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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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2017

The Caenorhabditis elegans RAD-51 isoform A is required for the induction of DNA-damage-dependent apoptosis

The rad-51 gene in Caenorhabditis elegans is transcribed into alternative mRNAs potentially coding three alternative protein isoforms. We have genetically modified this gene in order to investigate the potential roles of the longest isoform, namely isoform A, in genome stability. The RAD-51 isoform A appears to contribute to genome stability in late development, but is not implicated in meiosis or DNA repair in the germline. However, the RAD-51 isoform A has a pivotal role in DNA damage induced apoptosis, but not in DNA damage checkpoint activation or physiological cell death. This is a relevant new finding that improves our understanding of how DNA damage apoptosis is restricted to late pachytene stage preventing the inappropriate loss of nuclei undergoing the earlier stages of meiotic recombination, during which a large number of physiologically induced DSBs are present.

genetics↗
bioRxiv2017

Molecular chaperones maximize the native state yield per unit time by driving substrates out of equilibrium

Molecular chaperones have evolved to facilitate folding of proteins and RNA in vivo where spontaneous self-assembly is sometimes prohibited. Folding of Tetrahymena ribozyme, assisted by the RNA chaperone CYT-19, surprisingly shows that at physiological Mg2+ ion concentrations, increasing the chaperone concentration reduces the yield of native ribozymes. In contrast, the more extensively investigated protein chaperone GroEL works in exactly the opposite manner--the yield of native substrate increases with the increase in chaperone concentration. Thus, the puzzling observation on the assisted-ribozyme folding seems to contradict the expectation that a molecular chaperone acts as an efficient annealing machine. We suggest a resolution to this apparently paradoxical behavior by developing a minimal stochastic model that captures the essence of the Iterative Annealing Mechanism (IAM), providing a unified description of chaperone mediated-folding of proteins and RNA. Our theory provides a general relation involving the kinetic rates of the system, which quantitatively predicts how the yield of native state depends on chaperone concentration. By carefully analyzing a host of experimental data on Tetrahymena (and its mutants) as well as the protein Rubisco and Malate Dehydrogenase, we show that although the absolute yield of native states decreases in the ribozyme, the rate of native state production increases in both the cases. By utilizing energy from ATP hydrolysis, both CYT-19 and GroEL drive their substrate concentrations far out of equilibrium, in an endeavor to maximize the native yield in a short time. Our findings are consistent with the general expectation that proteins or RNA need to be folded by the cellular machinery on biologically relevant timescales, even if the final yield is lower than what equilibrium thermodynamics would dictate. Besides establishing the IAM as the basis for functions of RNA and protein chaperones, our work shows that cellular copy numbers have been adjusted to optimize the rate of native state production of the folded states of RNA and proteins under physiological conditions.\n\nSignificance statementMolecular chaperones have evolved to assist the folding of proteins and RNA, thus avoiding the deleterious consequences of misfolding. Thus, it is expected that increasing chaperone concentration should lead to an enhancement in native yield. While this has been observed in GroEL-mediated protein folding, experiments on Tetrahymena ribozyme folding assisted by CYT-19, surprisingly show the opposite trend. Here, we reconcile these divergent experimental observations by developing a unified stochastic model of chaperone assisted protein and RNA folding. We show that chaperones drive their substrates out of equilibrium, and in the process maximize the rate of native substrate production rather than the absolute yield or the folding rate. In vivo the number of chaperones is regulated to optimize their functions.

biophysics↗
bioRxiv2017

Synaptic homeostasis at the Drosophila neuromuscular junction is a reversible signaling process that is sensitive to high temperature

