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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2020

Physiological and head motion signatures in static and time-varying functional connectivity and their subject discriminability

Human brain connectivity yields significant potential as a noninvasive biomarker. Several studies have used fMRI-based connectivity fingerprinting to characterize individual patterns of brain activity. However, it is not clear whether these patterns mainly reflect neural activity or the effect of physiological and motion processes. To answer this question, we capitalize on a large data sample from the Human Connectome Project and rigorously investigate the contribution of the aforementioned processes on functional connectivity (FC) and time-varying FC, as well as their contribution to subject identifiability. We find that head motion, as well as heart rate and breathing fluctuations, induce artifactual connectivity within distinct resting-state networks and that they correlate with recurrent patterns in time-varying FC. Even though the spatiotemporal signatures of these processes yield above-chance levels in subject identifiability, removing their effects at the preprocessing stage improves identifiability, suggesting a neural component underpinning the inter-individual differences in connectivity.

neuroscience↗

bioRxiv2020

The RNA binding protein hnRNP-U is required for physiological hypertrophy of skeletal muscle

Skeletal muscle has the remarkable ability to modulate its mass in response to physiological changes associated with nutritional input, functional utilization, systemic disease, and age. A decreased responsiveness to anabolic stimuli is thought to contribute significantly to the loss of skeletal muscle mass and strength associated with sarcopenia, however the molecular mechanisms precipitating this are unclear. The signal transduction pathways that control the relative balance between anabolic and catabolic processes are tightly regulated at the transcriptional and post-transcriptional levels. Alternative splicing produces multiple protein isoforms from a single gene in a cell-type-specific manner and in response to environmental cues. We show that sustained activation of Akt1 in Hnrnpu deficient mice leads to premature muscle wasting, in part, through impaired autophagy while providing mechanistic insights into the development of anabolic resistance.

cell biology↗

bioRxiv2020

Assessment of mitochondrial physiology of murine white adipose tissue by mechanical permeabilization and lipid depletion

White adipose tissue (WAT) is classically associated with energy storage in the form of triacylglycerol and is directly associated with metabolic disorders, including obesity. Mitochondria regulates cellular expenditure and are active in WAT. Although isolated mitochondria have been classically used to assess their functions, several artifacts can be introduced by this approach. Although methods to assess mitochondrial physiology in permeabilized WAT were proposed, important limitations that affect organelle function exist. Here, we established and validated a method for functional evaluation of mice mesenteric WAT (mWAT) mitochondria by using mechanical permeabilization in combination with lipid depletion and high-resolution respirometry. We observed that mild stirring of mWAT for 20 minutes at room temperature with 4% fatty acid-free albumin selectively permeabilized white adipocytes plasma membrane. In these conditions, mWAT mitochondria were intact and coupled, exhibiting succinate-induced respiratory rates that were sensitive to classical modulators of oxidative phosphorylation. Finally, the respiratory capacity of mWAT in females was significantly higher than in males, an observation that agrees with reported data using isolated mitochondria. The functional assessment of mWAT mitochondria through mild mechanical permeabilization, lipid depletion and high resolution respirometry proposed here will contribute to a better understanding of WAT biology in several pathophysiological contexts.

biochemistry↗

bioRxiv2020

A CURE for physiological characterization of bacterioplankton in liquid culture

Bacterial characterization is an important aspect of microbiology that includes experimentally determining growth rates, environmental conditions conducive to growth, and the types of energy sources microorganisms can use. Researchers use this information to help understand and predict an organisms ecological distribution and environmental functions. Microbiology students generally conduct bacterial characterization experiments in their coursework; however they are frequently restricted to model organisms without ecological relevance and for which the results have been known for decades. We present a course-based undergraduate research experience (CURE) curriculum to involve students in characterization of previously untested, ecologically relevant bacterioplankton cultures to identify the carbon substrates used for growth, as well as the temperature and salinity ranges conducive to growth. Students use these results to connect their organisms physiology to the isolation environment. This curriculum also exposes students to advanced microbiology methods such as flow cytometry for measuring cell concentrations, teaches them to use the programming language R for data plotting, and emphasizes scientific communication through writing, speaking, poster creation/presentation, and social media. This CURE is an attractive introduction to scientific research and was successfully tested with 147 students during the fall semester of 2018.

scientific communication and education↗

bioRxiv2020

Seasonal variation in physiology and shell condition of the pteropod Limacina retroversa in the Gulf of Maine relative to life cycle and carbonate chemistry.

