The VNTR in complex disorders: The forgotten polymorphisms? A functional way forward?

AbstractIn the last few years, research has focused on single nucleotide polymorphisms (SNPs) in the search for underlying genetic aetiology of complex disorders. This has been afforded by the rapid technological advancement to enable the interrogation of hundreds of thousands of SNPs in one assay via microarrays. However SNPs are only one form of genetic variation and in the midst of the Genome-Wide Association Study (GWAS) explosion Variable Number Tandem Repeat (VNTR) polymorphism exploration has seemingly been left behind. This review will argue that VNTR investigations still hold substantial potential for a role in complex disorders via possible functional properties

Two spatially distinct posterior alpha sources fulfill different functional roles in attention

Directing attention helps extracting relevant information and suppressing distracters. Alpha brain oscillations (8-12Hz) are crucial for this process, with power decreases facilitating processing of important information and power increases inhibiting brain regions processing irrelevant information. Evidence for this phenomenon arises from visual attention studies (Worden et al., 2000b), however, the effect also exists in other modalities, including the somatosensory system (Haegens et al., 2011) and inter-sensory attention tasks (Foxe and Snyder, 2011). We investigated in human participants (10 females, 10 males) the role of alpha oscillations in focused (0/100%) vs. divided (40/60%) attention, both across modalities (visual/somatosensory; Experiment 1) and within the same modality (visual domain: across hemifields; Experiment 2) while recording EEG over 128 scalp electrodes. In Experiment 1 participants divided their attention between visual and somatosensory modality to determine the temporal/spatial frequency of a target stimulus (vibrotactile stimulus/Gabor grating). In Experiment 2, participants divided attention between two visual hemifields to identify the orientation of a Gabor grating. In both experiments, pre-stimulus alpha power in visual areas decreased linearly with increasing attention to visual stimuli. In contrast, pre-stimulus alpha power in parietal areas was lower when attention was divided between modalities/hemifields, compared to focused attention. These results suggest there are two alpha sources, where one reflects the ‘visual spotlight of attention’ and the other reflects attentional effort. To our knowledge, this is the first study to show that attention recruits two spatially distinct alpha sources in occipital and parietal brain regions, acting simultaneously but serving different functions in attention

Energy and symmetry of dd excitations in undoped layered cuprates measured By Cu L3 resonant inelastic x-ray scattering

We measured the high-resolution Cu L3 edge resonant inelastic x-ray scattering (RIXS) of undoped cuprates La2CuO4, Sr2CuO2Cl2, CaCuO2 and NdBa 2Cu3O6. The dominant spectral features were assigned to dd excitations and we extensively studied their polarization and scattering geometry dependence. In a pure ionic picture, we calculated the theoretical cross sections for those excitations and used these to fit the experimental data with excellent agreement. By doing so, we were able to determine the energy and symmetry of Cu-3d states for the four systems with unprecedented accuracy and confidence. The values of the effective parameters could be obtained for the singleion crystal field model but not for a simple two-dimensional cluster model. The firm experimental assessment of dd excitation energies carries important consequences for the physics of high-Tc superconductors. On the one hand, we found that the minimum energy of orbital excitation is always ≥ 1.4 eV, i.e. well above the mid-infrared spectral range, which leaves to magnetic excitations (up to 300 meV) a major role in Cooper pairing in cuprates. On the other hand, it has become possible to study quantitatively the effective influence of dd excitations on the superconducting gap in cuprates