Homeostasis is a vital mode of biological self-regulation. The hallmarks of homeostasis for any biological system are a baseline set point of physiological activity, detection of unacceptable deviations from the set point, and effective corrective measures to counteract deviations. Homeostatic synaptic plasticity (HSP) is a form of neuroplasticity in which neurons and circuits resist environmental perturbations in order to maintain appropriate levels of activity. One assumption is that if an environmental perturbation triggers homeostatic corrective changes in neuronal properties, those corrective measures should be reversed upon removal of the perturbation. We test the reversibility and limits of HSP at a well-studied model synapse, the Drosophila melanogaster neuromuscular junction (NMJ). At the Drosophila NMJ, impairment of glutamate receptors causes a decrease in quantal size, which is offset by a corrective, homeostatic increase in the number of vesicles released per evoked presynaptic stimulus, or quantal content. This process has been termed presynaptic homeostatic potentiation (PHP). Taking advantage of a GAL4/GAL80TS/UAS expression system, we triggered PHP by expressing a dominant-negative glutamate receptor subunit at the NMJ. We then reversed PHP by halting expression of the dominant-negative receptor. Our data show that PHP is fully reversible over a time course of 48-72 hours after the dominant-negative glutamate receptor stops being genetically expressed. Additionally, we found that the PHP response triggered by the dominant-negative subunit was ablated at high temperatures. Our data show that the long-term maintenance of PHP at the Drosophila NMJ is a reversible regulatory process that is sensitive to temperature.\n\nSIGNIFICANCE STATEMENTBiological homeostatic systems must upregulate or downregulate cellular parameters in order to maintain appropriate set points of physiological activity. Homeostasis is a well-documented mode of regulation in metazoan nervous systems. True homeostatic control should be a reversible process - but due to technical difficulties of presenting and removing functional challenges to living synapses, the reversibility of homeostatic forms of synapse regulation has not been rigorously examined in vivo over extended periods of developmental time. Here we formally demonstrate that homeostatic regulation of Drosophila melanogaster neuromuscular synapse function is reversible and temperature-labile. This is significant because developing methods to study how homeostatic regulatory systems are turned on and off could lead to fundamental new insights about control of synaptic output.

neuroscience↗
bioRxiv2017

Hormonal correlates of pathogen disgust: Testing the Compensatory Prophylaxis Hypothesis

Raised progesterone during the menstrual cycle is associated with suppressed physiological immune responses, reducing the probability that the immune system will compromise the blastocysts development. The Compensatory Prophylaxis Hypothesis proposes that this progesterone-linked immunosuppression triggers increased disgust responses to pathogen cues, compensating for the reduction in physiological immune responses by minimizing contact with pathogens. Although a popular and influential hypothesis, there is no direct, within-woman evidence for correlated changes in progesterone and pathogen disgust. To address this issue, we used a longitudinal design to test for correlated changes in salivary progesterone and pathogen disgust (measured using the pathogen disgust subscale of the Three Domain Disgust Scale) in a large sample of women (N=375). Our analyses showed no evidence that pathogen disgust tracked changes in progesterone, estradiol, testosterone, or cortisol. Thus, our results provide no support for the Compensatory Prophylaxis Hypothesis of variation in pathogen disgust.

animal behavior and cognition↗
bioRxiv2017

Long non-coding RNA repertoire and regulation by nuclear exosome, cytoplasmic exonuclease and RNAi in fission yeast

Transcriptomes feature pervasive, but poorly defined long non-coding RNAs (lncRNAs). We identify 5775 novel lncRNAs in Schizosaccharomyces pombe, nearly 4-times the previously annotated lncRNAs. Most lncRNAs become derepressed under genetic and physiological perturbations, especially during late meiosis. These lncRNAs are targeted by three RNA-processing pathways: the nuclear exosome, cytoplasmic exonuclease and RNAi, with substantial coordination and redundancy among pathways. We classify lncRNAs into cryptic unstable transcripts (CUTs), Xrn1-sensitive unstable transcripts (XUTs), and Dicer-sensitive unstable transcripts (DUTs). XUTs and DUTs are enriched for antisense lncRNAs, while CUTs are often bidirectional and actively translated. The cytoplasmic exonuclease and RNAi repress thousands of meiotically induced RNAs. Antisense lncRNA and sense mRNA expression often negatively correlate in the physiological, but not the genetic conditions. Intergenic and bidirectional lncRNAs emerge from nucleosome-depleted regions, upstream of positioned nucleosomes. This broad survey of the S. pombe lncRNA repertoire and characteristics provides a rich resource for functional analyses.

