Sleep abnormalities in the synaptopathies—SYNGAP1-related intellectual disability and Phelan–McDermid syndrome

Neurodevelopmental disorders are frequently associated with sleep disturbances. One class of neurodevelopmental disorders, the genetic synaptopathies, is caused by mutations in genes encoding proteins found at the synapse. Mutations in these genes cause derangement of synapse development and function. We utilized a validated sleep instrument, Children’s Sleep Habits Questionnaire (CSHQ) to examine the nature of sleep abnormalities occurring in individuals with two synaptopathies—Phelan–McDermid syndrome (PMD) (N = 47, male = 23, female = 24, age 1–46 years) and SYNGAP1-related intellectual disability (SYNGAP1-ID) (N = 64, male = 31, female = 33, age 1–64 years), when compared with unaffected siblings (N = 61, male = 25, female = 36, age 1–17 years). We found that both PMD and SYNGAP1-ID have significant sleep abnormalities with SYNGAP1-ID having greater severity of sleep disturbance than PMD. In addition, sleep disturbances were more severe for PMD in individuals 11 years and older compared with those less than 11 years old. Individuals with either disorder were more likely to use sleep aids than unaffected siblings. In conclusion, sleep disturbances are a significant phenotype in the synaptopathies PMD and SYNGAP1-ID. Improved sleep is a viable endpoint for future clinical trials for these neurodevelopmental disorders

Mapping cortical haemodynamics during neonatal seizures using diffuse optical tomography: A case study

AbstractSeizures in the newborn brain represent a major challenge to neonatal medicine. Neonatal seizures are poorly classified, under-diagnosed, difficult to treat and are associated with poor neurodevelopmental outcome. Video-EEG is the current gold-standard approach for seizure detection and monitoring. Interpreting neonatal EEG requires expertise and the impact of seizures on the developing brain remains poorly understood. In this case study we present the first ever images of the haemodynamic impact of seizures on the human infant brain, obtained using simultaneous diffuse optical tomography (DOT) and video-EEG with whole-scalp coverage. Seven discrete periods of ictal electrographic activity were observed during a 60 minute recording of an infant with hypoxic–ischaemic encephalopathy. The resulting DOT images show a remarkably consistent, high-amplitude, biphasic pattern of changes in cortical blood volume and oxygenation in response to each electrographic event. While there is spatial variation across the cortex, the dominant haemodynamic response to seizure activity consists of an initial increase in cortical blood volume prior to a large and extended decrease typically lasting several minutes. This case study demonstrates the wealth of physiologically and clinically relevant information that DOT–EEG techniques can yield. The consistency and scale of the haemodynamic responses observed here also suggest that DOT–EEG has the potential to provide improved detection of neonatal seizures

The 21 cm Signature of Cosmic String Wakes

We discuss the signature of a cosmic string wake in 21cm redshift surveys. Since 21cm surveys probe higher redshifts than optical large-scale structure surveys, the signatures of cosmic strings are more manifest in 21cm maps than they are in optical galaxy surveys. We find that, provided the tension of the cosmic string exceeds a critical value (which depends on both the redshift when the string wake is created and the redshift of observation), a cosmic string wake will generate an emission signal with a brightness temperature which approaches a limiting value which at a redshift of $z + 1 = 30$ is close to 400 mK in the limit of large string tension. The signal will have a specific signature in position space: the excess 21cm radiation will be confined to a wedge-shaped region whose tip corresponds to the position of the string, whose planar dimensions are set by the planar dimensions of the string wake, and whose thickness (in redshift direction) depends on the string tension. For wakes created at $z_i + 1 = 10^3$, then at a redshift of $z + 1 = 30$ the critical value of the string tension $\mu$ is $G \mu = 6 \times 10^{-7}$, and it decreases linearly with redshift (for wakes created at the time of equal matter and radiation, the critical value is a factor of two lower at the same redshift). For smaller tensions, cosmic strings lead to an observable absorption signal with the same wedge geometry.Comment: 11 pages, 4 figures; a couple of comments added in the discussion sectio

Plasmodium ARK2 and EB1 drive unconventional spindle dynamics, during chromosome segregation in sexual transmission stages

