Sleep spindles are characteristic electroencephalogram (EEG) signatures of stage 2 non-rapid eye movement sleep. Implicated in sleep regulation and cognitive functioning, spindles may represent ...heritable biomarkers of neuropsychiatric disease. Here we characterize spindles in 11,630 individuals aged 4 to 97 years, as a prelude to future genetic studies. Spindle properties are highly reliable but exhibit distinct developmental trajectories. Across the night, we observe complex patterns of age- and frequency-dependent dynamics, including signatures of circadian modulation. We identify previously unappreciated correlates of spindle activity, including confounding by body mass index mediated by cardiac interference in the EEG. After taking account of these confounds, genetic factors significantly contribute to spindle and spectral sleep traits. Finally, we consider topographical differences and critical measurement issues. Taken together, our findings will lead to an increased understanding of the genetic architecture of sleep spindles and their relation to behavioural and health outcomes, including neuropsychiatric disorders.
Animals actively sample the sensory world by generating complex patterns of movement that evolve in three dimensions. Whether or how such movements affect neuronal activity in sensory cortical areas ...remains largely unknown, because most experiments exploring movement-related modulation have been performed in head-fixed animals. Here, we show that 3D head-orienting movements (HOMs) modulate primary visual cortex (V1) activity in a direction-specific manner that also depends on light. We identify two overlapping populations of movement-direction-tuned neurons that support this modulation, one of which is direction tuned in the dark and the other in the light. Although overall movement enhanced V1 responses to visual stimulation, HOMs suppressed responses. We demonstrate that V1 receives a motor efference copy related to orientation from secondary motor cortex, which is involved in controlling HOMs. These results support predictive coding theories of brain function and reveal a pervasive role of 3D movement in shaping sensory cortical dynamics.
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•Primary visual cortex (V1) encodes 3D head-orienting movements (HOMs)•V1 neurons are modulated by HOMs depending on light and are tuned to HOM direction•Responses to visual stimulation are suppressed during HOMs•HOM encoding depends on secondary motor cortex (M2)
Guitchounts et al. find that the primary visual cortex (V1) of freely moving rats encodes 3D orienting movements of the head (HOMs). V1 is suppressed or enhanced by HOMs, depending on lighting condition, and individual neurons encode HOM direction. This encoding depends on secondary motor cortex (M2).
A pseudospectral model of linear elastic wave propagation is described based on the first order stress-velocity equations of elastodynamics. k-space adjustments to the spectral gradient calculations ...are derived from the dyadic Green's function solution to the second-order elastic wave equation and used to (a) ensure the solution is exact for homogeneous wave propagation for timesteps of arbitrarily large size, and (b) also allows larger time steps without loss of accuracy in heterogeneous media. The formulation in k-space allows the wavefield to be split easily into compressional and shear parts. A perfectly matched layer (PML) absorbing boundary condition was developed to effectively impose a radiation condition on the wavefield. The staggered grid, which is essential for accurate simulations, is described, along with other practical details of the implementation. The model is verified through comparison with exact solutions for canonical examples and further examples are given to show the efficiency of the method for practical problems. The efficiency of the model is by virtue of the reduced point-per-wavelength requirement, the use of the fast Fourier transform (FFT) to calculate the gradients in k space, and larger time steps made possible by the k-space adjustments.
We report the discovery of a gravitationally lensed hyperluminous infrared galaxy (intrinsic L
IR ≈ 1013 L⊙) with strong radio emission (intrinsic L
1.4 GHz ≈ 1025 W Hz−1) at z = 2.553. The source ...was identified in the citizen science project Space Warps through the visual inspection of tens of thousands of iJK
s colour composite images of luminous red galaxies (LRGs), groups and clusters of galaxies and quasars. Appearing as a partial Einstein ring (r
e
≈ 3 arcsec) around an LRG at z = 0.2, the galaxy is extremely bright in the sub-millimetre for a cosmological source, with the thermal dust emission approaching 1 Jy at peak. The redshift of the lensed galaxy is determined through the detection of the CO(3→2) molecular emission line with the Large Millimetre Telescope's Redshift Search Receiver and through O iii and Hα line detections in the near-infrared from Subaru/Infrared Camera and Spectrograph. We have resolved the radio emission with high-resolution (300–400 mas) eMERLIN L-band and Very Large Array C-band imaging. These observations are used in combination with the near-infrared imaging to construct a lens model, which indicates a lensing magnification of μ ≈ 10. The source reconstruction appears to support a radio morphology comprised of a compact (<250 pc) core and more extended component, perhaps indicative of an active nucleus and jet or lobe.
Please cite this paper as: Heazell A, McLaughlin M, Schmidt E, Cox P, Flenady V, Khong T, Downe S. A difficult conversation? The views and experiences of parents and professionals on the consent ...process for perinatal postmortem after stillbirth. BJOG 2012;119:987–997.
Objective To describe the experiences, knowledge and views of both parents and professionals regarding the consent process for perinatal postmortem.
Design Internet‐based survey.
Setting Obstetricians, midwives and perinatal pathologists currently working in the UK. Parents who have experienced a stillbirth in the UK in the previous 10 years.
Sample Obstetricians, midwives and perinatal pathologists registered with their professional bodies. Parents who accessed the Sands website or online forum.
Methods Online self‐completion questionnaire with both fixed‐choice and open‐ended questions.
Results Responses were analysed from 2256 midwives, 354 obstetricians, 21 perinatal pathologists and 460 parents. The most common reason for parents to request postmortem examination was to find a cause for their baby’s death; the prevention of stillbirths in others also ranked highly. Perinatal pathologists possessed greatest knowledge of the procedure and efficacy of postmortem, but were unlikely to meet bereaved parents. The majority of professionals and parents ranked emotional distress and a lengthy wait for results as barriers to consent. The majority of staff ranked workload, negative publicity, religion and cultural issues as important barriers, whereas most parents did not. Almost twice as many parents who declined postmortem examination later regretted their decision compared with those who accepted the offer (34.4 versus 17.4%).