Natural cycles in the seawater partial pressure of carbon dioxide (CO2) in the Gulf of Maine, which vary from [~]250-550 {micro}atm seasonally, provide an opportunity to observe how the life cycle and phenology of the shelled pteropod Limacina retroversa responds to changing food, temperature and carbonate chemistry conditions. Distributional, hydrographic, and physiological sampling suggest that pteropod populations are located in the upper portion of the water column (0-150 m) with a maximum abundance above 50 m, allowing them to generally avoid aragonite undersaturation. Gene expression and shell condition measurements show, however, that the population already experiences biomineralization stress in the winter months even when aragonite is slightly oversaturated, reinforcing the usefulness of this organism as a bio-indicator for pelagic ecosystem response to ocean acidification. There appear to be two reproductive events per year with one pulse timed to coincide with the spring bloom, the period with highest respiration rate, fluorescence, and pH, and a second more extended pulse in the late summer and fall. During the fall there is evidence of lipid storage for overwintering, allowing the second generation to survive the period of low food and aragonite saturation state. Based on these observations we predict that in the future pteropods will likely be most vulnerable to changing CO2 regionally during the fall reproductive event when CO2 concentration already naturally rises and there is the added stress of generating lipid stores.

ecology↗

bioRxiv2020

Behavioral, physiological, and neural signatures of surprise during naturalistic sports viewing

Surprise signals a discrepancy between past and current beliefs. It is theorized to be linked to affective experiences, the creation of particularly resilient memories, and segmentation of the flow of experience into discrete perceived events. However, the ability to precisely measure naturalistic surprise has remained elusive. We used advanced basketball analytics to derive a quantitative measure of surprise and characterized its behavioral, physiological, and neural correlates in human subjects observing basketball games. We found that surprise was associated with segmentation of ongoing experiences, as reflected by subjectively perceived event boundaries and shifts in neocortical patterns underlying belief states. Interestingly, these effects differed by whether surprising moments contradicted or bolstered current predominant beliefs. Surprise also positively correlated with pupil dilation, activation in subcortical regions associated with dopamine, game enjoyment, and long-term memory. These investigations support key predictions from event segmentation theory and extend theoretical conceptualizations of surprise to real-world contexts.

neuroscience↗

bioRxiv2020

The early development and physiology of Xenopus laevis tadpole lateral line system

Xenopus laevis has a lateral line mechanosensory system throughout its full life cycle. Previous studies of the tadpole lateral line system revealed that it may play a role in escape behaviour. In this study, we used DASPEI staining to reveal the location of tadpole lateral line neuromasts. Destroying these neuromasts with neomycin resulted in loss of escape responses in tadpoles. We then studied the physiology of anterior lateral line in immobilised tadpoles. Activating the neuromasts behind one eye could evoke asymmetrical motor nerve discharges when the tadpole was resting, suggestive of turning/escape, followed by fictive swimming. When the tadpole was already producing fictive swimming however, anterior lateral line activation reliably led to the termination of swimming. The anterior lateral line had spontaneous afferent discharges at rest, and when activated showed typical adaptation. There were also efferent activities during tadpole swimming, the activity of which was loosely in phase with ipsilateral motor nerve discharges, implying modulation by the motor circuit from the same side. Calcium imaging experiments located sensory interneurons in the primary anterior lateral line nucleus in the hindbrain. Future studies are needed to reveal how sensory information is processed by the central circuit to determine tadpole motor behaviour. Summary statementActivating tadpole anterior lateral line evokes escape responses followed by swimming and halts ongoing swimming. The afferent and efferent activities and sensory interneuron locations in the hindbrain are reported.

