem cells (ESCs), a large fraction of HIF1 target genes is not induced by hypoxia. Mechanistically, STAT3 does not regulate neither HIF1 expression nor stability, rather, it physically interacts with it in the nucleus. In vivo, we observed that both genetic and chemical inactivation of Stat3 blunted physiological responses to hypoxia, such as angiogenesis, erythropoiesis, and immune cell mobilization. Such defects were accompanied with faulty transcriptional activity of HIF1. In sum, our data reveal that STAT3 and HIF1 cooperatively mediate the physiological response to hypoxia.

developmental biology↗

bioRxiv2021

Rule-based and stimulus-based cues bias auditory decisions via different computational and physiological mechanisms

Expectations, such as those arising from either learned rules or recent stimulus regularities, can bias subsequent auditory perception in diverse ways. However, it is not well understood if and how these diverse effects depend on the source of the expectations. Further, it is unknown whether different sources of bias use the same or different computational and physiological mechanisms. We examined how rule-based and stimulus-based expectations influenced behavior and pupil- linked arousal, a marker of certain forms of expectation-based processing, of human subjects performing an auditory frequency-discrimination task. Rule-based cues consistently biased choices and response times (RTs) toward the more-probable stimulus. In contrast, stimulus-based cues had a complex combination of effects, including choice and RT biases toward and away from the frequency of recently presented stimuli. These different behavioral patterns also had: 1) distinct computational signatures, including different modulations of key components of a novel form of a drift-diffusion decision model and 2) distinct physiological signatures, including substantial bias- dependent modulations of pupil size in response to rule-based but not stimulus-based cues. These results imply that different sources of expectations can modulate auditory processing via distinct mechanisms: one that uses arousal-linked, rule-based information and another that uses arousal- independent, stimulus-based information to bias the speed and accuracy of auditory perceptual decisions. Author summaryPrior information about upcoming stimuli can bias our perception of those stimuli. Whether different sources of prior information bias perception in similar or distinct ways is not well understood. We compared the influence of two kinds of prior information on tone-frequency discrimination: rule-based cues, in the form of explicit information about the most-likely identity of the upcoming tone; and stimulus-based cues, in the form of sequences of tones presented before the to-be-discriminated tone. Although both types of prior information biased auditory decision- making, they demonstrated distinct behavioral, computational, and physiological signatures. Our results suggest that the brain processes prior information in a form-specific manner rather than utilizing a general-purpose prior. Such form-specific processing has implications for understanding decision biases real-world contexts, in which prior information comes from many different sources and modalities.

neuroscience↗

bioRxiv2022

Profiling of the human intestinal microbiome and bile acids under physiologic conditions using an ingestible sampling device

The spatiotemporal structure of the human microbiome and metabolome reflects and determines regional intestinal physiology and may have implications for disease. Yet, we know little about the distribution of microbes and their products in the gut because of reliance on stool samples and limited access only to some regions of the gut using endoscopy in fasting or sedated individuals. To address these deficiencies, we developed and evaluated a safe, ingestible device that collects samples from multiple regions of the human intestinal tract during normal digestion. The collection of 240 intestinal samples from 15 healthy individuals using the device revealed significant differences between microbes and metabolites present in the intestines versus stool. Certain microbial taxa were differentially enriched, and bile acid profiles varied along the intestines and were highly distinct from those of stool. Correlations between gradients in bile acid concentrations and microbial abundance predicted species that altered the bile acid pool through deconjugation. Overall, we identified heterogeneous intestinal profiles of bacterial taxa and metabolites indicating that non-invasive multi-regional sampling of the intestinal tract under physiological conditions can help elucidate the roles of the gut microbiome and metabolome in human physiology and disease.

microbiology↗

bioRxiv2022

Development of a physiological insulin resistance model in human stem cell-derived adipocytes

Adipocytes are key regulatory cells of human metabolism, and their dysfunction in insulin signaling is central to metabolic diseases such as type II diabetes mellitus (T2D). However, the progression of insulin resistance that leads to T2D is still poorly understood. This limited understanding is due, in part, to the dearth of suitable models of insulin signaling in human adipocytes. Traditionally, in vitro adipocyte models fail to recapitulate in vivo insulin signaling, possibly due to exposure to supraphysiological nutrient and hormone conditions. Here, we have developed a sensitization protocol for human pluripotent stem cell-derived adipocytes that uses physiologically relevant nutrient conditions to produce a potent signaling response comparable to in vivo adipocytes. After systematically optimizing conditions, this protocol allows for robust insulin-stimulated glucose uptake and transcriptional insulin response. Furthermore, exposure of these sensitized adipocytes to physiologically relevant hyperinsulinemic conditions dampens insulin-stimulated glucose uptake and dysregulates transcription of insulin-responsive genes. Overall, this sensitization methodology provides a novel platform for the mechanistic study of insulin signaling and resistance using human pluripotent stem cell-derived adipocytes. TeaserA new protocol to generate hPSC-adipocytes that respond to physiological insulin levels and can model diabetes.