Conclusion Emotional, practical and psychosocial issues can act as real or perceived barriers for staff and bereaved parents. Education is required for midwives and obstetricians, to increase their knowledge to ensure accurate counselling, with due regard for the highly individual responses of bereaved parents. The contribution of perinatal pathologists to staff education and parental decision‐making would be invaluable.
Open fractures are at risk of serious infection and, if infected, require several surgical interventions and courses of systemic antibiotics. We investigated a new injectable formulation that ...simultaneously hardens in vivo to form a porous scaffold for bone repair and delivers antibiotics at high concentrations to the local site of infection. Duration of antimicrobial activity against Staphylococcus aureus was determined using the serial plate transfer test. Ultimate compressive strength and porosity of the material was measured with and without antibiotics. The material was evaluated in vivo in an ovine medial femoral condyle defect model contaminated with S. aureus. Sheep were sacrificed at either 2 or 13 weeks and the defect and surrounding bone assessed using micro-computed tomography and histology. Antimicrobial activity in vitro persisted for 19-21 days. Sheep with antibiotic-free material and bacteria became infected, while those with antibiotic-containing material and bacteria did not. Similarly, new bone growth was seen in uninoculated animals with plain polymer, and in those with antibiotic polymer with bacteria, but not in sheep with plain polymer and bacteria. The antibiotic-impregnated scaffolds were effective in preventing S. aureus infections whilst supporting bone growth and repair. If translated into clinical practice, this approach might reduce the need for systemic antibiotics.
Investigating variation in genes involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs are key to characterizing pharmacogenomic (PGx) relationships. ADME gene variation ...is relatively well characterized in European and Asian populations, but data from African populations are under-studied-which has implications for drug safety and effective use in Africa.
We identified significant ADME gene variation in African populations using data from 458 high-coverage whole genome sequences, 412 of which are novel, and from previously available African sequences from the 1,000 Genomes Project. ADME variation was not uniform across African populations, particularly within high impact coding variation. Copy number variation was detected in 116 ADME genes, with equal ratios of duplications/deletions. We identified 930 potential high impact coding variants, of which most are discrete to a single African population cluster. Large frequency differences (i.e., >10%) were seen in common high impact variants between clusters. Several novel variants are predicted to have a significant impact on protein structure, but additional functional work is needed to confirm the outcome of these for PGx use. Most variants of known clinical outcome are rare in Africa compared to European populations, potentially reflecting a clinical PGx research bias to European populations.
The genetic diversity of ADME genes across sub-Saharan African populations is large. The Southern African population cluster is most distinct from that of far West Africa. PGx strategies based on European variants will be of limited use in African populations. Although established variants are important, PGx must take into account the full range of African variation. This work urges further characterization of variants in African populations including
and
studies, and to consider the unique African ADME landscape when developing precision medicine guidelines and tools for African populations.
Mutasynthesis of pyrichalasin H from Magnaporthe grisea NI980 yielded a series of unprecedented 4′‐substituted cytochalasin analogues in titres as high as the wild‐type system (≈60 mg L−1). ...Halogenated, O‐alkyl, O‐allyl and O‐propargyl examples were formed, as well as a 4′‐azido analogue. 4′‐O‐Propargyl and 4′‐azido analogues reacted smoothly in Huisgen cycloaddition reactions, whereas p‐Br and p‐I compounds reacted in Pd‐catalysed cross‐coupling reactions. A series of examples of biotin‐linked, dye‐linked and dimeric cytochalasins was rapidly created. In vitro and in vivo bioassays of these compounds showed that the 4′‐halogenated and azido derivatives retained their cytotoxicity and antifungal activities; but a unique 4′‐amino analogue was inactive. Attachment of larger substituents attenuated the bioactivities. In vivo actin‐binding studies with adherent mammalian cells showed that actin remains the likely intracellular target. Dye‐linked compounds revealed visualisation of intracellular actin structures even in the absence of phalloidin, thus constituting a potential new class of actin‐visualisation tools with filament‐barbed end‐binding specificity.
Molecular toolbox: Unprecedented cytochalasins functionalised at the 4′‐position were produced by mutasynthesis. These compounds were then chemically diversified to produce a range of molecular tools without the need for protecting strategies. As a pertinent example the Texas‐red‐modified compound was synthesised in a single step from 4′‐azidocytochalasin and used to visualise sub‐micrometer actin microstructures in immobilised U2OS cells.
Lesion verification and quantification is traditionally done via histological examination of sectioned brains, a time-consuming process that relies heavily on manual estimation. Such methods are ...particularly problematic in posterior cortical regions (e.g. visual cortex), where sectioning leads to significant damage and distortion of tissue. Even more challenging is the post hoc localization of micro-electrodes, which relies on the same techniques, suffers from similar drawbacks and requires even higher precision. Here, we propose a new, simple method for quantitative lesion characterization and electrode localization that is less labor-intensive and yields more detailed results than conventional methods. We leverage staining techniques standard in electron microscopy with the use of commodity micro-CT imaging. We stain whole rat and zebra finch brains in osmium tetroxide, embed these in resin and scan entire brains in a micro-CT machine. The scans result in 3D reconstructions of the brains with section thickness dependent on sample size (12-15 and 5-6 microns for rat and zebra finch respectively) that can be segmented manually or automatically. Because the method captures the entire intact brain volume, comparisons within and across studies are more tractable, and the extent of lesions and electrodes may be studied with higher accuracy than with current methods.
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