neuroscience↗

bioRxiv2020

Myelinating Schwann cells use Warburg effect to sustain axonal physiology and function

Despite the lactate shuttle theory, how glial cells support axonal metabolism and function remains unclear. Lactate production is a common occurrence following anaerobic glycolysis in muscles. However, several other cell types, including some stem cells, activatezd macrophages and tumor cells, can produce lactate in presence of oxygen and cellular respiration, using Pyruvate Kinase 2 (PKM2) to divert pyruvate to lactate dehydrogenase. We show here that PKM2 is also upregulated in mature myelinating Schwann cells (mSC) of mouse sciatic nerve. Deletion of this isoform in PLP-expressing cells in mice leads to a deficit of lactate in mSC and in peripheral nerves. This had no detectable consequences on the myelin sheath. However, mutant mice developed a peripheral neuropathy. Peripheral nerve axons of mutant mice failed to maintain lactate homeostasis upon activity, resulting in an impaired production of mitochondrial ATP. Action potential propagation was not altered but axonal mitochondria transport was slowed down, muscle axon terminals retracted and motor neurons displayed cellular stress. Additional reduction of lactate availability through dichloroacetate treatment, which diverts pyruvate to mitochondrial oxidative phosphorylation, further aggravated motor dysfunction in mutant mice. Thus, lactate production through aerobic glycolysis is essential in mSC for the long-term maintenance of peripheral nerve axon physiology and function.

neuroscience↗

bioRxiv2020

Profiling the effect of nafcillin on HA-MRSA D592 using bacteriological and physiological media

Staphylococcus aureus is a leading human pathogen associated with both hospital-acquired and community-acquired infections. The bacterium has steadily gained resistance to {beta}-lactams and other important first-line antibiotics culminating in its categorization as an urgent threat by the U.S. Centers for Disease Control and Prevention. Observations of a varying response to antimicrobial exposure as a function of media type has revealed that clinical susceptibility testing performed in standard bacteriological media might not adequately represent pharmacological responses in the patient. Such observations have encouraged research designed to identify media types that more closely mimic the in vivo environment. In this study, we examine the response of a hospital-acquired USA100 lineage methicillin-resistant, vancomycin-intermediate S. aureus (MRSA/VISA) strain (D592) to nafcillin in a bacteriological compared to a more physiological tissue culture-based medium. We performed multi-dimensional analysis including growth and bacterial cytological profiling, RNA sequencing, and exo-metabolomics measurements (both HPLC and LC/MS) to shed light on the media-dependent activity of the commonly prescribed {beta}-lactam antibiotic nafcillin. O_TBL View this table: org.highwire.dtl.DTLVardef@85b95borg.highwire.dtl.DTLVardef@14c1504org.highwire.dtl.DTLVardef@1f7e976org.highwire.dtl.DTLVardef@100598dorg.highwire.dtl.DTLVardef@1f770e9_HPS_FORMAT_FIGEXP M_TBL C_TBL

microbiology↗

bioRxiv2020

Clarithromycin Exerts an Antibiofilm Effect against Salmonella typhimurium rdar Biofilm Formation, and Transforms the Physiology towards an Apparent Oxygen-depleted Energy and Carbon Metabolism