Nonperturbative Effects in Gluon Radiation and Photoproduction of Quark Pairs

We introduce a nonperturbative interaction for light-cone fluctuations containing quarks and gluons. The $\bar qq$ interaction squeezes the transverse size of these fluctuations in the photon and one does not need to simulate this effect via effective quark masses. The strength of this interaction is fixed by data. Data on diffractive dissociation of hadrons and photons show that the nonperturbative interaction of gluons is much stronger. We fix the parameters for the nonperturbative quark-gluon interaction by data for diffractive dissociation to large masses (triple-Pomeron regime). This allows us to predict nuclear shadowing for gluons which turns out to be not as strong as perturbative QCD predicts. We expect a delayed onset of gluon shadowing at $x \leq 10^{-2}$ shadowing of quarks. Gluon shadowing turns out to be nearly scale invariant up to virtualities $Q^2\sim 4 GeV^2$ due to presence of a semihard scale characterizing the strong nonperturbative interaction of gluons. We use the same concept to improve our description of gluon bremsstrahlung which is related to the distribution function for a quark-gluon fluctuation and the interaction cross section of a $\bar qqG$ fluctuation with a nucleon. We expect the nonperturbative interaction to suppress dramatically the gluon radiation at small transverse momenta compared to perturbative calculations.Comment: 58 pages of Latex including 11 figures. Shadowing for soft gluons and Fig. 6 are added as well as a few reference

Evidence that the negative BOLD response is neuronal in origin: a simultaneous EEG–BOLD–CBF study in humans

Unambiguous interpretation of changes in the BOLD signal is challenging because of the complex neurovascular coupling that translates changes in neuronal activity into the subsequent haemodynamic response. In particular, the neurophysiological origin of the negative BOLD response (NBR) remains incompletely understood. Here, we simultaneously recorded BOLD, EEG and cerebral blood flow (CBF) responses to 10 s blocks of unilateral median nerve stimulation (MNS) in order to interrogate the NBR. Both negative BOLD and negative CBF responses to MNS were observed in the same region of the ipsilateral primary sensorimotor cortex (S1/M1) and calculations showed that MNS induced a decrease in the cerebral metabolic rate of oxygen consumption (CMRO2) in this NBR region. The ∆CMRO2/∆CBF coupling ratio (n) was found to be significantly larger in this ipsilateral S1/M1 region (n = 0.91 ± 0.04, M = 10.45%) than in the contralateral S1/M1 (n = 0.65 ± 0.03, M = 10.45%) region that exhibited a positive BOLD response (PBR) and positive CBF response, and a consequent increase in CMRO2 during MNS. The fMRI response amplitude in ipsilateral S1/M1 was negatively correlated with both the power of the 8–13 Hz EEG mu oscillation and somatosensory evoked potential amplitude. Blocks in which the largest magnitude of negative BOLD and CBF responses occurred therefore showed greatest mu power, an electrophysiological index of cortical inhibition, and largest somatosensory evoked potentials. Taken together, our results suggest that a neuronal mechanism underlies the NBR, but that the NBR may originate from a different neurovascular coupling mechanism to the PBR, suggesting that caution should be taken in assuming the NBR simply represents the neurophysiological inverse of the PBR

Post-stimulus fMRI and EEG responses: evidence for a neuronal origin hypothesised to be inhibitory

Post-stimulus undershoots, negative responses following cessation of stimulation, are widely observed in functional magnetic resonance (fMRI) blood oxygenation level dependent (BOLD) data. However, the debate surrounding whether the origin of this response phase is neuronal or vascular, and whether it provides functionally relevant information, that is additional to what is contained in primary response, means that undershoots are widely overlooked. We simultaneously recorded electroencephalography (EEG), BOLD and cerebral blood-flow (CBF) [obtained from arterial spin labelled (ASL) fMRI] fMRI responses to hemifield checkerboard stimulation to test the potential neural origin of the fMRI post-stimulus undershoot. The post-stimulus BOLD and CBF signal amplitudes in both contralateral and ipsilateral visual cortex depended on the post-stimulus power of the 8-13 Hz (alpha) EEG neuronal activity, such that trials with highest EEG power showed largest fMRI undershoots in contralateral visual cortex. This correlation in post-stimulus EEG-fMRI responses was not predicted by the primary response amplitude. In the contralateral visual cortex we observed a decrease in both cerebral rate of oxygen metabolism (CMRO2) and CBF during the post-stimulus phase. In addition, the coupling ratio (n) between CMRO2 and CBF was significantly lower during the positive contralateral primary response phase compared with the post-stimulus phase and we propose that this reflects an altered balance of excitatory and inhibitory neuronal activity. Together our data provide strong evidence that the post-stimulus phase of the BOLD response has a neural origin which reflects, at least partially, an uncoupling of the neuronal responses driving the primary and post-stimulus responses, explaining the uncoupling of the signals measured in the two response phases. We suggest our results are consistent with inhibitory processes driving the post-stimulus EEG and fMRI responses. We therefore propose that new methods are required to model the post-stimulus and primary responses independently, enabling separate investigation of response phases in cognitive function and neurological disease