genomics↗
bioRxiv2017

Time-resolved Interaction Proteomics of the Putative Scaffold Protein GIGANTEA in Arabidopsis thaliana

The large, plant-specific protein GIGANTEA (GI) is involved in many physiological processes, mediating rhythmic, post-translational regulation in part through circadian and light regulation of GI RNA expression. GI binds several proteins implicated in the circadian clock, the control of photoperiodic flowering, and abiotic stress responses, and has co-chaperone activity. By extension, further interaction partners might mediate the less well-understood roles of GI but the number and rhythmicity of these interactors is unknown. Here, we seek potential interactors in a time-specific manner, using quantitative proteomics from a time series study of transgenic Arabidopsis thaliana plants constitutively expressing an epitope-tagged GI protein. Previously-identified, direct and indirect interactors of GI were detected but no further F-box proteins related to known GI partners ZTL/FKF1/LKP2. The predominantly non-rhythmic, interacting proteins were implicated in protein folding or degradation, metabolism and chromatin modification, including a small set of partners shared with other clock-related proteins. A transcription factor homologue that we name CYCLING DOF FACTOR 6 (CDF6) was shown to interact both with GI and the ZTL/FKF1/LKP2 proteins and to control photoperiodic flowering. Our results indicate the biochemical pathways, beyond circadian and flowering regulation, that might be affected by GIGANTEAs rhythmic, post-translational control.\n\nSignificance StatementSignificance statement of up to two sentences of no more than 75 words total;\n\nThe GIGANTEA protein of Arabidopsis was known for circadian and flowering functions, mediated by the FKF1/LKP2/ZTL family of GI-interacting, F-box proteins, then for a co-chaperone activity of unknown scope. We performed time-resolved, interaction proteomics, identifying CDF6 (At1g26790) as a morning-specific GI interactor that controls flowering time. Unlike FKF1 and CDF proteins, most of the 240 candidate partners were not rhythmically enriched. They link GI to proteostasis and metabolic functions that might mediate GIs physiological functions.

plant biology↗
bioRxiv2017

A mathematical model relates intracellular TLR4 oscillations to sepsis progression

Oscillations drive many biological processes and their modulation is determinant for various pathologies. In sepsis syndrome, Toll-like receptor 4 (TLR4) is a key sensor for signaling the presence of Gram-negative bacteria. Its expression and activity, along with its intracellular trafficking rates shift the equilibrium between the pro- and anti-inflammatory downstream signaling cascades, leading to either the physiological resolution of the bacterial stimulation or to sepsis. We hypothesize that the initial tlr4 expression in patients diagnosed with sepsis and TLR4 dynamic concentration changes on the cell membrane or intracellularly, dictates how the sepsis syndrome is initiated. Using a set of three differential equations, we defined the TLR4 flux between relevant cell organelles. We obtained three different regions in the phase space: 1. a limit-cycle describing unstimulated physiological oscillations, 2. a fixed-point attractor resulting from moderate LPS stimulation that is resolved and 3. a double-attractor resulting from sustained LPS stimulation that leads to sepsis. We tested the models against hospital data of sepsis patients and we correctly evaluate the clinical outcome of these patients.