Upon biofilm formation, production of extracellular matrix components and alteration in physiology and metabolism allows bacteria to build up multicellular communities which can facilitate nutrient acquisition during unfavorable conditions and provide protection towards various forms of environmental stresses to individual cells. Thus, bacterial cells become tolerant against antimicrobials and the immune system within biofilms. In the current study, we evaluated the antibiofilm activity of the macrolides clarithromycin and azithromycin. Clarithromycin showed antibiofilm activity against rdar (red, dry and rough) biofilm formation of the gastrointestinal pathogen Salmonella typhimurium ATCC14028 Nalr at 1.56 M subinhibitory concentration in standing culture and dissolved cell aggregates at 15 M in a microaerophilic environment suggesting that the oxygen level affects the activity of the drug. Treatment with clarithromycin significantly decreased transcription and production of the rdar biofilm activator CsgD, with biofilm genes such as csgB and adrA to be consistently downregulated. While fliA and other flagellar regulon genes were upregulated, apparent motility was downregulated. RNA sequencing showed a holistic cell response upon clarithromycin exposure, whereby not only genes involved in the biofilm-related regulatory pathways, but also genes that likely contribute to intrinsic antimicrobial resistance, and the heat shock stress response were differentially regulated. Most significantly, clarithromycin exposure shifts the cells towards an apparent oxygen- and energy-depleted status, whereby the metabolism that channels into oxidative phosphorylation is downregulated, and energy gain by degradation of propane 1,2-diol, ethanolamine and L-arginine catabolism is upregulated. This initial analysis will allow the subsequent identification of novel intrinsic antimicrobial resistance determinants.

microbiology↗

bioRxiv2020

Physiological and transcriptomic responses to N-deficiency and ammonium: nitrate shift in Fugacium kawagutii (Symbiodiniaceae)

Symbiodiniaceae are the source of essential coral symbionts of reef building corals. The growth and density of endosymbiotic Symbodiniaceae within the coral host is highly dependent on nutrient availability, yet little is known about how Symbiodiniaceae respond to the dynamics of the nutrients, including switch between different chemical forms and changes in abundance. In this study, we investigated physiological, cytometric, and transcriptomic responses in Fugacium kawagutii to nitrogen (N)-nutrient deficiency and different chemical N forms (nitrate and ammonium) in batch culture conditions. We mainly found that ammonium was consumed faster than nitrate when provided separately, and was preferentially utilized over nitrate when both nitrogen compounds were supplied at 1:2, 1:1 and 2:1 molarity ratios. Besides, N-deficiency caused decreases in growth, energy production, antioxidative capacity and investment in photosynthate transport but increased energy consumption. Growing on ammonium produced a similar cell yield as nitrate, but with a decreased investment in nutrient transport and assimilation. These all have important implications of N nutrient to support symbiosis in coral ecosystem, especially regarding ammonium. In addition, by integrating our current results with previous data, we identified ten highly and stably expressed genes as candidate reference genes, which will be potentially useful for gene expression studies in the future.

microbiology↗

bioRxiv2020

Identifying the effect of vancomycin on HA-MRSA strains using bacteriological and physiological media

Healthcare-associated methicillin-resistant Staphylococcus aureus (HA-MRSA) USA100 strains are of major concern due to their evolving antibiotic resistant. They are resistant to a broad class of antibiotics like macrolides, aminoglycosides, fluoroquinolones, and many more. The selection of appropriate antibiotic susceptibility examination media is very important. Thus, we use bacteriological (CA-MHB) as well as physiological (R10LB) media to determine the effect of vancomycin on USA100 strains. The study includes the profiling behaviour of HA-MRSA USA100 D592 and D712 strains in the presence of vancomycin through various high-throughput assays. The US100 D592 and D712 strains were characterized at sub-inhibitory concentrations through growth curves, RNA sequencing, bacterial cytological profiling, and exo-metabolomics high throughput experiments. The study reveals the vancomycin resistance behavior of USA100 strains in dual media conditions using wide-ranging experiments.

microbiology↗

bioRxiv2020

Gbx2 identifies two amacrine cell subtypes with distinct molecular, morphological, and physiological properties