cell biology↗

bioRxiv2022

Physiologically Based Multiphysics Pharmacokinetic Model for Determining the Temporal Biodistribution of Targeted Nanoparticles

Nanoparticles (NP) are being increasingly explored as vehicles for targeted drug delivery because they can overcome free therapeutic limitations by drug encapsulation, thereby increasing solubility and transport across cell membranes. However, a translational gap exists from animal to human studies resulting in only several NP having FDA approval. Because of this, researchers have begun to turn toward physiologically based pharmacokinetic (PBPK) models to guide in vivo NP experimentation. However, typical PBPK models use an empirically derived framework that cannot be universally applied to varying NP constructs and experimental settings. The purpose of this study was to develop a physics-based multiscale PBPK compartmental model for determining continuous NP biodistribution. We successfully developed two versions of a physics-based compartmental model, models A and B, and validated the models with experimental data. The more physiologically relevant model (model B) had an output that more closely resembled experimental data as determined by normalized root mean squared deviation (NRMSD) analysis. A branched model was developed to enable the model to account for varying NP sizes. With the help of the branched model, we were able to show that branching in vasculature causes enhanced uptake of NP in the organ tissue. The models were solved using two of the most popular computational platforms, MATLAB and Julia. Our experimentation with the two suggests the highly optimized ODE solver package DifferentialEquations.jl in Julia outperforms MATLAB when solving a stiff system of ordinary differential equations (ODEs). We experimented with solving our PBPK model with a neural network using Julias Flux.jl package. We were able to demonstrate that a neural network can learn to solve a system of ODEs when the system can be made non-stiff via quasi-steady-state approximation (QSSA). In the future, this model will incorporate modules that account for varying NP surface chemistries, multiscale vascular hydrodynamic effects, and effects of the immune system to create a more comprehensive and modular model for predicting NP biodistribution in a variety of NP constructs. Author summaryNanoparticles (NP) have been used in various drug delivery contexts because they can target specific locations in the body. However, there is a translational gap between animals and humans, so researchers have begun toward computational models to guide in vivo NP experimentation. Here, we present several versions of physics-based multiscale physiologically based pharmacokinetic models (PBPK) for determining NP biodistribution. We successfully developed two versions of ODE-based compartmental models (models A and B) and an ODE-based branched vascular model implemented in MATLAB and Julia and validated models with experimental data. Additionally, we demonstrated using a neural network to solve our ODE system. In the future, this model can integrate different NP surface chemistries, immune system effects, multiscale vascular hydrodynamic effects, which will enhance the ability of this model to guide a variety of in vivo experiments.

bioengineering↗

bioRxiv2022

Tradeoffs in bacterial physiology determine the efficiency of antibiotic killing

Antibiotics can kill or stop the growth of bacteria, and their effectiveness depends on many factors. It is important to understand the relation between bacterial physiology, the environment and antibiotic action. While many of the mechanistic details of antibiotic action are known, the connection between death rate and bacterial physiology is poorly understood. Death rate in antibiotics has often been shown to rise linearly with growth rate; however, it remains unclear how environmental factors, in concert with whole-cell physiological properties, affect bactericidal activity. To address this, we developed a high-throughput assay to precisely measure antibiotic-mediated bacterial death. We found that death rate is linear in growth rate, but the slope depends on environmental conditions. Specifically, stressors lower the death rate compared to a non-stressed environment with the same growth rate. To understand the role of stress, we developed a mathematical model of bacterial death based on resource allocation that takes into account a newly defined stress-response sector; we identify this sector using RNA-seq. Our model accurately predicts the death rate and minimal inhibitory concentration of antibiotics across a wide range of conditions, including a previously unknown increase in the stress response and protection from death at very low levels of cAMP. The present death-growth model suggests conditions that may improve antibiotic efficacy.

systems biology↗