immunology↗
bioRxiv2017

Efficient hydrogen-dependent carbon dioxide reduction by Escherichia coli

The formate hydrogenlyase (FHL) complex of Escherichia coli is normally produced under anaerobic fermentative conditions when its physiological role is to oxidise formate to carbon dioxide and couple that reaction directly to the reduction of protons to molecular hydrogen. This forward reaction is the major route of hydrogen production by E. coli and the physiology, genetics and biochemistry of this process are reasonably well understood. However, studies of the reverse reaction - hydrogen-dependent carbon dioxide reduction - have been rather less extensive. Harnessing the alternative reverse reaction has the potential to unlock FHL as a carbon dioxide cycling enzyme, or could potentially lead to the development of bio-based carbon capture technologies. In this work, it is established that FHL can operate as a highly efficient CO2 reductase. A controllable pressure system was designed with the intention of maximising substrate availability to the FHL enzyme. By placing gaseous CO2 and H2 are under pressure (up to 10 bar), and by using a compartmentalised intact whole cell approach where the produced formate is excreted, the optimised experimental system was observed to convert 100 % of gaseous CO2 to formic acid and generate >500 mM formate in solution at an initial rate of 1.2 g formate per litre per hour.

microbiology↗
bioRxiv2017

How evolution draws trade-offs

Recent empirical evidence suggest that trade-off shapes can evolve, challenging the classical image of their high entrenchment. Here we model the evolution of the physiological mechanism that controls the allocation of a resource to two traits, by mutating the expression and the conformation of its constitutive hormones and receptors. We show that trade-off shapes do indeed evolve in this model through the combined action of genetic drift and selection, such that their evolutionarily expected curvature and length depend on context. In particular, a trade-offs shape should depend on the cost associated with the resource storage, itself depending on the traded resource and on the ecological context. Despite this convergence at the phenotypic level, we show that a variety of physiological mechanisms may evolve in similar simulations, suggesting redundancy at the genetic level. This model should provide a useful frame-work to interpret and link the overly complex observations of evolutionary endocrinology and evo-lutionary ecology.

evolutionary biology↗
bioRxiv2017

Improving the quality of combined EEG-TMS neural recordings: Introducing the ‘Coil Spacer’

BackgroundIn the last decade, interest in combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) approaches has grown substantially. Aside from the obvious artifacts induced by the magnetic pulses themselves, separate and more sinister signal disturbances arise as a result of contact between the TMS coil and EEG electrodes.\n\nNew methodHere we profile the characteristics of these artifacts and introduce a simple device - the coil spacer - to provide a platform allowing physical separation between the coil and electrodes during stimulation.\n\nResultsEEG data revealed high amplitude signal disturbances when the TMS coil was in direct contact with the EEG electrodes, well within the physiological range of viable EEG signals. The largest artifacts were located in the Delta and Theta frequency range, and standard data cleanup using independent components analysis (ICA) was ineffective due to the artifacts similarity to real brain oscillations.\n\nComparison with Existing MethodWhile the current best practice is to use a large coil holding apparatus to fixate the coil hovering over the head with an air gap, the spacer provides a simpler solution that ensures this distance is kept constant throughout testing.\n\nConclusionsThe results strongly suggest that data collected from combined TMS-EEG studies with the coil in direct contact with the EEG cap are polluted with low frequency artifacts that are indiscernible from physiological brain signals. The coil spacer provides a cheap and simple solution to this problem and is recommended for use in future simultaneous TMS-EEG recordings.

neuroscience↗
bioRxiv2017

Indole-3-Acetaldehyde Dehydrogenase-dependent Auxin Synthesis Contributes to Virulence of Pseudomonas syringae Strain DC3000

The bacterial pathogen Pseudomonas syringae modulates plant hormone signaling to promote infection and disease development. P. syringae uses several strategies to manipulate auxin physiology in Arabidopsis thaliana to promote pathogenesis, including synthesis of indole-3-acetic acid (IAA), the predominant form of auxin in plants, and production of virulence factors that alter auxin responses in the host; however, the role of pathogen-derived auxin in P. syringae pathogenesis is not well understood. Here we demonstrate that P. syringae strain DC3000 produces IAA via a previously uncharacterized pathway and identify a novel indole-3-acetaldehyde dehydrogenase, AldA, that functions in IAA biosynthesis by catalyzing the NAD-dependent formation of IAA from indole-3-acetaldehyde (IAAld). Biochemical analysis and solving of the 1.9 [A] resolution x-ray crystal structure reveal key features of AldA for IAA synthesis, including the molecular basis of substrate specificity. Disruption of aldA and a close homolog, aldB, lead to reduced IAA production in culture and reduced virulence on A. thaliana. We use these mutants to explore the mechanism by which pathogen-derived auxin contributes to virulence and show that IAA produced by DC3000 suppresses salicylic acid-mediated defenses in A. thaliana. Thus, auxin is a DC3000 virulence factor that promotes pathogenicity by suppressing host defenses.\n\nAuthor SummaryPathogens have evolved multiple strategies for suppressing host defenses and modulating host physiology to promote colonization and disease development. For example, the plant pathogen Pseudomonas syringae uses several strategies to the manipulate hormone signaling of its hosts, including production of virulence factors that alter hormone responses in and synthesis of plant hormones or hormone mimics. Synthesis of indole-3-acetic acid (IAA), a common form of the plant hormone auxin, by many plant pathogens has been implicated in virulence. However, the role of pathogen-derived IAA during pathogenesis by leaf spotting pathogens such as P. syringae strain DC3000 is not well understood. Here, we demonstrate that P. syringae strain DC3000 uses a previously uncharacterized biochemical pathway to synthesize IAA, catalyzed by a novel aldehyde dehydrogenase, AldA, and carry out biochemical and structural studies of the AldA protein to investigate AldA activity and substrate specificity. We also generate an aldA mutant disrupted in IAA synthesis to show that IAA is a DC3000 virulence factor that promotes pathogenesis by suppressing host defense responses.

microbiology↗
bioRxiv2017

Parasympathetic and sympathetic activity are associated with individual differences in neural indices of selective attention in adults

Multiple theoretical frameworks posit that interactions between the autonomic nervous system and higher-order neural networks are crucial for cognitive regulation. However, few studies have directly examined the relationship between measures of autonomic physiology and brain activity during cognitive tasks, and fewer studies have examined both the parasympathetic and sympathetic autonomic branches when doing so. Here, 93 adults completed an event-related potential (ERP) auditory selective attention task concurrently with measures of parasympathetic activity (high-frequency heart rate variability; HF-HRV) and sympathetic activity (pre-ejection period; PEP). We replicate previous findings showing effects of selective attention on mean amplitude of the N1 ERP component (Hillyard et al., 1973; Coch et al., 2005), and extend this result to show that the effects of selective attention were associated with baseline values of HF-HRV and PEP. Individuals with higher resting HF-HRV and shorter resting PEP showed larger effects of selective attention on their ERPs. Follow-up regression models demonstrated that HF-HRV and PEP accounted for unique variance in selective attention effects on N1 mean amplitude. These results are consistent with the neurovisceral integration model, which posits that greater parasympathetic activity is a marker of increased cognitive capacity, as well as other theoretical models which emphasize the role of heightened sympathetic activity in more efficient attention-related processing. The present findings highlight the importance of autonomic physiology in the study of individual differences in neurocognitive function, and given the foundational role of selective attention across cognitive domains, suggest that both parasympathetic and sympathetic activity may be key to understanding variability in brain function across a variety of cognitive tasks.

neuroscience↗
bioRxiv2017

On the bioconversion of dietary carotenoids to astaxanthin and its distribution in the marine copepod, Tigriopus californicus

Red carotenoid-based coloration is widely distributed across marine and terrestrial animals and has taken a prominent role in studies of how phenotypic traits evolve in response to natural and sexual selection. Key to these studies is an understanding of the physiological mechanisms that give rise to red coloration, yet an ideal model system for such work has not been identified. The red marine copepod Tigriopus californicus is used as a model system for studies in ecotoxicology, genetics, and physiology, but the mechanisms involved in its bright red coloration have not been well studied. Like nearly all animals that display red carotenoid coloration, T. californicus likely convert yellow carotenoids present in their algal diet to red carotenoids. We conducted precursor/product feeding experiments to demonstrate that T. californicus bioconverts dietary carotenoids to the red carotenoid, astaxanthin. In separate treatment groups, copepods were fed carotenoids that are precursors to specific astaxanthin bioconversion pathways. We found that copepods from each precursor pigment group produced astaxanthin, and that the amount produced depended on which carotenoid was supplemented. We also describe the distribution of astaxanthin in developing egg sacs and show that the red color of the naupliar eyespot is not due to astaxanthin. We briefly discuss the potential of Tigriopus californicus to serve as a model system for the study of carotenoid metabolism in animals.

zoology↗
bioRxiv2017

N-terminal sumoylation of centromeric histone H3 variant Cse4 regulates its proteolysis to prevent mislocalization to non-centromeric chromatin

Stringent regulation of cellular levels of evolutionarily conserved centromeric histone H3 variant (CENP-A in humans, CID in flies, Cse4 in yeast) prevents its mislocalization to non-centromeric chromatin. Overexpression and mislocalization of CENP-A has been observed in cancers and leads to aneuploidy in yeast, flies, and human cells. Ubiquitin-mediated proteolysis of Cse4 by E3 ligases such as Psh1 and Sumo-Targeted Ubiquitin Ligase (STUbL) Slx5 prevent mislocalization of Cse4. Previously, we identified Siz1 and Siz2 as the major E3 ligases for sumoylation of Cse4. In this study, we identify lysine 65 (K65) in Cse4 as a SUMO site and show that sumoylation of Cse4 K65 regulates its ubiquitin-mediated proteolysis by Slx5. Strains expressing cse4 K65R exhibit reduced levels of sumoylated and ubiquitinated Cse4 in vivo. Furthermore, co-immunoprecipitation experiments reveal reduced interaction of cse4 K65R with Slx5. Defects in sumoylation of cse4 K65R contribute to increased stability and mislocalization of cse4 K65R under normal physiological conditions. Based on the increased stability of cse4 K65R in psh1{triangleup} strains but not in slx5{triangleup} strains, we conclude that Slx5 targets sumoylated Cse4 K65 for ubiquitination-mediated proteolysis independent of Psh1. In summary, we have identified and characterized the physiological role of Cse4 sumoylation and determined that sumoylation of Cse4 K65 regulates ubiquitin-mediated proteolysis and prevents mislocalization of Cse4 which is required for genome stability.

molecular biology↗
bioRxiv2017

Population-based mechanistic modeling allows for quantitative predictions of drug responses across cell types

Quantitative mismatches between human physiology and experimental models can present serious limitations for the development of effective therapeutics. We addressed this issue, in the context of cardiac electrophysiology, through mechanistic mathematical modeling combined with statistical analyses. Physiological metrics were simulated in heterogeneous populations describing cardiac myocytes from adult ventricles and those derived from induced pluripotent stem cells (iPSC-CMs). These simulated measures were used to construct a cross-cell type regression model that predicts adult myocyte drug responses from iPSC-CM behaviors. We found that quantitatively accurate predictions of responses to selective or non-selective drugs could be generated based on iPSC-CM responses and that the method can be extended to predict drug responses in diseased as well as healthy cells. This cross-cell type model can be of great value in drug development, and the approach, which can be applied to other fields, represents an important strategy for overcoming experimental model limitations.

systems biology↗
bioRxiv2017

Low-level mitochondrial heteroplasmy modulates DNA replication, glucose metabolism and lifespan in mice