The Aurora family of kinases orchestrates chromosome segregation and cytokinesis during cell division, with precise spatiotemporal regulation of its catalytic activities by distinct protein scaffolds. Plasmodium spp., the causative agents of malaria, are unicellular eukaryotes with three unique and highly divergent aurora-related kinases (ARK1-3) that are essential for asexual cellular proliferation but lack most canonical scaffolds/activators. Here we investigate the role of ARK2 during sexual proliferation of the rodent malaria Plasmodium berghei, using a combination of super-resolution microscopy, mass spectrometry, and live-cell fluorescence imaging. We find that ARK2 is primarily located at spindle microtubules in the vicinity of kinetochores during both mitosis and meiosis. Interactomic and co-localisation studies reveal several putative ARK2-associated interactors including the microtubule-interacting protein EB1, together with MISFIT and Myosin-K, but no conserved eukaryotic scaffold proteins. Gene function studies indicate that ARK2 and EB1 are complementary in driving endomitotic division and thereby parasite transmission through the mosquito. This discovery underlines the flexibility of molecular networks to rewire and drive unconventional mechanisms of chromosome segregation in the malaria parasite.</p

Quantitative localized proton-promoted dissolution kinetics of calcite using scanning electrochemical microscopy (SECM)

Scanning electrochemical microscopy (SECM) has been used to determine quantitatively the kinetics of proton-promoted dissolution of the calcite (101̅4) cleavage surface (from natural “Iceland Spar”) at the microscopic scale. By working under conditions where the probe size is much less than the characteristic dislocation spacing (as revealed from etching), it has been possible to measure kinetics mainly in regions of the surface which are free from dislocations, for the first time. To clearly reveal the locations of measurements, studies focused on cleaved “mirror” surfaces, where one of the two faces produced by cleavage was etched freely to reveal defects intersecting the surface, while the other (mirror) face was etched locally (and quantitatively) using SECM to generate high proton fluxes with a 25 μm diameter Pt disk ultramicroelectrode (UME) positioned at a defined (known) distance from a crystal surface. The etch pits formed at various etch times were measured using white light interferometry to ascertain pit dimensions. To determine quantitative dissolution kinetics, a moving boundary finite element model was formulated in which experimental time-dependent pit expansion data formed the input for simulations, from which solution and interfacial concentrations of key chemical species, and interfacial fluxes, could then be determined and visualized. This novel analysis allowed the rate constant for proton attack on calcite, and the order of the reaction with respect to the interfacial proton concentration, to be determined unambiguously. The process was found to be first order in terms of interfacial proton concentration with a rate constant k = 6.3 (± 1.3) × 10–4 m s–1. Significantly, this value is similar to previous macroscopic rate measurements of calcite dissolution which averaged over large areas and many dislocation sites, and where such sites provided a continuous source of steps for dissolution. Since the local measurements reported herein are mainly made in regions without dislocations, this study demonstrates that dislocations and steps that arise from such sites are not needed for fast proton-promoted calcite dissolution. Other sites, such as point defects, which are naturally abundant in calcite, are likely to be key reaction sites

Reviving Abandoned Reservoirs with High-Pressure Air Injection: Application in a Fractured and Karsted Dolomite Reservoir

