2,903 research outputs found

    Enhancing research culture in academia: a spotlight on early career researchers

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    This editorial highlights common challenges faced by early career researchers (ECRs) who play a crucial role in our research community. We propose that enhancing the experiences of ECRs will yield benefits to the entire scientific community and we give practical suggestions on how such improvements may be achieved

    Hypothermia protects brain mitochondrial function from hypoxemia in a murine model of sepsis

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    Sepsis is commonly associated with brain dysfunction, but the underlying mechanisms remain unclear, although mitochondrial dysfunction and microvascular abnormalities have been implicated. We therefore assessed whether cerebral mitochondrial dysfunction during systemic endotoxemia in mice increased mitochondrial sensitivity to a further bioenergetic insult (hyoxemia), and whether hypothermia could improve outcome. Mice (C57bl/6) were injected intraperitoneally with lipopolysaccharide (LPS) (5 mg/kg; n = 85) or saline (0.01 ml/g; n = 47). Six, 24 and 48 h later, we used confocal imaging in vivo to assess cerebral mitochondrial redox potential and cortical oxygenation in response to changes in inspired oxygen. The fraction of inspired oxygen (FiO2) at which the cortical redox potential changed was compared between groups. In a subset of animals, spontaneous hypothermia was maintained or controlled hypothermia induced during imaging. Decreasing FiO2 resulted in a more reduced cerebral redox state around veins, but preserved oxidation around arteries. This pattern appeared at a higher FiO2 in LPS-injected animals, suggesting an increased sensitivity of cortical mitochondria to hypoxemia. This increased sensitivity was accompanied by a decrease in cortical oxygenation, but was attenuated by hypothermia. These results suggest that systemic endotoxemia influences cortical oxygenation and mitochondrial function, and that therapeutic hypothermia can be protective

    Assessing spontaneous sensory neuron activity usingin vivocalcium imaging

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    Heightened spontaneous activity in sensory neurons is often reported in individuals living with chronic pain. It is possible to study this activity in rodents using electrophysiology, but these experiments require great skill and can be prone to bias. Here, we have examined whether in vivo calcium imaging with GCaMP6s can be used as an alternative approach. We show that spontaneously active calcium transients can be visualised in the fourth lumbar dorsal root ganglion (L4 DRG) via in vivo imaging in a mouse model of pain. Application of lidocaine to the nerve, between the inflamed site and the DRG, silenced spontaneous firing and revealed the true baseline level of calcium for spontaneously active neurons. We used this data to train a machine leaning algorithm to predict when a neuron is spontaneously active. We show that our algorithm is accurate in two different models of pain: intraplantar Complete Freund’s Adjuvant and antigen-induced arthritis, with accuracies of 90.0% +/-1.2 and 85.9 % +/-2.1, respectively, assessed against visual inspection by an experienced observer. The algorithm can also detect neuronal activity in imaging experiments generated in a different lab using a different microscope configuration (Accuracy = 94.0 % +/2.2). We provide a Google Colaboratory Notebook to allow anyone easy access to this novel tool, for assessment of peripheral neuron activity in their own calcium imaging setups

    Divergent Perturbation Series

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    Various perturbation series are factorially divergent. The behavior of their high-order terms can be found by Lipatov's method, according to which they are determined by the saddle-point configurations (instantons) of appropriate functional integrals. When the Lipatov asymptotics is known and several lowest order terms of the perturbation series are found by direct calculation of diagrams, one can gain insight into the behavior of the remaining terms of the series. Summing it, one can solve (in a certain approximation) various strong-coupling problems. This approach is demonstrated by determining the Gell-Mann - Low functions in \phi^4 theory, QED, and QCD for arbitrary coupling constants. An overview of the mathematical theory of divergent series is presented, and interpretation of perturbation series is discussed. Explicit derivations of the Lipatov asymptotic forms are presented for some basic problems in theoretical physics. A solution is proposed to the problem of renormalon contributions, which hampered progress in this field in the late 1970s. Practical schemes for summation of perturbation series are described for a coupling constant of order unity and in the strong-coupling limit. An interpretation of the Borel integral is given for 'non-Borel-summable' series. High-order corrections to the Lipatov asymptotics are discussed.Comment: Review article, 45 pages, PD

    Characterising the stimulus-response function of mouse C-Low threshold mechanoreceptors to mechanical stimuliin vivo

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    C-low threshold mechanoreceptors (C-LTMRs) in animals (termed C-tactile (CT) fibres in humans) are a subgroup of C-fibre primary afferents, which innervate hairy skin and respond to low threshold punctate indentations and brush stimuli. These afferents respond to gentle, touch stimuli and are implicated in mediating pleasant/affective touch. These afferents have traditionally been studied using low-throughput, technically challenging approaches, including microneurography in humans and teased fibre electrophysiology in other mammals. Here we suggest a new approach to studying genetically labelled C-LTMRs using in vivo calcium imaging. We used an automated rotating brush stimulus and Von Frey filaments, applied to the hairy skin of anaesthetised mice to mirror light and affective touch. Simultaneously we visualised changes in C-LTMR activity and confirmed that these neurons are sensitive to low-threshold punctate mechanical stimuli and brush stimuli with a strong preference for slow brushing speeds. We also reveal that C-LMTRs are directionally sensitive, showing more activity when brushed against the natural orientation of the hair. We present in vivo calcium imaging of genetically labelled C-LTMRs as a useful approach that can reveal new aspects of C-LTMR physiology

    Immune or genetic-mediated disruption of CASPR2 causes pain hypersensitivity due to enhanced primary afferent excitability

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    Human autoantibodies to contactin-associated protein-like 2 (CASPR2) are often associated with neuropathic pain, and CASPR2 mutations have been linked to autism spectrum disorders, in which sensory dysfunction is increasingly recognized. Human CASPR2 autoantibodies, when injected into mice, were peripherally restricted and resulted in mechanical pain-related hypersensitivity in the absence of neural injury. We therefore investigated the mechanism by which CASPR2 modulates nociceptive function. Mice lacking CASPR2 (Cntnap2 ) demonstrated enhanced pain-related hypersensitivity to noxious mechanical stimuli, heat, and algogens. Both primary afferent excitability and subsequent nociceptive transmission within the dorsal horn were increased in Cntnap2 mice. Either immune or genetic-mediated ablation of CASPR2 enhanced the excitability of DRG neurons in a cell-autonomous fashion through regulation of Kv1 channel expression at the soma membrane. This is the first example of passive transfer of an autoimmune peripheral neuropathic pain disorder and demonstrates that CASPR2 has a key role in regulating cell-intrinsic dorsal root ganglion (DRG) neuron excitability

    Protection of cerebral microcirculation, mitochondrial function and electrocortical activity by small-volume resuscitation with terlipressin in a model of haemorrhagic shock

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    Background: During early treatment of haemorrhagic shock, cerebral perfusion pressure can be restored by small-volume resuscitation with vasopressors. Whether this therapy is improved with additional fluid remains unknown. We assessed the value of terlipressin and lactated Ringer's solution (LR) on the early recovery of the microcirculation, tissue oxygenation, and mitochondrial and electrophysiological function in the rat cerebral cortex. Methods: Animals treated with LR replacing three times (3LR) the volume bled (n=26), terlipressin (n=27), terlipressin plus 1LR (n=26), 2LR (n=16), or 3LR (n=15) were compared with untreated (n=36) and sham-operated rats (n=17) rats. In vivo confocal microscopy was used to assess cortical capillary perfusion, changes in tissue oxygen concentration, and mitochondrial membrane potential and redox state. Electrophysiological function was assessed by cortical somatosensory evoked potentials, spinal cord dorsum potential, and peripheral electromyography. Results: Compared with sham, haemorrhagic shock reduced the mean (standard deviation) area of perfused vessels [82% (sd 10%) vs 38% (12%); P<0.001] and impaired oxygen concentration, mitochondrial redox state [99% (4%) vs 59% (15%) of baseline; P<0.001], and somatosensory evoked potentials [97% (13%) vs 27% (19%) of baseline]. Administration of terlipressin plus 1LR or 2LR was able to recover these measures, but terlipressin plus 3LR or 3LR alone were not as effective. Spinal cord dorsum potential was preserved in all groups, but no therapy protected electromyographic function. Conclusions: Resuscitation from haemorrhagic shock using terlipressin with small-volume LR was superior to high-volume LR, with regard to cerebral microcirculation, and mitochondrial and electrophysiological function

    New constraints on the primordial black hole number density from Galactic gamma-ray astronomy

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    Primordial black holes are unique probes of cosmology, general relativity, quantum gravity and non standard particle physics. They can be considered as the ultimate particle accelerator in their last (explosive) moments since they are supposed to reach, very briefly, the Planck temperature. Upper limits on the primordial black hole number density of mass M⋆=51014M_{\star} = 5 10^{14} g, the Hawking mass (born in the big-bang terminating their life presently), is determined comparing their predicted cumulative γ\gamma-ray emission, galaxy-wise, to the one observed by the EGRET satellite, once corrected for non thermal γ\gamma-ray background emission induced by cosmic ray protons and electrons interacting with light and matter in the Milky Way. A model with free gas emissivities is used to map the Galaxy in the 100 MeV photon range, where the peak of the primordial black hole emission is expected. The best gas emissivities and additional model parameters are obtained by fitting the EGRET data and are used to derive the maximum emission of the primordial black hole of the Hawking mass, assuming that they are distributed like the dark matter in the Galactic halo. The bounds we obtain, depending on the dark matter distribution, extrapolated to the whole Universe (ΩPBH(M⋆)=2.410−10\Omega_{PBH}(M_{\star}) = 2.4 10^{-10} to 2.610−92.6 10^{-9} are more stringent than the previous ones derived from extragalactic γ\gamma-ray background and antiprotons fluxes, though less model dependent and based on more robust data. These new limits have interesting consequences on the theory of the formation of small structures in the Universe, since they are the only constraint on very small scale density fluctuations left by inflation.Comment: 8 pages, 6 figures ; accepted in Astronomy and Astrophysic

    The Arabidopsis Resistance-Like Gene SNC1 Is Activated by Mutations in SRFR1 and Contributes to Resistance to the Bacterial Effector AvrRps4

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    The SUPPRESSOR OF rps4-RLD1 (SRFR1) gene was identified based on enhanced AvrRps4-triggered resistance in the naturally susceptible Arabidopsis accession RLD. No other phenotypic effects were recorded, and the extent of SRFR1 involvement in regulating effector-triggered immunity was unknown. Here we show that mutations in SRFR1 in the accession Columbia-0 (Col-0) lead to severe stunting and constitutive expression of the defense gene PR1. These phenotypes were temperature-dependent. A cross between srfr1-1 (RLD background) and srfr1-4 (Col-0) showed that stunting was caused by a recessive locus in Col-0. Mapping and targeted crosses identified the Col-0-specific resistance gene SNC1 as the locus that causes stunting. SRFR1 was proposed to function as a transcriptional repressor, and SNC1 is indeed overexpressed in srfr1-4. Interestingly, co-regulated genes in the SNC1 cluster are also upregulated in the srfr1-4 snc1-11 double mutant, indicating that the overexpression of SNC1 is not a secondary effect of constitutive defense activation. In addition, a Col-0 RPS4 mutant showed full susceptibility to bacteria expressing avrRps4 at 24°C but not at 22°C, while RLD susceptibility was not temperature-dependent. The rps4-2 snc1-11 double mutant showed increased, but not full, susceptibility at 22°C, indicating that additional cross-talk between resistance pathways may exist. Intriguingly, when transiently expressed in Nicotiana benthamiana, SRFR1, RPS4 and SNC1 are in a common protein complex in a cytoplasmic microsomal compartment. Our results highlight SRFR1 as a convergence point in at least a subset of TIR-NBS-LRR protein-mediated immunity in Arabidopsis. Based on the cross-talk evident from our results, they also suggest that reports of constitutive resistance phenotypes in Col-0 need to consider the possible involvement of SNC1

    Uptake of alkaline earth metals in Alcyonarian spicules (Octocorallia)

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    Alcyonarian corals (Octocorallia) living in shallow tropical seas produce spicules of high-Mg calcite with ∼13 mol% MgCO3. We cultured the tropical alcyonarian coral Rhythisma fulvum in experiments varying temperature (19–32 °C) and pH (8.15–8.44). Alkalinity depletion caused by spicule formation systematically varied in the temperature experiments increasing from 19 to 29 °C. Spicules were investigated for their elemental ratios (Mg/Ca, Sr/Ca) using ICP-OES, δ44/40Ca using TIMS, as well as δ18O and δ13C by IRMS. Mg/Ca increased with temperature from 146 to 164 mmol/mol, in good agreement with the range observed for marine inorganic calcite. Mg/Ca increased by 1.0 ± 0.4 mmol/mol/°C, similar to the sensitivity of Miliolid foraminifera. The pH experiments revealed a linear relationship between Mg/Ca and carbonate ion concentration of +0.03 ± 0.02 mmol/mol/μMol. Sr/Ca ranges from 2.5 to 2.9 mmol/mol being in good agreement with other high-Mg calcites. Temperature and pH experiments showed linear dependencies of Sr/Ca matching inorganic calcite trends and pointing to a decoupling of crystal precipitation rate and calcification rate. Ca isotopes range between 0.7‰ and 0.9‰ in good agreement with aragonitic scleractinian corals and calcitic coccoliths. Presumably Ca isotopes are fractionated by a biological mechanism that may be independent of the skeletal mineralogy. We observe no temperature trend, but a significant decrease of δ44/40Ca with increasing pH. This inverse correlation may characterise biologically controlled intracellular calcification. Oxygen isotope ratios are higher than expected for isotopic equilibrium with a temperature sensitivity of −0.15 ± 0.03‰/°C. Carbon isotope ratios are significantly lower than expected for equilibrium and positively correlated with temperature with a slope of 0.20 ± 0.04‰/°C. Many of our observations on trace element incorporation in R. fulvum may be explained by inorganic processes during crystal formation, which do not comply with the intracellular mode of calcification in Alcyonarian corals. The observed elemental and isotopic compositions, however, could be explained if the partitioning caused by biological mechanisms mimics the effects of inorganic processes
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