Our understanding of how the nervous sytem works is limited by our ability to identify the neuronal subtypes that comprise functional circuits. Using a genetic approach, we show that the transcription factor Gbx2 labels two amacrine cell (AC) subtypes in the mouse retina that have distinct morphological, physiological, and molecular properties. One subtype of Gbx2+ ACs are likely the previously characterized On-type GABAergic CRH-1 AC. The other Gbx2+ AC population is a previously uncharacterized non-GABAergic, non-Glycinergic (nGnG) AC subtype. Gbx2+ nGnG ACs are On-Off type cells with asymmetric dendritic arbors. Gbx2+ nGnG ACs also exhibit tracer coupling to bipolar cells (BCs) through gap junctions that are modulated by dopamine signaling. This study genetically identifies a previously uncharacterized AC subtype and reveals an unusual AC-BC connectivity through gap junctions that may provide a novel model of synaptic communication and visual circuit function.

neuroscience↗

bioRxiv2020

Physiological Artifacts and the Implications for Brain-Machine-Interface Design

The accurate measurement of brain activity by Brain-Machine-Interfaces (BMI) and closed-loop Deep Brain Stimulators (DBS) is one of the most important steps in communicating between the brain and subsequent processing blocks. In conventional chest-mounted systems, frequently used in DBS, a significant amount of artifact can be induced in the sensing interface, often as a common-mode signal applied between the case and the sensing electrodes. Attenuating this common-mode signal can be a serious challenge in these systems due to finite commonmode-rejection-ratio (CMRR) capability in the interface. Emerging BMI and DBS devices are being developed which can mount on the skull. Mounting the system on the cranial region can potentially suppress these induced physiological signals by limiting the artifact amplitude. In this study, we model the effect of artifacts by focusing on cardiac activity, using a current-source dipole model in a torso-shaped volume conductor. Performing finite element simulation with the different DBS architectures, we estimate the ECG common mode artifacts for several device architectures. Using this model helps define the overall requirements for the total system CMRR to maintain resolution of brain activity. The results of the simulations estimate that the cardiac artifacts for skull-mounted systems will have a significantly lower effect than non-cranial systems that include the pectoral region. It is expected that with a pectoral mounted device, a minimum of 60-80 dB CMRR is required to suppress the ECG artifact, while in cranially-mounted devices, a 20 dB CMRR is sufficient, in the worst-case scenario. The methods used for estimating cardiac artifacts can be extended to other sources such as motion/muscle sources. The susceptibility of the device to artifacts has significant implications for the practical translation of closed-loop DBS and BMI, including the choice of biomarkers and the design requirements for insulators and lead systems.

bioengineering↗

bioRxiv2020

Identification and physiological significance of temporal NFκB signaling codewords deployed by macrophages to classify immune threats

Acute and chronic inflammatory pathologies involve misregulation of macrophage functions. Physiologically, macrophages are immune sentinels that initiate inflammatory responses via the transcription factor NF{kappa}B. The temporal pattern of NF{kappa}B activity determines which genes are expressed, suggesting that a temporal signaling code specifies a stimulus-appropriate immune response. To identify the signaling codewords, we developed tools to enable high-throughput analysis of live, primary macrophages responding to host- and pathogen-derived stimuli. An information-theoretic workflow identified six dynamical features that constitute codewords that convey stimulus information to the nucleus. In particular, "oscillatory" trajectories are a hallmark of the responses to host cytokine TNF. Remarkably, examining macrophages derived from a systemic autoimmune disease model suggests that confusion of two NF{kappa}B signaling codewords, and thus miscoding of TNF as a pathogen-derived stimulus, may underlie sporadic inflammatory pathology. Overall, this study identifies six codewords of the temporal NF{kappa}B signaling code for classifying immune threats and demonstrates their biological significance.

immunology↗

bioRxiv2020

Underpinning wheat physiological and molecular responses to co-occurring iron and phosphate deficiency stress

Iron (Fe) and phosphorus (P) are the essential mineral nutrient for plant growth and development. However, the molecular interaction of the Fe and P pathways in crops remained largely obscure. In this study, we provide a comprehensive physiological and molecular analysis of hexaploid wheat response to single (Fe, P) and its combinatorial deficiencies. Our data showed that inhibition of the primary root growth occurs in response to Fe deficiency; however, growth was rescued when combinatorial deficiencies occurred. Analysis of RNAseq revealed that distinct molecular rearrangements during combined deficiencies with predominance for genes related to metabolic pathways and secondary metabolite biosynthesis primarily include genes for UDP-glycosyltransferase, cytochrome-P450s, and glutathione metabolism. Interestingly, the Fe-responsive cis-regulatory elements in the roots in Fe stress conditions were enriched compared to the combined stress. Our metabolome data also revealed the accumulation of distinct metabolites such as amino-isobutyric acid, arabinonic acid, and aconitic acid in the combined stress environment. Overall, these results are essential in developing new strategies to improve the resilience of crops in limited nutrients. HIGHLIGHTSO_LIThis study was performed to understand the molecular changes occurring during the interaction of Phosphorus (P) and Iron (Fe) in hexaploid wheat roots. C_LIO_LIP and Fe show cross-talk as Fe deficiency-induced phenotype that was restored by the withdrawal of P. C_LIO_LIA total of 2780 differentially expressed genes were identified in the roots with the combined -Fe-P deficiencies with predominance for UDP-glycosyltransferases, cytochrome-450 and glutathione-S-transferases transcripts. C_LIO_LIThe metabolomic changes identified the importance of amino-isobutyric acid, arabinonic acid and aconitic acid during dual deficiency C_LIO_LIThis work provides a comprehensive insight to understand the molecular rearrangements occurring in wheat roots during Fe and P interaction. C_LI

plant biology↗

bioRxiv2020

Compensatory ion transport buffers daily protein rhythms to regulate osmotic balance and cellular physiology

Between 6-20% of the cellular proteome is under circadian control to tune cell function with cycles of environmental change. For cell viability, and to maintain volume within narrow limits, the osmotic pressure exerted by changes in the soluble proteome must be compensated. The mechanisms and consequences underlying compensation are not known. Here, we show in cultured mammalian cells and in vivo that compensation requires electroneutral active transport of Na+, K+, and Cl- through differential activity of SLC12A family cotransporters. In cardiomyocytes ex vivo and in vivo, compensatory ion fluxes alter their electrical activity at different times of the day. Perturbation of soluble protein abundance has commensurate effects on ion composition and cellular function across the circadian cycle. Thus, circadian regulation of the proteome impacts ion homeostasis with substantial consequences for the physiology of electrically active cells such as cardiomyocytes.

cell biology↗

bioRxiv2020

A mesocosm experiment in ecological physiology: adaptive modulation of energy budget in a hibernating marsupial under chronic caloric restriction

During the last sixty years, mammalian hibernation (i.e., seasonal torpor) has been interpreted as a physiological adaptation for energy economy. However -and crucially for validating this idea - direct field comparisons of energy expenditure in hibernating and active free-ranging animals are scarce. Using replicated mesocosms and a combination of energy budgeting approaches (i.e., doubly labelled water, rates of CO2 production and food intake), we experimentally manipulated energy availability and quantified net energy costs of hibernation in a marsupial. We hypothesized that, when facing chronic caloric restriction (CCR), a hibernator should maximize torpor use for compensating the energetic deficit, compared to ad libitum fed individuals (=controls). However, intensifying torpor duration at low temperatures could increase other burdens (e.g., cost of rewarming, freezing risk). In order to explore this trade-off, we followed the complete hibernation cycle of the relict marsupial Dromiciops gliroides, and estimated its total energy requirements, and compared this with a control condition. Our results revealed: (1) that energy restricted animals, instead of promoting heat conservation strategies during hibernation (e.g., social clustering and thermoregulation), maximized torpor use and saved just enough energy to cover the deficit, and (2) that hibernation represents a net energy saving of 51% compared with animals that remained active. This work provides compelling evidence of a fine-tuning use of hibernation in response to food availability and presents the first direct estimation of energy savings by hibernation encompassing the total hibernation cycle.

ecology↗