Global signal modulation of single-trial fMRI response variability: effect on positive vs negative BOLD response relationship

In functional magnetic resonance imaging (fMRI), the relationship between positive BOLD responses (PBRs) and negative BOLD responses (NBRs) to stimulation is potentially informative about the balance of excitatory and inhibitory brain responses in sensory cortex. In this study, we performed three separate experiments delivering visual, motor or somatosensory stimulation unilaterally, to one side of the sensory field, to induce PBR and NBR in opposite brain hemispheres. We then assessed the relationship between the evoked amplitudes of contralateral PBR and ipsilateral NBR at the level of both single-trial and average responses. We measure single-trial PBR and NBR peak amplitudes from individual time-courses, and show that they were positively correlated in all experiments. In contrast, in the average response across trials the absolute magnitudes of both PBR and NBR increased with increasing stimulus intensity, resulting in a negative correlation between mean response amplitudes. Subsequent analysis showed that the amplitude of single-trial PBR was positively correlated with the BOLD response across all grey-matter voxels and was not specifically related to the ipsilateral sensory cortical response. We demonstrate that the global component of this single-trial response modulation could be fully explained by voxel-wise vascular reactivity, the BOLD signal standard deviation measured in a separate resting-state scan (resting state fluctuation amplitude, RSFA). However, bilateral positive correlation between PBR and NBR regions remained. We further report that modulations in the global brain fMRI signal cannot fully account for this positive PBR-NBR coupling and conclude that the local sensory network response reflects a combination of superimposed vascular and neuronal signals. More detailed quantification of physiological and noise contributions to the BOLD signal is required to fully understand the trial-by-trial PBR and NBR relationship compared with that of average responses

Consensus standards of healthcare for adults and children with inflammatory bowel disease in the UK

Objective Symptoms and clinical course during inflammatory bowel disease (IBD) vary among individuals. Personalised care is therefore essential to effective management, delivered by a strong patient-centred multidisciplinary team, working within a well-designed service. This study aimed to fully rewrite the UK Standards for the healthcare of adults and children with IBD, and to develop an IBD Service Benchmarking Tool to support current and future personalised care models. Design Led by IBD UK, a national multidisciplinary alliance of patients and nominated representatives from all major stakeholders in IBD care, Standards requirements were defined by survey data collated from 689 patients and 151 healthcare professionals. Standards were drafted and refined over three rounds of modified electronic-Delphi. Results Consensus was achieved for 59 Standards covering seven clinical domains; (1) design and delivery of the multidisciplinary IBD service; (2) prediagnostic referral pathways, protocols and timeframes; (3) holistic care of the newly diagnosed patient; (4) flare management to support patient empowerment, self-management and access to specialists where required; (5) surgery including appropriate expertise, preoperative information, psychological support and postoperative care; (6) inpatient medical care delivery (7) and ongoing long-term care in the outpatient department and primary care setting including shared care. Using these patient-centred Standards and informed by the IBD Quality Improvement Project (IBDQIP), this paper presents a national benchmarking framework. Conclusions The Standards and Benchmarking Tool provide a framework for healthcare providers and patients to rate the quality of their service. This will recognise excellent care, and promote quality improvement, audit and service development in IBD

New insights into the genetic etiology of Alzheimer's disease and related dementias.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele