619 research outputs found
The coproporphyrin ferrochelatase of Staphylococcus aureus: mechanistic insights into a regulatory iron binding site
The majority of characterised ferrochelatase enzymes catalyse the final step of classical haem synthesis, inserting ferrous iron into protoporphyrin IX. However, for the recently-discovered coproporphyrin-dependent pathway, ferrochelatase catalyses the penultimate reaction where ferrous iron is inserted into coproporphyrin III. Ferrochelatase enzymes from the bacterial phyla Firmicutes and Actinobacteria have previously been shown to insert iron into coproporphyrin, and those from Bacillus subtilis and Staphylococcus aureus are known to be inhibited by elevated iron concentrations. The work herein reports a Km (coproporphyrin III) for S. aureus ferrochelatase of 1.5 µM and it is shown that elevating the iron concentration increases the Km for coproporphyrin III, providing a potential explanation for the observed iron-mediated substrate inhibition. Together, structural modelling, site-directed mutagenesis, and kinetic analyses confirm residue Glu271 as being essential for the binding of iron to the inhibitory regulatory site on S. aureus ferrochelatase, providing a molecular explanation for the observed substrate inhibition patterns. This work therefore has implications for how haem biosynthesis in S. aureus is regulated by iron availability
Bound states between dark matter particles and emission of gravitational radiation
Bound states of two weakly interactive massive particles are studied. It is
assumed that the WIMPonium is formed due to the gravitational interaction,
since the weak interaction can sometimes be repulsive. The lifetimes of the
spontaneous emission of gravitational radiation and of the WIMPs annihilation
into a pair of gravitons are computed, and are shown to be many orders of
magnitude larger than the age of the universe.Comment: Accepted for publication in GER
Kirschmann's Fourth Law
Kirschmann's Fourth Law states that the magnitude of simultaneous color contrast increases with the saturation of the inducing surround, but that the rate of increase reduces as saturation increases. Others since Kirschmann have agreed and disagreed. Here we show that the form of the relationship between simultaneous color contrast and inducer saturation depends on the method of measurement. Functions were measured by four methods: (i) asymmetric matching with a black surround, (ii) asymmetric matching with a surround metameric to equal energy white, (iii) dichoptic matching, and (iv) nulling an induced sinusoidal modulation. Results from the asymmetric matching conditions agreed with Kirschmann, whereas results from nulling and from dichoptic matching showed a more linear increase in simultaneous contrast with the saturation of the inducer. We conclude that the method certainly affects the conclusions reached, and that there may not be any "fair" way of measuring simultaneous contrast
The temporal dynamics of Arc expression regulate cognitive flexibility
YesNeuronal activity regulates the transcription and
translation of the immediate-early gene Arc/Arg3.1,
a key mediator of synaptic plasticity. Proteasomedependent
degradation of Arc tightly limits its
temporal expression, yet the significance of this
regulation remains unknown. We disrupted the temporal
control of Arc degradation by creating an Arc
knockin mouse (ArcKR) where the predominant Arc
ubiquitination sites were mutated. ArcKR mice had
intact spatial learning but showed specific deficits
in selecting an optimal strategy during reversal
learning. This cognitive inflexibility was coupled to
changes in Arc mRNA and protein expression resulting
in a reduced threshold to induce mGluR-LTD and
enhanced mGluR-LTD amplitude. These findings
show that the abnormal persistence of Arc protein
limits the dynamic range of Arc signaling pathways
specifically during reversal learning. Our work
illuminates how the precise temporal control of activity-dependent
molecules, such as Arc, regulates synaptic
plasticity and is crucial for cognition.Open access funded by Biotechnology and Biological Sciences Research Counci
A stochastic model for heart rate fluctuations
Normal human heart rate shows complex fluctuations in time, which is natural,
since heart rate is controlled by a large number of different feedback control
loops. These unpredictable fluctuations have been shown to display fractal
dynamics, long-term correlations, and 1/f noise. These characterizations are
statistical and they have been widely studied and used, but much less is known
about the detailed time evolution (dynamics) of the heart rate control
mechanism. Here we show that a simple one-dimensional Langevin-type stochastic
difference equation can accurately model the heart rate fluctuations in a time
scale from minutes to hours. The model consists of a deterministic nonlinear
part and a stochastic part typical to Gaussian noise, and both parts can be
directly determined from the measured heart rate data. Studies of 27 healthy
subjects reveal that in most cases the deterministic part has a form typically
seen in bistable systems: there are two stable fixed points and one unstable
one.Comment: 8 pages in PDF, Revtex style. Added more dat
Occupational Communication as Boundary Mechanism
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/69000/2/10.1177_073088847400100404.pd
A historical perspective on the discovery of statins
Cholesterol is essential for the functioning of all human organs, but it is nevertheless the cause of coronary heart disease. Over the course of nearly a century of investigation, scientists have developed several lines of evidence that establish the causal connection between blood cholesterol, atherosclerosis, and coronary heart disease. Building on that knowledge, scientists and the pharmaceutical industry have successfully developed a remarkably effective class of drugs—the statins—that lower cholesterol levels in blood and reduce the frequency of heart attacks
Independent evolution of intermediate bill widths in a seabird clade
16 pages, 5 figures, 5 tables, supplementary information https://doi.org/10.1007/s00438-021-01845-3.-- Availability of data and material: DNA sequences: GenBank accession numbers are provided in Table 1. All data are available in the manuscript or in the Supplementary information fileInterspecific introgression can occur between species that evolve rapidly within an adaptive radiation. Pachyptila petrels differ in bill size and are characterised by incomplete reproductive isolation, leading to interspecific gene flow. Salvin’s prion (Pachyptila salvini), whose bill width is intermediate between broad-billed (P. vittata) and Antarctic (P. desolata) prions, evolved through homoploid hybrid speciation. MacGillivray’s prion (P. macgillivrayi), known from a single population on St Paul (Indian Ocean), has a bill width intermediate between salvini and vittata and could also be the product of interspecies introgression or hybrid speciation. Recently, another prion population phenotypically similar to macgillivrayi was discovered on Gough (Atlantic Ocean), where it breeds 3 months later than vittata. The similarity in bill width between the medium-billed birds on Gough and macgillivrayi suggest that they could be closely related. In this study, we used genetic and morphological data to infer the phylogenetic position and evolutionary history of P. macgillivrayi and the Gough medium-billed prion relative other Pachyptila taxa, to determine whether species with medium bill widths evolved through common ancestry or convergence. We found that Gough medium-billed prions belong to the same evolutionary lineage as macgillivrayi, representing a new population of MacGillivray’s prion that originated through a colonisation event from St Paul. We show that macgillivrayi’s medium bill width evolved through divergence (genetic drift) and independently from that of salvini, which evolved through hybridisation (gene flow). This represents the independent convergence towards a similarly medium-billed phenotype. The newly discovered MacGillivray’s prion population on Gough is of utmost conservation relevance, as the relict macgillivrayi population in the Indian Ocean is very smallOpen Access funding enabled and organized by Projekt DEAL. PQ, JFM, TLC and LC were supported by the Deutsche Forschungsgemeinschaft (Germany), Heisenberg program (grant number DFG, Qu 148-5 to P.Q.). Logistical and financial support was obtained from the South African Department of Environmental Affairs, through the South African National Antarctic Programme. LDS was supported by a Rutherford Discovery Fellowship from the Royal Society of New ZealandWith the institutional support of the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000928-S)Peer reviewe
Dark Matter Signals from Cascade Annihilations
A leading interpretation of the electron/positron excesses seen by PAMELA and
ATIC is dark matter annihilation in the galactic halo. Depending on the
annihilation channel, the electron/positron signal could be accompanied by a
galactic gamma ray or neutrino flux, and the non-detection of such fluxes
constrains the couplings and halo properties of dark matter. In this paper, we
study the interplay of electron data with gamma ray and neutrino constraints in
the context of cascade annihilation models, where dark matter annihilates into
light degrees of freedom which in turn decay into leptons in one or more steps.
Electron and muon cascades give a reasonable fit to the PAMELA and ATIC data.
Compared to direct annihilation, cascade annihilations can soften gamma ray
constraints from final state radiation by an order of magnitude. However, if
dark matter annihilates primarily into muons, the neutrino constraints are
robust regardless of the number of cascade decay steps. We also examine the
electron data and gamma ray/neutrino constraints on the recently proposed
"axion portal" scenario.Comment: 36 pages, 11 figures, 7 tables; references adde
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