Mutations in mitochondrial DNA (mtDNA) lead to heteroplasmy, i.e. the intracellular coexistence of wild-type and mutant mtDNA strands, which impact a wide spectrum of diseases but also physiological processes, including endurance exercise performance in athletes. However, the phenotypic consequences of limited levels of naturally-arising heteroplasmy have not been experimentally studied to date. We hence generated a conplastic mouse strain carrying the mitochondrial genome of a AKR/J mouse strain (B6-mtAKR) together with a C57BL/6J nuclear genomic background, leading to >20% heteroplasmy in the origin of light-strand DNA replication (OriL). These conplastic mice demonstrate a shorter lifespan as well as dysregulation of multiple metabolic pathways, culminating in impaired glucose metabolism, compared to wild-type C57BL/6J mice carrying lower levels of heteroplasmy. Our results indicate that physiologically relevant differences in mtDNA heteroplasmy levels at a single, functionally important site impair metabolic health and lifespan in mice.\n\nHighlightsO_LIWe identify heteroplasmy of the adenine-repeat variation (9 to 13A) in nt5172 in the origin of light-strand DNA replication (OriL) in inbred mice.\nC_LIO_LIB6-mtAKR mice carry >20% 12A heteroplasmy in the OriL, while B6 mice carry only [~] 10% heteroplasmy.\nC_LIO_LIThe level of 12A heteroplasmy correlates to mtDNA copy number, glucose metabolism, and lifespan in mice.\nC_LIO_LIGiven the established role of mtDNA heteroplasmy in regards to endurance exercise performance in athletes, these findings may impact our understanding of metabolism and aging in humans.\nC_LI

genetics↗
bioRxiv2017

Preventing photomorbidity in long-term multi-color fluorescence imaging of S. cerevisiae and S. pombe

Time-lapse imaging using multiple fluorescent reporters is an essential tool to study molecular processes in single cells. However, exposure to even moderate doses of visible excitation light can disturb cellular physiology and alter the quantitative behavior of the cells under study. Here, we set out to develop guidelines to avoid the confounding effects of excitation light in multi-color long-term imaging. We use widefield fluorescence microscopy to measure the effect of the administered excitation light on growth (here called photomorbidity) in yeast. We find that photomorbidity is determined by the cumulative light dose at each wavelength, but independent of the way excitation light is applied. Importantly, photomorbidity possesses a threshold light dose below which no effect is detectable (NOEL, no-observed-effect level). We found, that the suitability of fluorescent proteins for live-cell imaging at the respective excitation light NOEL is equally determined by the cellular autofluorescence and the fluorescent protein brightness. Last, we show that photomorbidity of multiple wavelengths is additive and imaging conditions absent of photomorbidity can be predicted. Our findings enable researchers to find imaging conditions with minimal impact on physiology and can provide a framework for how to approach photomorbidity in other organisms.

cell biology↗
bioRxiv2017

Quasi-Periodic Patterns of Intrinsic Brain Activity in Individuals and their Relationship to Global Signal

Quasiperiodic patterns (QPPs) as reported by Majeed et al., 2011 are prominent features of the brains intrinsic activity that involve important large-scale networks (default mode, DMN; task positive, TPN) and are likely to be major contributors to widely used measures of functional connectivity. We examined the variability of these patterns in 470 individuals from the Human Connectome Project resting state functional MRI dataset. The QPPs from individuals can be coarsely categorized into two types: one where strong anti-correlation between the DMN and TPN is present, and another where most areas are strongly correlated. QPP type could be predicted by an individuals global signal, with lower global signal corresponding to QPPs with strong anti-correlation. After regression of global signal, all QPPs showed strong anti-correlation between DMN and TPN. QPP occurrence and type was similar between a subgroup of individuals with extremely low motion (or even high motion) and the rest of the sample, which shows that motion is not a major contributor to the QPPs. After regression of estimates of slow respiratory and cardiac induced signal fluctuations, more QPPs showed strong anti-correlation between DMN and TPN, an indication that while physiological noise influences the QPP type, it is not the primary source of the QPP itself. QPPs were more similar for the same subjects scanned on different days than for different subjects. These results provide the first assessment of the variability in individual QPPs and their relationship to physiological parameters.

neuroscience↗