Despite declining production rates, existing reservoirs in the United States contain vast volumes of remaining oil that is not being effectively recovered. This oil resource constitutes a huge target for the development and application of modern, cost-effective technologies for producing oil. Chief among the barriers to the recovery of this oil are the high costs of designing and implementing conventional advanced recovery technologies in these mature, in many cases pressure-depleted, reservoirs. An additional, increasingly significant barrier is the lack of vital technical expertise necessary for the application of these technologies. This lack of expertise is especially notable among the small operators and independents that operate many of these mature, yet oil-rich, reservoirs. We addressed these barriers to more effective oil recovery by developing, testing, applying, and documenting an innovative technology that can be used by even the smallest operator to significantly increase the flow of oil from mature U.S. reservoirs. The Bureau of Economic Geology and Goldrus Producing Company assembled a multidisciplinary team of geoscientists and engineers to evaluate the applicability of high-pressure air injection (HPAI) in revitalizing a nearly abandoned carbonate reservoir in the Permian Basin of West Texas. The Permian Basin, the largest oil-bearing basin in North America, contains more than 70 billion barrels of remaining oil in place and is an ideal venue to validate this technology. We have demonstrated the potential of HPAI for oil-recovery improvement in preliminary laboratory tests and a reservoir pilot project. To more completely test the technology, this project emphasized detailed characterization of reservoir properties, which were integrated to access the effectiveness and economics of HPAI. The characterization phase of the project utilized geoscientists and petroleum engineers from the Bureau of Economic Geology and the Department of Petroleum Engineering (both at The University of Texas at Austin) to define the controls on fluid flow in the reservoir as a basis for developing a reservoir model. The successful development of HPAI technology has tremendous potential for increasing the flow of oil from deep carbonate reservoirs in the Permian Basin, a target resource that can be conservatively estimated at more than 1.5 billion barrels. Successful implementation in the field chosen for demonstration, for example, could result in the recovery of more than 34 million barrels of oil that will not otherwise be produced. Geological and petrophysical analysis of available data at Barnhart field reveals the following important observations: (1) the Barnhart Ellenburger reservoir is similar to most other Ellenburger reservoirs in terms of depositional facies, diagenesis, and petrophysical attributes; (2) the reservoir is characterized by low to moderate matrix porosity much like most other Ellenburger reservoirs in the Permian Basin; (3) karst processes (cave formation, infill, and collapse) have substantially altered stratigraphic architecture and reservoir properties; (4) porosity and permeability increase with depth and may be associated with the degree of karst-related diagenesis; (5) tectonic fractures overprint the reservoir, improving overall connectivity; (6) oil-saturation profiles show that the oil-water contact (OWC) is as much as 125 ft lower than previous estimations; (7) production history and trends suggest that this reservoir is very similar to other solution-gas-drive reservoirs in the Permian Basin; and (8) reservoir simulation study showed that the Barnhart reservoir is a good candidate for HPAI and that application of horizontal-well technology can improve ultimate resource recovery from the reservoir

Characterization of the N -Acetyl-α- d -glucosaminyl l -Malate Synthase and Deacetylase Functions for Bacillithiol Biosynthesis in Bacillus anthracis ,

Bacillithiol (Cys-GlcN-malate, BSH) has recently been identified as a novel low-molecular-weight thiol in Bacillus anthracis, Staphylococcus aureus, and several other Gram-positive bacteria lacking glutathione and mycothiol. We have now characterized the first two enzymes for the BSH biosynthetic pathway in B. anthracis, which combine to produce α-D-glucosaminyl L-malate (GlcN-malate) from UDP-GlcNAc and L-malate. The structure of the GlcNAc-malate intermediate has been determined, as have the kinetic parameters for the BaBshA glycosyltransferase (→GlcNAc-malate) and the BaBshB deacetylase (→GlcN-malate). BSH is one of only two natural products reported to contain a malyl glycoside, and the crystal structure of the BaBshA-UDP-malate ternary complex, determined in this work at 3.3 Å resolution, identifies several active-site interactions important for the specific recognition of L-malate, but not other α-hydroxyacids, as acceptor substrate. In sharp contrast to the structures reported for the GlcNAc—1-D-myo-inositol-3-phosphate synthase (MshA) apo and ternary complex forms, there is no major conformational change observed in the structures of the corresponding BaBshA forms. A mutant strain of B. anthracis deficient in the BshA glycosyltransferase fails to produce BSH, as predicted. This B. anthracis bshA locus (BA1558) has been identified in a transposon site hybridization study as required for growth, sporulation, or germination, suggesting that the biosynthesis of BSH could represent a target for development of novel antimicrobials with broad spectrum activity against Gram-positive pathogens like B. anthracis. The metabolites that function in thiol redox buffering and homeostasis in Bacillus are not well understood, and we present a composite picture based on this and other recent work

An empirical approach to selecting community-based alcohol interventions:combining research evidence, rural community views and professional opinion

<p>Abstract</p> <p>Background</p> <p>Given limited research evidence for community-based alcohol interventions, this study examines the intervention preferences of rural communities and alcohol professionals, and factors that influence their choices.</p> <p>Method</p> <p>Community preferences were identified by a survey of randomly selected individuals across 20 regional Australian communities. The preferences of alcohol professionals were identified by a survey of randomly selected members of the Australasian Professional Society on Alcohol and Other Drugs. To identify preferred interventions and the extent of support for them, a budget allocation exercise was embedded in both surveys, asking respondents to allocate a given budget to different interventions. Tobit regression models were estimated to identify the characteristics that explain differences in intervention preferences.</p> <p>Results</p> <p>Community respondents selected school programs most often (88.0%) and allocated it the largest proportion of funds, followed by promotion of safer drinking (71.3%), community programs (61.4%) and police enforcement of alcohol laws (60.4%). Professionals selected GP training most often (61.0%) and allocated it the largest proportion of funds, followed by school programs (36.6%), community programs (33.8%) and promotion of safer drinking (31.7%). Community views were susceptible to response bias. There were no significant predictors of professionals' preferences.</p> <p>Conclusions</p> <p>In the absence of sufficient research evidence for effective community-based alcohol interventions, rural communities and professionals both strongly support school programs, promotion of safer drinking and community programs. Rural communities also supported police enforcement of alcohol laws and professionals supported GP training. The impact of a combination of these strategies needs to be rigorously evaluated.</p

Very-high energy gamma-ray astronomy: A 23-year success story in high-energy astroparticle physics

Very-high energy (VHE) gamma quanta contribute only a minuscule fraction - below one per million - to the flux of cosmic rays. Nevertheless, being neutral particles they are currently the best "messengers" of processes from the relativistic/ultra-relativistic Universe because they can be extrapolated back to their origin. The window of VHE gamma rays was opened only in 1989 by the Whipple collaboration, reporting the observation of TeV gamma rays from the Crab nebula. After a slow start, this new field of research is now rapidly expanding with the discovery of more than 150 VHE gamma-ray emitting sources. Progress is intimately related with the steady improvement of detectors and rapidly increasing computing power. We give an overview of the early attempts before and around 1989 and the progress after the pioneering work of the Whipple collaboration. The main focus of this article is on the development of experimental techniques for Earth-bound gamma-ray detectors; consequently, more emphasis is given to those experiments that made an initial breakthrough rather than to the successors which often had and have a similar (sometimes even higher) scientific output as the pioneering experiments. The considered energy threshold is about 30 GeV. At lower energies, observations can presently only be performed with balloon or satellite-borne detectors. Irrespective of the stormy experimental progress, the success story could not have been called a success story without a broad scientific output. Therefore we conclude this article with a summary of the scientific rationales and main results achieved over the last two decades.Comment: 45 pages, 38 figures, review prepared for EPJ-H special issue "Cosmic rays, gamma rays and neutrinos: A survey of 100 years of research

The XMM Cluster Survey: Forecasting cosmological and cluster scaling-relation parameter constraints

We forecast the constraints on the values of sigma_8, Omega_m, and cluster scaling relation parameters which we expect to obtain from the XMM Cluster Survey (XCS). We assume a flat Lambda-CDM Universe and perform a Monte Carlo Markov Chain analysis of the evolution of the number density of galaxy clusters that takes into account a detailed simulated selection function. Comparing our current observed number of clusters shows good agreement with predictions. We determine the expected degradation of the constraints as a result of self-calibrating the luminosity-temperature relation (with scatter), including temperature measurement errors, and relying on photometric methods for the estimation of galaxy cluster redshifts. We examine the effects of systematic errors in scaling relation and measurement error assumptions. Using only (T,z) self-calibration, we expect to measure Omega_m to +-0.03 (and Omega_Lambda to the same accuracy assuming flatness), and sigma_8 to +-0.05, also constraining the normalization and slope of the luminosity-temperature relation to +-6 and +-13 per cent (at 1sigma) respectively in the process. Self-calibration fails to jointly constrain the scatter and redshift evolution of the luminosity-temperature relation significantly. Additional archival and/or follow-up data will improve on this. We do not expect measurement errors or imperfect knowledge of their distribution to degrade constraints significantly. Scaling-relation systematics can easily lead to cosmological constraints 2sigma or more away from the fiducial model. Our treatment is the first exact treatment to this level of detail, and introduces a new `smoothed ML' estimate of expected constraints.Comment: 28 pages, 17 figures. Revised version, as accepted for publication in MNRAS. High-resolution figures available at http://xcs-home.org (under "Publications"